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Sample records for brainstem glioblastoma multiforme

  1. Difficult diagnosis of brainstem glioblastoma multiforme in a woman: a case report and review of the literature

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    Lakhan Shaheen E

    2009-10-01

    Full Text Available Abstract Introduction Brainstem gliomas are rare in adults. They most commonly occur in the pons and are most likely to be high-grade lesions. The diagnosis of a high-grade brainstem glioma is usually reached due to the presentation of rapidly progressing brainstem, cranial nerve and cerebellar symptoms. These symptoms do, however, overlap with a variety of other central nervous system disorders. Magnetic resonance imaging is the radiographic modality of choice, but can still be misleading. Case presentation A 48-year-old Caucasian woman presented with headache and vomiting followed by cerebellar signs and confusion. Magnetic resonance imaging findings were suggestive of a demyelinating process, but the patient failed to respond to therapy. Her condition rapidly progressed and she died. At autopsy, a high-grade invasive pontine tumor was identified. Histological evaluation revealed glioblastoma multiforme. Conclusion While pontine gliomas are rare in adults, those that do occur tend to be high-grade and rapidly progressive. Progression of symptoms from non-specific findings of headache and vomiting to rapid neurological deterioration, as occurred in our patient, is common in glioblastoma multiforme. While radiographic findings are often suggestive of the underlying pathology, this case represents the possibility of glioblastoma multiforme presenting as a deceptively benign appearing lesion.

  2. Lactate levels with glioblastoma multiforme.

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    Kahlon, Arunpreet Singh; Alexander, Mariam; Kahlon, Arundeep; Wright, Jonathan

    2016-07-01

    A 37-year-old woman with known glioblastoma multiforme was admitted for treatment of new deep vein thrombosis. Anion gap and plasma lactate levels were found to be elevated. Magnetic resonance imaging of the brain showed a stable, advanced glioblastoma multiforme. All causes of lactic acidosis, including infections and medications, were ruled out. Aggressive tumors have been shown to produce lactate levels in minute quantities in their microenvironment, which helps them metastasize and evade immune response and even radiation. PMID:27365883

  3. Lactate levels with glioblastoma multiforme

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    Kahlon, Arunpreet Singh; Alexander, Mariam; Kahlon, Arundeep; Wright, Jonathan

    2016-01-01

    A 37-year-old woman with known glioblastoma multiforme was admitted for treatment of new deep vein thrombosis. Anion gap and plasma lactate levels were found to be elevated. Magnetic resonance imaging of the brain showed a stable, advanced glioblastoma multiforme. All causes of lactic acidosis, including infections and medications, were ruled out. Aggressive tumors have been shown to produce lactate levels in minute quantities in their microenvironment, which helps them metastasize and evade ...

  4. TSPO Imaging in Glioblastoma Multiforme

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    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......-up gadolinium-enhanced MR images or contrast-enhanced CT scans. RESULTS: The percentage overlap between volumes of interest (VOIs) of increased (18)F-FET uptake and (123)I-CLINDE binding was variable (12%-42%). The percentage overlap of MR imaging baseline VOIs was greater for (18)F-FET (79%-93%) than (123)I...

  5. Advanced case of glioblastoma multiforme and pregnancy

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

    2015-01-01

    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 medica...

  6. Current data and strategy in glioblastoma multiforme

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    Iacob, G; Dinca, EB

    2009-01-01

    Glioblastoma multiforme (GBM) or astrocytoma grade Ⅳ on WHO classification is the most aggressive and the most frequent of all primary brain tumors. Glioblastoma is multiforme , resistant to therapeutic interventions illustrating the heterogeneity exhibited by this tumor in its every aspect, including clinical presentation, pathology, genetic signature. Current data and treatment strategy in GBM are presented focusing on basic science data and key clinical aspects like surgery, including pers...

  7. Multiple extraneural metastasis of glioblastoma multiforme

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    J. Undabeitia

    2015-04-01

    Full Text Available Introduction. Glioblastoma multiforme is the most frequent primary tumor in the brain. Despite improvements in its surgical, chemotherapy and radiotherapy treatment, prognosis remains poor. Extracranial metastases of glioblastoma are a rare complication in this disease. Its appearance has been described in lung, liver, bone or lymph nodes. Case report. We describe the case of a 20 year-old patient who complained of a subacute-onset headache. In the MRI an enhancing right temporal lesion was detected suggesting a high grade glioma as first diagnosis. Surgery was performed, obtaining a gross total resection of the lesion. Our patient underwent adjuvant radiotherapy and chemotherapy treatment, according to our hospital´s protocol. Five months after initial surgery our patient complained of chest pain and a hacking cough. A thoracic-abdominal-pelvic CT scan was obtained, which showed bilateral lung infiltrates with pleural effusion, a pancreatic nodule and several vertebral lytic lesions. The lung lesions were biopsied. The pathologic diagnosis was metastatic glioblastoma multiforme. The patient died eight months after initial diagnosis. Conclusion. Extracranial metastases of glioblastoma remain a rare event although its incidence is increasing, probably due to the improvement in survival among these patients and better imaging techniques. The mechanisms for extracranial dissemination of glioblastoma are not entirely known, as several theories exist in this regard. Physicians must be aware of this complication and keep it in mind as a differential diagnosis to improve the quality of life of our patients.

  8. Glioblastoma multiforme after radiotherapy for acromegaly

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    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.

  9. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme

    OpenAIRE

    Bradshaw, Amy; Wickremsekera, Agadha; Tan, Swee T.; Peng, Lifeng; Davis, Paul F.; Itinteang, Tinte

    2016-01-01

    Glioblastoma multiforme (GBM), an aggressive tumor that typically exhibits treatment failure with high mortality rates, is associated with the presence of cancer stem cells (CSCs) within the tumor. CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells that drive tumor growth. Studies of many cancer types have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is ...

  10. Management of glioblastoma multiforme in pregnancy.

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    Jayasekera, Bodiabaduge A P; Bacon, Andrew D; Whitfield, Peter C

    2012-06-01

    Glioblastoma multiforme presenting during pregnancy presents unique challenges to the clinician. In planning treatment, potential benefits to the mother must be balanced against the risks to the fetus. In addition, evidence relating to timing of surgery and the use of radiotherapy and chemotherapy in pregnancy is limited. Management of peritumoral edema and seizures in pregnancy is also complicated by the potential for drug-related teratogenic effects and adverse neonatal outcomes on the fetus. The general anesthetic used for surgery must factor obstetric and neurosurgical considerations. In this review article, the authors seek to examine the role, safety, and timing of therapies for glioblastoma in the context of pregnancy. This covers the use of radiotherapy and chemotherapy, timing of surgery, postoperative care, anesthetic considerations, and use of anticonvulsant medications and steroids. The authors hope that this will provide a framework for clinicians treating pregnant patients with glioblastomas. PMID:22404670

  11. Cerebellar glioblastoma multiforme in an adult

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    Mattos João Paulo; Marenco Horacio Armando; Campos José Maria; Faria Andréa Vasconcellos; Queiroz Luciano de Souza; Borges Guilherme; Oliveira Evandro de

    2006-01-01

    Cerebellar glioblastoma multiforme (GBM) is a rare tumor. This is the third case published in Brazilian literature and, the last one has been described more than 15 years ago. The aggressive behavior of GBM prompts for fast treatment, which can be hampered by the fact that the diagnosis of GBM requires a high degree of suspicion. We describe a case of GBM in a 46 years old man. In conjunction, we present a literature review including particular issues, clinical data, advances in imaging studi...

  12. Cerebellar glioblastoma multiforme in an adult

    Directory of Open Access Journals (Sweden)

    Mattos João Paulo

    2006-01-01

    Full Text Available Cerebellar glioblastoma multiforme (GBM is a rare tumor. This is the third case published in Brazilian literature and, the last one has been described more than 15 years ago. The aggressive behavior of GBM prompts for fast treatment, which can be hampered by the fact that the diagnosis of GBM requires a high degree of suspicion. We describe a case of GBM in a 46 years old man. In conjunction, we present a literature review including particular issues, clinical data, advances in imaging studies, pathological characteristics, treatment options and the behavior of such malignant tumor.

  13. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme.

    Science.gov (United States)

    Bradshaw, Amy; Wickremsekera, Agadha; Tan, Swee T; Peng, Lifeng; Davis, Paul F; Itinteang, Tinte

    2016-01-01

    Glioblastoma multiforme (GBM), an aggressive tumor that typically exhibits treatment failure with high mortality rates, is associated with the presence of cancer stem cells (CSCs) within the tumor. CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells that drive tumor growth. Studies of many cancer types have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple GBM and glioblastoma cancer stem cell subtypes, making investigation and establishment of a universal treatment difficult. This review examines the current knowledge on the CSC markers SALL4, OCT-4, SOX2, STAT3, NANOG, c-Myc, KLF4, CD133, CD44, nestin, and glial fibrillary acidic protein, specifically focusing on their use and validity in GBM research and how they may be utilized for investigations into GBM's cancer biology. PMID:27148537

  14. TCGA Workshop: Genomics and Biology of Glioblastoma Multiforme (GBM) - TCGA

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    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.

  15. Glioblastoma Multiforme Presenting as Spontaneous Intracerebral Hemorrhage

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    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.

  16. Irinotecan and bevacizumab in recurrent glioblastoma multiforme

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    Jakobsen, Jan Nyrop; Hasselbalch, Benedikte; Stockhausen, Marie-Thérése;

    2011-01-01

    BVZ and CPT-11 in recurrent GBM. Particular attention is placed on the literature and a discussion on whether treatment with BVZ and CPT-11 improves clinical outcome. Antiangiogenic treatment has led to difficulties when evaluating objective response by the conventional MacDonald criteria. In the......INTRODUCTION: Glioblastoma multiforme (GBM) is the most common high grade primary brain tumor in adults. Despite significant advances in treatment, the prognosis remains poor. Bevacizumab (BVZ) and irinotecan (CPT-11) are currently being investigated in the treatment of GBM patients. Although...... treatment with BVZ and irinotecan provides impressive response rates (RR), it is still uncertain if this treatment translates into improved clinical benefit in GBM patients. AREAS COVERED: This review discusses the clinical efficacy, safety and difficulties regarding response evaluation when treating with...

  17. Morphometic analysis of TCGA glioblastoma multiforme

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    Chang Hang

    2011-12-01

    Full Text Available Abstract Background Our goals are to develop a computational histopathology pipeline for characterizing tumor types that are being generated by The Cancer Genome Atlas (TCGA for genomic association. TCGA is a national collaborative program where different tumor types are being collected, and each tumor is being characterized using a variety of genome-wide platforms. Here, we have developed a tumor-centric analytical pipeline to process tissue sections stained with hematoxylin and eosin (H&E for visualization and cell-by-cell quantitative analysis. Thus far, analysis is limited to Glioblastoma Multiforme (GBM and kidney renal clear cell carcinoma tissue sections. The final results are being distributed for subtyping and linking the histology sections to the genomic data. Results A computational pipeline has been designed to continuously update a local image database, with limited clinical information, from an NIH repository. Each image is partitioned into blocks, where each cell in the block is characterized through a multidimensional representation (e.g., nuclear size, cellularity. A subset of morphometric indices, representing potential underlying biological processes, can then be selected for subtyping and genomic association. Simultaneously, these subtypes can also be predictive of the outcome as a result of clinical treatments. Using the cellularity index and nuclear size, the computational pipeline has revealed five subtypes, and one subtype, corresponding to the extreme high cellularity, has shown to be a predictor of survival as a result of a more aggressive therapeutic regime. Further association of this subtype with the corresponding gene expression data has identified enrichment of (i the immune response and AP-1 signaling pathways, and (ii IFNG, TGFB1, PKC, Cytokine, and MAPK14 hubs. Conclusion While subtyping is often performed with genome-wide molecular data, we have shown that it can also be applied to categorizing histology

  18. Cerebellar glioblastoma multiforme presenting as a cerebellopontine angle mass

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    Anupam Jindal

    2006-01-01

    Full Text Available Cerebellar glioblastoma multiforme (GBM is a highly malignant brain tumour, which is exceedingly rare and such tumour presenting as cerebellopontine angle (CPA mass is even rarer. We here discuss the case of a 15-year-old girl who had cerebellar GBM presenting as CPA mass that resembled meningioma on CT scan and was managed successfully with minimal problems.

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

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    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. PMID:26492122

  20. Nanoparticles of carbon allotropes inhibit glioblastoma multiforme angiogenesis in ovo

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    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...... antiangiogenic activity of carbon nanoparticles, making them potential factors for anticancer therapy.......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 incubation......, were treated with carbon nanoparticles administered in ovo to the tumor. Both types of nanoparticles significantly decreased tumor mass and volume, fibroblast growth factor-2 and vascular endothelial growth factor expression at the messenger ribonucleic acid level. The present results demonstrate...

  1. Antivascular Endothelial Growth Factor Antibody for Treatment of Glioblastoma Multiforme

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    Hanson, Joseph A.; Hsu, Frank P K; Jacob, Arun T; Bota, Daniela A.; Alexandru, Daniela

    2013-01-01

    Despite aggressive investigation, glioblastoma multiforme (GBM) remains one of the deadliest cancers, with low progression-free survival and high one-year mortality. Current first-line therapy includes surgery with adjuvant radiation therapy and cytotoxic chemotherapy, but virtually all tumors recur. Given the highly vascular nature of GBM and its high expression of vascular endothelial growth factor and other angiogenic factors, recent investigation has turned to bevacizumab, an antivascular...

  2. Recurrent Glioblastoma Multiforme: Implication of Nonenhancing Lesions on Bevacizumab Treatment

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    Daniela Alexandru; Hung-Wen Kao; Mark Linskey; Ronald Kim; Hasso, Anton N; Daniela Bota

    2013-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumors, accounting for 15-20% of all intracranial tumors. It is one of the most lethal tumors of the central nervous system with a median survival from diagnosis on the order of 6 to 18 months. Despite aggressive resection and chemoradiation, the tumor always recurs. Magnetic Resonance (MR) imaging is an essential component in the diagnosis, treatment planning, and following response. However, the imaging features of recurrent GBM...

  3. Current Trends in Targeted Therapies for Glioblastoma Multiforme

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    Fumiharu Ohka; Atsushi Natsume; Toshihiko Wakabayashi

    2012-01-01

    Glioblastoma multiforme (GBM) is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas. Despite aggressive treatment including surgery, adjuvant TMZ-based chemotherapy, and radiotherapy, GBM still has a dismal prognosis: the median survival is 14.6 months from diagnosis. To date, many studies report several determinants of resistance to this aggressive therapy: (1) O6-methylguanine-DNA methyltransferase (MGMT), (2) the complexity ...

  4. Glioblastoma multiforme of the pineal region: case report

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    Gasparetto Emerson Leandro

    2003-01-01

    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.

  5. Glioblastoma multiforme in the very elderly.

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    Connon, Felicity V; Rosenthal, Mark A; Drummond, Katherine

    2016-01-01

    Glioblastoma is the most malignant and most common primary brain tumour and is treated with resection followed by post-operative radiotherapy and chemotherapy. However, a significant amount of patients are older than 80 years, and such an approach may not be appropriate. Data on patients aged 80 or older with glioblastoma from two hospitals was collected using the CNS Tumour Database on the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD) system operated by BioGrid. Between 2008 and July 2011, 40 patients aged 80 years or older were diagnosed with glioblastoma. The median ECOG PS was 2 and the ASA score was 3. All 40 patients underwent surgery and 33% had a gross total resection. Only six patients (15%) had either post-operative radiotherapy or chemotherapy. The overall median survival was 4 months (range 0-18 months) and 28% of patients lived between 6 and 24 months. This is the largest reported cohort of very elderly patients with glioblastoma. Patients tolerated surgery but few went on to receive post-operative radiotherapy or chemotherapy. This patient population requires special attention and in particular would benefit from participation in suitable clinical trials to determine the best care regime. PMID:26208944

  6. Initiation and characterization of a glioblastoma multiforme derived cell line.

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    Carmen Lucía Roa

    2009-11-01

    Full Text Available Introducción: Las líneas celulares y los cultivos primarios son una excelente herramienta para el estudio de la biología, desarrollo y respuesta a la terapia en tumores cerebrales. Objetivo: Establecer y caracterizar una línea celular derivada de un glioblastoma multiforme como un modelo de estudio in vitro para la extrapolación y aplicación futura en terapia génica. Material y métodos: Se obtuvo una muestra de un paciente con diagnóstico clínico e histopatológico de glioblastoma multiforme, se caracterizó mediante inmunohistoquímica en cortes de tejido y por inmunocitoquímica sobre células cultivadas a partir del tumor desde el inicio del cultivo y durante los seis primeros pases, con dos tipos de marcadores específicos para glía: GFAP (glial fibrillary acidic protein y S-100 (proteína de unión a calcio. Además, se evaluó la expresión de p53 y Bcl-2, como moduladores de apoptosis. Por último se hizo la caracterización citogenética. Resultados: Histopatológicamente, se confirmó el diagnóstico de glioblastoma multiforme. En los cultivos primarios se encontraron características citomorfológicas propias de un glioblastoma: células fibroblastoides planas, células con escaso citoplasma con 3 ó más procesos y por último bipolares o unipolares. Se encontró una expresión diferencial con los cuatro marcadores, con un patrón de marcaciones a nivel citoplasmático y nuclear a través de los pases estudiados. La línea celular se caracterizó por ser en su mayoría aneuploide con un número modal cromosómico entre 43 y 45, con un gran número de poliploidías (55-102 , XXYY y endo-reduplicaciones (end 45, X, -Y. Conclusión: Se estableció una línea celular derivada de un glioblastoma multiforme con un fenotipo estable, con un notable mantenimiento del perfil glial y citogenético.

  7. Primary spinal cord glioblastoma multiforme presenting with transverse myelitis

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    Melikhan Cerci

    2014-06-01

    Full Text Available Primary spinal cord tumors are rarely encountered in childhood period. Ependymomas and pilocytic astrocytomas comprise the majority of spinal cord tumors in children. Spinal glioblastoma multiforme (GM (grade IV astrocytoma is a rare clinical entity accounting for only 1-3% of all pediatric intramedullary tumors. We report a 3- year-8- month-old male with primary spinal cord GM who presented with back pain, paraparesis, gait disturbance and loss of sphincter control and initially diagnosed as transverse myelitis. [Cukurova Med J 2014; 39(3.000: 606-610

  8. Radiation and concomitant chemotherapy for patients with glioblastoma multiforme

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    Salvador Vill; Carme Bala; Slvia Comas

    2014-01-01

    Postoperative external beam radiotherapy was considered the standard adjuvant treatment for patients with glioblastoma multiforme until the advent of using the drug temozolomide (TMZ) in addition to radiotherapy. High-dose volume should be focal, minimizing whole brain irradiation. Modern imaging, using several magnetic resonance sequences, has improved the planning target volume definition. The total dose delivered should be in the range of 60 Gy in fraction sizes of 1.8-2.0 Gy. Currently, TMZ concomitant and adjuvant to radiotherapy has become the standard of care for glioblastoma multiforme patients. Radiotherapy dose-intensification and radiosensitizer approaches have not improved the outcome. In spite of the lack of high quality evidence, stereotactic radiotherapy can be considered for a selected group of patients. For elderly patients, data suggest that the same survival benefit can be achieved with similar morbidity using a shorter course of radiotherapy (hypofractionation). Elderly patients with tumors that exhibit methylation of the O-6-methylguanine-DNA methyltransferase promoter can benefit from TMZ alone.

  9. Autopsy findings in a long-term survivor with glioblastoma multiforme. Case report

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    Yamada, Shozo; Endo, Yuzo; Takada, Koji; Usui, Masaaki; Hara, Mitsuru [Toranomon Hospital, Tokyo (Japan); Hirose, Takanori

    1998-02-01

    Autopsy detected no tumor tissues in a patient who died 6.5 years after the diagnosis of glioblastoma multiforme. A 54-year-old male developed left hemiparesis one month prior to admission. Computed tomography demonstrated a cystic lesion in the right frontal region with irregular ring-like enhancement. The tumor was extensively removed together with the surrounding tissues followed by irradiation (whole brain 32.4 Gy, local 28.8 Gy), and intravenous administration of interferon-{beta}. Histological examination confirmed the diagnosis of glioblastoma multiform. He died of accidental head trauma 6.5 years after surgery. Autopsy of the brain detected no evidence of glioblastoma multiform. The only findings were cerebral edema and hematoma caused by head trauma, as well as histological changes due to radiation damage. This case apparently confirms the histological disappearance of tumor tissue in a long-term survivor with glioblastoma multiform. (author)

  10. Brain Cancer Stem Cells: Current Status on Glioblastoma Multiforme

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM), an aggressive brain tumor of astrocytic/neural stem cell origin, represents one of the most incurable cancers. GBM tumors are highly heterogeneous. However, most tumors contain a subpopulation of cells that display neural stem cell characteristics in vitro and that can generate a new brain tumor upon transplantation in mice. Hence, previously identified molecular pathways regulating neural stem cell biology were found to represent the cornerstone of GBM stem cell self-renewal mechanism. GBM tumors are also notorious for their resistance to radiation therapy. Notably, GBM “cancer stem cells” were also found to be responsible for this radioresistance. Herein, we will analyze the data supporting or not the cancer stem cell model in GBM, overview the current knowledge regarding GBM stem cell self-renewal and radioresistance molecular mechanisms, and discuss the potential therapeutic application of these findings

  11. Patterns of Failure for Pediatric Glioblastoma Multiforme Following Radiation Therapy.

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    Shabason, Jacob E; Sutton, David; Kenton, Owen; Guttmann, David M; Lustig, Robert A; Hill-Kayser, Christine

    2016-08-01

    Despite aggressive multimodal therapy for pediatric glioblastoma multiforme (GBM), patient survival remains poor. This retrospective review of patients with GBM aims to evaluate the patterns of failure after radiation therapy (RT). The study included 14 pediatric patients treated with RT at the Children's Hospital of Philadelphia from 2007 to 2015. With a median follow-up of 16.9 months, 13 (92.9%) developed recurrent disease. Of recurrences, nine (69.2%) were in-field, three (23.1%) were marginal, and one (7.7%) was distant. The majority of patients treated with adjuvant radiation failed in the region of high-dose RT, indicating the need for improvements in local therapy. PMID:27128519

  12. Cerebellar giant cell glioblastoma multiforme in an adult

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    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.

  13. Protocols for BNCT of glioblastoma multiforme at Brookhaven: Practical considerations

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    Chanana, A.D.; Coderre, J.A.; Joel, D.D.; Slatkin, D.N.

    1996-12-31

    In this report we discuss some issues considered in selecting initial protocols for boron neutron capture therapy (BNCT) of human glioblastoma multiforme. First the tolerance of normal tissues, especially the brain, to the radiation field. Radiation doses limits were based on results with human and animal exposures. Estimates of tumor control doses were based on the results of single-fraction photon therapy and single fraction BNCT both in humans and experimental animals. Of the two boron compounds (BSH and BPA), BPA was chosen since a FDA-sanctioned protocol for distribution in humans was in effect at the time the first BNCT protocols were written and therapy studies in experimental animals had shown it to be more effective than BSH.

  14. Current Trends in Targeted Therapies for Glioblastoma Multiforme

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    Fumiharu Ohka

    2012-01-01

    Full Text Available Glioblastoma multiforme (GBM is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas. Despite aggressive treatment including surgery, adjuvant TMZ-based chemotherapy, and radiotherapy, GBM still has a dismal prognosis: the median survival is 14.6 months from diagnosis. To date, many studies report several determinants of resistance to this aggressive therapy: (1 O6-methylguanine-DNA methyltransferase (MGMT, (2 the complexity of several altered signaling pathways in GBM, (3 the existence of glioma stem-like cells (GSCs, and (4 the blood-brain barrier. Many studies aim to overcome these determinants of resistance to conventional therapy by using various approaches to improve the dismal prognosis of GBM such as modifying TMZ administration and combining TMZ with other agents, developing novel molecular-targeting agents, and novel strategies targeting GSCs. In this paper, we review up-to-date clinical trials of GBM treatments in order to overcome these 4 hurdles and to aim at more therapeutical effect than conventional therapies that are ongoing or are about to launch in clinical settings and discuss future perspectives.

  15. The role of metabolic therapy in treating glioblastoma multiforme

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    Joseph C Maroon

    2015-01-01

    Full Text Available Glioblastoma multiforme (GBM is an aggressive and nearly uniformly fatal malignancy of the central nervous system. Despite extensive research and clinical trials over the past 50 years, very little progress has been made to significantly alter its lethal prognosis. The current standard of care (SOC includes maximal surgical resection, radiation therapy and chemotherapy and temozolomide (TMZ, including the selective use of glucocorticoids for symptom control. These same treatments, however, have the potential to create an environment that may actually facilitate tumor growth and survival. Research investigating the unique metabolic needs of tumor cells has led to the proposal of a new metabolic treatment for various cancers including GBMs that may enhance the effectiveness of the SOC. The goal of metabolic cancer therapy is to restrict GBM cells of glucose, their main energy substrate. By recognizing the underlying energy production requirements of cancer cells, newly proposed metabolic therapy is being used as an adjunct to standard GBM therapies. This review will discuss the calorie restricted ketogenic diet (CR-KD as a promising potential adjunctive metabolic therapy for patients with GBMs. The effectiveness of the CR-KD is based on the "Warburg Effect" of cancer metabolism and the microenvironment of GBM tumors. We will review recent case reports, clinical studies, review articles, and animal model research using the CR-KD and explain the principles of the Warburg Effect as it relates to CR-KD and GBMs.

  16. The role of metabolic therapy in treating glioblastoma multiforme.

    Science.gov (United States)

    Maroon, Joseph C; Seyfried, Thomas N; Donohue, Joseph P; Bost, Jeffrey

    2015-01-01

    Glioblastoma multiforme (GBM) is an aggressive and nearly uniformly fatal malignancy of the central nervous system. Despite extensive research and clinical trials over the past 50 years, very little progress has been made to significantly alter its lethal prognosis. The current standard of care (SOC) includes maximal surgical resection, radiation therapy and chemotherapy and temozolomide (TMZ), including the selective use of glucocorticoids for symptom control. These same treatments, however, have the potential to create an environment that may actually facilitate tumor growth and survival. Research investigating the unique metabolic needs of tumor cells has led to the proposal of a new metabolic treatment for various cancers including GBMs that may enhance the effectiveness of the SOC. The goal of metabolic cancer therapy is to restrict GBM cells of glucose, their main energy substrate. By recognizing the underlying energy production requirements of cancer cells, newly proposed metabolic therapy is being used as an adjunct to standard GBM therapies. This review will discuss the calorie restricted ketogenic diet (CR-KD) as a promising potential adjunctive metabolic therapy for patients with GBMs. The effectiveness of the CR-KD is based on the "Warburg Effect" of cancer metabolism and the microenvironment of GBM tumors. We will review recent case reports, clinical studies, review articles, and animal model research using the CR-KD and explain the principles of the Warburg Effect as it relates to CR-KD and GBMs. PMID:25949849

  17. Prognostic factors influencing clinical outcomes of glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    LI Shou-wei; QIU Xiao-guang; CHEN Bao-shi; ZHANG Wei; REN Huan; WANG Zhong-cheng; JIANG Tao

    2009-01-01

    Background Glioblastoma multiforme (GBM) is the most malignant kind of astrocytic tumors and is associated with a poor prognosis. In this retrospective study, we assessed the clinical, radiological, genetic molecular and treatment factors that influence clinical outcomes of patients with GBM.Methods A total of 116 patients with GBM who received surgery and radiation between January 2006 and December 2007 were included in this study. Kaplan-Meier survival analysis and Cox regression analysis were used to find the factors independently influencing patients' progression free survival (PFS) time and overall survival (OS) time.Results Age, preoperative Kamofsky Performance Scale (KPS) score, KPS score change at 2 weeks after operation, neurological deficit symptoms, tumor resection extent, maximal tumor diameter, involvement of eloquent cortex or deep structure, involvement of brain lobe, Ki-67 expression level and adjuvant chemotherapy were statistically significant factors (P <0.05) for both PFS and OS in the univariate analysis. Cox proportional hazards modeling revealed that age ≤50 years, preoperative KPS score ≥80, KPS score change after operation ≥0, involvement of single frontal lobe,non-eloquent area or deep structure involvement, low Ki-67 expression and adjuvant chemotherapy were independent favorable factors (P <0.05) for patients' clinical outcomes.Conclusions Age at diagnosis, preoperative KPS score, KPS score change at 2 weeks postoperation, involvement of brain lobe, involvement of eloquent cortex or deep structure, Ki-67 expression level and adjuvant chemotherapy correlate significantly with the prognosis of patients with GBM.

  18. Recurrent Glioblastoma Multiforme: Implication of Nonenhancing Lesions on Bevacizumab Treatment

    Directory of Open Access Journals (Sweden)

    Daniela Alexandru

    2013-08-01

    Full Text Available Glioblastoma multiforme (GBM is the most common primary brain tumors, accounting for 15-20% of all intracranial tumors. It is one of the most lethal tumors of the central nervous system with a median survival from diagnosis on the order of 6 to 18 months. Despite aggressive resection and chemoradiation, the tumor always recurs. Magnetic Resonance (MR imaging is an essential component in the diagnosis, treatment planning, and following response. However, the imaging features of recurrent GBM may be challenging, particularly in patients undertaking novel antiangiogenic therapy. We present such a case treated with repeated surgeries, combined chemoradiation, and bevacizumab. The patient benefited from the regimen with a 6-month progression-free survival, evidenced on both stable clinical condition and MR imaging findings. However, despite chemotherapy, a fulminant progression developed with growth multiple tumors in different locations and variable imaging characteristics, ranging from typical enhancing nodules to nonenhancing signal changes. The lesions of different imaging features were biopsy-proved to be recurrent GBM. We discuss the use of MR imaging in the evaluation of GBM treated with bevacizumab and emphasize the implication of signal abnormality on fluid-attenuated inversion recovery (FLAIR images for early evidence of recurrence. [J Interdiscipl Histopathol 2013; 1(4.000: 217-222

  19. 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.

  20. Postoperative epilepsy in patients undergoing craniotomy for glioblastoma multiforme.

    Science.gov (United States)

    Telfeian, A E; Philips, M F; Crino, P B; Judy, K D

    2001-03-01

    Glioblastoma multiforme (GBM) has associated with it one of the poorest prognoses among brain tumors. Postoperative seizures and the side effects of anticonvulsants, routinely given for prophylactic purposes, add to patient morbidity. The primary goal of this study was to determine who, of those undergoing craniotomy for GBM resection, is at risk for epilepsy. We studied 72 consecutive patients who underwent craniotomy and palliative resection for GBM. Twenty-nine presented with seizures and 17 had postoperative seizures. All patients were treated with a postoperative anticonvulsant for at least six months; anticonvulsants were continued longer if there was a postoperative seizure. Patient factors examined for an association with risk for postoperative seizure included age, sex, tumor size, tumor location, adjuvant therapy, postoperative complications and history of preoperative seizures. The majority of patients with no prior seizure history and who seized postoperatively had their first seizure after withdrawal from their anticonvulsant medication. All, but one, of the patients with both pre- and postoperative seizures had their first postoperative seizure while still on anticonvulsants. Smaller tumor size and frontal resection were associated with an increased risk of postoperative seizures. Our data suggests that those who do not present with seizures and undergo GBM resection may still be prone to seize but more easily protected from postoperative seizures with anticonvulsant therapy than patients who present with seizures; resection of frontal tumors and smaller tumors seemed to indicate an increased risk for postoperative seizures. PMID:11370829

  1. 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.)

  2. Evaluation of early imaging response criteria in glioblastoma multiforme

    International Nuclear Information System (INIS)

    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

  3. Understanding cytoskeleton regulators in glioblastoma multiforme for therapy design

    Science.gov (United States)

    Masoumi, Samaneh; Harisankar, Aditya; Gracias, Aileen; Bachinger, Fabian; Fufa, Temesgen; Chandrasekar, Gayathri; Gaunitz, Frank; Walfridsson, Julian; Kitambi, Satish S

    2016-01-01

    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 Administration (FDA)-approved oncology drugs, and its effect on cellular cytoskeleton was compared to treatment with temozolomide. This study identifies various groups of cytoskeletal regulators that have an important effect on patient survival and tumor development. Importantly, this work highlights the advantage of using cytoskeleton regulators as biomarkers for assessing prognosis and treatment design for GBM. PMID:27672311

  4. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

    International Nuclear Information System (INIS)

    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 (CTV46 and CTV60, respectively). MTVCho and MTVNAA 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 MTVNAA 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 MTVCho was outside of the edema (median, 33%) and for some patients it was also outside of the CTV46 and CTV60. 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 MTVCho for these patients were outside of CTV60. 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 metabolic information

  5. Uptake of the BPA into glioblastoma multiforme correlates with tumor cellularity

    Energy Technology Data Exchange (ETDEWEB)

    Joel, D.D.; Chanana, A.D.; Coderre, J.A. [and others

    1996-12-31

    Fourteen patients scheduled to undergo craniotomy for glioblastoma multiforme were infused with p-boronophenylalanine fructose intravenously for 2 hours prior to surgery. Tissues removed during the procedure and blood obtained at its conclusion were analyzed for boron by direct current plasma-atomic emission spectroscopy. The results are presented herein.

  6. 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...

  7. Drop metastases to the spinal cord from infratentorial glioblastoma multiforme in post-temozolomide era

    Directory of Open Access Journals (Sweden)

    Shripad Brahmanand Pande

    2015-01-01

    Full Text Available Drop metastases from glioblastoma multiforme (GBM to the spinal cord are extremely rare in clinical practice. We report herewith multiple drop metastases to the cervical and thoracic spinal cord presenting as paraplegia in a patient treated initially with tumor resection followed by chemoradiation and later with temozolomide-.based adjuvant chemotherapy.

  8. Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme

    DEFF Research Database (Denmark)

    Michaelsen, Signe Regner; Christensen, Ib Jarle; Grunnet, Kirsten;

    2013-01-01

    Although implementation of temozolomide (TMZ) as a part of primary therapy for glioblastoma multiforme (GBM) has resulted in improved patient survival, the disease is still incurable. Previous studies have correlated various parameters to survival, although no single parameter has yet been...

  9. Glioblastoma multiforme in a child with acute lymphoblastic leukemia: Case report and review of literature

    Directory of Open Access Journals (Sweden)

    Shah Kirit

    2004-07-01

    Full Text Available An 11-year-old boy with acute lymphoblastic leukemia had received prophylactic cranial irradiation (1800 cGy /10 fractions and intrathecal methotrexate. Five years later, he developed a glioblastoma multiforme in the right frontal region while the leukemia was in remission. It is possible that the glioma may have been induced by radiation and /or chemotherapy.

  10. Glioblastoma multiforme in four siblings : a cytogenetic and molecular genetic study

    NARCIS (Netherlands)

    DIRVEN, CMF; TUERLINGS, J; MOLENAAR, W.M.; GO, KG; LOUIS, DN

    1995-01-01

    The familial occurrence of gliomas, in the absence of well-defined neurological tumor syndromes such as the neurofibromatoses, is uncommon, We present a family of ten children in which the four eldest suffered from gliomas. Three of these siblings had histologically verified glioblastoma multiforme,

  11. RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls

    Directory of Open Access Journals (Sweden)

    Noerholm Mikkel

    2012-01-01

    Full Text Available Abstract Background RNA from exosomes and other microvesicles contain transcripts of tumour origin. In this study we sought to identify biomarkers of glioblastoma multiforme in microvesicle RNA from serum of affected patients. Methods Microvesicle RNA from serum from patients with de-novo primary glioblastoma multiforme (N = 9 and normal controls (N = 7 were analyzed by microarray analysis. Samples were collected according to protocols approved by the Institutional Review Board. Differential expressions were validated by qRT-PCR in a separate set of samples (N = 10 in both groups. Results Expression profiles of microvesicle RNA correctly separated individuals in two groups by unsupervised clustering. The most significant differences pertained to down-regulated genes (121 genes > 2-fold down in the glioblastoma multiforme patient microvesicle RNA, validated by qRT-PCR on several genes. Overall, yields of microvesicle RNA from patients was higher than from normal controls, but the additional RNA was primarily of size Conclusions Serum microvesicle RNA from patients with glioblastoma multiforme has significantly down-regulated levels of RNAs coding for ribosome production, compared to normal healthy controls, but a large overabundance of RNA of unknown origin with size

  12. RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls

    International Nuclear Information System (INIS)

    RNA from exosomes and other microvesicles contain transcripts of tumour origin. In this study we sought to identify biomarkers of glioblastoma multiforme in microvesicle RNA from serum of affected patients. Microvesicle RNA from serum from patients with de-novo primary glioblastoma multiforme (N = 9) and normal controls (N = 7) were analyzed by microarray analysis. Samples were collected according to protocols approved by the Institutional Review Board. Differential expressions were validated by qRT-PCR in a separate set of samples (N = 10 in both groups). Expression profiles of microvesicle RNA correctly separated individuals in two groups by unsupervised clustering. The most significant differences pertained to down-regulated genes (121 genes > 2-fold down) in the glioblastoma multiforme patient microvesicle RNA, validated by qRT-PCR on several genes. Overall, yields of microvesicle RNA from patients was higher than from normal controls, but the additional RNA was primarily of size < 500 nt. Gene ontology of the down-regulated genes indicated these are coding for ribosomal proteins and genes related to ribosome production. Serum microvesicle RNA from patients with glioblastoma multiforme has significantly down-regulated levels of RNAs coding for ribosome production, compared to normal healthy controls, but a large overabundance of RNA of unknown origin with size < 500 nt

  13. Genome-wide allelotype study of primary glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    胡杰; 江澄川; 吴浩强; 彭颂先; 唐婉君; 陈商群

    2003-01-01

    Objective To investigate the molecular genetic pathogenesis of primary glioblastoma multiforme (GBM) and identify which chromosomes or chromosomal regions of the entire genome may harbor tumor suppressor genes (TSGs) associated with GBM.Methods A high-resolution allelotype study of 21 cases of primary GBM was performed by PCR-based loss of heterozygosity (LOH)analysis. Three hundred and eighty-two fluorescent dye-labeled microsatellite markers covering all 22 autosomes were applied. The mean genetic distance between two flanking markers was about 10 cM.Results LOH was observed on all 39 nonacrocentric autosomal arms examined in this study. The LOH frequencies of 10q, 10p, 9p, 17p and 13q were the highest (>50%). Furthermore, high LOH frequencies were detected in the regions containing known TSGs including PTEN, DMBT1, p16, p15, p53 and RB; the LOH frequencies on 14q, 3q, 22q, 11p, 9q, 19q were also high (>40.5%). Our study observed the following commonly deleted regions: 9p22-23, 10p12.2-14, 10q21.3, 13q12.1-14.1, 13q14.3-31, 17p11.2-12, 17p13, 3q25.2-26.2, 11p12-13, 14q13-31, 14q32.1, 14q11.1-13, 22q13.3, 4q35, 4q31.1-31.2, 6q27 and 6q21-23.3. Conclusions The molecular pathogenesis of GBM is very complicated and associated with a variety of genetic abnormalities on many chromosomal arms. The most closely related chromosomal arms to the pathogenesis of GBM are 10q, 10p, 9p, 17p and 13q. Besides the well-known TSGs including PTEN, DMBT1, p16, p15, p53 and RB, multiple unknown TSGs associated with GBM may be present on the commonly deleted regions detected in the present study.

  14. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

    Energy Technology Data Exchange (ETDEWEB)

    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

  15. Virtual mutagenesis of isocitrate dehydrogenase 1 involved in glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    WANG Ming-dong; SHI Yan-fang; WANG Hong; WANG Jia-liang; MA Wen-bin; WANG Ren-zhi

    2011-01-01

    Background Site A132Arg mutations potentially impair the affinity of isocitrate dehydrogenase 1 (IDH1) for its substrate isocitrate (ICT),consequently reducing the production of α-ketoglutarate and leading to tumor growth through the induction of the hypoxia-inducible factor-1 (HIF-1) pathway.However,given that the roles of other active sites in IDH1 substrate binding remain unclear,we aimed to investigate IDH1 mutation pattern and its influence on enzyme function.Methods Fifteen IDH1 catalytic active site candidates were selected for in silico mutagenesis and protein homology modeling.Binding free energy of the IDH1/ICT complexes with single-site mutations was compared with that of the wild type.The affinity of 10 IDH1 catalytic active sites for the ICT substrate was further calculated.Results The IDH1 active site included seven residues from chain A (A77Thr,A94Ser,A100Arg,A132Arg,A1O9Arg,A275Asp,and A279Asp) and three residues from chain B (B214Thr,B212Lys,and B252Asp) that constituted the substrate ICT-binding site.These residues were located within 0.5 nm of ICT,indicating a potential interaction with the substrate.IDH1 changes of binding free energy (△E) suggested that the A132Arg residue from chain A contributes three hydrogen bonds to the ICT α-carboxyl and β-carboxyl groups,while the other nine residues involved in ICT binding form only one or two hydrogen bonds.Amino acid substitutes at A132Arg,A109Arg,and B212Lys sites,had the greatest effect on enzyme affinity for its substrate.Conclusions Mutations at sites A132Arg,A109Arg,and B212Lys reduced IDH1 affinity for ICT,indicating these active sites may play a central role in substrate binding.Mutations at sites A77Thr,A94Ser,and A275Asp increased the affinity of IDH1 for ICT,which may enhance IDN1 catalytic activity.Mutant IDH1 proteins with higher catalytic activity than the wild-type IDH1 could potentially be used as a novel gene therapy for glioblastoma multiforme.

  16. Gliosarcoma: A rare variant of glioblastoma multiforme in paediatric patient: Case report and review of literature.

    Science.gov (United States)

    Meena, Ugan Singh; Sharma, Sumit; Chopra, Sanjeev; Jain, Shashi Kant

    2016-09-16

    Gliosarcoma is rare central nervous system tumour and a variant of glioblastoma multiforme with bimorphic histological pattern of glial and sarcomatous differentiation. It occurs in elderly between 5(th) and 6(th) decades of life and extremely rare in children. It is highly aggressive tumour and managed like glioblastoma multiforme. A 12-year-old female child presented with complaints of headache and vomiting from 15 d and blurring of vision from 3 d. Magnetic resonance imaging of brain shows heterogeneous mass in right parieto-occipital cortex. A right parieto-occipito-temporal craniotomy with complete excision of mass revealed a primary glioblastoma on histopathological investigation. Treatment consists of maximum surgical excision followed by adjuvant radiotherapy. The etiopathogenesis, treatment modalities and prognosis is discussed. The available literature is also reviewed. PMID:27672648

  17. Gene expressions of TRP channels in glioblastoma multiforme and relation with survival.

    Science.gov (United States)

    Alptekin, M; Eroglu, S; Tutar, E; Sencan, S; Geyik, M A; Ulasli, M; Demiryurek, A T; Camci, C

    2015-12-01

    Glioblastoma multiforme (GBM) is one of the most lethal forms of cancer in humans, with a median survival of 10 to 12 months. Glioblastoma is highly malignant since the cells are supported by a great number of blood vessels. Although new treatments have been developed by increasing knowledge of molecular nature of the disease, surgical operation remains the standard of care. The TRP (transient receptor potential) superfamily consists of cation-selective channels that have roles in sensory physiology such as thermo- and osmosensation and in several complex diseases such as cancer, cardiovascular, and neuronal diseases. The aim of this study was to investigate the expression levels of TRP channel genes in patients with glioblastoma multiforme and to evaluate the relationship between TRP gene expressions and survival of the patients. Thirty-three patients diagnosed with glioblastoma were enrolled to the study. The expression levels of 21 TRP genes were quantified by using qRT-PCR with dynamic array 48 × 48 chip (BioMark HD System, Fluidigm, South San Francisco, CA, USA). TRPC1, TRPC6, TRPM2, TRPM3, TRPM7, TRPM8, TRPV1, and TRPV2 were found significantly higher in glioblastoma patients. Moreover, there was a significant relationship between the overexpression of TRP genes and the survival of the patients. These results demonstrate for the first time that TRP channels contribute to the progression and survival of the glioblastoma patients. PMID:26088448

  18. Canadian recommendations for the treatment of glioblastoma multiforme.

    Science.gov (United States)

    Mason, W P; Maestro, R Del; Eisenstat, D; Forsyth, P; Fulton, D; Laperrière, N; Macdonald, D; Perry, J; Thiessen, B

    2007-06-01

    RECOMMENDATION 1: Management of patients with glioblastoma multiforme (GBM) should be highly individualized and should take a multidisciplinary approach involving neuro-oncology, neurosurgery, radiation oncology, and pathology, to optimize treatment outcomes. Patients and caregivers should be kept informed of the progress of treatment at every stage. RECOMMENDATION 2: Sufficient tissue should be obtained during surgery for cytogenetic analysis and, whenever feasible, for tumour banking. RECOMMENDATION 3: Surgery is an integral part of the treatment plan, to establish a histopathologic diagnosis and to achieve safe, maximal, and feasible tumour resection, which may improve clinical signs and symptoms. RECOMMENDATION 4: The preoperative imaging modality of choice is magnetic resonance imaging (MRI) with gadolinium as the contrast agent. Other imaging modalities, such as positron emission tomography with [(18)F]-fluoro-deoxy-d-glucose, may also be considered in selected cases. Postoperative imaging (mri or computed tomography) is recommended within 72 hours of surgery to evaluate the extent of resection. RECOMMENDATION 5: Postoperative external-beam radiotherapy is recommended as standard therapy for patients with gbm. The recommended dose is 60 Gy in 2-Gy fractions. The recommended clinical target volume should be identified with gadolinium-enhanced T1-weighted mri, with a margin in the order of 2-3 cm. Target volumes should be determined based on a postsurgical planning MRI. A shorter course of radiation may be considered for older patients with poor performance status. RECOMMENDATION 6: During RT, temozolomide 75 mg/m(2) should be administered concurrently for the full duration of radio-therapy, typically 42 days. Temozolomide should be given approximately 1 hour before radiation therapy, and at the same time on the days that no radiotherapy is scheduled. RECOMMENDATION 7: Adjuvant temozolomide 150 mg/m(2), in a 5/28-day schedule, is recommended for cycle 1

  19. Pediatric glioblastoma multiforme in association with Turner's syndrome: a case report.

    Science.gov (United States)

    Hanaei, Sara; Habibi, Zohreh; Nejat, Farideh; Sayarifard, Fatemeh; Vasei, Mohammad

    2015-01-01

    The Ullrich-Turner syndrome (complete or partial X-chromosome monosomy) has been found to be associated with an increased rate of some extragonadal neoplasms. Sporadic reports of the Turner syndrome with various brain tumors, including few cases of glioblastoma multiforme, have been found in the literature. However, published data are insufficient to establish a definite relationship between these tumors and the Turner syndrome. Herein, a rare case of primary pediatric glioblastoma multiforme in a 7-year-old girl with Turner's syndrome is reported, and various aspects regarding clinical and pathophysiological issues have been discussed. Although Turner's syndrome is not one of the congenital chromosomal abnormalities which demand routine CNS screening, neurological assessment may be of value in those with relevant clinical findings. PMID:25720952

  20. Fractionated stereotactic radiosurgery with concurrent temozolomide chemotherapy for locally recurrent glioblastoma multiforme: a prospective cohort study

    OpenAIRE

    Greenspoon JN; Sharieff W; Hirte H; Overholt A; Devillers R; Gunnarsson T; Whitton A

    2014-01-01

    Jeffrey Noah Greenspoon,1 Waseem Sharieff,1 Holger Hirte,1 Andrew Overholt,1 Rocco Devillers,2 Thorsteinn Gunnarsson,2 Anthony Whitton11Department of Oncology, McMaster University, ON, Canada; 2Department of Surgery, McMaster University, ON, CanadaAbstract: Local recurrence represents a significant challenge in the management of patients with glioblastoma multiforme. Salvage treatment options are limited by lack of clinical efficacy. Recent studies have demonstrated a significant response rat...

  1. Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme

    OpenAIRE

    Oberstadt, Moritz C.; Bien-Möller, Sandra; Weitmann, Kerstin; Herzog, Susann; Hentschel, Katharina; Rimmbach, Christian; Vogelgesang, Silke; Balz, Ellen; Fink, Matthias; Michael, Heike; Zeden, Jan-Philip; Bruckmüller, Henrike; Werk, Anneke N.; Cascorbi, Ingolf; Hoffmann, Wolfgang

    2013-01-01

    Background Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient’s prognosis. Beside promoter methylation of the O 6 -methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM. Methods Therefore, we evaluated the proportion and pr...

  2. Neuronal Activity, Mitogens, and mTOR: Overcoming the Hurdles for the Treatment of Glioblastoma Multiforme

    OpenAIRE

    Maiese, Kenneth

    2015-01-01

    Glioblastoma multiforme (GBM) and other malignant gliomas are considered to be the most prevalent of primary malignant brain tumors. The incidence of these tumors per year is reported as 4.13 per 100,000 individuals per year. The median survival time following the diagnosis of GBM is approximately fifteen months in the setting of providing presently available treatments with surgical resection, radiation, and chemotherapy. Given these statistics, new strategies for the treatment of GBM and ot...

  3. Positron emission tomography-guided conformal fast neutron therapy for glioblastoma multiforme

    OpenAIRE

    Stelzer, Keith J.; Douglas, James G.; Mankoff, David A.; Silbergeld, Daniel L.; Krohn, Kenneth A.; Laramore, George E.; Spence, Alexander M.

    2008-01-01

    Glioblastoma multiforme (GBM) continues to be a difficult therapeutic challenge. Our study was conducted to determine whether improved survival and tumor control could be achieved with modern delivery of fast neutron radiation using three-dimensional treatment planning. Ten patients were enrolled. Eligibility criteria included pathologic diagnosis of GBM, age ≥ 18 years, and KPS ≥60. Patients underwent MRI and 18F-fluorodeoxyglucose PET (FDG PET) as part of initial three-dimensional treatment...

  4. Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme

    OpenAIRE

    Puduvalli, Vinay K.; Giglio, Pierre; Groves, Morris D.; Hess, Kenneth R.; Gilbert, Mark R.; Mahankali, Srikanth; Jackson, Edward F.; Levin, Victor A.; Conrad, Charles A.; Hsu, Sigmund H.; Colman, Howard; de Groot, John F.; Ritterhouse, MeLesa G.; Ictech, Sandra E.; Alfred Yung, W. K.

    2008-01-01

    This phase II study aimed at determining the efficacy and safety of irinotecan combined with thalidomide in adults with recurrent glioblastoma multiforme (GBM) not taking enzyme-inducing anticonvulsants (EIACs). Adult patients (⩾18 years) with recurrent GBM with up to three relapses following surgery and radiation therapy were eligible for this trial. The primary end point was rate of progression-free survival at 6 months (PFS-6); secondary end points were response rate, overall survival, and...

  5. New treatment options in the management of glioblastoma multiforme: a focus on bevacizumab

    OpenAIRE

    Argirios Moustakas; Kreisl, Teri N.

    2010-01-01

    Argirios Moustakas, Teri N KreislNational Cancer Institute, Neuro-Oncology Branch, National Institutes of Health, Bethesda, Maryland, USAAbstract: Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults and carries the poorest prognosis. Despite recent progress in molecular biology, neuro-imaging and neuro-surgical care, the management of patients with GBM continues to harbor significant challenges. Survival after diagnosis is poor even with the most aggressiv...

  6. 13-cis-Retinoic acid in the treatment of recurrent glioblastoma multiforme

    OpenAIRE

    See, Siew-Ju; Levin, Victor A.; Yung, W.-K. Alfred; Hess, Kenneth R.; Groves, Morris D.

    2004-01-01

    Basic science and clinical investigations have demonstrated that 13-cis-retinoic acid (cRA) has activity against malignant gliomas. To assess its effectiveness in the setting of recurrent glioblastoma multiforme (GBM), we performed a retrospective analysis of the medical records and neuroimaging results of patients with recurrent GBM who were treated with cRA. The toxicity profile of cRA, response, and effect on progression-free survival from initiation of treatment were end points of our ana...

  7. Specificity Protein 1 Expression Contributes to Bcl-w-Induced Aggressiveness in Glioblastoma Multiforme

    OpenAIRE

    Lee, Woo Sang; Kwon, Junhye; Yun, Dong Ho; Lee, Young Nam; Woo, Eun Young; Park, Myung-Jin; Lee, Jae-Seon; Han, Young-Hoon; Bae, In Hwa

    2014-01-01

    We already had reported that Bcl-w promotes invasion or migration in gastric cancer cells and glioblastoma multiforme (GBM) by activating matrix metalloproteinase-2 (MMP-2) via specificity protein 1 (Sp1) or β-cateinin, respectively. High expression of Bcl-w also has been reported in GBM which is the most common malignant brain tumor and exhibits aggressive and invasive behavior. These reports propose that Bcl-w-induced signaling is strongly associated with aggressive characteristic of GBM. W...

  8. Standards of care and novel approaches in the management of glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    Andreas F. Hottinger; Roger Stupp; Krisztian Homicsko

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Standard therapeutic approaches provide modest improvement in the progression-free and overall survival, necessitating the investigation of novel therapies. We review the standard treatment options for GBM and evaluate the results obtained in clinical trials for promising novel approaches, including the inhibition of angiogenesis, targeted approaches against molecular pathways, immunotherapies, and local treatment with low voltage electric fields.

  9. Mechanisms of Tumor Development and Anti-angiogenic Therapy in Glioblastoma Multiforme

    OpenAIRE

    Onishi, Manabu; Kurozumi, Kazuhiko; Ichikawa, Tomotsugu; Date, Isao

    2013-01-01

    Despite advances in surgical and medical therapy, glioblastoma multiforme (GBM) remains a fatal disease. There has been no significant increase in survival for patients with this disease over the last 20 years. Tumor vasculature formation and glioma cell invasion along the white matter tracts both play a pivotal role in glioma development. Angiogenesis and invasion are the major factors believed to be responsible for treatment resistance in tumors, and a better understanding of the glioma inv...

  10. Metástases intrarraquidianas de glioblastoma multiforme supratentorial da infância: relato de caso Spinal cord metastatic glioblastoma multiforme of childhood: case report

    Directory of Open Access Journals (Sweden)

    Patricia Imperatriz Porto Rondinelli

    2002-09-01

    Full Text Available Relatamos o caso de uma menina de onze anos de idade com glioblastoma multiforme na região têmporo-parietal direita, completamente ressecado cirurgicamente, submetida a radioterapia craniana pós-operatória. Houve recaída três meses após, em topografia distante do sítio primário, na porção caudal do canal raquidiano. Após, ocorreu evolução rápida para o óbito. A propósito desse caso, discutimos nossa experiência quanto à conduta nesses tumores e a literatura sobre o assunto.We report the case of an eleven years-old girl with a right temporo-parietal glioblastoma multiforme. The tumor was totally resected on neurossurgery, and cranial radioteraphy was applied at next. The tumor recurred three months later, far from primary site, in the caudal portion of the spinal canal. Death occurred in less than one month later. Taking into account the data of this case, we discuss our experience in the management of such tumors and the literature on the subject.

  11. BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors

    Directory of Open Access Journals (Sweden)

    Pinsker Marcus O

    2010-02-01

    Full Text Available Abstract Background The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU, one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare. Methods We performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m2 BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS, tumor burden, pretreatment with temozolomide (TMZ, type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model. Results The median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15, median overall survival 22 weeks (95% CI: 18-27. The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression. No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off. Conclusion In summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are

  12. Glioblastoma Multiforme: Relationship to Subventricular Zone and Recurrence

    OpenAIRE

    Kimura, Margareth; Lee, Yeuh; Miller, Ryan; Castillo, Mauricio

    2013-01-01

    Neurogenesis in the adult mammalian brain is active in two areas: the subgranular zone in the dentate gyrus of the hippocampus and the subventricular zone. Cancer stem cells have been isolated from malignant brain tumors and it is widely believed they arise from transformed endogenous stem cells. We sought to determine if the initial location of glioblastoma (GB) as seen on conventional MRI and its relationship to the subventricular zone (SVZ) predicts the pattern of recurrence. We analyzed t...

  13. Intermediate-term outcome in lung transplantation from a donor with glioblastoma multiforme.

    Science.gov (United States)

    Chen, Fengshi; Karolak, Wojtek; Cypel, Marcelo; Keshavjee, Shaf; Pierre, Andrew

    2009-10-01

    A 19-year-old man with cystic fibrosis, who was on extracorporeal membrane oxygenation, underwent bilateral lung transplantation from a donor with glioblastoma multiforme. Because the risk of tumor transmission from donor-related central nervous system malignancies remains unclear, the use of these extended donors remains controversial. In fact, there are few reports on the outcomes of lung transplantation from donors with central nervous system malignancy. This patient was critically ill with extracorporeal membrane oxygenation support before transplantation, but is well without any sign of malignancy 20 months after transplantation. PMID:19782299

  14. Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme

    OpenAIRE

    Chua, Susan L.; Rosenthal, Mark A.; Wong, Shirley S.; Ashley, David M.; Woods, Anne-marie; Dowling, Anthony; Cher, Lawrence M.

    2004-01-01

    Temozolomide has established activity in the treatment of recurrent glioblastoma multiforme (GBM). Caelyx (liposomal doxorubicin) has established activity in a broad range of tumors but has not been extensively evaluated in the treatment of GBM. Phase 1 data suggest that temozolomide and Caelyx can be combined safely at full dose. In this phase 2 study, combination temozolomide (200 mg/m2 orally, days 1–5) and Caelyx (40 mg/m2 i.v., day 1) was given every 4 weeks to a cohort of 22 patients wi...

  15. Pharmacologic inhibition of cdk4/6 arrests the growth of glioblastoma multiforme intracranial xenografts

    OpenAIRE

    Michaud, Karine; Solomon, David A.; Oermann, Eric; Kim, Jung-Sik; Zhong, Wei-Zhu; Prados, Michael D.; Ozawa, Tomoko; James, C. David; Waldman, Todd

    2010-01-01

    Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6 specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induc...

  16. Retrospective Analysis of Bevacizumab in Combination with Fotemustine in Chinese Patients with Recurrent Glioblastoma Multiforme

    OpenAIRE

    Zhiguang Liu; Guanqun Zhang; Liang Zhu; Jiangbo Wang; Dongbo Liu; Lifei Lian; Jianlin Liu; Tianbao Lai; Xiaorong Zhuang

    2015-01-01

    The aim of this study was to assess the activity and safety of bevacizumab (BEV) and fotemustine (FTM) for the treatment of recurrent glioblastoma multiforme (GBM) patients and explore the potential prognostic parameters on survival. This study retrospectively analyzed all patients with GBM who were treated with at least one cycle of BEV and FTM from July 2010 to October 2012. A total of 176 patients with recurrent GBM were enrolled. The response rate and disease control rate were 46.6% and 9...

  17. 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

    2015-01-01

    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 glioblastoma multiforme (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 after 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 for GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse.

  18. Diffusion tensor imaging for target volume definition in glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Berberat, Jatta; Remonda, Luca [Cantonal Hospital, Department of Neuro-radiology, Aarau (Switzerland); McNamara, Jane; Rogers, Susanne [Cantonal Hospital, Department of Radiation Oncology, Aarau (Switzerland); Bodis, Stephan [Cantonal Hospital, Department of Radiation Oncology, Aarau (Switzerland); University Hospital, Department of Radiation Oncology, Zurich (Switzerland)

    2014-10-15

    Diffusion tensor imaging (DTI) is an MR-based technique that may better detect the peritumoural region than MRI. Our aim was to explore the feasibility of using DTI for target volume delineation in glioblastoma patients. MR tensor tracts and maps of the isotropic (p) and anisotropic (q) components of water diffusion were coregistered with CT in 13 glioblastoma patients. An in-house image processing program was used to analyse water diffusion in each voxel of interest in the region of the tumour. Tumour infiltration was mapped according to validated criteria and contralateral normal brain was used as an internal control. A clinical target volume (CTV) was generated based on the T{sub 1}-weighted image obtained using contrast agent (T{sub 1Gd}), tractography and the infiltration map. This was compared to a conventional T{sub 2}-weighted CTV (T{sub 2}-w CTV). Definition of a diffusion-based CTV that included the adjacent white matter tracts proved highly feasible. A statistically significant difference was detected between the DTI-CTV and T{sub 2}-w CTV volumes (p < 0.005, t = 3.480). As the DTI-CTVs were smaller than the T{sub 2}-w CTVs (tumour plus peritumoural oedema), the pq maps were not simply detecting oedema. Compared to the clinical planning target volume (PTV), the DTI-PTV showed a trend towards volume reduction. These diffusion-based volumes were smaller than conventional volumes, yet still included sites of tumour recurrence. Extending the CTV along the abnormal tensor tracts in order to preserve coverage of the likely routes of dissemination, whilst sparing uninvolved brain, is a rational approach to individualising radiotherapy planning for glioblastoma patients. (orig.) [German] Die Diffusions-Tensor-Bildgebung (DTI) ist eine MR-Technik, die dank der Erfassung des peritumoralen Bereichs eine Verbesserung bezueglich MRI bringt. Unser Ziel war die Pruefung der Machbarkeit der Verwendung der DTI fuer die Zielvolumenabgrenzung fuer Patienten mit

  19. New treatment options in the management of glioblastoma multiforme: a focus on bevacizumab

    Directory of Open Access Journals (Sweden)

    Argirios Moustakas

    2010-03-01

    Full Text Available Argirios Moustakas, Teri N KreislNational Cancer Institute, Neuro-Oncology Branch, National Institutes of Health, Bethesda, Maryland, USAAbstract: Glioblastoma multiforme (GBM is the most common malignant primary brain tumor in adults and carries the poorest prognosis. Despite recent progress in molecular biology, neuro-imaging and neuro-surgical care, the management of patients with GBM continues to harbor significant challenges. Survival after diagnosis is poor even with the most aggressive approach using multimodality therapy. Although the etiology of malignant gliomas is not known, the dependency of tumor growth on angiogenesis has identified this pathway as a promising therapeutic target. Bevacizumab was the first antiangiogenic therapy approved for use in cancer and received accelerated Food and Drug Administration approval for the treatment of recurrent GBM in 2009, the first new drug for this disease in over a decade. This review describes the rationale behind the treatment of GBM with bevacizumab. The pharmacology, efficacy, safety and tolerability of bevacizumab will also be reviewed.Keywords: glioblastoma multiforme, angiogenesis, bevacizumab

  20. CHROMOSOME 17P MAY HARBOR MULTIPLE TUMOR SUPPRESSOR GENES ASSOCIATED WITH PRIMARY GLIOBLASTOMA MULTIFORME

    Institute of Scientific and Technical Information of China (English)

    胡杰; 江澄川; 吴浩强; 彭颂先; 唐婉君

    2002-01-01

    Objective: To investigate whether deletion of chromosome 17 is involved in the carcinogenesis of primary glioblastoma multiforme and to localize the possible common deletion region in the aforementioned chromosome. Methods: Polymerase chain reaction-based microsatellite analysis was used to assess loss of heterozygosity (LOH) on chromosome 17 in 20 primary glioblastoma multiforme (GBM). Fifteen fluorescent dye-labeled polymorphic markers were used. Results: Thirteen of twenty (65%) GBM displayed LOH on at least one marker of chromosome 17p. Two tumors showed either LOH or non-informativeness on all markers tested. The most frequent LOH was observed at loci including D17s799 (53.3%), Dl7s1852 (53.8%), Dl7s938 (63.20/o), Dl7s831 (55.6%). The loci D17s831 (on 17pl3) and D17s799(Dl7sl852 (17p11.2(pl2) are distal and proximal to p53 respectively. The frequencies of LOH at all loci examined on chromosome 17q were relatively low (<30%). None of informative loci exhibited microsatellite instability in this study. Conclusion: Loss of genetic material on chromosome 17p may play an important role in the pathogenesis of GBM. Besides the well-known TSG p53 on 17p, other unknown TSCs associated with GBM may be present on the chromosomal regions 17pl3 and 17p11.2(pl2, which are distal and proximal to p53 respectively.

  1. ET-54 immunotherapy based on tumor transplant antigen recognition emerges as a promising strategy for recurrent glioblastoma multiform (GBM) patients

    NARCIS (Netherlands)

    Schijns, V.E.J.C.; Pretto, C.; Devillers, L.; Pierre, D.; Hofman, F.

    2014-01-01

    Glioblastoma multiforme (GBM) prognosis remains very poor. This is especially true when the tumors relapse on the current standard of care treatments. Our preclinical data, generated in a rat CNS-1 glioma model in Lewis rats, provided the scientific rationale for a prototype clinical vaccine prepara

  2. Use of ERC-1671 vaccine in a patient with recurrent glioblastoma multiforme after progression during bevacizumab therapy: first published report

    NARCIS (Netherlands)

    Bota, D.A.; Alexandru-Abrams, D.; Pretto, C.; Hofman, F.M.; Chen, T.C.; Fu, B.; Carrillo, J.A.; Schijns, V.E.J.C.; Stathopoulos, A.

    2015-01-01

    Objectives: Glioblastoma multiforme (GBM) is a highly aggressive tumor, which recurs despite resection, focal beam radiation, and temozolomide chemotherapy. At recurrence, the only second-line treatment approved by the US Food and Drug Administration is bevacizumab (Avastin). To date, no single agen

  3. Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy

    International Nuclear Information System (INIS)

    Standard therapies for high grade glioma have failed to substantially improve survival and are associated with significant morbidity. At relapse, high grade gliomas, such as glioblastoma multiforme, are refractory to therapy and universally fatal. BRAF V600E-mutations have been described in a modest 6% to 7% of primary central nervous system (CNS) tumors, but with increased prevalence in the pediatric population and in certain brain tumor subtypes. The use of BRAF inhibitors have transformed melanoma therapy however their use in brain tumors remains unproven. We describe the pediatric case of a now 12 year old Caucasian male who originally presented at age 9 with a right fronto-parietal glioblastoma multiforme that recurred 2 ½ years from diagnosis. Molecular analysis of the primary tumor revealed a BRAF V600E mutation and the patient was placed on the BRAF inhibitor vemurafenib. A complete response was observed after 4 months of therapy and remains sustained at 6 months. This is the first report of a complete response of relapsed glioblastoma multiforme to targeted BRAF inhibitor therapy. While not a predominant mutation in glioblastoma multiforme, the increased prevalence of BRAF V600 mutations in pediatric CNS tumors and certain subtypes marks a population to whom this therapy could be applied. Response to this therapy suggests that BRAF inhibitors can affect primary CNS lesions when a documented and targetable mutation is present

  4. GlioLab-a space system for Glioblastoma multiforme cells on orbit behavior study

    Science.gov (United States)

    Cappelletti, Chantal; Twiggs, Robert J.

    Microgravity conditions and ionizing radiation pose significant health risks for human life in space. This is a concern for future missions and also for future space tourism flights. Nev-ertheless, at the same time it is very interesting to study the effects of these conditions in unhealthy organism like biological samples affected by cancer. It is possible that space envi-ronment increases, decreases or doesn't have any effect on cancer cells. In any case the test results give important informations about cancer treatment or space tourism flight for people affected by cancer. GlioLab is a joint project between GAUSS-Group of Astrodynamics at the "Sapienza" University of Roma and the Morehead State University (MSU) Space Science Center in Kentucky. The main goal of this project is the design and manufacturing of an autonomous space system to investigate potential effects of the space environment exposure on a human glioblastoma multiforme cell line derived from a 65-year-old male and on Normal Human Astrocytes (NHA). In particular the samples are Glioblastoma multiforme cancer cells because the radiotherapy using ionizing radiation is the only treatment after surgery that can give on ground an improvement on the survival rate for this very malignant cancer. During a mission on the ISS, GlioLab mission has to test the in orbit behavior of glioblastoma cancer cells and healthy neuronal cells, which are extremely fragile and require complex experimentation and testing. In this paper engineering solutions to design and manufacturing of an autonomous space system that can allow to keep alive these kind of cells are described. This autonomous system is characterized also by an optical device dedicated to cells behavior analysis and by microdosimeters for monitoring space radiation environment.

  5. The role of basic fibroblast growth factor in glioblastoma multiforme and glioblastoma stem cells and in their in vitro culture.

    Science.gov (United States)

    Haley, Elizabeth M; Kim, Yonghyun

    2014-04-28

    Glioblastoma multiforme (GBM) is the most malignant form of central nervous system tumor, and current therapies are largely ineffective at treating the cancer. Developing a more complete understanding of the mechanisms controlling the tumor is important in order to explore new possible treatment options. It is speculated that the presence of glioblastoma stem or stem-like cells (GSCs), a rare type of pluripotent cancer cell that possesses the ability to self-renew and generate tumors, could be an important factor contributing to the resistance to treatment and deadliness of the cancer. A comprehensive knowledge of the mechanisms controlling the expression and properties of GSCs is currently lacking, and one promising area for further exploration is in the influence of basic fibroblast growth factor (FGF-2) on GSCs. Recent studies reveal that FGF-2 plays a significant part in regulating GBM, and the growth factor is commonly included as a supplement in media used to culture GSCs in vitro. However, the particular role that FGF-2 plays in GSCs has not been as extensively explored. Therefore, understanding how FGF-2 is involved in GSCs and in GBMs could be an important step towards a more complete comprehension of the managing the disease. In this review, we look at the structure, signaling pathways, and specific role of FGF-2 in GBM and GSCs. In addition, we explore the use of FGF-2 in cell culture and using its synthetic analogs as a potential alternative to the growth factor in culture medium.

  6. Prognostic factors in glioblastoma multiforme. 10 years experience of a single institution

    International Nuclear Information System (INIS)

    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

  7. Fractionated stereotactic radiosurgery with concurrent temozolomide chemotherapy for locally recurrent glioblastoma multiforme: a prospective cohort study

    Directory of Open Access Journals (Sweden)

    Greenspoon JN

    2014-03-01

    Full Text Available Jeffrey Noah Greenspoon,1 Waseem Sharieff,1 Holger Hirte,1 Andrew Overholt,1 Rocco Devillers,2 Thorsteinn Gunnarsson,2 Anthony Whitton11Department of Oncology, McMaster University, ON, Canada; 2Department of Surgery, McMaster University, ON, CanadaAbstract: Local recurrence represents a significant challenge in the management of patients with glioblastoma multiforme. Salvage treatment options are limited by lack of clinical efficacy. Recent studies have demonstrated a significant response rate and acceptable toxicity with the use of fractionated stereotactic radiosurgery in this patient population. Our primary objective was to determine the efficacy and toxicity of fractionated stereotactic radiosurgery combined with concurrent temozolomide chemotherapy as a salvage treatment for recurrent glioblastoma multiforme. We prospectively collected treatment and outcome data for patients having fractionated stereotactic radiosurgery for locally recurrent glioblastoma multiforme after radical radiotherapy. Eligible patients had a maximum recurrence diameter of 60 mm without causing significant mass effect. The gross tumor volume was defined as the enhancing lesion on an enhanced fine-slice T1 (spin–lattice magnetic resonance imaging, and a circumferential setup margin of 1 mm was used to define the planning target volume. All patients were treated using robotic radiosurgery with three dose/fractionation schedules ranging from 25 to 35 Gy in five fractions, depending on the maximum tumor diameter. Concurrent temozolomide 75 mg/m2 was prescribed to all patients. Tumor response was judged using the Macdonald criteria, and toxicity was assessed using the CTCAE (Common Terminology Criteria for Adverse Events. A total of 31 patients were enrolled in this study. The median overall survival was 9 months, and progression-free survival was 7 months. The 6-month progression-free survival was 60% with a 95% confidence interval of 43%–77%. The a priori

  8. 5-aminolevulinic acid guidance during awake craniotomy to maximise extent of safe resection of glioblastoma multiforme.

    Science.gov (United States)

    Corns, Robert; Mukherjee, Soumya; Johansen, Anja; Sivakumar, Gnanamurthy

    2015-01-01

    Overall survival for patients with glioblastoma multiforme (GBM) has been consistently shown to improve when the surgeon achieves a gross total resection of the tumour. It has also been demonstrated that surgical adjuncts such as 5-aminolevulinic acid (5-ALA) fluorescence--which delineates malignant tumour tissue--normal brain tissue margin seen using violet-blue excitation under an operating microscope--helps achieve this. We describe the case of a patient with recurrent left frontal GBM encroaching on Broca's area (eloquent brain). Gross total resection of the tumour was achieved by combining two techniques, awake resection to prevent damage to eloquent brain and 5-ALA fluorescence guidance to maximise the extent of tumour resection.This technique led to gross total resection of all T1-enhancing tumour with the avoidance of neurological deficit. The authors recommend this technique in patients when awake surgery can be tolerated and gross total resection is the aim of surgery. PMID:26177997

  9. A genome-wide allelotype study of primary and corresponding recurrent glioblastoma multiforme in one patient

    Institute of Scientific and Technical Information of China (English)

    胡杰; 江澄川; 吴浩强; 彭颂先; 唐婉君; 陈商群

    2004-01-01

    @@Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor. Although comprehensive therapeutic measures are available, recurrence is very frequent and the prognosis of GBM remains dismal. To date, little is known about the molecular pathogenesis associated with GBM recurrence. According to Knudson ' s two-hit hypothesis of tumor suppressor gene (TSG) inactivation,1 deletion of a chromosomal region, as revealed by loss of heterozygosity (LOH), is often indicative of the presence of a potential TSG. Allelotype studies involving a comprehensive LOH analysis of the whole genome can provide more detailed and thorough information for detecting genetic anomalies than traditional LOH analysis. The present study is designed to conduct a genome-wide allelotype analysis of one patient ' s primary and corresponding recurrent GBM tumors in an effort to reveal molecular genetic alterations associated with the recurrence of this malignancy.

  10. Irinotecan-based regimens for recurrent glioblastoma multiforme: [corrected] a systematic review.

    Science.gov (United States)

    Abdel-Rahman, Omar; Fouad, Mona

    2015-01-01

    This systematic review aims to assess irinotecan-based salvage regimens for patients with recurrent glioblastoma multiforme (GBM) beyond first line treatment. Eligible trials were identified using databases search and 25 studies were included in the final analysis. Among the 25 studies, PFS-6 rate was reported in 15 studies and it ranged from 16% to 63%. Median PFS was reported in 18 studies and it ranged from 1 to 7.6 months. While for median OS, it was reported in 17 studies and it ranged from 5.8 months to 17.9 months. The available data suggests that routine use of irinotecan-based salvage regimens cannot be recommended outside the setting of well-controlled prospective randomized studies investigating novel combinations of irinotecan. PMID:26469869

  11. Comparing predictive models of glioblastoma multiforme built using multi-institutional and local data sources.

    Science.gov (United States)

    Singleton, Kyle W; Hsu, William; Bui, Alex A T

    2012-01-01

    The growing amount of electronic data collected from patient care and clinical trials is motivating the creation of national repositories where multiple institutions share data about their patient cohorts. Such efforts aim to provide sufficient sample sizes for data mining and predictive modeling, ultimately improving treatment recommendations and patient outcome prediction. While these repositories offer the potential to improve our understanding of a disease, potential issues need to be addressed to ensure that multi-site data and resultant predictive models are useful to non-contributing institutions. In this paper we examine the challenges of utilizing National Cancer Institute datasets for modeling glioblastoma multiforme. We created several types of prognostic models and compared their results against models generated using data solely from our institution. While overall model performance between the data sources was similar, different variables were selected during model generation, suggesting that mapping data resources between models is not a straightforward issue.

  12. Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: An assessment of clinical potential

    Energy Technology Data Exchange (ETDEWEB)

    Hopewell, J.W., E-mail: john.hopewell@gtc.ox.ac.uk [Green Templeton College and Particle Therapy Cancer Research Institute, University of Oxford, Oxford (United Kingdom); Gorlia, T. [Data Center, EORTC, Brussels (Belgium); Pellettieri, L. [Hammercap Medical AB, Stockholm (Sweden)] [Department of Neurosurgery, Goeteborg University, Goeteborg (Sweden); Giusti, V. [Hammercap Medical AB, Stockholm (Sweden)] [Department of Mechanical, Nuclear and Production Engineering, University of Pisa, Pisa (Italy); H-Stenstam, B. [Nykoeping Hospital, County of Sormland (Sweden); Skoeld, K. [Hammercap Medical AB, Stockholm (Sweden)

    2011-12-15

    The purpose of this analysis was to assess the potential of BNCT, with L-boronophenylalanine (L-BPA), as first line radiotherapy for glioblastoma multiforme (GBM). The survival of patients with newly diagnosed GBM from a phase II BNCT study was compared with those from the two arms of a phase III study with conventional radiotherapy (RT) vs. RT plus concomitant and adjuvant medication with temozolomide (TMZ). A small subgroup, for which the methylation status of the O{sup 6}-methylguanine-DNA methyltransferase (MGMT) DNA-repair gene was known, was also considered. The results indicated that the use of BNCT with BPA should be explored in a stratified randomized phase II trial in which patients with the unmethylated MGMT DNA-repair gene are offered BNCT vs. RT plus TMZ.

  13. 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

  14. Glioblastoma multiforme and papillary thyroid carcinoma - A rare combination of multiple primary malignancies

    Directory of Open Access Journals (Sweden)

    Swaroopa Pulivarthi

    2015-01-01

    Full Text Available We are describing a 19-year-old white woman who presented with two synchronous primary cancers, namely glioblastoma multiforme and papillary thyroid cancer. The patient was admitted with dizziness, headache, and vomiting. CT head revealed acute intraparenchymal hematoma in the right cingulate gyrus and the splenium of the corpus callosum. Carotid and cerebral angiogram were unremarkable. MRI of the brain demonstrated a non-enhancing and non-hemorrhagic component of the lesion along the lateral margin of the hemorrhage just medial to the atrium of the right lateral ventricle that was suspicious for a tumor or metastasis. Brain biopsy confirmed it as glioblastoma mutiforme. CT chest was done to rule out primary cancer that revealed a 11 mm hypodense lesion in the left lobe of the thyroid and ultrasound-guided fine-needle aspiration biopsy confirmed it as papillary thyroid carcinoma. We should evaluate for multiple primary malignancies in young patients who are found to have primary index cancer.

  15. Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme

    Science.gov (United States)

    2013-01-01

    Background Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient’s prognosis. Beside promoter methylation of the O 6 -methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM. Methods Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples. Results Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM. Conclusions In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients’ survival. PMID:24380367

  16. MR-guided laser-induced interstitial thermotherapy of recurrent glioblastoma multiforme: Preliminary results in 16 patients

    Energy Technology Data Exchange (ETDEWEB)

    Schwarzmaier, Hans-Joachim [Center for Medical Research, Klinikum Krefeld, University of Duesseldorf Medical School at Krefeld (Germany)]. E-mail: schwarzmaier@klinikum-krefeld.de; Eickmeyer, Frank [Department of Radiology, Coordination Center for Clinical Studies, Klinikum Krefeld, University of Duesseldorf Medical School at Krefeld (Germany); Tempelhoff, Wernholt von [Department of Neurosurgery, Klinikum Krefeld, University of Duesseldorf Medical School at Krefeld (Germany); Fiedler, Volkhard Ulrich [Department of Radiology, Coordination Center for Clinical Studies, Klinikum Krefeld, University of Duesseldorf Medical School at Krefeld (Germany); Niehoff, Hendrik [Department of Neurosurgery, Klinikum Krefeld, University of Duesseldorf Medical School at Krefeld (Germany); Ulrich, Slif Dagobert [Department of Radiology, Coordination Center for Clinical Studies, Klinikum Krefeld, University of Duesseldorf Medical School at Krefeld (Germany); Yang Qin [University of Duesseldorf (Germany); Ulrich, Frank [Department of Neurosurgery, Klinikum Krefeld, University of Duesseldorf Medical School at Krefeld (Germany)

    2006-08-15

    We investigated the survival after laser-induced interstitial thermotherapy in 16 patients suffering from recurrent glioblastoma multiforme. The concept underlying the intervention is the cytoreduction of the tumor tissue by local thermocoagulation. All patients received standard chemotherapy (temozolomide). The median overall survival time after the first relapse was 9.4 months, corresponding to a median overall survival time after laser irradiation of 6.9 months. During the study, however, the median survival after laser coagulation increased to 11.2 months. This survival time is substantially longer than those reported for the natural history (<5 months) or after chemotherapy (temozolomide: 5.4-7.1 months). We conclude that cytoreduction by laser irradiation might be a promising option for patients suffering from recurrent glioblastoma multiforme. In addition, the data indicate the presence of a substantial learning curve. Future work should optimize the therapeutic regimen and evaluate this treatment approach in controlled clinical trials.

  17. Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

    OpenAIRE

    Tivnan, Amanda; Zakaria, Zaitun; O'Leary, Caitrín; Kögel, Donat; Pokorny, Jenny L.; Sarkaria, Jann N.; Prehn, Jochen H M

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30–40% response rate, many fall into the range of 10–20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB ...

  18. ET-54IMMUNOTHERAPY BASED ON TUMOR TRANSPLANT ANTIGEN RECOGNITION EMERGES AS A PROMISING STRATEGY FOR RECURRENT GLIOBLASTOMA MULTIFORME (GBM) PATIENTS

    OpenAIRE

    Schijns, Virgil; Pretto, Chrystel; Devillers, Laurent; Pierre, Denis; Hofman, Florence; Kruse, Carol; Chen, Thomas; Oertel, Joachim; Hantos, Peter; Bota, Daniela; Stathopoulos, Apostolos

    2014-01-01

    Glioblastoma multiforme (GBM) prognosis remains very poor. This is especially true when the tumors relapse on the current standard of care treatments. Our preclinical data, generated in a rat CNS-1 glioma model in Lewis rats, provided the scientific rationale for a prototype clinical vaccine preparation, named ERC 1671 (Gliovac). ERC1671 is composed of autologous antigens, derived from the patient's own tumour tissue, and administered in conjunction with allogeneic antigens from histologicall...

  19. Salvage Fractionated Stereotactic Radiotherapy with or without Chemotherapy and Immunotherapy for Recurrent Glioblastoma Multiforme: A Single Institution Experience

    OpenAIRE

    Hasan, Shaakir; Chen, Eda; Lanciano, Rachelle; Yang, Jun; Hanlon, Alex; Lamond, John; Arrigo, Stephen; Ding, William; Mikhail, Michael; Ghaneie, Arezoo; Brady, Luther

    2015-01-01

    Background The current standard of care for salvage treatment of glioblastoma multiforme (GBM) is gross total resection and adjuvant chemoradiation for operable patients. Limited evidence exists to suggest that any particular treatment modality improves survival for recurrent GBM, especially if inoperable. We report our experience with fractionated stereotactic radiotherapy (fSRT) with and without chemo/immunotherapy, identifying prognostic factors associated with prolonged survival. ...

  20. Impact of therapy on quality of life, neurocognitive function and their correlates in glioblastoma multiforme: a review

    OpenAIRE

    Henriksson, Roger; Asklund, Thomas; Poulsen, Hans Skovgaard

    2011-01-01

    The maintenance of quality of life (QoL) in patients with high-grade glioma is an important endpoint during treatment, particularly in those with glioblastoma multiforme (GBM) given its dismal prognosis despite limited advances in standard therapy. It has proven difficult to identify new therapies that extend survival in patients with recurrent GBM, so one of the primary aims of new therapies is to reduce morbidity, restore or preserve neurologic functions, and the capacity to perform daily a...

  1. Inhibition of Multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

    OpenAIRE

    Amanda eTivnan; Zaitun eZakaria; Caitrin eO'Leary; Donat eKogel; Pokorny, Jenny L.; Sarkaria, Jann N.; Prehn, Jochen H M

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it’s role in BB...

  2. Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients

    OpenAIRE

    Rose Frank; You An; Juricko Janko; Fokas Emmanouil; Wang Lin-Fang; Pagenstecher Axel; Engenhart-Cabillic Rita; An Han-Xiang

    2008-01-01

    Abstract Background Malignant gliomas are lethal cancers, highly dependent on angiogenesis and treatment options and prognosis still remain poor for patients with recurrent glioblastoma multiforme (GBM). Ephs and ephrins have many well-defined functions during embryonic development of central nervous system such as axon mapping, neural crest cell migration, hindbrain segmentation and synapse formation as well as physiological and abnormal angiogenesis. Accumulating evidence indicates that Eph...

  3. Treatment of glioblastoma multiforme cells with temozolomide-BioShuttle ligated by the inverse Diels-Alder ligation chemistry

    OpenAIRE

    Braun, Klaus; Wiessler, Manfred; Ehemann, Volker; Pipkorn, Ruediger; Spring, Herbert; Debus, Juergen; Didinger, Bernd; Koch, Mario; Muller, Gabriele; Waldeck, Waldemar

    2009-01-01

    Recurrent glioblastoma multiforme (GBM), insensitive against most therapeutic interventions, has low response and survival rates. Temozolomide (TMZ) was approved for second-line therapy of recurrent anaplastic astrocytoma. However, TMZ therapy in GBM patients reveals properties such as reduced tolerability and inauspicious hemogram. The solution addressed here concerning GBM therapy consolidates and uses the potential of organic and peptide chemistry with molecular medicine. We enhanced the p...

  4. Therapy and progression – induced O6-methylguanine-DNA methyltransferase and mismatch repair alterations in recurrent glioblastoma multiforme

    OpenAIRE

    Agarwal, S.; Suri, V.; M C Sharma; C. Sarkar

    2015-01-01

    Despite multimodality treatment protocol including surgical resection, radiotherapy, and chemotherapy in patients with glioblastoma multiforme (GBM), most suffer from treatment failure and tumor recurrence within a few months of initial surgery. The effectiveness of temozolomide (TMZ), the most commonly used chemotherapeutic agent, is largely dependent on the methylation status of the promoter of the gene O6-methylguanine-DNA methyltransferase (MGMT) and the integrity of the mismatch repair (...

  5. Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, Arnulf; Vaupel, Peter; Stockinger, Marcus; Schmidberger, Heinz [University Medical Center, Department of Radiooncology and Radiotherapy, Mainz (Germany); Struss, Hans-Garlich [University Medical Center, Department of Laboratory Medicine, Mainz (Germany); Giese, Alf [University Medical Center, Department of Neurosurgery, Mainz (Germany)

    2014-10-15

    In comparison to normal brain tissue, glioblastomas exhibit significantly increased glucose uptake. Brain edema is a common complication during adjuvant chemoradiotherapy, leading to a requirement for glucocorticoid treatment. Glucocorticoid treatment frequently causes considerable deregulation of blood glucose levels. Therefore, episodes of hyperglycemia may contribute to radio- and/or chemoresistance. This study comprises a retrospective analysis of the influence of hyperglycemic episodes (HEs) during adjuvant therapy on the overall survival of 106 glioblastoma multiforme patients. The occurrence of one or more deregulated blood glucose value(s) > 10 mM is associated with a reduction in median overall survival from 16.7 to 8.8 months. A significantly poorer overall survival of patients with hyperglycemia could also be detected in subgroup analyses of patients with complete tumor resection and complete treatment according to the EORTC 22891/26891 trial protocol, as well as in a multivariate Cox proportional hazards analysis. A history of diabetes mellitus had no influence on prognosis. Our data suggest that the observed negative impact of elevated blood glucose levels on overall survival may not solely be explained by the patients' poorer general condition; the elevated blood glucose concentration itself may play a pathogenetic role. This could be due to increased activity of antioxidant systems, elevated expression of DNA damage response proteins and protection of hypoxic tumor cells against apoptosis combined with hypoxia-mediated radioresistance. A possible prognostic impact of elevated blood glucose levels during the period of adjuvant (chemo-) radiotherapy of glioblastoma should be evaluated in a prospective clinical trial. (orig.) [German] Glioblastome zeigen im Vergleich mit normalem Gehirngewebe eine deutlich vermehrte Glukoseaufnahme. Im Rahmen der adjuvanten Radio(chemo)therapie von Glioblastomen treten vielfach Hirnoedeme auf, die eine

  6. Pathway analysis of single-nucleotide polymorphisms potentially associated with glioblastoma multiforme susceptibility using random forests.

    Science.gov (United States)

    Chang, Jeffrey S; Yeh, Ru-Fang; Wiencke, John K; Wiemels, Joseph L; Smirnov, Ivan; Pico, Alexander R; Tihan, Tarik; Patoka, Joe; Miike, Rei; Sison, Jennette D; Rice, Terri; Wrensch, Margaret R

    2008-06-01

    Glioma is a complex disease that is unlikely to result from the effect of a single gene. Genetic analysis at the pathway level involving multiple genes may be more likely to capture gene-disease associations than analyzing genes one at a time. The current pilot study included 112 Caucasians with glioblastoma multiforme and 112 Caucasian healthy controls frequency matched to cases by age and gender. Subjects were genotyped using a commercially available (ParAllele/Affymetrix) assay panel of 10,177 nonsynonymous coding single-nucleotide polymorphisms (SNP) spanning the genome known at the time the panel was constructed. For this analysis, we selected 10 pathways potentially involved in gliomagenesis that had SNPs represented on the panel. We performed random forests (RF) analyses of SNPs within each pathway group and logistic regression to assess interaction among genes in the one pathway for which the RF prediction error was better than chance and the permutation P < 0.10. Only the DNA repair pathway had a better than chance classification of case-control status with a prediction error of 45.5% and P = 0.09. Three SNPs (rs1047840 of EXO1, rs12450550 of EME1, and rs799917 of BRCA1) of the DNA repair pathway were identified as promising candidates for further replication. In addition, statistically significant interactions (P < 0.05) between rs1047840 of EXO1 and rs799917 or rs1799966 of BRCA1 were observed. Despite less than complete inclusion of genes and SNPs relevant to glioma and a small sample size, RF analysis identified one important biological pathway and several SNPs potentially associated with the development of glioblastoma. PMID:18559551

  7. Theranostic Application of Mixed Gold and Superparamagnetic Iron Oxide Nanoparticle Micelles in Glioblastoma Multiforme.

    Science.gov (United States)

    Sun, Lova; Joh, Daniel Y; Al-Zaki, Ajlan; Stangl, Melissa; Murty, Surya; Davis, James J; Baumann, Brian C; Alonso-Basanta, Michelle; Kaol, Gary D; Tsourkas, Andrew; Dorsey, Jay F

    2016-02-01

    The treatment of glioblastoma multiforme, the most prevalent and lethal form of brain cancer in humans, has been limited in part by poor delivery of drugs through the blood-brain barrier and by unclear delineation of the extent of infiltrating tumor margins. Nanoparticles, which selectively accumulate in tumor tissue due to their leaky vasculature and the enhanced permeability and retention effect, have shown promise as both therapeutic and diagnostic agents for brain tumors. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) have been leveraged as T2-weighted MRI contrast agents for tumor detection and imaging; and gold nanoparticles (AuNP) have been demonstrated as radiosensitizers capable of propagating electron and free radical-induced radiation damage to tumor cells. In this study, we investigated the potential applications of novel gold and SPION-loaded micelles (GSMs) coated by polyethylene glycol-polycaprolactone (PEG-PCL) polymer. By quantifying gh2ax DNA damage foci in glioblastoma cell lines, we tested the radiosensitizing efficacy of these GSMs, and found that GSM administration in conjunction with radiation therapy (RT) led to ~2-fold increase in density of double-stranded DNA breaks. For imaging, we used GSMs as a contrast agent for both computed tomography (CT) and magnetic resonance imaging (MRI) studies of stereotactically implanted GBM tumors in a mouse model, and found that MRI but not CT was sufficiently sensitive to detect and delineate tumor borders after administration and accumulation of GSMs. These results suggest that with further development and testing, GSMs may potentially be integrated into both imaging and treatment of brain tumors, serving a theranostic purpose as both an MRI-based contrast agent and a radiosensitizer. PMID:27305768

  8. Improved Outcomes with Intensity Modulated Radiation Therapy Combined with Temozolomide for Newly Diagnosed Glioblastoma Multiforme

    Directory of Open Access Journals (Sweden)

    Noel J. Aherne

    2014-01-01

    Full Text Available Purpose. Glioblastoma multiforme (GBM is optimally treated by maximal debulking followed by combined chemoradiation. Intensity modulated radiation therapy (IMRT is gaining widespread acceptance in other tumour sites, although evidence to support its use over three-dimensional conformal radiation therapy (3DCRT in the treatment of gliomas is currently lacking. We examined the survival outcomes for patients with GBM treated with IMRT and Temozolomide. Methods and Materials. In all, 31 patients with GBM were treated with IMRT and 23 of these received chemoradiation with Temozolomide. We correlated survival outcomes with patient functional status, extent of surgery, radiation dose, and use of chemotherapy. Results. Median survival for all patients was 11.3 months, with a median survival of 7.2 months for patients receiving 40.05 Gray (Gy and a median survival of 17.4 months for patients receiving 60 Gy. Conclusions. We report one of the few series of IMRT in patients with GBM. In our group, median survival for those receiving 60 Gy with Temozolomide compared favourably to the combined therapy arm of the largest randomised trial of chemoradiation versus radiation to date (17.4 months versus 14.6 months. We propose that IMRT should be considered as an alternative to 3DCRT for patients with GBM.

  9. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting-Ideal Versus Reality.

    Science.gov (United States)

    Lee, Chooi Yeng; Ooi, Ing Hong

    2016-09-08

    Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ's efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach.

  10. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting—Ideal Versus Reality

    Directory of Open Access Journals (Sweden)

    Chooi Yeng Lee

    2016-09-01

    Full Text Available Temozolomide (TMZ is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ’s efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS. Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach.

  11. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting—Ideal Versus Reality

    Science.gov (United States)

    Lee, Chooi Yeng; Ooi, Ing Hong

    2016-01-01

    Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ’s efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach. PMID:27618068

  12. Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Guckenberger, Matthias; Mayer, Mario; Sweeney, Reinhart A.; Flentje, Michael [University Hospital Wuerzburg (Germany). Dept. of Radiation Oncology; Buttmann, Mathias [University Hospital Wuerzburg (Germany). Dept. of Neurology; Vince, Giles H. [University Hospital Wuerzburg (Germany). Dept. of Neurosurgery

    2011-09-15

    The goal of this study was to evaluate accelerated radiotherapy with and without temozolomide (TMZ) for glioblastoma multiforme (GBM). This retrospective analysis evaluated 86 patients with histologically proven GBM who were treated with accelerated radiotherapy of 1.8 Gy twice daily to a total dose of 54 Gy within 3 weeks. Median age was 62 years and median Karnofsky index was 90. A total of 41 patients received radiotherapy only from 2002-2005 and 45 patients were treated with TMZ concomitantly and after radiotherapy from 2005-2007. Median overall survival (OS) was 12.5 months and 2-year OS was 15.4%. Patient characteristics were well balanced between the two groups except for better performance status (p = 0.05) and higher frequency of retreatment for the first recurrence (p = 0.02) in the TMZ group. Age at diagnosis (HR 2.83) and treatment with TMZ (HR 0.60) were correlated with OS in the multivariate analysis: treatment with and without TMZ resulted in median OS of 16 months and 11.3 months, respectively. Hematological toxicity grade > II was observed in 2/45 patients and 5/37 patients during simultaneous radiochemotherapy and adjuvant TMZ. TMZ added to accelerated radiotherapy for GBM resulted in prolonged overall survival with low rates of severe hematological toxicity. (orig.)

  13. CT-guided interstitial HDR brachytherapy for recurrent glioblastoma multiforme. Long-term results

    Energy Technology Data Exchange (ETDEWEB)

    Tselis, N.; Roeddiger, S.; Filipowicz, I.; Kontova, M.; Heyd, R.; Zamboglou, N. [Offenbach Hospital (Germany). Dept. of Radiotherapy and Interdisciplinary Oncology; Kolotas, C. [Offenbach Hospital (Germany). Dept. of Radiotherapy and Interdisciplinary Oncology; Hirslanden Medical Center, Aarau (Switzerland). Inst. of Radiotherapy; Birn, G. [Offenbach Hospital (Germany). Dept. of Neurosurgery; Fountzilas, G.; Selviaridis, P. [Aristotle Univ. of Thessaloniki School of Medicine, Thessaloniki (Greece); Baltas, D.; Anagnostopoulos, G. [Offenbach Hospital (Germany). Dept. of Medical Physics and Engineering

    2007-10-15

    Background and Purpose: Recurrences of glioblastoma multiforme (GBM) within previously irradiated volumes pose a serious therapeutic challenge. This retrospective study evaluates the long-term tumor control of recurrent GBM treated with interstitial high-dose-rate brachytherapy (HDR-BRT). Patients and Methods: Between 1995 and 2003, 84 patients were treated for recurrent cerebral GBM located within previously irradiated volumes. All patients had received adjuvant external radiotherapy following primary surgery, with a focal dose up to 60 Gy. The median recurrent tumor volume was 51 cm{sup 3} (3-207 cm{sup 3}), and the HDR-BRT consisted of an afterloading {sup 192}Ir implant which delivered a median dose of 40 Gy (30-50 Gy). Catheter implantation was implemented using interactive computed tomography (CT) guidance under local anesthesia and sedoanalgesia. Results: After a median follow-up of 61 months, 5/84 patients (6%) were alive. The median post-BRT survival was 37 weeks, and the median overall survival 78 weeks. Moderate to severe complications occurred in 5/84 cases (6%). Conclusion: For patients with recurrences of GBM within previously irradiated volumes, CT-guided interstitial HDR-BRT is a feasible treatment option that can play an important role in providing palliation. (orig.)

  14. PET imaging of glioblastoma multiforme EGFR expression for therapeutic decision guidance.

    Science.gov (United States)

    Wehrenberg-Klee, Eric; Redjal, Navid; Leece, Alicia; Turker, N Selcan; Heidari, Pedram; Shah, Khalid; Mahmood, Umar

    2015-01-01

    After initial therapy and total resection of glioblastoma multiforme (GBM), 80-90% of recurrences occur at the surgical margins. Insufficient sensitivity and specificity of current imaging techniques based on non-specific vascular imaging agents lead to delay in diagnosis of residual and/or recurrent disease. A tumor-specific imaging agent for GBM may improve detection of small residual disease in the post-operative period, and improve ability to distinguish tumor recurrence from its imaging mimics that can delay diagnosis. To this end, we developed an EGFR-targeted PET probe and assessed its ability to image EGFR WT (U87) and EGFRvIII (Gli36vIII) expressing GBMs in both murine intra-cranial xenografts and in a surgical-resection model. The developed imaging probe, (64)Cu-DOTAcetuximab-F(ab´)2, binds with a Kd of 11.2 nM to EGFR expressing GBM. (64)Cu-DOTA-cetuximab-F(ab´)2 specifically localized to intra-cranial tumor with a significant difference in SUVmean between tumor and contralateral brain for both Gli36vIII and U87 tumors (PGBM, demonstrates excellent TBR, and specifically images small residual tumor in a surgical model, suggesting future clinical utility in identifying true tumor recurrence. PMID:26269775

  15. Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields

    Directory of Open Access Journals (Sweden)

    Rulseh Aaron

    2012-10-01

    Full Text Available Abstract Glioblastoma multiforme (GBM is the most common and malignant primary intracranial tumor, and has a median survival of only 10 to 14 months with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM is nearly universal, and further decreases the median survival to only five to seven months with optimal therapy. Tumor-treating fields (TTField therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz may induce apoptosis in specific cell types. Our center was the first to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals in 2004 and 2005, and four of those original 20 patients are still alive today. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence.

  16. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting-Ideal Versus Reality.

    Science.gov (United States)

    Lee, Chooi Yeng; Ooi, Ing Hong

    2016-01-01

    Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ's efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach. PMID:27618068

  17. CHROMOSOME 3 MAY HARBOR MULTIPLE TUMOR SUPPRESSOR GENES ASSOCIATED WITH PRIMARY GLIOBLASTOMA MULTIFORME

    Institute of Scientific and Technical Information of China (English)

    胡杰; 江澄川; 吴浩强; 彭颂先; 唐婉君; 陈商群

    2002-01-01

    Objective: To investigate whether deletion of chromosome 3 is involved in the carcinogenesis of primary glioblastoma multiforme (GBM) and to localize the possible common deletion region in the aforementioned chromosome. Methods: PCR based microsatellite polymorphism analyses were performed to detect loss of heterozygosity (LOH). Twenty-three loci on chromosome 3 were examined in 20 cases of GBM. Fluorescence-labeled primers and Perkin Elmer 377 DNA Sequencer were applied. Results: 50% informative cases of GBM displayed LOH on chromosome 3. 50% of informative cases displayed LOH on 3q and 35% on 3p. 25.6% of informative loci showed LOH in our series, in which frequent LOH were observed in the chromosomal region from loci D3S1614 (42.9%) to D3S1565 (35.3%) on 3q24(27 and at loci D3S1569 (35.3%) on 3q22(23 and D3S1289 (33.3%) on 3p14.1(14.3. Conclusion: Loss of genetic material on chromosome 3 may play an important part in the tumorigenesis of GBM. The chromosomal regions from loci D3S1614 to D3S1565 on 3q24(27 and at loci D3S1569 on 3q22(23 and D3S1289 on 3p14.1(14.3 are potential sites for novel tumor suppressor genes associated with GBM.

  18. Fast Neutron Induced Autophagy Leads To Necrosis In Glioblastoma Multiforme Cells

    Science.gov (United States)

    Yasui, Linda; Gladden, Samantha; Andorf, Christine; Kroc, Thomas

    2011-06-01

    Fast neutrons are highly effective at killing glioblastoma multiforme (GBM), U87 and U251 cells. The mode of cell death was investigated using transmission electron microscopy (TEM) to identify the fraction of irradiated U87 or U251 cells having morphological features of autophagy and/or necrosis. U87 or U251 cells were irradiated with 2 Gy fast neturons or 10 Gy γ rays. A majority of U87 and U251 cells exhibit features of cell death with autophagy after irradiation with either 10 Gy γ rays or 2 Gy fast neutrons. Very few γ irradiated cells had features of necrosis (U87 or U251 cell samples processed for TEM 1 day after 10 Gy γ irradiation). In contrast, a significant increase was observed in necrotic U87 and U251 cells irradiated with fast neutrons. These results show a greater percentage of cells exhibit morphological evidence of necrosis induced by a lower dose of fast neutron irradiation compared to γ irradiation. Also, the evidence of necrosis in fast neutron irradiated U87 and U251 cells occurs in a background of autophagy. Since autophagy is observed before necrosis, autophagy may play a role in signaling programmed necrosis in fast neutron irradiated U87 and U251 cells.

  19. Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study

    Directory of Open Access Journals (Sweden)

    Cristina Ferrari

    2015-01-01

    Full Text Available Glioblastoma multiforme (GBM is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [64Cu]CuCl2. To evaluate the potential theranostic role of [64Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [64Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy.

  20. 5-ALA Fluorescence Image Guided Resection of Glioblastoma Multiforme: A Meta-Analysis of the Literature

    Directory of Open Access Journals (Sweden)

    Samy Eljamel

    2015-05-01

    Full Text Available Background: Glioblastoma multiforme (GBM is one of the most deadly cancers in humans. Despite recent advances in anti-cancer therapies, most patients with GBM die from local disease progression. Fluorescence image guided surgical resection (FIGR was recently advocated to enhance local control of GBM. This is meta-analyses of 5-aminolevulinic (5-ALA induced FIGR. Materials: Review of the literature produced 503 potential publications; only 20 of these fulfilled the inclusion criteria of this analysis, including a total of 565 patients treated with 5-ALA-FIGR reporting on its outcomes and 800 histological samples reporting 5-ALA-FIGR sensitivity and specificity. Results: The mean gross total resection (GTR rate was 75.4% (95% CI: 67.4–83.5, p < 0.001. The mean time to tumor progression (TTP was 8.1 months (95% CI: 4.7–12, p < 0.001. The mean overall survival gain reported was 6.2 months (95% CI: −1–13, p < 0.001. The specificity was 88.9% (95% CI: 83.9–93.9, p < 0.001 and the sensitivity was 82.6% (95% CI: 73.9–91.9, p < 0.001. Conclusion: 5-ALA-FIGR in GBM is highly sensitive and specific, and imparts significant benefits to patients in terms of improved GTR and TTP.

  1. Standard fractionation intensity modulated radiation therapy (IMRT) of primary and recurrent glioblastoma multiforme

    International Nuclear Information System (INIS)

    Intensity-modulated radiation therapy (IMRT) affords unparalleled capacity to deliver conformal radiation doses to tumors in the central nervous system. However, to date, there are few reported outcomes from using IMRT, either alone or as a boost technique, for standard fractionation radiotherapy for glioblastoma multiforme (GBM). Forty-two patients were treated with IMRT alone (72%) or as a boost (28%) after 3-dimensional conformal radiation therapy (3D-CRT). Thirty-three patients with primary disease and 9 patients with recurrent tumors were included. Thirty-four patients (81%) had surgery, with gross tumor resection in 13 patients (36%); 22 patients (53%) received chemo-radiotherapy. The median total radiation dose for all patients was 60 Gy with a range from 30.6 to 74 Gy. Standard fractions of 1.8 Gy/day to 2.0 Gy/day were utilized. Median survival was 8.7 months, with 37 patients (88%) deceased at last contact. Nonparametric analysis showed no survival difference in IMRT-boost vs. IMRT-only groups. While technically feasible, preliminary results suggest delivering standard radiation doses by IMRT did not improve survival outcomes in this series compared to historical controls. In light of this lack of a survival benefit and the costs associated with use of IMRT, future prospective trials are needed to evaluate non-survival endpoints such as quality of life and functional preservation. Short of such evidence, the use of IMRT for treatment of GBM needs to be carefully rationalized

  2. Integrative Network-based Analysis of Magnetic Resonance Spectroscopy and Genome Wide Expression in Glioblastoma multiforme.

    Science.gov (United States)

    Heiland, Dieter Henrik; Mader, Irina; Schlosser, Pascal; Pfeifer, Dietmar; Carro, Maria Stella; Lange, Thomas; Schwarzwald, Ralf; Vasilikos, Ioannis; Urbach, Horst; Weyerbrock, Astrid

    2016-01-01

    The goal of this study was to identify correlations between metabolites from proton MR spectroscopy and genetic pathway activity in glioblastoma multiforme (GBM). Twenty patients with primary GBM were analysed by short echo-time chemical shift imaging and genome-wide expression analyses. Weighed Gene Co-Expression Analysis was used for an integrative analysis of imaging and genetic data. N-acetylaspartate, normalised to the contralateral healthy side (nNAA), was significantly correlated to oligodendrocytic and neural development. For normalised creatine (nCr), a group with low nCr was linked to the mesenchymal subtype, while high nCr could be assigned to the proneural subtype. Moreover, clustering of normalised glutamine and glutamate (nGlx) revealed two groups, one with high nGlx being attributed to the neural subtype, and one with low nGlx associated with the classical subtype. Hence, the metabolites nNAA, nCr, and nGlx correlate with a specific gene expression pattern reflecting the previously described subtypes of GBM. Moreover high nNAA was associated with better clinical prognosis, whereas patients with lower nNAA revealed a shorter progression-free survival (PFS). PMID:27350391

  3. Bromodeoxyuridine labeling index in glioblastoma multiforme: relation to radiation response, age, and survival

    International Nuclear Information System (INIS)

    Purpose: Various measures of the rate of tumor cell proliferation have been found to predict survival in patients with intracerebral gliomas. We correlated the bromodeoxyuridine labeling index (BrdUrd LI) with the response to radiation therapy, survival, and known prognostic factors in a series of patients with glioblastoma multiforme (GM) to test its utility as a prognostic factor. Methods and Materials: The BrdUrd LI was determined in 200 newly diagnosed intracranial GMs. Age and sex were known for all patients. The response to radiation therapy was determined in 116 patients by comparing neuroimaging studies obtained before and after external beam radiation therapy. Survival was analyzed in 64 patients who were treated according to two consecutive prospective clinical protocols. Results: The median BrdUrd LI was 6.5% (mean, 7.2%; range, 1.1-25.4%). The BrdUrd LI did not correlate significantly with age, sex, radiation response, or survival. Age and Karnofsky performance score were independent prognostic factors in our cohort. Conclusion: The proliferative rate as measured by BrdUrd LI was not a prognostic factor in our GM cohort. The BrdUrd LI did not correlate significantly with known prognostic factors in GM. There was no significant relationship between the BrdUrd LI and radiation response

  4. Establecimiento y caracterización de una línea celular derivada de un glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Verónica Rincón

    2007-03-01

    Full Text Available Introducción: Las líneas celulares y los cultivos primarios son una excelente herramienta para el estudio de la biología, desarrollo y respuesta a la terapia en tumores cerebrales.Objetivo: Establecer y caracterizar una línea celular derivada de un glioblastoma multiforme como un modelo de estudio in vitro para la extrapolación y aplicación futura en terapia génica. Material y métodos: Se obtuvo una muestra de un paciente con diagnóstico clínico e histopatológico de glioblastoma multiforme, se caracterizó mediante inmunohistoquímica en cortes de tejido y por inmunocitoquímica sobre células cultivadas a partir del tumor desde el inicio del cultivo y durante los seis primeros pases, con dos tipos de marcadores específicos para glía: GFAP (glial fibrillary acidic protein y S-100 (proteína de unión a calcio. Además, se evaluó la expresión de p53 y Bcl-2, como moduladores de apoptosis. Por último se hizo la caracterización citogenética.Resultados: Histopatológicamente, se confirmó el diagnóstico de glioblastoma multiforme. En los cultivos primarios se encontraron características citomorfológicas propias de un glioblastoma: células fibroblastoides planas, células con escaso citoplasma con 3 ó más procesos y por último bipolares o unipolares. Se encontró una expresión diferencial con los cuatro marcadores, con un patrón de marcaciones a nivel citoplasmático y nuclear a través de los pases estudiados. La línea celular se caracterizó por ser en su mayoría aneuploide con un número modal cromosómico entre 43 y 45, con un gran número de poliploidías (55-102 , XXYY y endo-reduplicaciones (end 45, X, -Y.Conclusión: Se estableció una línea celular derivada de un glioblastoma multiforme con un fenotipo estable, con un notable mantenimiento del perfil glial y citogenético.

  5. 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

  6. Boron neutron capture therapy (BNCT) for glioblastoma multiforme using the epithermal neutron beam at the Brookhaven Medical Research Reactor

    Energy Technology Data Exchange (ETDEWEB)

    Capala, J. [Brookhaven National Lab., Upton, NY (United States); Diaz, A.Z.; Chadha, M. [Univ. Hospital, State Univ. of New York, NY (United States)] [and others

    1997-12-31

    The abstract describes evaluation of boron neutron capture therapy (BNCT) for two groups of glioblastoma multiforme patients. From September 1994 to February 1996 15 patients have been treated. In September 1997 another 34 patients were examined. Authors determined a safe starting dose for BNCT using epithermal neutrons and BPA-F. They have also evaluated adverse effects of BNCT at this starting dose. Therapeutic effectiveness of this starting dose has been evaluated. No significant side effects from BPA-F infusion or BNCT treatment were observed in normal brains.

  7. Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan

    DEFF Research Database (Denmark)

    Hasselbalch, Benedikte; Eriksen, Jesper Grau; Broholm, Helle;

    2010-01-01

    , hypoxia and mediators of the epidermal growth factor receptor (EGFR) pathway were investigated. Tumor tissue was obtained from a previous phase II study, treating recurrent primary glioblastoma multiforme (GBM) patients with the EGFR inhibitor cetuximab in combination with bevacizumab and irinotecan...... that they share the same regulatory mechanisms. None of the EGFR-related biomarkers showed any significant correlations with each other. None of the biomarkers tested alone or in combination could identify a patient population likely to benefit from bevacizumab and irinotecan, with or without the addition...

  8. Partial correlation analyses of global diffusion tensor imaging-derived metrics in glioblastoma multiforme: Pilot study

    Institute of Scientific and Technical Information of China (English)

    David; Cortez-Conradis; Camilo; Rios; Sergio; Moreno-Jimenez; Ernesto; Roldan-Valadez; Ernesto; Roldan-Valadez

    2015-01-01

    AIM: To determine existing correlates among diffusion tensor imaging(DTI)-derived metrics in healthy brains and brains with glioblastoma multiforme(GBM). METHODS: Case-control study using DTI data from brain magnetic resonance imaging of 34 controls(mean, 41.47; SD, ± 21.94 years; range, 21-80 years) and 27 patients with GBM(mean, SD; 48.41 ± 15.18 years; range, 18-78 years). Image postprocessing using FSL software calculated eleven tensor metrics: fractional(FA) and relative anisotropy; pure isotropic(p) and anisotropic diffusions(q), total magnitude of diffusion(L); linear(Cl), planar(Cp) and spherical tensors(Cs); mean(MD), axial(AD) and radial diffusivities(RD). Partial correlation analyses(controlling the effect of ageand gender) and multivariate Mancova were performed.RESULTS: There was a normal distribution for all metrics. Comparing healthy brains vs brains with GBM, there were significant very strong bivariate correlations only depicted in GBM: [FA?Cl(+)], [FA?q(+)], [p?AD(+)], [AD?MD(+)], and [MD?RD(+)]. Among 56 pairs of bivariate correlations, only seven were significantly different. The diagnosis variable depicted a main effect [F-value(11, 23) = 11.842, P ≤ 0.001], with partial eta squared = 0.850, meaning a large effect size; age showed a similar result. The age also had a significant influence as a covariate [F(11, 23) = 10.523, P < 0.001], with a large effect size(partial eta squared = 0.834).CONCLUSION: DTI-derived metrics depict significant differences between healthy brains and brains with GBM, with specific magnitudes and correlations. This study provides reference data and makes a contribution to decrease the underlying empiricism in the use of DTI parameters in brain imaging.

  9. Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

    Energy Technology Data Exchange (ETDEWEB)

    Badiyan, Shahed N.; Markovina, Stephanie; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Tran, David D.; Linette, Gerry [Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri (United States); Jalalizadeh, Rohan [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Dacey, Ralph; Rich, Keith M.; Chicoine, Michael R.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H. [Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri (United States); Huang, Jiayi, E-mail: jhuang@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States)

    2014-11-15

    Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM. Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.

  10. Temozolomide combined with irradiation as postoperative treatment of primary glioblastoma multiforme. Phase I/II study

    Energy Technology Data Exchange (ETDEWEB)

    Combs, S.E.; Gutwein, S.; Schulz-Ertner, D.; Thilmann, C.; Wannenmacher, M.M.; Debus, J. [Dept. of Radiation Oncology, Univ. of Heidelberg, Heidelberg (Germany); Kampen, M. van [Dept. of Radiation Oncology, Nordwestkrankenhaus Frankfurt, Frankfurt/Main (Germany); Edler, L. [Central Unit Biostatistics, German Cancer Research Center (DKFZ), Heidelberg (Germany)

    2005-06-01

    Background and purpose: the role of radiochemotherapy in the treatment of primary glioblastoma multiforme is still discussed controversially. To evaluate the feasibility and toxicity of irradiation and concomitant administration of 50 mg/m{sup 2} temozolomide in patients with primary malignant glioma, this phase I/II study was conducted. Patients and methods: 53 patients with histologically confirmed WHO grade IV malignant glioma were enrolled into the study. All patients were treated with radiation therapy up to a total dose of 60 Gy using conventional fractionation of 5 x 2.0 Gy/week. Temozolomide was administered orally each therapy day at a dose of 50 mg/m{sup 2}. Results: prior to radiochemotherapy, complete resection (n = 14), subtotal resection (n = 22) or a biopsy (n = 17) of the tumor was performed. The median time interval between surgery and radiochemotherapy was 21 days. Treatment-related toxicity was very mild. Acute toxicity > grade 2 was observed in one patient who developed grade 4 hemotoxicity. Minor side effects of chemotherapy included nausea and vomiting. No severe late effects were observed. Median progression-free and overall survival were 8 and 19 months, respectively. The overall survival rate was 72% at 1 and 26% at 2 years. Age and extent of surgery significantly influenced survival. Conclusion: the combination of temozolomide plus radiation therapy is feasible and safe in terms of toxicity. Overall survival times were relatively long compared to survival times reported for radiotherapy alone. The application of 50 mg/m{sup 2} of temozolomide can be performed throughout the whole time course without interruption due to side effects and might largely contribute to the prolonged overall survival. Further evaluation is warranted as to which dose of temozolomide is optimal with regard to tumor response and toxicity. (orig.)

  11. Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: A phase I study†

    Science.gov (United States)

    Butowski, Nicholas; Chang, Susan M.; Lamborn, Kathleen R.; Polley, Mei Yin; Parvataneni, R.; Hristova-Kazmierski, Maria; Musib, Luna; Nicol, Steven J.; Thornton, Donald E.; Prados, Michael D.

    2010-01-01

    We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCβ] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status ≥60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m2 daily) followed by adjuvant temozolomide (200 mg/m2) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if ≤1/6 patients had dose-limiting toxicity (DLT) during RT and the first adjuvant cycle. Patients continued treatment for 12 adjuvant cycles unless disease progression or unacceptable toxicity occurred. Twelve patients enrolled. There was no DLT in the first 6 patients treated with 250 mg enzastaurin. At 500 mg, 2 of 6 patients experienced a DLT (1 Grade 4 and 1 Grade 3 thrombocytopenia). The patient with Grade 3 DLT recovered to Grade <1 within 28 days and adjuvant temozolomide and enzastaurin was reinitiated with dose reductions. The other patient recovered to Grade <1 toxicity after 28 days and did not restart treatment. Enzastaurin 250 mg/d given concomitantly with RT and temozolomide and adjuvantly with temozolomide was well tolerated and is the recommended phase II dose. The proceeding phase II trial has finished accrual and results will be reported in 2009. PMID:20156802

  12. Involvement of miRNAs in the differentiation of human glioblastoma multiforme stem-like cells.

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    Beatriz Aldaz

    Full Text Available Glioblastoma multiforme (GBM-initiating cells (GICs represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process.

  13. Involvement of miRNAs in the Differentiation of Human Glioblastoma Multiforme Stem-Like Cells

    Science.gov (United States)

    Aldaz, Beatriz; Sagardoy, Ainara; Nogueira, Lorena; Guruceaga, Elizabeth; Grande, Lara; Huse, Jason T.; Aznar, Maria A.; Díez-Valle, Ricardo; Tejada-Solís, Sonia; Alonso, Marta M.; Fernandez-Luna, Jose L.

    2013-01-01

    Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process. PMID:24155920

  14. Glioblastoma multiforme of the optic chiasm: A rare case of common pathology

    Science.gov (United States)

    Lyapichev, Kirill A.; Bregy, Amade; Cassel, Adrienne; Handfield, Chelsea; Velazquez-Vega, Jose; Kay, Matthew D.; Basil, Gregory; Komotar, Ricardo J.

    2016-01-01

    Background: Malignant optic and chiasmatic gliomas are extremely rare, and are classified pathologically as anaplastic astrocytoma or glioblastoma multiforme (GBM). Approximately 40 cases of optic GBM in adults have been reported in the literature, and only five of them were described to originate from the optic chiasm. Case Description: An 82-year-old male patient with a past medical history of diabetes mellitus type 2, melanoma, and bladder cancer presented with gradual vision loss of the left eye in a period of 1 month. After neuro-ophthalmological examination, the decision of thither magnetic resonance imaging (MRI) studies was made. It showed a contrast enhancing mass in the region of the optic chiasm. In this case, imaging study was not enough to establish an accurate diagnosis and a left pterional craniotomy for biopsy and resection of the optic chiasmal mass was performed. After histological evaluation of the mass tissue, the diagnosis of GBM was made. Taking into account the patient's poor condition and unfavorable prognosis he was moved to inpatient hospice. The patient deceased within 2 months after surgery. Conclusion: Chiasmal GBM is an extremely rare condition where a biopsy is necessary for accurate diagnosis and optimal treatment. Differential diagnosis for such lesions can be very difficult and include demyelinating optic neuritis and non-demyelinating inflammatory optic neuropathy (e.g., sarcoid), vascular lesions (e.g., cavernoma), compressive lesions of the optic apparatus, metastatic malignancy, and primary tumors of the anterior optic pathway. The role of chemotherapy and radiotherapy including novel stereotaxic radiosurgery methods is still unclear and will need to be evaluated. PMID:27512611

  15. Standard fractionation intensity modulated radiation therapy (IMRT of primary and recurrent glioblastoma multiforme

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    Fuller Clifton D

    2007-07-01

    Full Text Available Abstract Background Intensity-modulated radiation therapy (IMRT affords unparalleled capacity to deliver conformal radiation doses to tumors in the central nervous system. However, to date, there are few reported outcomes from using IMRT, either alone or as a boost technique, for standard fractionation radiotherapy for glioblastoma multiforme (GBM. Methods Forty-two patients were treated with IMRT alone (72% or as a boost (28% after 3-dimensional conformal radiation therapy (3D-CRT. Thirty-three patients with primary disease and 9 patients with recurrent tumors were included. Thirty-four patients (81% had surgery, with gross tumor resection in 13 patients (36%; 22 patients (53% received chemo-radiotherapy. The median total radiation dose for all patients was 60 Gy with a range from 30.6 to 74 Gy. Standard fractions of 1.8 Gy/day to 2.0 Gy/day were utilized. Results Median survival was 8.7 months, with 37 patients (88% deceased at last contact. Nonparametric analysis showed no survival difference in IMRT-boost vs. IMRT-only groups. Conclusion While technically feasible, preliminary results suggest delivering standard radiation doses by IMRT did not improve survival outcomes in this series compared to historical controls. In light of this lack of a survival benefit and the costs associated with use of IMRT, future prospective trials are needed to evaluate non-survival endpoints such as quality of life and functional preservation. Short of such evidence, the use of IMRT for treatment of GBM needs to be carefully rationalized.

  16. Retrospective Analysis of Bevacizumab in Combination with Fotemustine in Chinese Patients with Recurrent Glioblastoma Multiforme

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    Zhiguang Liu

    2015-01-01

    Full Text Available The aim of this study was to assess the activity and safety of bevacizumab (BEV and fotemustine (FTM for the treatment of recurrent glioblastoma multiforme (GBM patients and explore the potential prognostic parameters on survival. This study retrospectively analyzed all patients with GBM who were treated with at least one cycle of BEV and FTM from July 2010 to October 2012. A total of 176 patients with recurrent GBM were enrolled. The response rate and disease control rate were 46.6% and 90.9%, respectively. A 6-month PFS rate of 33.3% (95% CI: 26.5%–40.3% and a median PFS of 5.0 (95% CI: 2.4–7.5 months were observed. The median OS was 8.0 (95% CI: 6.7–9.2 months. Multivariate analysis showed that risk factors with a significant influence on the PFS of all patients were Karnofsky Performance Status (KPS (≥70 versus <70, HR=0.53, 95% CI: 0.39–0.73, and P=0.01 and MGMT status (methylated versus unmethylated, HR=0.69, 95% CI: 0.52–0.97, and P=0.04. The most common treatment-related adverse events were fatigue, proteinuria, hypophonia, hypertension, thrombocytopenia, anemia, and neutropenia. In conclusion, combination of BEV with FTM is well tolerated and may derive some clinical benefits in recurrent GBM patients. Higher KPS and MGMT promoter hypermethylation were suggested to be associated with prolonged survival.

  17. A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme

    Science.gov (United States)

    de Aquino, Priscila F.; Carvalho, Paulo Costa; Nogueira, Fábio C. S.; da Fonseca, Clovis Orlando; de Souza Silva, Júlio Cesar Thomé; Carvalho, Maria da Gloria da Costa; Domont, Gilberto B.; Zanchin, Nilson I. T.; Fischer, Juliana de Saldanha da Gama

    2016-01-01

    Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM. For this, we profiled tumor fragments from the profound region of the same patient’s GBM but obtained from two surgeries a year’s time apart. Our analysis also included GBM‘s fragments from different anatomical regions. Our quantitative proteomic strategy employed 4-plex iTRAQ peptide labeling followed by a four-step strong cation chromatographic separation; each fraction was then analyzed by reversed-phase nano-chromatography coupled on-line with an Orbitrap-Velos mass spectrometer. Unsupervised clustering grouped the proteomic profiles into four major distinct groups and showed that most changes were related to the tumor’s anatomical region. Nevertheless, we report differentially abundant proteins from GBM’s fragments of the same region but obtained 1 year apart. We discuss several key proteins (e.g., S100A9) and enriched pathways linked with GBM such as the Ras pathway, RHO GTPases activate PKNs, and those related to apoptosis, to name a few. As far as we know, this is the only report that compares GBM fragments proteomic profiles from the same patient. Ultimately, our results fuel the forefront of scientific discussion on the importance in exploring the richness of subproteomes within a single tissue sample for a better understanding of the disease, as each tumor is unique. PMID:27597932

  18. Contrast-enhancing computed tomography ring in glioblastoma multiforme after intraoperative endocurietherapy

    International Nuclear Information System (INIS)

    The significance of the contrast-enhancing ring seen on serial follow-up postirradiation computed tomograms (CT) of the brain was evaluated in a group of 41 patients with glioblastoma multiforme (GM) who were treated in a phase I/II study by means of intraoperative remote afterloading endocurietherapy (ECT) with a high activity cobalt 60 probe (20.00 Gy) in one high-dose rate fraction), and conventional fractionated external-beam (EXRT) radiotherapy (60.00 Gy in 30 fractions in 7.5 weeks). All received minimum total tumor doses of 80.00 Gy. After completion of treatment, all patients were followed with serial CT scans of the brain. Two to 6 months after treatment, 27 of 41 patients developed the similar thin-walled, regular, contrast-enhancing CT rings with low-density attenuation inside and outside the ring. Postmortem study in two of these patients revealed that the thin-walled, regular, contrast-enhancing ring represented a continuous capsule of dilated cerebral vessels with inner low-density attenuation corresponding to necrosis, and outer low-density attenuation corresponding to edema. The CT appearance of the thin-walled, regular, contrast-enhancing ring produced after high-dose rate intraoperative ECT and EXRT is distinctly different from the CT ring characteristic of untreated or recurrent GM. After high-dose rate intracranial ECT and EXRT, the appearance of a post-ECT contrast-enhancing CT ring should not be automatically interpreted as recurrent disease as previously reported after conventional fractionated EXRT

  19. Comparison of radiation regimens in the treatment of Glioblastoma multiforme: results from a single institution

    International Nuclear Information System (INIS)

    The optimal fractionation schedule of radiotherapy (RT) for Glioblastoma multiforme (GBM) is yet to be determined. We aim to compare different fractionation regimens and identify prognostic factors to better tailor RT for newly diagnosed GBM patients. All data for patients who underwent surgery for GBM between January 2005 and December 2012 were compiled. Clinical information was collected using patient charts and government registry. Cox analysis was used to identify variables affecting survival and treatment outcome. The median follow-up time was 13.2 months. Two hundred and seventy-six patients met the inclusion criteria, including 147 patients in the 60 Gy in 30 fractions (ConvRT) group, 86 patients in the 60 Gy in 20 fractions (HF60) group, and 43 patients in the 40 Gy in 15 fractions (HF40) group. Median survival (MS) was 16.0 months with a median progression-free survival (PFS) of 9.23 months in the ConvRT group. This was comparable to outcome in the HF60 group with MS 15.0 months and a median PFS of 9.1 months. Patients in the HF40 group had MS of 8 months, with a median PFS 5.4 months. Cox analysis showed no significant difference in OS between the ConvRT and HF60 groups but worse outcome in the HF40 group (HR 2.22, P = 0.04). MGMT methylation, extent of resection, use of chemotherapy, and repeat surgery were found to be significant independent prognostic factors for survival. HF60 constitutes a safe RT approach that shows survival comparable to standard RT while allowing for a shorter treatment time

  20. Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo

    Institute of Scientific and Technical Information of China (English)

    Adarsh Shankar; Robert A. Knight; Stephen Brown; Ali S. Arbab; Sanath Kumar; Asm Iskander; Nadimpalli RS Varma; Branislava Janic; Ana deCarvalho; Tom Mikkelsen; Joseph A. Frank; Meser M. Ali

    2014-01-01

    Tumor cellproliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme (GBM). The purpose of this study was to determine the effect of radiation on the growth characteristics of primary human GBM developed in a nude rat. Primary GBM cells grown from explanted GBM tissues were implanted orthotopically in nude rats. Tumor growth was confirmed by magnetic resonance imaging on day 77 (baseline) after implantation. The rats underwent irradiation to a dose of 50 Gy delivered subcuratively on day 84 postimplantation (n= 8), or underwent no radiation (n= 8). Brain tissues were obtained on day 112 (nonirradiated) or day 133 (irradiated). Immunohistochemistry was performed to determine tumor cell proliferation (Ki-67) and to assess the expression of infiltration marker (matrix metalloproteinase-2, MMP-2) and cell migration marker (CD44). Tumor neovascularization was assessed by microvessel density using von-Willebrand factor (vWF) staining. Magnetic resonance imaging showed well-developed, infiltrative tumors in 11 weeks postimplantation. The proportion of Ki-67-positive cells in tumors undergoing radiation was (71 ± 15)%compared with (25 ± 12)%in the nonirradiated group (P=0.02). The number of MMP-2-positive areas and proportion of CD44-positive cells were also high in tumors receiving radiation, indicating great invasion and infiltration. Microvessel density analysis did not show a significant difference between nonirradiated and irradiated tumors. Taken together, we found that subcurative radiation significantly increased proliferation, invasion, and migration of primary GBM. Our study provides insights into possible mechanisms of treatment resistance fol owing radiation therapy for GBM.

  1. Diffusion Tensor Imaging in Patients with Glioblastoma Multiforme Using the Supertoroidal Model.

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    Choukri Mekkaoui

    Full Text Available Diffusion Tensor Imaging (DTI is a powerful imaging technique that has led to improvements in the diagnosis and prognosis of cerebral lesions and neurosurgical guidance for tumor resection. Traditional tensor modeling, however, has difficulties in differentiating tumor-infiltrated regions and peritumoral edema. Here, we describe the supertoroidal model, which incorporates an increase in surface genus and a continuum of toroidal shapes to improve upon the characterization of Glioblastoma multiforme (GBM.DTI brain datasets of 18 individuals with GBM and 18 normal subjects were acquired using a 3T scanner. A supertoroidal model of the diffusion tensor and two new diffusion tensor invariants, one to evaluate diffusivity, the toroidal volume (TV, and one to evaluate anisotropy, the toroidal curvature (TC, were applied and evaluated in the characterization of GBM brain tumors. TV and TC were compared with the mean diffusivity (MD and fractional anisotropy (FA indices inside the tumor, surrounding edema, as well as contralateral to the lesions, in the white matter (WM and gray matter (GM.The supertoroidal model enhanced the borders between tumors and surrounding structures, refined the boundaries between WM and GM, and revealed the heterogeneity inherent to tumor-infiltrated tissue. Both MD and TV demonstrated high intensities in the tumor, with lower values in the surrounding edema, which in turn were higher than those of unaffected brain parenchyma. Both TC and FA were effective in revealing the structural degradation of WM tracts.Our findings indicate that the supertoroidal model enables effective tensor visualization as well as quantitative scalar maps that improve the understanding of the underlying tissue structure properties. Hence, this approach has the potential to enhance diagnosis, preoperative planning, and intraoperative image guidance during surgical management of brain lesions.

  2. Magnetic resonance imaging in 67 cases of glioblastoma multiform and occurrence of metastases; Estudo atraves da ressonancia magnetica de 67 casos de glioblastoma multiforme e a ocorrencia de metastases

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    Ferreira, Nelson Fortes; Barbosa, Marcelo; Amaral, Lazaro L. Faria do; Mendonca, Renato Adam; Lima, Sergio Santos [Hospital Beneficencia Portuguesa de Sao Paulo, SP (Brazil). Med Imagem]. E-mail: neldiz@hotmail.com

    2004-09-01

    The purpose of this paper is to demonstrate the main MRI characteristics of glioblastoma multiform (GBM), the most common CNS primary tumor, emphasizing its location and the occurrence of metastases. The MR imaging of 67 pathologically proven cases of glioblastoma multiform were retrospectively reviewed. The exams were realized in the period between 1995 and 2003, in one of three 1.5 Signa GE units (Milwaukee, WI). The ages of the patients ranged from 4 years to 86 years, mean 60 years, and the occurrence of the tumor was preponderant among men, with 39 cases (58%). The most common location was in the frontal lobes (47%) followed by the temporal lobes (18%) and the parietal lobes (16%). In 19% of the cases there were involvement of more than one site and long distance metastases were seen in 22% of the patients. According to the literature, the most common location of GBM was in the frontal lobe of older than 50 years old men. Metastases occurred in 22% of our cases. (author)

  3. Comparação da dose calculada entre a tomoterapia helicoidal e a arcoterapia de intensidade modulada em glioblastomas multiformes

    OpenAIRE

    Pires, Cidália; Carvalho, Filipa; Sá, Ana Cravo; Coelho, Carina Marques; Monsanto, Fátima; Sacco, Vincenzo; Pereira, Daniela

    2015-01-01

    Objetivo do estudo - Comparar a dose calculada nos órgãos de risco (OR’s) e no volume alvo de planeamento (PTV), entre a tomoterapia helicoidal (TH) e a arcoterapia de intensidade modulada (RapidArc®), em glioblastomas multiformes (GBM).

  4. Phase II Trial of Hypofractionated IMRT With Temozolomide for Patients With Newly Diagnosed Glioblastoma Multiforme

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    Reddy, Krishna [Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado (United States); Damek, Denise [Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado (United States); Gaspar, Laurie E. [Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado (United States); Ney, Douglas [Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado (United States); Waziri, Allen; Lillehei, Kevin [Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado (United States); Stuhr, Kelly; Kavanagh, Brian D. [Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado (United States); Chen Changhu, E-mail: changhu.chen@ucdenver.edu [Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado (United States)

    2012-11-01

    Purpose: To report toxicity and overall survival (OS) in patients with newly diagnosed glioblastoma multiforme (GBM) treated with hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concurrent and adjuvant temozolomide (TMZ). Methods and Materials: Patients with newly diagnosed GBM after biopsy or resection and with adequate performance status and organ or bone marrow function were eligible for this study. Patients received postoperative hypo-IMRT to the surgical cavity and residual tumor seen on T1-weighted brain MRI with a 5-mm margin to a total dose of 60 Gy in 10 fractions (6 Gy/fraction) and to the T2 abnormality on T2-weighted MRI with 5-mm margin to 30 Gy in 10 fractions (3 Gy/fraction). Concurrent TMZ was given at 75 mg/m{sup 2}/day for 28 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m{sup 2}/day for 5 days every 28 days. Toxicities were defined using Common Terminology Criteria for Adverse Events version 3.0. Results: Twenty-four patients were treated, consisting of 14 men, 10 women; a median age of 60.5 years old (range, 27-77 years); and a median Karnofsky performance score of 80 (range, 60-90). All patients received hypo-IMRT and concurrent TMZ according to protocol, except for 2 patients who received only 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 6.5 (range, 0-14).With a median follow-up of 14.8 months (range, 2.7-34.2 months) for all patients and a minimum follow-up of 20.6 months for living patients, no instances of grade 3 or higher nonhematologic toxicity were observed. The median OS was 16.6 months (range, 4.1-35.9 months). Six patients underwent repeated surgery for suspected tumor recurrence; necrosis was found in 50% to 100% of the resected specimens. Conclusion: In selected GBM patients, 60 Gy hypo-IMRT delivered in 6-Gy fractions over 2 weeks with concurrent and adjuvant TMZ is safe. OS in this small cohort of patients was comparable to that treated with current standard of care

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

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    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

  6. {sup 23}Na-MRI of recurrent glioblastoma multiforme after intraoperative radiotherapy: technical note

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    Haneder, Stefan; Buesing, Karen A.; Schoenberg, Stefan O.; Ong, Melissa M. [Heidelberg University, Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim (Germany); Giordano, Frank A.; Wenz, Frederik [University of Heidelberg, Department of Radiation Oncology, University Medical Center Mannheim, Mannheim (Germany); Konstandin, Simon; Schad, Lothar R. [Heidelberg University, Computer Assisted Clinical Medicine, Mannheim (Germany); Brehmer, Stefanie; Schmiedek, Peter [Heidelberg University, Department of Neurosurgery, University Medical Center Mannheim, Mannheim (Germany)

    2015-03-01

    We report the first case of an intraoperative radiotherapy (IORT) in a patient with recurrent glioblastoma multiforme (GBM) who was followed up with a novel magnetic resonance imaging (MRI) method - {sup 23}Na-MRI - in comparison to a standard contrast-enhanced {sup 1}H-MRI and {sup 18}F-FET-PET. A 56-year-old female patient with diagnosed GBM in July 2012 underwent tumor resection, radiochemotherapy, and three cycles of chemotherapy. After a relapse, 6 months after the initial diagnosis, an IORT was recommended which was performed in March 2013 using the INTRABEAM system (Carl Zeiss Meditec AG, Germany) with a 3-cm applicator and a surface dose of 20 Gy. Early post-operative contrast-enhanced and 1-month follow-up {sup 1}H-MRI and a {sup 18}F-FET-PET were performed. In addition, an IRB-approved {sup 23}Na-MRI was performed on a 3.0-T MR scanner (MAGNETOM TimTrio, Siemens Healthcare, Germany). After re-surgery and IORT in March 2013, only a faint contrast enhancement but considerable surrounding edema was visible at the medio-posterior resection margins. In April 2013, new and progressive contrast enhancement, edema, {sup 23}Na content, and increased uptake in the {sup 18}F-FET-PET were visible, indicating tumor recurrence. Increased sodium content within the area of contrast enhancement was found in the {sup 23}Na-MRI, but also exceeding this area, very similar to the increased uptake depicted in the {sup 18}F-FET-PET. The clearly delineable zone of edema in both examinations exhibits a lower {sup 23}Na content compared to areas with suspected proliferating tumor tissue. {sup 23}Na-MRI provided similar information in the suspicious area compared to {sup 18}F-FET-PET, exceeding conventional {sup 1}H-MRI. Still, {sup 23}Na-MRI remains an investigational technique, which is worth to be further evaluated. (orig.)

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

    International Nuclear Information System (INIS)

    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. 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. 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). Reduced radiosensitizer dosing of temozolomide concomitant with radiotherapy in glioblastoma multiforme exhibited comparable efficacy with a classic continuous daily schedule, though with better tolerability

  8. Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Lin YL

    2015-09-01

    Full Text Available Yu-Ling Lin,1,2,* Kai-Fu Chang,3,* Xiao-Fan Huang,3 Che-Lun Hung,4 Shyh-Chang Chen,5 Wan-Ru Chao,6,7 Kuang-Wen Liao,1,8 Nu-Man Tsai3,9 1College of Biological Science and Technology, 2Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, 3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, 4Department of Computer Science and Communication Engineering, Providence University, 5Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, 6Institute of Medicine, Chung Shan Medical University, 7Department of Pathology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, 8Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 9Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan *These authors contributed equally to this work Background: The natural compound n-butylidenephthalide (BP can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.Objective: The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.Methods: To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC. Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.Results: When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than

  9. Impact of waiting time after surgery and overall time of postoperative radiochemotherapy on treatment outcome in glioblastoma multiforme

    International Nuclear Information System (INIS)

    A time factor of radiooncological treatment has been demonstrated for several tumours, most prominently for head and neck squamous cell carcinoma and lung cancer. In glioblastoma multiforme studies of the impact of postoperative waiting times before initiation of radio- or radiochemotherapy were inconclusive. Moreover analysis of the impact of overall treatment time of radiochemotherapy as well as overall duration of local treatment from surgery to the end of radiochemotherapy is lacking to date. In this retrospective cohort study, we included 369 consecutive patients treated at our institution between 2001 and 2014. Inclusion criteria were histologically proven glioblastoma multiforme, age ≥ 18 years, ECOG performance status 0–2 before radiotherapy, radiotherapy or radiochemotherapy with 33 × 1.8 Gy to 59.4 Gy or with 30 × 2.0 Gy to 60 Gy. The impact of postoperative waiting time, radiation treatment time and overall duration of local treatment from surgery to the end of radiotherapy on overall (OS) and progression-free (PFS) survival were evaluated under consideration of known prognostic factors by univariate Log-rank tests and multivariate Cox-regression analysis. The majority of patients had received simultaneous and further adjuvant chemotherapy, mainly with temozolomide. Median survival time and 2-year OS were 18.0 months and 38.9 % after radiochemotherapy compared to 12.7 months and 12.6 % after radiotherapy alone. Median progression-free survival time was 7.5 months and PFS at 2 years was 14.3 % compared to 6.0 months and 3.3 %, respectively. Significant prognostic factors in multivariate analysis were age, resection status and application of simultaneous chemotherapy. No effect of the interval between surgery and adjuvant radiotherapy (median 27, range 11–112 days), radiation treatment time (median 45, range 40–71 days) and of overall time from surgery until the end of radiotherapy (median 54, range 71–154 days) on overall and progression

  10. Outcome and prognostic factors in cerebellar glioblastoma multiforme in adults: A retrospective study from the Rare Cancer Network

    International Nuclear Information System (INIS)

    Purpose: The aim of this study was to assess the outcome in patients with cerebellar glioblastoma (GBM) treated in 15 institutions of the Rare Cancer Network. Methods and Materials: Data from a series of 45 adult patients with cerebellar GBM were collected in a retrospective multicenter study. Median age was 50.3 years. Brainstem invasion was observed in 9 (20%) patients. Radiotherapy (RT) was administered to 36 patients (with concomitant chemotherapy, 7 patients). Adjuvant chemotherapy after RT was administered in 8 patients. Median RT dose was 59.4 Gy. Median follow-up was 7.2 months (range, 3.4-39.0). Results: The 1-year and 2-year actuarial overall survival rate was 37.8% and 14.7%, respectively, and was significantly influenced by salvage treatment (p = 0.048), tumor volume (p = 0.044), extent of neurosurgical resection (p = 0.019), brainstem invasion (p = 0.0013), additional treatment after surgery (p < 0.001), and completion of the initial treatment (p < 0.001) on univariate analysis. All patients experienced local progression: 8 and 22 had progression with and without a distant failure, respectively. The 1- and 2-year actuarial progression free survival was 25% and 10.7%, respectively, and was significantly influenced by brainstem invasion (p = 0.002), additional treatment after surgery (p = 0.0016), and completion of the initial treatment (p < 0.001). On multivariate analysis, survival was negatively influenced by the extent of surgery (p = 0.03) and brainstem invasion (p = 0.02). Conclusions: In this multicenter retrospective study, the observed pattern of failure was local in all cases, but approximately 1 patient of 4 presented with an extracerebellar component. Brainstem invasion was observed in a substantial number of patients and was an adverse prognostic factor

  11. Maintenance of EGFR and EGFRvIII expressions in an in vivo and in vitro model of human glioblastoma multiforme

    DEFF Research Database (Denmark)

    Stockhausen, Marie-Thérése; Broholm, Helle; Villingshøj, Mette;

    2011-01-01

    with mutation of EGFR, and the constitutive activated deletion variant EGFRvIII is the most common EGFR mutation found in GBM. Activated EGFR signaling, through overexpression and/or mutation, is involved in increased tumorigenic potential. As such, EGFR is an attractive target for GBM therapy. However...... the expressions of EGFR and EGFRvIII are maintained both in xenograft tumors growing subcutaneously on mice and in cell cultures established in stem cell conditions. With this model it will be possible to further study the role of EGFR and EGFRvIII, and response to targeted therapy, in GBM.......Glioblastoma multiforme (GBM) is the most common, and most aggressive primary brain tumor among adults. A vast majority of the tumors express high levels of the epidermal growth factor receptor (EGFR) as a consequence of gene amplification. Furthermore, gene amplification is often associated...

  12. Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan

    DEFF Research Database (Denmark)

    Hasselbalch, Benedikte; Eriksen, Jesper Grau; Broholm, Helle;

    2010-01-01

    , hypoxia and mediators of the epidermal growth factor receptor (EGFR) pathway were investigated. Tumor tissue was obtained from a previous phase II study, treating recurrent primary glioblastoma multiforme (GBM) patients with the EGFR inhibitor cetuximab in combination with bevacizumab and irinotecan. Of......Several recent studies have demonstrated a beneficial effect of anti-angiogenic treatment with the vascular endothelial growth factor-neutralizing antibody bevacizumab in recurrent high-grade glioma. In the current study, immunohistochemical evaluation of biomarkers involved in angiogenesis...... the 37 patients with available tumor tissue, 29 were evaluable for response. We concurrently performed immunohistochemical stainings on tumor tissue from 21 GBM patients treated with bevacizumab and irinotecan. We found a tendency of correlation between the hypoxia-related markers, indicating that...

  13. Impact of therapy on quality of life, neurocognitive function and their correlates in glioblastoma multiforme: a review

    DEFF Research Database (Denmark)

    Henriksson, Roger; Asklund, Thomas; Poulsen, Hans Skovgaard

    2011-01-01

    that extend survival in patients with recurrent GBM, so one of the primary aims of new therapies is to reduce morbidity, restore or preserve neurologic functions, and the capacity to perform daily activities. Apart from temozolomide, cytotoxic chemotherapeutic agents do not appear to significantly...... impact response or survival, but produce toxicity that is likely to negatively impact QoL. New biological agents, such as bevacizumab, can induce a clinically meaningful proportion of durable responses among patients with recurrent GBM with an acceptable safety profile. Emerging evidence suggests that......The maintenance of quality of life (QoL) in patients with high-grade glioma is an important endpoint during treatment, particularly in those with glioblastoma multiforme (GBM) given its dismal prognosis despite limited advances in standard therapy. It has proven difficult to identify new therapies...

  14. Bilateral posterior RION after concomitant radiochemotherapy with temozolomide in a patient with glioblastoma multiforme: a case report

    International Nuclear Information System (INIS)

    Radiation induced optic neuropathy (RION) is a rare but severe consequence of radiation therapy that is associated with adjuvant chemotherapy, specifically therapy with vincristine or nitrosoureas. However, there is very little evidence regarding the occurrence of RION after concomitant radiochemotherapy with temozolomide. The case of a 63 year old woman with glioblastoma multiforme and concomitant radiochemotherapy with temozolomide is described. Due to a slight depressive episode the patient also took hypericum perforatum. Five months after cessation of fractionated radiation and adjuvant chemotherapy with temozolomide (cumulative dose of 11040 mg) the patient developed bilateral amaurosis due to RION. Tumor regrowth was excluded by magnetic resonance imaging. After the application of gadolinium a pathognomonic contrast enhancement of both prechiasmatic optic nerves could be observed. In this patient, the occurrence of RION may have been the result of radiosensitization by temozolomide, which could have been strengthened by hypericin. Consequently, physicians should avoid a concomitant application of hypericum perforatum and radiochemotherapy

  15. Boron neutron capture therapy of glioblastoma multiforme using the p- boronophenylalanine-fructose complex and epithermal neutrons

    International Nuclear Information System (INIS)

    The amino acid analogue p-boronophenylalanine (BPA) is under investigation as a neutron capture agent for BNCT of glioblastoma multiforme. A series of patients undergoing surgical removal of tumor received BPA orally as the free amino acid. Favorable tumor/blood boron concentration ratios were obtained but the absolute amount of boron in the tumor would have been insufficient for BNCT. BPA can be solubilized at neutral pH by complexation with fructose (BPA-F). Studies with rats suggest that intraperitoneal injection of BPA-F complex produces a much higher tumor boron concentration to rat intracerebral 9L gliosarcoma that were possible with oral BPA. Higher boron concentrations have allowed higher tumor radiation doses to be delivered while maintaining the dose to the normal brain vascular endothelium below the threshold of tolerance. The experience to date of the administration of BPA-F to one patient is provided in this report

  16. {sup 18}F-Fluoromisonidazole positron emission tomography may differentiate glioblastoma multiforme from less malignant gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Hirata, Kenji; Shiga, Tohru; Tamaki, Nagara [Hokkaido University, Department of Nuclear Medicine, Graduate School of Medicine, Sapporo, Hokkaido (Japan); Terasaka, Shunsuke; Kobayashi, Hiroyuki; Yamaguchi, Shigeru; Houkin, Kiyohiro [Graduate School of Medicine, Hokkaido University, Department of Neurosurgery, Sapporo (Japan); Hattori, Naoya [Graduate School of Medicine, Hokkaido University, Department of Molecular Imaging, Sapporo (Japan); Magota, Keiichi [Hokkaido University Hospital, Department of Radiology, Sapporo (Japan); Tanaka, Shinya [Graduate School of Medicine, Hokkaido University, Department of Cancer Pathology, Sapporo (Japan); Kuge, Yuji [Hokkaido University, Central Institute of Isotope Science, Sapporo (Japan)

    2012-05-15

    Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and its prognosis is significantly poorer than those of less malignant gliomas. Pathologically, necrosis is one of the most important characteristics that differentiate GBM from lower grade gliomas; therefore, we hypothesized that {sup 18}F fluoromisonidazole (FMISO), a radiotracer for hypoxia imaging, accumulates in GBM but not in lower grade gliomas. We aimed to evaluate the diagnostic value of FMISO positron emission tomography (PET) for the differential diagnosis of GBM from lower grade gliomas. This prospective study included 23 patients with pathologically confirmed gliomas. All of the patients underwent FMISO PET and {sup 18}F-fluorodeoxyglucose (FDG) PET within a week. FMISO images were acquired 4 h after intravenous administration of 400 MBq of FMISO. Tracer uptake in the tumor was visually assessed. Lesion to normal tissue ratios and FMISO uptake volume were calculated. Of the 23 glioma patients, 14 were diagnosed as having GBM (grade IV glioma in the 2007 WHO classification), and the others were diagnosed as having non-GBM (5 grade III and 4 grade II). In visual assessment, all GBM patients showed FMISO uptake in the tumor greater than that in the surrounding brain tissues, whereas all the non-GBM patients showed FMISO uptake in the tumor equal to that in the surrounding brain tissues (p {<=} 0.001). One GBM patient was excluded from FDG PET study because of hyperglycemia. All GBM patients and three of the nine (33%) non-GBM patients showed FDG uptake greater than or equal to that in the gray matter. The sensitivity and specificity for diagnosing GBM were 100 and 100% for FMISO, and 100 and 66% for FDG, respectively. The lesion to cerebellum ratio of FMISO uptake was higher in GBM patients (2.74 {+-} 0.60, range 1.71-3.81) than in non-GBM patients (1.22 {+-} 0.06, range 1.09-1.29, p {<=} 0.001) with no overlap between the groups. The lesion to gray matter ratio of FDG was also

  17. Treatment of glioblastoma multiforme cells with temozolomide-BioShuttle ligated by the inverse Diels-Alder ligation chemistry

    Directory of Open Access Journals (Sweden)

    Klaus Braun

    2009-01-01

    Full Text Available Klaus Braun1, Manfred Wiessler1, Volker Ehemann2, Ruediger Pipkorn3, Herbert Spring4, Juergen Debus5, Bernd Didinger5, Mario Koch3, Gabriele Muller6, Waldemar Waldeck61German Cancer Research Center, Dept of Imaging and Radiooncology, Heidelberg, Germany; 2University of Heidelberg, Institute of Pathology, Heidelberg, Germany; 3German Cancer Research Center, Central Peptide Synthesis Unit, Heidelberg, Germany; 4German Cancer Research Center, Dept of Structural Analysis of Gene Structure and Function, Heidelberg, Germany; 5University of Heidelberg, Dept of Radiation Oncology, Heidelberg, Germany; 6German Cancer Research Center,Division of Biophysics of Macromolecules, Heidelberg, GermanyAbstract: Recurrent glioblastoma multiforme (GBM, insensitive against most therapeutic interventions, has low response and survival rates. Temozolomide (TMZ was approved for second-line therapy of recurrent anaplastic astrocytoma. However, TMZ therapy in GBM patients reveals properties such as reduced tolerability and inauspicious hemogram. The solution addressed here concerning GBM therapy consolidates and uses the potential of organic and peptide chemistry with molecular medicine. We enhanced the pharmacologic potency with simultaneous reduction of unwanted adverse reactions of the highly efficient chemotherapeutic TMZ. The TMZ connection to transporter molecules (TMZ-BioShuttle was investigated, resulting in a much higher pharmacological effect in glioma cell lines and also with reduced dose rate. From this result we can conclude that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation. The TMZ-BioShuttle dramatically enhanced the potential of TMZ for the treatment of brain tumors and is an attractive drug for combination chemotherapy.Keywords: drug delivery, carrier molecules, facilitated transport, glioblastoma multiforme, temozolomide

  18. Phase II study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group 9513

    International Nuclear Information System (INIS)

    Purpose: A Phase II trial was conducted by the Radiation Therapy Oncology Group (RTOG) to compare the survival of patients with glioblastoma multiforme treated with topotecan combined with standard cranial radiotherapy (RT) for matched patients treated in prior RTOG studies. A secondary objective was to document the acute and late toxicities of this combination of chemotherapy and RT. Methods and Materials: Eighty-seven patients with histologically confirmed glioblastoma multiforme received standard cranial RT (60 Gy/30 fractions in 6 weeks) plus topotecan 1.5 mg/m2 per day i.v. for 5 d/wk every 3 weeks for 3 cycles. Eighty-four patients were evaluated, of whom 60 (71%) were ≥50 years, 44 (52%) were men, and 61 (73%) had a Karnofsky performance status of ≥80. Twenty-nine percent of patients had undergone biopsies, 48% partial resections, and 21% gross total resections. Two resections were unspecified as to the extent of tumor removal. Fourteen percent of patients were recursive partitioning analysis Class III, 46% were Class IV, 35% were Class V, and 5% were Class VI. Results: The median survival was 9.3 months. Sixty-seven patients (80%) had progression. The 1-year survival rate was 32%. One patient remained alive without recurrence. RTOG 9513 patients were matched with patients in an RTOG clinical trial database from previous clinical trials. The matching variables were age, Karnofsky performance status, mental status, and prior surgery. No statistically significant difference was found between the survival of the study patients and that of the matched patients from the RTOG database. Fifty-four percent of patients had Grade IV acute toxicity. The toxicity was primarily hematologic. Four patients had Grade III late central nervous system toxicities. Conclusion: Topotecan administered at a dose of 1.5 mg/m2 per day i.v. for 5 d/wk every 3 weeks for 3 cycles given concurrently with standard cranial RT for glioblastoma does not produce a statistically

  19. Optimizing cancer radiotheraphy with 2-deoxy-D-glucose. Dose escalation studies in patients with glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Singh, D.; Gupta, J.P. [Dharmshila Cancer Hospital, New Delhi (India); Banerji, A.K. [Vidyasagar Inst. of Mental Health and Neurosciences, New Delhi (India); Dwarakanath, B.S.; Tripathi, R.P.; Mathew, T.L.; Ravindranath, T. [Institute of Nuclear Medicine and Allied Sciences, Delhi (India); Jain, V. [Wright State University, Dayton, OH (United States). Kettering Medical Center

    2005-08-01

    Background and purpose: Higher rates of glucose utilization and glycolysis generally correlate with poor prognosis in several types of malignant tumors. Own earlier studies on model systems demonstrated that the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) could enhance the efficacy of radiotherapy in a dose-dependent manner by selectively sensitizing cancer cells while protecting normal cells. Phase I/II clinical trials indicated that the combination of 2-DG, at an oral dose of 200 mg/kg body weight (BW), with large fractions of {gamma}-radiation was well tolerated in cerebral glioma patients. Since higher 2-DG doses are expected to improve the therapeutic gain, present studies were undertaken to examine the tolerance and safety of escalating 2-DG dose during combined treatment (2-DG + radiotherapy) in glioblastoma multiforme patients. Patients and methods: Untreated patients with histologically proven glioblastoma multiforme (WHO criteria) were included in the study. Seven weekly fractions of {sup 60}C {gamma}-rays (5 Gy/fraction) were delivered to the tumor volume (presurgical CT/MRI evaluation) plus 3 cm margin. Escalating 2-DG doses (200-250-300 mg/kg BW) were administered orally 30 min before irradiation after overnight fasting. Acute toxicity and tolerance were studied by monitoring the vital parameters and side effects. Late radiation damage and treatment responses were studied radiologically and clinically in surviving patients. Results: Transient side effects similar to hypoglycemia were observed in most of the patients. Tolerance and patient compliance to the combined treatment were very good up to a 2-DG dose of 250 mg/kg BW. However, at the higher dose of 300 mg/kg BW, two out of six patients were very restless and could not complete treatment, though significant changes in the vital parameters were not observed even at this dose. No significant damage to the normal brain tissue was observed during follow-up in seven out of ten patients who

  20. Reinduction of Bevacizumab in Combination with Pegylated Liposomal Doxorubicin in a Patient with Recurrent Glioblastoma Multiforme Who Progressed on Bevacizumab/Irinotecan

    OpenAIRE

    Ramin Altaha; Mohammed Almubarak; Michael Newton

    2008-01-01

    Glioblastoma multiforme (GBM) carries a dismal prognosis despite the current standard of multimodality treatments. Recent studies showed promising results to a regimen consisting of a VEGF inhibitor, (bevacizumab) and a topoisomerase I inhibitor (irinotecan) [BI] in recurrent GBM. However, those patients with GBM who progress on BI will succumb to their disease generally in a very short period of time. We report a case of a 56-year-old male patient with GBM who declined surgical resection and...

  1. The autotaxin-lysophosphatidic acid–lysophosphatidic acid receptor cascade: proposal of a novel potential therapeutic target for treating glioblastoma multiforme

    OpenAIRE

    Tabuchi, Sadaharu

    2015-01-01

    Glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Its prognosis is one of the worst among all cancer types, and it is considered a fatal malignancy, incurable with conventional therapeutic strategies. As the bioactive multifunctional lipid mediator lysophosphatidic acid (LPA) is well recognized to be involved in the tumorigenesis of cancers by acting on G-protein-coupled receptors, LPA receptor (LPAR) antagonists and LPA synthesis inhibitors have b...

  2. Two phase II trials of temozolomide with interferon-α2b (pegylated and non-pegylated) in patients with recurrent glioblastoma multiforme

    OpenAIRE

    Groves, M. D.; Puduvalli, V K; Gilbert, M. R.; Levin, V. A.; Conrad, C. A.; Liu, V H; Hunter, K; Meyers, C.; Hess, K. R.; Alfred Yung, W. K.

    2009-01-01

    Background: Because of the poor outcomes for patients with recurrent glioblastoma multiforme (GBM), and some laboratory and clinical evidence of efficacy using interferon in GBM, we assessed the toxicity and efficacy of temozolomide (TMZ) combined with either short-acting (IFN) or long-acting (pegylated) interferon α2b (PEG) in two single-arm phase II studies, and compared the results to 6-month progression-free survival (PFS-6) data from historical controls. Methods: Two single-arm phase II ...

  3. The Role of a Single Angiogenesis Inhibitor in the Treatment of Recurrent Glioblastoma Multiforme: A Meta-Analysis and Systematic Review

    OpenAIRE

    Yawei Wang; Dan Xing; Meng Zhao; Jie Wang; Yang Yang

    2016-01-01

    Background Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in th...

  4. Long-Term Survival and Improved Quality of Life following Multiple Repeat Gamma Knife Radiosurgeries for Recurrent Glioblastoma Multiforme: A Case Report and Review of the Literature

    OpenAIRE

    Larson, Erik W.; Peterson, Halloran E.; Fairbanks, Robert K; Lamoreaux, Wayne T.; Mackay, Alexander R.; Call, Jason A.; Demakas, John J.; Cooke, Barton S; Lee, Christopher M

    2013-01-01

    The management of glioblastoma multiforme (GBM) is in most cases complex and must be specifically tailored to the needs of the patient with the goals of extended survival and improved quality of life. Despite advancements in therapy, treatment outcomes remain almost universally poor. Salvage treatment options for the recurrence of the disease is an area of intense study. The following case highlights the utility of Gamma Knife Radiosurgery (GKRS) as a salvage treatment. In this clinical situa...

  5. The influence of regional health system characteristics on the surgical management and receipt of post operative radiation therapy for glioblastoma multiforme

    OpenAIRE

    Aneja, Sanjay; Khullar, Dhruv; Yu, James B.

    2013-01-01

    Despite a known optimal treatment protocol for the management of glioblastoma multiforme (GBM), many patients fail to receive complete surgical resection or postoperative radiation therapy (PORT). The underlying reasons behind this disparity are unclear. Our study investigates the influence of regional health system resources on the surgical management and PORT receipt in patients with GBM. Surgical intervention, PORT receipt and patient data for patients diagnosed with GBM were obtained from...

  6. Salmonella enterica serovar Enteritidis brain abscess mimicking meningitis after surgery for glioblastoma multiforme: a case report and review of the literature

    OpenAIRE

    Luciani, Léa; Dubourg, Grégory; Graillon, Thomas; Honnorat, Estelle; Lepidi, Hubert; Drancourt, Michel; Seng, Piseth; Stein, Andreas

    2016-01-01

    Background Salmonella brain abscess associated with brain tumor is rare. Only 11 cases have been reported to date. Here we report a case of brain abscess caused by Salmonella enterica serovar Enteritidis mimicking post-surgical meningitis in a patient with glioblastoma multiforme. Case presentation A 60-year-old Algerian woman was admitted through an emergency department for a 4-day history of headache, nausea and vomiting, and behavioral disorders. Surgery for cerebral tumor excision was per...

  7. Clinical Observation of Chemotherapy with Temozolomide in Glioblastoma Multiforme%替莫唑胺对胶质母细胞瘤化疗的临床观察

    Institute of Scientific and Technical Information of China (English)

    王樑; 李刚; 李宝福; 冯富强; 冀培刚; 高国栋

    2012-01-01

    目的 探讨胶质母细胞瘤应用替莫唑胺化疗的疗效.方法 回顾性分析接受替莫唑胺化疗的31例胶质母细胞瘤患者的临床疗效.结果 所有患者均接受超过3个周期的替莫唑胺治疗,6个月有效率29.0%,无进展生存率64.5%.仅1例出现Ⅲ度骨髓抑制.结论 胶质母细胞瘤手术和放射治疗后可以应用替莫唑胺化疗.%Objective To discuss clinical results of chemotherapy with temozolomide in glioblastoma multiforme. Methods The clinical results of 31 patients underwent chemotherapy with temozolomide in glioblastoma multiforme were retrospective analyzed. Results All of patients completed more than 3 circle chemotherapy with temozolomide. 6 - raon effective rate was 29. 0% ,and 6 - mon progression - free survival rate was 64.5%. Only one case appeared myelosuppression. Conclusion Chemotherapy with temozolomidea is a good choice in glioblastoma multiforme after surgical and radical therapy.

  8. Correlação clínico-topográfica em glioblastomas multiformes nas síndromes motoras: significados fisiopatológicos Clinical topographic findings in glioblastoma multiforme and the relation with motor impairment

    Directory of Open Access Journals (Sweden)

    Rita de Cássia G. Lucena

    2006-06-01

    Full Text Available O glioblastoma multiforme (GBM é o tumor glial com maior grau de malignidade. Acomete principalmente os hemisférios cerebrais apresentando sintomas e sinais focais ou gerais, relacionados ao tamanho, localização e taxa de crescimento tumoral. OBJETIVO: Analisar a relação do déficit motor com a topografia do GBM. MÉTODO: Foram estudados 43 casos de GBM, referidos quanto à idade, sexo, localização e a síndrome motora. RESULTADOS: O tumor predominou em adultos (média de 55 anos, sexo masculino (55,82%, localização frontal (aproximadamente 40%. A hemiparesia prevaleceu como distúrbio motor, somente não ocorrendo em 2 casos de lesão frontal, 2 temporais, 1 parietal, 1 occipital e 1 fronto-temporal. CONCLUSÃO: Os achados clínico-topográficos favorecem os efeitos infiltrativos (lesões extensas como responsáveis pela síndrome motora em detrimento aos efeitos compressivos (lesões localizadas.Glioblastoma multiforme (GBM is the glial tumor with the highest grade of malignity. It mainly affects the cerebral hemispheres, presenting general or focal signs and symptoms, which depend on the size, the location of the lesion and rate of growth of the tumor. OBJECTIVE: To analyze the relationship between motor impairment and GBM topography. METHOD: We studied 43 cases of GBM, related to the age, gender, localization and motor impairment. RESULTS: The occurrence of the tumor was preponderant in adults (mean age 55 years old, men (55.82%, and frontal lobe (approximately 40%. The principal motor impairment was hemiparesis, with the exception of 2 cases in the frontal lobe, 2 temporal, 1 parietal, 1 occipital and 1 frontotemporal. CONCLUSION: The clinical-topographic findings lead to consider the infiltrative effects (broad lesions are responsible for the motor impairment rather than compressive effects (located lesions.

  9. Glioblastoma multiforme: Effect of hypoxia and hypoxia inducible factors on therapeutic approaches

    Science.gov (United States)

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors. Hypoxic regions of glioblastoma exacerbate the prognosis and clinical outcomes of the patients as hypoxic tumor cells are resistant to chemo- and radiation therapy and are also protected by the malfunctional vasculature that developed due to hypoxia. Predominantly, hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF)/VEGF receptor, transforming growth factor-β, epidermal growth factor receptor and PI3 kinase/Akt signaling systems are involved in tumor progression and growth. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Abnormal vessel formation is crucial in generating pseudopalisading necrosis regions that protect cancer stem cells residing in that region from therapeutic agents and this facilitates the cancer stem cell niche to expand and contribute to cell proliferation and tumor growth. Therapeutic approaches that target hypoxia-induced factors, such as use of the monoclonal antibody against VEGF, bevacizumab, have been useful only in stabilizing the disease but failed to increase overall survival. Hypoxia-activated TH-302, a nitroimidazole prodrug of cytotoxin bromo-isophosphoramide mustard, appears to be more attractive due to its better beneficial effects in glioblastoma patients. A better understanding of the hypoxia-mediated protection of glioblastoma cells is required for developing more effective therapeutics.

  10. Phase I Trial of Hypofractionated Intensity-Modulated Radiotherapy With Temozolomide Chemotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Chen Changhu, E-mail: changhu.chen@ucdenver.edu [Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO (United States); Damek, Denise [Department of Neurology, University of Colorado School of Medicine, Aurora, CO (United States); Gaspar, Laurie E. [Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO (United States); Waziri, Allen; Lillehei, Kevin [Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO (United States); Kleinschmidt-DeMasters, B.K. [Department of Pathology, University of Colorado School of Medicine, Aurora, CO (United States); Robischon, Monica; Stuhr, Kelly; Rusthoven, Kyle E.; Kavanagh, Brian D. [Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO (United States)

    2011-11-15

    Purpose: To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme. Methods and Materials: Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m{sup 2}/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m{sup 2}/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used. Results: A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis. Conclusions: The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with

  11. Phase I Trial of Hypofractionated Intensity-Modulated Radiotherapy With Temozolomide Chemotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

    International Nuclear Information System (INIS)

    Purpose: To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme. Methods and Materials: Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m2/d for 28 consecutive days. Adjuvant TMZ was given at 150–200 mg/m2/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used. Results: A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34–84. The median Karnofsky performance status was 80 (range, 60–90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0–12). The median survival was 16.2 months (range, 3–33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6–12 months after IMRT; 3 had radionecrosis. Conclusions: The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with

  12. The role of factor inhibiting HIF (FIH-1 in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Enfeng Wang

    Full Text Available Glioblastoma multiforme (GBM accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1, which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis.

  13. Perfusion MR Imaging and Proton MR Spectroscopic Imaging in Differentiating Necrotizing Cerebritis from Glioblastoma Multiforme

    OpenAIRE

    Pivawer, Gabriel; Law, Meng; Zagzag, David

    2006-01-01

    We describe a lesion with the MR imaging characteristics of a glioblastoma mutiforme and demonstrate how perfusion MR imaging and proton MR spectroscopic imaging can be used to differentiate necrotizing cerebritis from what appeared to be a high-grade glioma. A 43 year old woman presented to her physician complaining of progressive visual disturbance and headache for several weeks. Conventional MR imaging demonstrated a parietal peripherally enhancing mass with central necrosis and moderate t...

  14. Stem cell associated gene expression in glioblastoma multiforme: relationship to survival and the subventricular zone

    OpenAIRE

    Kappadakunnel, Melanie; Eskin, Ascia; DONG, JUN; Nelson, Stanley F.; Mischel, Paul S.; Liau, Linda M.; Ngheimphu, Phioanh; Lai, Albert; Cloughesy, Timothy F.; Goldin, Jonathan; Pope, Whitney B.

    2009-01-01

    Current therapies for glioblastoma (GBM) target bulk tumor through measures such as resection and radiotherapy. However, recent evidence suggests that targeting a subset of tumor cells, so-called cancer stem cells, may be critical for inhibiting tumor growth and relapse. The subventricular zone (SVZ), which lines the ventricles of the brain, is thought to be the origin for the majority of neural stem cells and potentially cancer stem cells. Therefore, we assessed the relationship between tumo...

  15. Bilateral posterior RION after concomitant radiochemotherapy with temozolomide in a patient with glioblastoma multiforme: a case report

    Directory of Open Access Journals (Sweden)

    Gademann Guenther

    2010-10-01

    Full Text Available Abstract Background Radiation induced optic neuropathy (RION is a rare but severe consequence of radiation therapy that is associated with adjuvant chemotherapy, specifically therapy with vincristine or nitrosoureas. However, there is very little evidence regarding the occurrence of RION after concomitant radiochemotherapy with temozolomide. Case Presentation The case of a 63 year old woman with glioblastoma multiforme and concomitant radiochemotherapy with temozolomide is described. Due to a slight depressive episode the patient also took hypericum perforatum. Five months after cessation of fractionated radiation and adjuvant chemotherapy with temozolomide (cumulative dose of 11040 mg the patient developed bilateral amaurosis due to RION. Tumor regrowth was excluded by magnetic resonance imaging. After the application of gadolinium a pathognomonic contrast enhancement of both prechiasmatic optic nerves could be observed. Conclusions In this patient, the occurrence of RION may have been the result of radiosensitization by temozolomide, which could have been strengthened by hypericin. Consequently, physicians should avoid a concomitant application of hypericum perforatum and radiochemotherapy.

  16. Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling.

    Science.gov (United States)

    Atif, Fahim; Yousuf, Seema; Stein, Donald G

    2015-02-01

    Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with a mean patient survival of 13-15 months despite surgical resection, radiation therapy and standard-of-care chemotherapy. We investigated the chemotherapeutic effects of the hormone progesterone (P4) on the growth of human GBM in four genetically different cell lines (U87MG, U87dEGFR, U118MG, LN-229) in vitro and in a U87MG subcutaneous xenograft mouse model. At high concentrations (20, 40, and 80 μM), P4 significantly (Pmatrix metalloproteinase-9. Apoptosis in tumor tissue was detected by the expression of cleaved caspase-3, BCl-2, BAD and p53 proteins and confirmed by TUNEL assay. P4 treatment also suppressed PI3K/Akt/mTOR signaling, which regulates tumor growth, as demonstrated by the suppression of proliferating cell nuclear antigen. Our data can be interpreted to suggest that P4 suppresses the growth of human GBM cells both in vitro and in vivo and enhances survival time in mice without any demonstrable side effects. This article is part of a Special Issue entitled 'Sex steroids and brain disorders'.

  17. C-Myc negatively controls the tumor suppressor PTEN by upregulating miR-26a in glioblastoma multiforme cells

    International Nuclear Information System (INIS)

    Highlights: •The c-Myc oncogene directly upregulates miR-26a expression in GBM cells. •ChIP assays demonstrate that c-Myc interacts with the miR-26a promoter. •Luciferase reporter assays show that PTEN is a specific target of miR-26a. •C-Myc–miR-26a suppression of PTEN may regulate the PTEN/AKT pathway. •Overexpression of c-Myc enhances the proliferative capacity of GBM cells. -- Abstract: The c-Myc oncogene is amplified in many tumor types. It is an important regulator of cell proliferation and has been linked to altered miRNA expression, suggesting that c-Myc-regulated miRNAs might contribute to tumor progression. Although miR-26a has been reported to be upregulated in glioblastoma multiforme (GBM), the mechanism has not been established. We have shown that ectopic expression of miR-26a influenced cell proliferation by targeting PTEN, a tumor suppressor gene that is inactivated in many common malignancies, including GBM. Our findings suggest that c-Myc modulates genes associated with oncogenesis in GBM through deregulation of miRNAs via the c-Myc–miR-26a–PTEN signaling pathway. This may be of clinical relevance

  18. MiR-26a enhances the radiosensitivity of glioblastoma multiforme cells through targeting of ataxia–telangiectasia mutated

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM) is notoriously resistant to radiation, and consequently, new radiosensitizers are urgently needed. MicroRNAs are a class of endogenous gene modulators with emerging roles in DNA repair. We found that overexpression of miR-26a can enhance radiosensitivity and reduce the DNA repair ability of U87 cells. However, knockdown miR-26a in U87 cells could act the converse manner. Mechanistically, this effect is mediated by direct targeting of miR-26a to the 3′UTR of ATM, which leads to reduced ATM levels and consequent inhibition of the homologous recombination repair pathway. These results suggest that miR-26a may act as a new radiosensitizer of GBM. - Highlights: ●miR-26a directly target ATM in GBM cells. ●miR-26a enhances the radiosensitivity of GBM cells. ●miR-26a could reduce the DNA repair capacity of GBM cells

  19. FNAB cytology of extra-cranial metastasis of glioblastoma multiforme may resemble a lung primary: A diagnostic pitfall

    Directory of Open Access Journals (Sweden)

    Dincer HE

    2005-01-01

    Full Text Available Abstract Background As extra-cranial metastasis of glioblastoma multiforme (GBM is rare, it may create a diagnostic dilemma especially during interpretation of fine needle aspiration biopsy (FNAB cytology. Case presentation We present transbronchial FNAB findings in a 62-year-old smoker with lung mass clinically suspicious for a lung primary. The smears of transbronchial FNAB showed groups of cells with ill-defined cell margins and cytological features overlapping with poorly differentiated non-small cell carcinoma. The tumor cells demonstrated lack of immunoreactivity for cytokeratin, thyroid transcription factor-1, and usual neuroendocrine markers, synaptophysin and chromogranin in formalin-fixed cellblock sections. However, they were immunoreactive for the other neuroendocrine immunomarker, CD56, suggesting neural nature of the cells. Further scrutiny of clinical details revealed a history of GBM, 13 months status-post surgical excision with radiation therapy and systemic chemotherapy. The tumor recurred 7 months earlier and was debulked surgically and with intra-cranial chemotherapy. Additional evaluation of tumor cells for glial fibrillary acidic protein (GFAP immunoreactivity with clinical details resulted in final interpretation of metastatic GBM. Conclusion Lack of clinical history and immunophenotyping may lead to a diagnostic pitfall with possible misinterpretation of metastatic GBM as poorly differentiated non-small cell carcinoma of lung in a smoker.

  20. Therapy and progression--induced O6-methylguanine-DNA methyltransferase and mismatch repair alterations in recurrent glioblastoma multiforme.

    Science.gov (United States)

    Agarwal, S; Suri, V; Sharma, M C; Sarkar, C

    2015-01-01

    Despite multimodality treatment protocol including surgical resection, radiotherapy, and chemotherapy in patients with glioblastoma multiforme (GBM), most suffer from treatment failure and tumor recurrence within a few months of initial surgery. The effectiveness of temozolomide (TMZ), the most commonly used chemotherapeutic agent, is largely dependent on the methylation status of the promoter of the gene O6-methylguanine-DNA methyltransferase (MGMT) and the integrity of the mismatch repair (MMR) system. Changes in these regulatory mechanisms at the time of recurrence may influence response to therapy. Deciphering the molecular mechanisms of resistance to these drugs may in future lead to improvised patient management. In this article, we provide an update of the spectrum of molecular changes that occur in recurrent GBMs, and thus may have an impact on patient survival and treatment response. For review, electronic search for the keywords "Recurrent GBM", "Recurrent GBM AND MGMT" "Recurrent glioma AND MGMT", "Recurrent GBM AND MMR" and "Recurrent glioma AND MMR", "Recurrent GBM AND MMR" and "Recurrent glioma AND MMR" was done on PubMed and relevant citations were screened including cross-references. PMID:26960480

  1. Therapy and progression – induced O6-methylguanine-DNA methyltransferase and mismatch repair alterations in recurrent glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    S Agarwal

    2015-01-01

    Full Text Available Despite multimodality treatment protocol including surgical resection, radiotherapy, and chemotherapy in patients with glioblastoma multiforme (GBM, most suffer from treatment failure and tumor recurrence within a few months of initial surgery. The effectiveness of temozolomide (TMZ, the most commonly used chemotherapeutic agent, is largely dependent on the methylation status of the promoter of the gene O6-methylguanine-DNA methyltransferase (MGMT and the integrity of the mismatch repair (MMR system. Changes in these regulatory mechanisms at the time of recurrence may influence response to therapy. Deciphering the molecular mechanisms of resistance to these drugs may in future lead to improvised patient management. In this article, we provide an update of the spectrum of molecular changes that occur in recurrent GBMs, and thus may have an impact on patient survival and treatment response. For review, electronic search for the keywords “Recurrent GBM”, “Recurrent GBM AND MGMT” “Recurrent glioma AND MGMT”, “Recurrent GBM AND MMR” and “Recurrent glioma AND MMR”, “Recurrent GBM AND MMR” and “Recurrent glioma AND MMR” was done on PubMed and relevant citations were screened including cross-references.

  2. High mobility group A1 expression shows negative correlation with recurrence time in patients with glioblastoma multiforme.

    Science.gov (United States)

    Liu, Bin; Pang, Bo; Liu, Huajie; Arakawa, Yoshiki; Zhang, Rui; Feng, Bin; Zhong, Peng; Murata, Daiki; Fan, Haitao; Xin, Tao; Zhao, Guangyu; Liu, Wei; Guo, Hua; Luan, Liming; Xu, Shangchen; Miyamoto, Susumu; Pang, Qi

    2015-08-01

    The aim of this study was to explore the difference in high mobility group A1 (HMGA1) expression and isocitrate dehydrogenase (IDH) 1 R132H point mutation in initial and recurrent glioblastoma multiforme (GBM), and to further identify whether the expression of HMGA1 has a role in the malignant progression of GBM. Paired initial and recurrent GBM specimens from the same patient were evaluated using immunohistochemical analysis. The association between HMGA1 expression and progression-free survival time (PFST) was analyzed. Three patients were confirmed with IDH-1 R132H mutations in both initial and recurrent groups (3/25, 12%). There was a significant difference in HMGA1 expression between initial and recurrent GBM (P=0.002), and patients with tumors expressing HMGA1 at higher level had a significantly shorter PFST (7.3 months versus 11.1months; P=0.044). Our study indicates that recurrent GBM express HMGA1 at a higher level and that HMGA1 overexpressoin is associated with shorter PFST in patients with GBM. These findings suggest that HMGA1 potentially plays an important role in the treatment of GBM. PMID:26092597

  3. Treatment of glioblastoma multiforme cells with temozolomide-BioShuttle ligated by the inverse Diels-Alder ligation chemistry

    Science.gov (United States)

    Braun, Klaus; Wiessler, Manfred; Ehemann, Volker; Pipkorn, Ruediger; Spring, Herbert; Debus, Juergen; Didinger, Bernd; Koch, Mario; Muller, Gabriele; Waldeck, Waldemar

    2008-01-01

    Recurrent glioblastoma multiforme (GBM), insensitive against most therapeutic interventions, has low response and survival rates. Temozolomide (TMZ) was approved for second-line therapy of recurrent anaplastic astrocytoma. However, TMZ therapy in GBM patients reveals properties such as reduced tolerability and inauspicious hemogram. The solution addressed here concerning GBM therapy consolidates and uses the potential of organic and peptide chemistry with molecular medicine. We enhanced the pharmacologic potency with simultaneous reduction of unwanted adverse reactions of the highly efficient chemotherapeutic TMZ. The TMZ connection to transporter molecules (TMZ-BioShuttle) was investigated, resulting in a much higher pharmacological effect in glioma cell lines and also with reduced dose rate. From this result we can conclude that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation. The TMZ-BioShuttle dramatically enhanced the potential of TMZ for the treatment of brain tumors and is an attractive drug for combination chemotherapy. PMID:19920915

  4. 18F-Fluorothymidine-Pet Imaging of Glioblastoma Multiforme: Effects of Radiation Therapy on Radiotracer Uptake and Molecular Biomarker Patterns

    Directory of Open Access Journals (Sweden)

    Sanjay Chandrasekaran

    2013-01-01

    Full Text Available Introduction. PET imaging is a useful clinical tool for studying tumor progression and treatment effects. Conventional 18F-FDG-PET imaging is of limited usefulness for imaging Glioblastoma Multiforme (GBM due to high levels of glucose uptake by normal brain and the resultant signal-to-noise intensity. 18F-Fluorothymidine (FLT in contrast has shown promise for imaging GBM, as thymidine is taken up preferentially by proliferating cells. These studies were undertaken to investigate the effectiveness of 18F-FLT-PET in a GBM mouse model, especially after radiation therapy (RT, and its correlation with useful biomarkers, including proliferation and DNA damage. Methods. Nude/athymic mice with human GBM orthografts were assessed by microPET imaging with 18F-FDG and 18F-FLT. Patterns of tumor PET imaging were then compared to immunohistochemistry and immunofluorescence for markers of proliferation (Ki-67, DNA damage and repair (γH2AX, hypoxia (HIF-1α, and angiogenesis (VEGF. Results. We confirmed that 18F-FLT-PET uptake is limited in healthy mice but enhanced in the intracranial tumors. Our data further demonstrate that 18F-FLT-PET imaging usefully reflects the inhibition of tumor by RT and correlates with changes in biomarker expression. Conclusions. 18F-FLT-PET imaging is a promising tumor imaging modality for GBM, including assessing RT effects and biologically relevant biomarkers.

  5. Piperlongumine selectively kills glioblastoma multiforme cells via reactive oxygen species accumulation dependent JNK and p38 activation.

    Science.gov (United States)

    Liu, Ju Mei; Pan, Feng; Li, Li; Liu, Qian Rong; Chen, Yong; Xiong, Xin Xin; Cheng, Kejun; Yu, Shang Bin; Shi, Zhi; Yu, Albert Cheung-Hoi; Chen, Xiao Qian

    2013-07-19

    Piperlongumine (PL), a natural alkaloid isolated from the long pepper, may have anti-cancer properties. It selectively targets and kills cancer cells but leaves normal cells intact. Here, we reported that PL selectively killed glioblastoma multiforme (GBM) cells via accumulating reactive oxygen species (ROS) to activate JNK and p38. PL at 20μM could induce severe cell death in three GBM cell lines (LN229, U87 and 8MG) but not astrocytes in cultures. PL elevated ROS prominently and reduced glutathione levels in LN229 and U87 cells. Antioxidant N-acetyl-L-cysteine (NAC) completely reversed PL-induced ROS accumulation and prevented cell death in LN229 and U87 cells. In LN229 and U87 cells, PL-treatment activated JNK and p38 but not Erk and Akt, in a dosage-dependent manner. These activations could be blocked by NAC pre-treatment. JNK and p38 specific inhibitors, SB203580 and SP600125 respectively, significantly blocked the cytotoxic effects of PL in LN229 and U87 cells. Our data first suggests that PL may have therapeutic potential for one of the most malignant and refractory tumors GBM. PMID:23796709

  6. C-Myc negatively controls the tumor suppressor PTEN by upregulating miR-26a in glioblastoma multiforme cells

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Pin; Nie, Quanmin; Lan, Jin; Ge, Jianwei [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Qiu, Yongming, E-mail: qiuzhoub@hotmail.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China); Mao, Qing, E-mail: maoq@netease.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China)

    2013-11-08

    Highlights: •The c-Myc oncogene directly upregulates miR-26a expression in GBM cells. •ChIP assays demonstrate that c-Myc interacts with the miR-26a promoter. •Luciferase reporter assays show that PTEN is a specific target of miR-26a. •C-Myc–miR-26a suppression of PTEN may regulate the PTEN/AKT pathway. •Overexpression of c-Myc enhances the proliferative capacity of GBM cells. -- Abstract: The c-Myc oncogene is amplified in many tumor types. It is an important regulator of cell proliferation and has been linked to altered miRNA expression, suggesting that c-Myc-regulated miRNAs might contribute to tumor progression. Although miR-26a has been reported to be upregulated in glioblastoma multiforme (GBM), the mechanism has not been established. We have shown that ectopic expression of miR-26a influenced cell proliferation by targeting PTEN, a tumor suppressor gene that is inactivated in many common malignancies, including GBM. Our findings suggest that c-Myc modulates genes associated with oncogenesis in GBM through deregulation of miRNAs via the c-Myc–miR-26a–PTEN signaling pathway. This may be of clinical relevance.

  7. MiR-26a enhances the radiosensitivity of glioblastoma multiforme cells through targeting of ataxia–telangiectasia mutated

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Pin; Lan, Jin; Ge, Jianwei; Nie, Quanmin; Guo, Liemei [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Qiu, Yongming, E-mail: qiuzhoub@hotmail.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China); Mao, Qing, E-mail: maoq@netease.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China)

    2014-01-15

    Glioblastoma multiforme (GBM) is notoriously resistant to radiation, and consequently, new radiosensitizers are urgently needed. MicroRNAs are a class of endogenous gene modulators with emerging roles in DNA repair. We found that overexpression of miR-26a can enhance radiosensitivity and reduce the DNA repair ability of U87 cells. However, knockdown miR-26a in U87 cells could act the converse manner. Mechanistically, this effect is mediated by direct targeting of miR-26a to the 3′UTR of ATM, which leads to reduced ATM levels and consequent inhibition of the homologous recombination repair pathway. These results suggest that miR-26a may act as a new radiosensitizer of GBM. - Highlights: ●miR-26a directly target ATM in GBM cells. ●miR-26a enhances the radiosensitivity of GBM cells. ●miR-26a could reduce the DNA repair capacity of GBM cells.

  8. Quantitative proteomics reveals the novel co-expression signatures in early brain development for prognosis of glioblastoma multiforme.

    Science.gov (United States)

    Yu, Xuexin; Feng, Lin; Liu, Dianming; Zhang, Lianfeng; Wu, Bo; Jiang, Wei; Han, Zujing; Cheng, Shujun

    2016-03-22

    Although several researches have explored the similarity across development and tumorigenesis in cellular behavior and underlying molecular mechanisms, not many have investigated the developmental characteristics at proteomic level and further extended to cancer clinical outcome. In this study, we used iTRAQ to quantify the protein expression changes during macaque rhesus brain development from fetuses at gestation 70 days to after born 5 years. Then, we performed weighted gene co-expression network analysis (WGCNA) on protein expression data of brain development to identify co-expressed modules that highly expressed on distinct development stages, including early stage, middle stage and late stage. Moreover, we used the univariate cox regression model to evaluate the prognostic potentials of these genes in two independent glioblastoma multiforme (GBM) datasets. The results showed that the modules highly expressed on early stage contained more reproducible prognostic genes, including ILF2, CCT7, CCT4, RPL10A, MSN, PRPS1, TFRC and APEX1. These genes were not only associated with clinical outcome, but also tended to influence chemoresponse. These signatures identified from embryonic brain development might contribute to precise prediction of GBM prognosis and identification of novel drug targets in GBM therapies. Thus, the development could become a viable reference model for researching cancers, including identifying novel prognostic markers and promoting new therapies. PMID:26895104

  9. Graphene Functionalized with Arginine Decreases the Development of Glioblastoma Multiforme Tumor in a Gene-Dependent Manner.

    Science.gov (United States)

    Sawosz, Ewa; Jaworski, Sławomir; Kutwin, Marta; Vadalasetty, Krishna Prasad; Grodzik, Marta; Wierzbicki, Mateusz; Kurantowicz, Natalia; Strojny, Barbara; Hotowy, Anna; Lipińska, Ludwika; Jagiełło, Joanna; Chwalibog, André

    2015-10-23

    Our previous studies revealed that graphene had anticancer properties in experiments in vitro with glioblastoma multiforme (GBM) cells and in tumors cultured in vivo. We hypothesized that the addition of arginine or proline to graphene solutions might counteract graphene agglomeration and increase the activity of graphene. Experiments were performed in vitro with GBM U87 cells and in vivo with GBM tumors cultured on chicken embryo chorioallantoic membranes. The measurements included cell morphology, mortality, viability, tumor morphology, histology, and gene expression. The cells and tumors were treated with reduced graphene oxide (rGO) and rGO functionalized with arginine (rGO + Arg) or proline (rGO + Pro). The results confirmed the anticancer effect of graphene on GBM cells and tumor tissue. After functionalization with amino acids, nanoparticles were distributed more specifically, and the flakes of graphene were less agglomerated. The molecule of rGO + Arg did not increase the expression of TP53 in comparison to rGO, but did not increase the expression of MDM2 or the MDM2/TP53 ratio in the tumor, suggesting that arginine may block MDM2 expression. The expression of NQO1, known to be a strong protector of p53 protein in tumor tissue, was greatly increased. The results indicate that the complex of rGO + Arg has potential in GBM therapy.

  10. The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme

    OpenAIRE

    Ballman, Karla V.; Buckner, Jan C.; Brown, Paul D.; Giannini, Caterina; Flynn, Patrick J.; LaPlant, Betsy R.; Jaeckle, Kurt A.

    2007-01-01

    Common end points for phase II trials in patients with glioblastoma multiforme (GBM) are six-month progression-free survival (PFS6) and 12-month overall survival (OS12). OS12 can be accurately measured but may be confounded with subsequent therapies upon progression, whereas the converse is true for PFS6. Our goal was to assess the relationship between these end points separately for phase II trials in patients with newly diagnosed GBM and patients with recurrent GBM. Data were pooled from 11...

  11. Computerized axial tomographic and magnetic resonance imaging scan follow-up of two patients after boron neutron capture therapy for Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Marano, S.R.; Spickard, J.H.; Griebenow, M.L.

    1988-01-01

    Using computer tomography (CT) and magnetic resonance imaging (MRI), we are following a 30-year old, white female and a 64-year old, white female and a 64-year old, white male, both with biopsy-proven Glioblastoma Multiforme, from their preoperative through post-operative stages and pre- and post-BNCT treatment. The images visually demonstrate the evolving changes in the tumor and surrounding cortex. These patients were treated by Hiroshi Hatanaka of Teikyo University, at the Musashi Institute of Technology (MIT) reactor which is a 100 kW Triga-II facility that has been used by Hatanaka for many years for BNCT therapy. 10 figs.

  12. Computerized axial tomographic and magnetic resonance imaging scan follow-up of two patients after boron neutron capture therapy for Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Marano, S.R.; Spickard, J.H.; Griebenow, M.L.

    1988-01-01

    Using computed tomography (CT) and magnetic resonance imaging (MRI), we are following a 30-year old, white female and a 64-year old, white female and a 64-year old, white male, both with biopsy-proven Glioblastoma Multiforme, from their preoperative through post-operative stages and pre- and post-BNCT treatment. The images visually demonstrate the evolving changes in the tumor and surrounding cortex. These patients were treated by Hiroshi Hatanaka of Teikyo University, at the Musashi Institute of Technology (MIT) reactor is a 100 kW Triga-II facility that has been used by Hatanaka for many years for BNCT therapy. 7 figs.

  13. TSPO imaging in glioblastoma multiforme: A direct comparison between 123ICLINDE-SPECT, 18F-FET PET and gadolinium-enhanced MRI.

    OpenAIRE

    Jensen, Per; Feng, Li; Law, Ian; Svarer, Claus; Knudsen, Gitte M; Mikkelsen, Jens D.; de Nijs, Robin; Larsen, Vibeke A; Dyssegaard, Agnete; Thomsen, Gerda; Fischer, Walter; GUILLOTEAU, Denis; Pinborg, Lars H.

    2015-01-01

    Here we compare TSPO imaging using 123 I-CLINDE and amino acid transport imaging using 18 F-FET and investigate if 123 I-CLINDE is superior to 18 F-FET in predictingprogression of glioblastoma multiforme (GBM) at follow up. Methods  Three patients with WHO grade IV GBM were scanned with 123 I-CLINDE SPECT, 18 F-FET PET and Gadolinium enhanced magnetic resonance imaging (gadolinium-MRI). Molecular imaging data were compared to follow-up gadolinium-MRI or contrast enhanc...

  14. Differentiation of glioblastoma multiforme stem-like cells leads to downregulation of EGFR and EGFRvIII and decreased tumorigenic and stem-like cell potential

    DEFF Research Database (Denmark)

    Stockhausen, Marie-Thérése; Kristoffersen, Karina; Stobbe, Louise;

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and devastating primary brain tumor among adults. Despite recent treatment progress, most patients succumb to their disease within 2 years of diagnosis. Current research has highlighted the importance of a subpopulation of cells, assigned brain...... and activation of the epidermal growth factor receptor (EGFR) and expression of a deletion variant EGFRvIII. In the normal brain, EGFR is expressed in neurogenic areas where also NSC are located and it has been shown that EGFR is involved in regulation of NSC proliferation, migration, and differentiation...

  15. Prognosis classification in glioblastoma multiforme using multimodal MRI derived heterogeneity textural features: impact of pre-processing choices

    Science.gov (United States)

    Upadhaya, Taman; Morvan, Yannick; Stindel, Eric; Le Reste, Pierre-Jean; Hatt, Mathieu

    2016-03-01

    Heterogeneity image-derived features of Glioblastoma multiforme (GBM) tumors from multimodal MRI sequences may provide higher prognostic value than standard parameters used in routine clinical practice. We previously developed a framework for automatic extraction and combination of image-derived features (also called "Radiomics") through support vector machines (SVM) for predictive model building. The results we obtained in a cohort of 40 GBM suggested these features could be used to identify patients with poorer outcome. However, extraction of these features is a delicate multi-step process and their values may therefore depend on the pre-processing of images. The original developed workflow included skull removal, bias homogeneity correction, and multimodal tumor segmentation, followed by textural features computation, and lastly ranking, selection and combination through a SVM-based classifier. The goal of the present work was to specifically investigate the potential benefit and respective impact of the addition of several MRI pre-processing steps (spatial resampling for isotropic voxels, intensities quantization and normalization) before textural features computation, on the resulting accuracy of the classifier. Eighteen patients datasets were also added for the present work (58 patients in total). A classification accuracy of 83% (sensitivity 79%, specificity 85%) was obtained using the original framework. The addition of the new pre-processing steps increased it to 93% (sensitivity 93%, specificity 93%) in identifying patients with poorer survival (below the median of 12 months). Among the three considered pre-processing steps, spatial resampling was found to have the most important impact. This shows the crucial importance of investigating appropriate image pre-processing steps to be used for methodologies based on textural features extraction in medical imaging.

  16. A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

    International Nuclear Information System (INIS)

    Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4–5 acute neurotoxicity attributable to radiotherapy. Results: All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

  17. Addition of Bevacizumab to Standard Radiation Therapy and Daily Temozolomide Is Associated With Minimal Toxicity in Newly Diagnosed Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Vredenburgh, James J., E-mail: vrede001@mc.duke.edu [Department of Medicine, Duke University Medical Center, Durham, NC (United States); Desjardins, Annick [Department of Neurology, Duke University Medical Center, Durham, NC (United States); Kirkpatrick, John P. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Reardon, David A. [Department of Surgery, Duke University Medical Center, Durham, NC (United States); Department of Pediatrics, Duke University Medical Center, Durham, NC (United States); Peters, Katherine B. [Department of Neurology, Duke University Medical Center, Durham, NC (United States); Herndon, James E.; Marcello, Jennifer [Department of Cancer Center Biostatistics, Duke University Medical Center, Durham, NC (United States); Bailey, Leighann; Threatt, Stevie; Sampson, John; Friedman, Allan [Department of Surgery, Duke University Medical Center, Durham, NC (United States); Friedman, Henry S. [Department of Surgery, Duke University Medical Center, Durham, NC (United States); Department of Pediatrics, Duke University Medical Center, Durham, NC (United States)

    2012-01-01

    Purpose: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM). Methods and Materials: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m{sup 2} daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively. Results: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study. Conclusions: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.

  18. Pulsed Versus Conventional Radiation Therapy in Combination With Temozolomide in a Murine Orthotopic Model of Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Lee, David Y.; Chunta, John L.; Park, Sean S.; Huang, Jiayi; Martinez, Alvaro A.; Grills, Inga S.; Krueger, Sarah A.; Wilson, George D. [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States); Marples, Brian, E-mail: brian.marples@beaumont.edu [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States)

    2013-08-01

    Purpose: To evaluate the efficacy of pulsed low-dose radiation therapy (PLRT) combined with temozolomide (TMZ) as a novel treatment approach for radioresistant glioblastoma multiforme (GBM) in a murine model. Methods and Materials: Orthotopic U87MG hGBM tumors were established in Nu-Foxn1{sup nu} mice and imaged weekly using a small-animal micropositron emission tomography (PET)/computed tomography (CT) system. Tumor volume was determined from contrast-enhanced microCT images and tumor metabolic activity (SUVmax) from the F18-FDG microPET scan. Tumors were irradiated 7 to 10 days after implantation with a total dose of 14 Gy in 7 consecutive days. The daily treatment was given as a single continuous 2-Gy dose (RT) or 10 pulses of 0.2 Gy using an interpulse interval of 3 minutes (PLRT). TMZ (10 mg/kg) was given daily by oral gavage 1 hour before RT. Tumor vascularity and normal brain damage were assessed by immunohistochemistry. Results: Radiation therapy with TMZ resulted in a significant 3- to 4-week tumor growth delay compared with controls, with PLRT+TMZ the most effective. PLRT+TMZ resulted in a larger decline in SUVmax than RT+TMZ. Significant differences in survival were evident. Treatment after PLRT+TMZ was associated with increased vascularization compared with RT+TMZ. Significantly fewer degenerating neurons were seen in normal brain after PLRT+TMZ compared with RT+TMZ. Conclusions: PLRT+TMZ produced superior tumor growth delay and less normal brain damage when compared with RT+TMZ. The differential effect of PLRT on vascularization may confirm new treatment avenues for GBM.

  19. Expression of S1P metabolizing enzymes and receptors correlate with survival time and regulate cell migration in glioblastoma multiforme

    Science.gov (United States)

    Bien-Möller, Sandra; Lange, Sandra; Holm, Tobias; Böhm, Andreas; Paland, Heiko; Küpper, Johannes; Herzog, Susann; Weitmann, Kerstin; Havemann, Christoph; Vogelgesang, Silke; Marx, Sascha; Hoffmann, Wolfgang; Schroeder, Henry W.S.; Rauch, Bernhard H.

    2016-01-01

    A signaling molecule which is involved in proliferation and migration of malignant cells is the lipid mediator sphingosine-1-phosphate (S1P). There are hints for a potential role of S1P signaling in malignant brain tumors such as glioblastoma multiforme (GBM) which is characterized by a poor prognosis. Therefore, a comprehensive expression analysis of S1P receptors (S1P1-S1P5) and S1P metabolizing enzymes in human GBM (n = 117) compared to healthy brain (n = 10) was performed to evaluate their role for patient's survival. Furthermore, influence of S1P receptor inhibition on proliferation and migration were studied in LN18 GBM cells. Compared to control brain, mRNA levels of S1P1, S1P2, S1P3 and S1P generating sphingosine kinase-1 were elevated in GBM. Kaplan-Meier analyses demonstrated an association between S1P1 and S1P2 with patient's survival times. In vitro, an inhibitory effect of the SphK inhibitor SKI-II on viability of LN18 cells was shown. S1P itself had no effect on viability but stimulated LN18 migration which was blocked by inhibition of S1P1 and S1P2. The participation of S1P1 and S1P2 in LN18 migration was further supported by siRNA-mediated silencing of these receptors. Immunoblots and inhibition experiments suggest an involvement of the PI3-kinase/AKT1 pathway in the chemotactic effect of S1P in LN18 cells. In summary, our data argue for a role of S1P signaling in proliferation and migration of GBM cells. Individual components of the S1P pathway represent prognostic factors for patients with GBM. Perspectively, a selective modulation of S1P receptor subtypes could represent a therapeutic approach for GBM patients and requires further evaluation. PMID:26887055

  20. Inhibition of Multidrug resistance protein 1 (MRP1 improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Amanda eTivnan

    2015-06-01

    Full Text Available Glioblastoma multiforme (GBM is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1 in high grade glioma, and it’s role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150µM, vincristine (100nM and etoposide (2µM. Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and Multidrug resistance protein 4 (MRP4 led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 hour period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients.

  1. Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients

    Directory of Open Access Journals (Sweden)

    Rose Frank

    2008-03-01

    Full Text Available Abstract Background Malignant gliomas are lethal cancers, highly dependent on angiogenesis and treatment options and prognosis still remain poor for patients with recurrent glioblastoma multiforme (GBM. Ephs and ephrins have many well-defined functions during embryonic development of central nervous system such as axon mapping, neural crest cell migration, hindbrain segmentation and synapse formation as well as physiological and abnormal angiogenesis. Accumulating evidence indicates that Eph and ephrins are frequently overexpressed in different tumor types including GBM. However, their role in tumorigenesis remains controversial, as both tumor growth promoter and suppressor potential have been ascribed to Eph and ephrins while the function of EphA7 in GBM pathogenesis remains largely unknown. Methods In this study, we investigated the immunohistochemical expression of EphA7 in a series of 32 primary and recurrent GBM and correlated it with clinical pathological parameters and patient outcome. In addition, intratumor microvascular density (MVD was quantified by immunostaining for endothelial cell marker von Willebrand factor (vWF. Results Overexpression of EphA7 protein was predictive of the adverse outcome in GBM patients, independent of MVD expression (p = 0.02. Moreover, high density of MVD as well as higher EphA7 expression predicted the disease outcome more accurately than EphA7 variable alone (p = 0.01. There was no correlation between MVD and overall survival or recurrence-free survival (p > 0.05. However, a statistically significant correlation between lower MVD and tumor recurrence was observed (p = 0.003. Conclusion The immunohistochemical assessment of tissue EphA7 provides important prognostic information in GBM and would justify its use as surrogate marker to screen patients for tyrosine kinase inhibitor therapy.

  2. Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme.

    Science.gov (United States)

    Tivnan, Amanda; Zakaria, Zaitun; O'Leary, Caitrín; Kögel, Donat; Pokorny, Jenny L; Sarkaria, Jann N; Prehn, Jochen H M

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150 μM), vincristine (100 nM), and etoposide (2 μM). Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein) led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and multidrug resistance protein 4 (MRP4) led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 h period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients. PMID:26136652

  3. Differentiation of solitary brain metastasis from glioblastoma multiforme: a predictive multiparametric approach using combined MR diffusion and perfusion

    Energy Technology Data Exchange (ETDEWEB)

    Bauer, Adam Herman; Moser, Franklin G.; Maya, Marcel [Cedars-Sinai Medical Center, Department of Medical Imaging, Los Angeles, CA (United States); Erly, William; Nael, Kambiz [University of Arizona Medical Center, Department of Medical Imaging, Tucson, AZ (United States)

    2015-07-15

    Solitary brain metastasis (MET) and glioblastoma multiforme (GBM) can appear similar on conventional MRI. The purpose of this study was to identify magnetic resonance (MR) perfusion and diffusion-weighted biomarkers that can differentiate MET from GBM. In this retrospective study, patients were included if they met the following criteria: underwent resection of a solitary enhancing brain tumor and had preoperative 3.0 T MRI encompassing diffusion tensor imaging (DTI), dynamic contrast-enhanced (DCE), and dynamic susceptibility contrast (DSC) perfusion. Using co-registered images, voxel-based fractional anisotropy (FA), mean diffusivity (MD), K{sup trans}, and relative cerebral blood volume (rCBV) values were obtained in the enhancing tumor and non-enhancing peritumoral T2 hyperintense region (NET2). Data were analyzed by logistic regression and analysis of variance. Receiver operating characteristic (ROC) analysis was performed to determine the optimal parameter/s and threshold for predicting of GBM vs. MET. Twenty-three patients (14 M, age 32-78 years old) met our inclusion criteria. Pathology revealed 13 GBMs and 10 METs. In the enhancing tumor, rCBV, K{sup trans}, and FA were higher in GBM, whereas MD was lower, neither without statistical significance. In the NET2, rCBV was significantly higher (p = 0.05) in GBM, but MD was significantly lower (p < 0.01) in GBM. FA and K{sup trans} were higher in GBM, though not reaching significance. The best discriminative power was obtained in NET2 from a combination of rCBV, FA, and MD, resulting in an area under the curve (AUC) of 0.98. The combination of MR diffusion and perfusion matrices in NET2 can help differentiate GBM over solitary MET with diagnostic accuracy of 98 %. (orig.)

  4. Tumor-associated macrophages in glioblastoma multiforme-a suitable target for somatostatin receptor-based imaging and therapy?

    Directory of Open Access Journals (Sweden)

    Constantin Lapa

    Full Text Available Glioblastoma multiforme (GBM is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN',N″,N'″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM.15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68, proliferative activity (Ki67 as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET imaging using 68Ga-DOTATATE was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry.The amount of microglia/macrophages ranged from 50% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns.SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM.

  5. Addition of Bevacizumab to Standard Radiation Therapy and Daily Temozolomide Is Associated With Minimal Toxicity in Newly Diagnosed Glioblastoma Multiforme

    International Nuclear Information System (INIS)

    Purpose: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM). Methods and Materials: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m2 daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively. Results: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study. Conclusions: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.

  6. Perfusion MR imaging and proton MR spectroscopic imaging in differentiating necrotizing cerebritis from glioblastoma multiforme.

    Science.gov (United States)

    Pivawer, Gabriel; Law, Meng; Zagzag, David

    2007-02-01

    We describe a lesion with the magnetic resonance imaging (MRI) characteristics of a glioblastoma mutiforme and demonstrate how perfusion MRI and proton MR spectroscopic imaging can be used to differentiate necrotizing cerebritis from what appeared to be a high-grade glioma. A 43-year-old woman presented to her physician complaining of progressive visual disturbance and headache for several weeks. Conventional MRI demonstrated a parietal peripherally enhancing mass with central necrosis and moderate to severe surrounding T2 hyperintensity, suggesting an infiltrating high-grade glioma. However, advanced imaging, including dynamic susceptibility contrast MRI (DSC MRI) and magnetic resonance spectroscopic imaging (MRSI), suggested a nonneoplastic lesion. The DSC MRI data demonstrated no hyperperfusion within the lesion and surrounding T2 signal abnormality, and the MRSI data showed overall decrease in metabolites in this region, except for lactate. Because of the aggressive appearance to the lesion and the patients' worsening symptoms, a biopsy was performed. The pathologic diagnosis was necrotizing cerebritis. After the commencement of steroid therapy, imaging findings and patient symptoms improved. This report will review the utility of advanced imaging for differentiating inflammatory from neoplastic appearing lesions on conventional imaging. PMID:17275620

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

    NARCIS (Netherlands)

    Schijns, V.E.J.C.; Pretto, C.; Devillers, L.; Pierre, D.; Hofman, F.M.; Chen, T.C.; Mespouille, P.; Hantos, P.; Glorieux, P.; Bota, D.A.; Stathopolous, A.

    2015-01-01

    Glioblastoma multiforme (GBM) patients have a poor prognosis. After tumor recurrence statistics suggestan imminent death within 1–4.5 months. Supportive preclinical data, from a rat model, provided therational for a prototype clinical vaccine preparation, named Gliovac (or ERC 1671) composed of auto

  8. 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

  9. Protein phosphatase 2A mediates dormancy of glioblastoma multiforme-derived tumor stem-like cells during hypoxia.

    Directory of Open Access Journals (Sweden)

    Christoph P Hofstetter

    Full Text Available PURPOSE: The hypoxic microenvironment of glioblastoma multiforme (GBM is thought to increase resistance to cancer therapies. Recent evidence suggests that hypoxia induces protein phosphatase 2A (PP2A, a regulator of cell cycle and cell death. The effects of PP2A on GBM tumor cell proliferation and survival during hypoxic conditions have not been studied. EXPERIMENTAL DESIGN: Expression of PP2A subunits and HIF-α proteins was measured in 65 high-grade astrocytoma and 18 non-neoplastic surgical brain specimens by western blotting. PP2A activity was measured by an immunoprecipitation assay. For in vitro experiments, GBM-derived tumor stem cell-like cells (TSCs were exposed to severe hypoxia produced by either CoCl₂ or 1% O₂. PP2A activity was inhibited either by okadaic acid or by shRNA depletion of the PP2A C subunit. Effects of PP2A activity on cell cycle progression and cell survival during hypoxic conditions were assessed using flow cytometry. RESULTS: In our patient cohort, PP2A activity was positively correlated with HIF-1∝ protein expression (P = 0.002. Patients with PP2A activity levels above 160 pMP had significantly worse survival compared to patients with levels below this threshold (P = 0.002. PP2A activity was an independent predictor of survival on multivariable analysis (P = 0.009. In our in vitro experiments, we confirmed that severe hypoxia induces PP2A activity in TSCs 6 hours after onset of exposure. PP2A activity mediated G1/S phase growth inhibition and reduced cellular ATP consumption in hypoxic TSCs. Conversely, inhibition of PP2A activity led to increased cell proliferation, exhaustion of intracellular ATP, and accelerated P53-independent cell death of hypoxic TSCs. CONCLUSIONS: Our results suggest that PP2A activity predicts poor survival in GBM. PP2A appears to reduce the metabolic demand of hypoxic TSCs and enhances tumor cell survival. Modulation of PP2A may be a potential target for cancer therapy.

  10. Impact of [11C]Methionine Positron Emission Tomography for Target Definition of Glioblastoma Multiforme in Radiation Therapy Planning

    International Nuclear Information System (INIS)

    Purpose: The purpose of this work was to define the optimal margins for gadolinium-enhanced T1-weighted magnetic resonance imaging (Gd-MRI) and T2-weighted MRI (T2-MRI) for delineating target volumes in planning radiation therapy for postoperative patients with newly diagnosed glioblastoma multiforme (GBM) by comparison to carbon-11-labeled methionine positron emission tomography ([11C]MET-PET) findings. Methods and Materials: Computed tomography (CT), MRI, and [11C]MET-PET were separately performed for radiation therapy planning for 32 patients newly diagnosed with GBM within 2 weeks after undergoing surgery. The extent of Gd-MRI (Gd-enhanced clinical target volume [CTV-Gd]) uptake and that of T2-MRI of the CTV (CTV-T2) were compared with the extent of [11C]MET-PET (CTV--[11C]MET-PET) uptake by using CT--MRI or CT--[11C]MET-PET fusion imaging. We defined CTV-Gd (x mm) and CTV-T2 (x mm) as the x-mm margins (where x = 0, 2, 5, 10, and 20 mm) outside the CTV-Gd and the CTV-T2, respectively. We evaluated the relationship between CTV-Gd (x mm) and CTV-- [11C]MET-PET and the relationship between CTV-T2 (x mm) and CTV-- [11C]MET-PET. Results: The sensitivity of CTV-Gd (20 mm) (86.4%) was significantly higher than that of the other CTV-Gd. The sensitivity of CTV-T2 (20 mm) (96.4%) was significantly higher than that of the other CTV-T2 (x = 0, 2, 5, 10 mm). The highest sensitivity and lowest specificity was found with CTV-T2 (x = 20 mm). Conclusions: It is necessary to use a margin of at least 2 cm for CTV-T2 for the initial target planning of radiation therapy. However, there is a limit to this setting in defining the optimal margin for Gd-MRI and T2-MRI for the precise delineation of target volumes in radiation therapy planning for postoperative patients with GBM.

  11. Identification of hub genes and regulatory factors of glioblastoma multiforme subgroups by RNA-seq data analysis.

    Science.gov (United States)

    Li, Yanan; Min, Weijie; Li, Mengmeng; Han, Guosheng; Dai, Dongwei; Zhang, Lei; Chen, Xin; Wang, Xinglai; Zhang, Yuhui; Yue, Zhijian; Liu, Jianmin

    2016-10-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor. This study aimed to identify the hub genes and regulatory factors of GBM subgroups by RNA sequencing (RNA-seq) data analysis, in order to explore the possible mechanisms responsbile for the progression of GBM. The dataset RNASeqV2 was downloaded by TCGA-Assembler, containing 169 GBM and 5 normal samples. Gene expression was calculated by the reads per kilobase per million reads measurement, and nor malized with tag count comparison. Following subgroup classification by the non-negative matrix factorization, the differentially expressed genes (DEGs) were screened in 4 GBM subgroups using the method of significance analysis of microarrays. Functional enrichment analysis was performed by DAVID, and the protein-protein interaction (PPI) network was constructed based on the HPRD database. The subgroup-related microRNAs (miRNAs or miRs), transcription factors (TFs) and small molecule drugs were predicted with pre-defined criteria. A cohort of 19,515 DEGs between the GBM and control samples was screened, which were predominantly enriched in cell cycle- and immunoreaction-related pathways. In the PPI network, lymphocyte cytosolic protein 2 (LCP2), breast cancer 1 (BRCA1), specificity protein 1 (Sp1) and chromodomain-helicase-DNA-binding protein 3 (CHD3) were the hub nodes in subgroups 1-4, respectively. Paired box 5 (PAX5), adipocyte protein 2 (aP2), E2F transcription factor 1 (E2F1) and cAMP-response element-binding protein-1 (CREB1) were the specific TFs in subgroups 1-4, respectively. miR‑147b, miR‑770-5p, miR‑220a and miR‑1247 were the particular miRNAs in subgroups 1-4, respectively. Natalizumab was the predicted small molecule drug in subgroup 2. In conclusion, the molecular regulatory mechanisms of GBM pathogenesis were distinct in the different subgroups. Several crucial genes, TFs, miRNAs and small molecules in the different GBM subgroups were identified

  12. The regulating role of mutant IκBα in expression of TIMP-2 and MMP-9 in human glioblastoma multiform

    Institute of Scientific and Technical Information of China (English)

    HU Yu-hua; YU Li-Jie; SHAO En-de; WU Jian-liang; JI Jian-wen

    2009-01-01

    Background Our previous studies demonstrated that mutant IκBα (IκBαM) inhibited the occurrence, growth and angiogenesis of human glioblastoma multiform (GBM). However, the specific mechanism by which IKBαM regulates protein-degrading enzymes secreted from GBM to inhibit invasion and metastasis has remained unclear. The aim of the present study was to investigate the regulatory role and significance of IκBαM genes in the expression of tissue inhibitor of metalloproteinase (TIMP)-2 and matrix metalloproteinase (MMP)-9 in human GBM. Methods We established the following four GBM cell lines stably expressing IκBαM by plasmid construction, gene transfection and screening for IκBαM protein expression: mutant IκBα-transfected cells (G36△-M), wild-type IκBα-transfected cells (G36△-W), empty plasmid transfected cells (G36△-P) and untransfected cells (G36△). The TIMP-2 and MMP-9 expression was detected by RT-PCR and Western blotting. Tumor cells were then implanted subcutaneously into nude mice to establish an animal model of ectopic tumor growth, and TIMP-2 and MMP-9 expression was determined by immunohistochemical methods. Results The results showed that there was a significant increase in TIMP-2 expression and a significant decrease in MMP-9 expression in the G36A-M group at both the RNA and protein levels compared with the G36A-W group, G36△-P group and G36△ group. Similar results were observed in the immunohistochemical staining analysis of tumor tissues. In the G36A-M group, TIMP-2 expression was significantly higher while MMP-9 expression was significantly lower than in the other three groups. Conclusions Our findings indicate that IκBαM inhibits the activation of NF-κB. It significantly up-regulates TIMP-2 expression in human malignant glioma cells and down-regulates the expression of MMP-9. Thus, IκBαM maintains the integrity of the extracellular matrix and further inhibits the growth and metastasis of tumor tissues.

  13. Clinical radiobiology of glioblastoma multiforme. Estimation of tumor control probability from various radiotherapy fractionation schemes

    Energy Technology Data Exchange (ETDEWEB)

    Pedicini, Piernicola [I.R.C.C.S.-Regional-Cancer-Hospital-C.R.O.B, Unit of Nuclear Medicine, Department of Radiation and Metabolic Therapies, Rionero-in-Vulture (Italy); Department of Radiation and Metabolic Therapies, I.R.C.C.S.-Regional-Cancer-Hospital-C.R.O.B, Unit of Radiotherapy, Rionero-in-Vulture (Italy); Fiorentino, Alba [Sacro Cuore - Don Calabria Hospital, Radiation Oncology Department, Negrar, Verona (Italy); Simeon, Vittorio [I.R.C.C.S.-Regional-Cancer-Hospital-C.R.O.B, Laboratory of Preclinical and Translational Research, Rionero-in-Vulture (Italy); Tini, Paolo; Pirtoli, Luigi [University of Siena and Tuscany Tumor Institute, Unit of Radiation Oncology, Department of Medicine Surgery and Neurological Sciences, Siena (Italy); Chiumento, Costanza [Department of Radiation and Metabolic Therapies, I.R.C.C.S.-Regional-Cancer-Hospital-C.R.O.B, Unit of Radiotherapy, Rionero-in-Vulture (Italy); Salvatore, Marco [I.R.C.C.S. SDN Foundation, Unit of Nuclear Medicine, Napoli (Italy); Storto, Giovanni [I.R.C.C.S.-Regional-Cancer-Hospital-C.R.O.B, Unit of Nuclear Medicine, Department of Radiation and Metabolic Therapies, Rionero-in-Vulture (Italy)

    2014-10-15

    The aim of this study was to estimate a radiobiological set of parameters from the available clinical data on glioblastoma (GB). A number of clinical trial outcomes from patients affected by GB and treated with surgery and adjuvant radiochemotherapy were analyzed to estimate a set of radiobiological parameters for a tumor control probability (TCP) model. The analytical/graphical method employed to fit the clinical data allowed us to estimate the intrinsic tumor radiosensitivity (α), repair capability (b), and repopulation doubling time (T{sub d}) in a first phase, and subsequently the number of clonogens (N) and kick-off time for accelerated proliferation (T{sub k}). The results were used to formulate a hypothesis for a scheduleexpected to significantly improve local control. The 95 % confidence intervals (CI{sub 95} {sub %}) of all parameters are also discussed. The pooled analysis employed to estimate the parameters summarizes the data of 559 patients, while the studies selected to verify the results summarize data of 104 patients. The best estimates and the CI{sub 95} {sub %} are α = 0.12 Gy{sup -1} (0.10-0.14), b = 0.015 Gy{sup -2} (0.013-0.020), α/b = 8 Gy (5.0-10.8), T{sub d} = 15.4 days (13.2-19.5), N = 1 . 10{sup 4} (1.2 . 10{sup 3} - 1 . 10{sup 5}), and T{sub k} = 37 days (29-46). The dose required to offset the repopulation occurring after 1 day (D{sub prolif}) and starting after T{sub k} was estimated as 0.30 Gy/day (0.22-0.39). The analysis confirms a high value for the α/b ratio. Moreover, a high intrinsic radiosensitivity together with a long kick-off time for accelerated repopulation and moderate repopulation kinetics were found. The results indicate a substantial independence of the duration of the overall treatment and an improvement in the treatment effectiveness by increasing the total dose without increasing the dose fraction. (orig.) [German] Schaetzung eines strahlenbiologischen Parametersatzes auf der Grundlage klinischer Daten bei

  14. Osthole Suppresses the Migratory Ability of Human Glioblastoma Multiforme Cells via Inhibition of Focal Adhesion Kinase-Mediated Matrix Metalloproteinase-13 Expression

    Directory of Open Access Journals (Sweden)

    Cheng-Fang Tsai

    2014-03-01

    Full Text Available Glioblastoma multiforme (GBM is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells.

  15. Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression.

    Science.gov (United States)

    Gao, Yong-Tao; Chen, Xiao-Bing; Liu, Hong-Lin

    2016-01-01

    MicroRNAs (miRNA) are believed to play an important role in glioblastoma multiforme (GBM)chemotherapy. Our study aims to investigate potential miRNA biomarkers in GBM. Sixty GBM patients, which were given temozolomide (TMZ) chemotherapy and recurrent radiotherapy, were recruited. miRNA array was performed in cancerous and in paired normal tissues. Microarray results were further validated by a quantitative real-time PCR in selected tissues and GBM cell lines. TMZ resistance cells were developed and cell proliferation along with colony formation assays was determined. Our study employed H2AX formation and flow cytometry to analyse the role of miRNA in DNA damage and apoptosis. Our study illustrated 16 miRNA in which 9 were up-regulated and 7 down-regulated. and their differential expression were demonstrated in a recurrent GBM tissue. Among them, miRNA-370-3p demonstrated the highest level of down- regulation in tissues and in TMZ resistance cells. miRNA-370-3p mimic increased its expression and sensitivity of GBM cells to TMZ by suppressing the self-reparative ability of tumour cell DNA. O(6)-methylguanine-DNA methyltransferase (MGMT) was identified as the direct target gene of miR-370-3p, and it was found to be inversely correlated with miR-370-3p expression in tissue samples obtained. Thus, our study demonstrated a critical clinical role of an up-regulated miR-370-3p expression in glioblastoma multiforme chemotherapy sensitivity.

  16. European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme

    OpenAIRE

    Bent, Martin; Stupp, Roger; Lacombe, Denis; Desir, J.P.; Lesimple, T; Dittrich, Christian; Baron, B.; Fumoleau, Pierre; de Jonge, Maja; Brandes, Alba; Oliveira, J.,; Frenay, Marc; Chollet, P; Schuessler, M.; Carpentier, A F

    2003-01-01

    textabstractBACKGROUND: Glufosfamide is a new alkylating agent in which the active metabolite of isophosphoramide mustard is covalently linked to beta-D-glucose to target the glucose transporter system and increase intracellular uptake in tumor cells. We investigated this drug in a multicenter prospective phase II trial in recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Eligible patients had recurrent GBM following surgery, radiotherapy and no more than one prior line of chemot...

  17. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy†

    OpenAIRE

    Raizer, Jeffrey J.; Abrey, Lauren E; Lassman, Andrew B.; Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Yung, W.K. Alfred; Gilbert, Mark R.; Aldape, Kenneth A.; Wen, Patrick Y.; Fine, Howard A.; Mehta, Minesh; DeAngelis, Lisa M.; Lieberman, Frank; Cloughesy, Timothy F.

    2009-01-01

    Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was ...

  18. Volumetry of [11C]-methionine PET uptake and MRI contrast enhancement in patients with recurrent glioblastoma multiforme

    OpenAIRE

    Galldiks, Norbert; Ullrich, Roland; Schroeter, Michael; Fink, Gereon R.; Kracht, Lutz W.

    2009-01-01

    Purpose We investigated the relationship between three-dimensional volumetric data of the metabolically active tumour volume assessed using [11C]-methionine positron emission tomography (MET-PET) and the area of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) enhancement assessed using magnetic resonance imaging (MRI) in patients with recurrent glioblastoma (GBM). Material and methods MET-PET and contrast-enhanced MRI with Gd-DTPA were performed in 12 uniformly pretreated patients wit...

  19. Pilot Study to Explore the Accuracy of Current Prediction Equations in Assessing Energy Needs of Patients with Newly Diagnosed Glioblastoma Multiforme.

    Science.gov (United States)

    Little, Rebecca B; Oster, Robert A; Darnell, Betty E; Demark-Wahnefried, Wendy; Nabors, L Burt

    2016-01-01

    Glioblastoma multiforme (GBM) is rare, yet it is the most common brain malignancy and has a poor prognosis. In regard to GBM, there is a dearth of research on resting energy expenditure (REE) and the accuracy of extant prediction equations. The aim of this cross-sectional study was to compare measured REE (mREE) to commonly used prediction equations in newly diagnosed GBM patients. REE was collected by indirect calorimetry in 20 GBM patients. Calculated REE was derived from Harris-Benedict (again with weight adjusted for obesity), Mifflin-St Jeor, and the 20 kcal/kg body weight ratio method. Paired t-tests and Bland-Altman analyses were used to compare group means, evaluate the bias, and find the limits of agreement. Clinical accuracy was assessed by determining the percentage of patients with predicted REE within ±10% of mREE. Subjects were evenly distributed with regard to gender, primarily Caucasian, and largely overweight or obese and had a mean age of 57 years. All equations overestimated mREE. Mifflin-St Jeor and adjusted Harris-Benedict had the narrowest limits of agreement and accurately predicted 60% and 65% of subjects, respectively. Clinicians should be aware of the discrepancy between commonly used prediction equations and REE. More research is needed to verify these findings and decipher the cause and significance in the GBM population. PMID:27341142

  20. Radioactive 125I seeds inhibit cell growth and epithelial-mesenchymal transition in human glioblastoma multiforme via a ROS-mediated signaling pathway

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM) is the most common primary central nervous system neoplasm in adults. Radioactive 125I seed implantation has been widely applied in the treatment of cancers. Moreover, previous clinical trials have confirmed that 125I seeds treatment was an effective therapy in GBM. We sought to investigate the effect of 125I seed on GBM cell growth and Epithelial-mesenchymal transition (EMT). Cells were exposed to irradiation at different doses. Colony-formation assay, EdU assay, cell cycle analysis, and TUNEL assay were preformed to investigate the radiation sensitivity. The effects of 125I seeds irradiation on EMT were measured by transwell, Boyden and wound-healing assays. The levels of reactive oxygen species (ROS) were measured by DCF-DA assay. Moreover, the radiation sensitivity and EMT were investigated with or without pretreatment with glutathione. Additionally, nude mice with tumors were measured after treated with radiation. Radioactive 125I seeds are more effective than X-ray irradiation in inhibiting GBM cell growth. Moreover, EMT was effectively inhibited by 125I seed irradiation. A mechanism study indicated that GBM cell growth and EMT inhibition were induced by 125I seeds with the involvement of a ROS-mediated signaling pathway. Radioactive 125I seeds exhibit novel anticancer activity via a ROS-mediated signaling pathway. These findings have clinical implications for the treatment of patients with GBM by 125I seeds

  1. Reinduction of Bevacizumab in Combination with Pegylated Liposomal Doxorubicin in a Patient with Recurrent Glioblastoma Multiforme Who Progressed on Bevacizumab/Irinotecan

    Directory of Open Access Journals (Sweden)

    Mohammed Almubarak

    2008-01-01

    Full Text Available Glioblastoma multiforme (GBM carries a dismal prognosis despite the current standard of multimodality treatments. Recent studies showed promising results to a regimen consisting of a VEGF inhibitor, (bevacizumab and a topoisomerase I inhibitor (irinotecan [BI] in recurrent GBM. However, those patients with GBM who progress on BI will succumb to their disease generally in a very short period of time. We report a case of a 56-year-old male patient with GBM who declined surgical resection and received chemoradiation with temozolomide. This treatment was withheld secondary to significant thrombocytopenia. Subsequently, he achieved stable disease for 10 months with a regimen consisting of thalidomide and tamoxifen before progressing. This was followed by bevacizumab with irinotecan [BI], for which he had a significant partial response for 8 months with subsequent progression. Reinducing the patient with bevacizumab in combination with a pegylated liposomal doxorubicin [PLD] (a topoisomerase II inhibitor demonstrated antitumor activity with significant shrinkage of contrast enhancing mass and peritumoral edema.

  2. Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system.

    Science.gov (United States)

    Sarganas, Giselle; Orzechowski, Hans D; Klimpel, Andreas; Thomae, Michael; Kauffmann, Wolfgang; Herbst, Hermann; Bronder, Elisabeth; Garbe, Edeltraut

    2012-05-01

    Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults. Its established first-line adjuvant treatment is radiotherapy in combination with temozolomide (TZM). Hematotoxicity is listed as a frequent adverse drug reaction in the US prescribing information and hepatotoxicity has been reported infrequently in the postmarketing period. We here present the case of a patient diagnosed with GBM who developed severe sustained cholestatic hepatitis following treatment with TZM. The cholestasis was not reversible after withdrawal of TZM during 6 months before the patient's death. Another 2 published case reports of sustained cholestasis following TZM treatment were identified; however, the sustained nature of cholestasis was not emphasized in these reports. Sixteen cases of cholestatic hepatitis/cholestasis associated with TZM were identified in the FDA spontaneous reporting system between 2007 and 2010. Information on the course of the cholestasis in these cases could not be retrieved. In the literature there are other published reports of hepatotoxicity associated with TZM that have reported reversibility upon withdrawal of the drug. Thus, TZM appears to cause different types of hepatotoxicity. Particular attention should be paid to sustained cholestasis as a very serious type of TZM-associated liver toxicity. PMID:22394496

  3. Assessing Response Using Tc99m-MIBI Early after Interstitial Chemotherapy with Carmustine-Loaded Polymers in Glioblastoma Multiforme: Preliminary Results

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    D. Cecchin

    2014-01-01

    Full Text Available Introduction. Early signs of response after applying wafers of carmustine-loaded polymers (gliadel are difficult to assess with imaging because of time-related imaging changes. Tc99m-sestamibi (MIBI brain single-photon emission tomography (SPET has reportedly been used to reveal areas of cellularity distinguishing recurrent neoplasm from radionecrosis. Our aim was to explore the role of MIBI SPET in assessing response soon after gliadel application in glioblastoma multiforme (GBM. Methods. We retrospectively reviewed the charts on 28 consecutive patients with a radiological diagnosis of GBM who underwent MIBI SPET/CT before surgery (with intracavitary gliadel placement in 17 patients, soon after surgery, and at 4 months. The area of uptake was selected using a volume of interest that was then mirrored contralaterally to obtain a semiquantitative ratio. Results. After adjusting for ratio at the baseline, the effect of treatment (gliadel versus non-gliadel was not statistically significant. Soon after surgery, however, 100% of patients treated with gliadel had a decreased ratio, as opposed to 62.5% of patients in the non-gliadel group P=0.0316. The difference between ratios of patients with radical versus partial resection reached statistical significance by a small margin P=0.0528. Conclusions. These data seem to suggest that the MIBI ratio could be a valuable tool for monitoring the effect of gliadel early after surgery.

  4. Long-Term Survival and Improved Quality of Life following Multiple Repeat Gamma Knife Radiosurgeries for Recurrent Glioblastoma Multiforme: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Erik W. Larson

    2013-01-01

    Full Text Available The management of glioblastoma multiforme (GBM is in most cases complex and must be specifically tailored to the needs of the patient with the goals of extended survival and improved quality of life. Despite advancements in therapy, treatment outcomes remain almost universally poor. Salvage treatment options for the recurrence of the disease is an area of intense study. The following case highlights the utility of Gamma Knife Radiosurgery (GKRS as a salvage treatment. In this clinical situation, three sequential GKRS treatments led to prolonged survival (beyond four years after diagnosis and improved quality of life in a patient who was unable to receive further chemotherapy regimens and was unwilling to undergo further aggressive resection. To date, there have been few reports of three or more sequential GKRS treatment sessions utilized as salvage therapy for recurrent GBM in patients who can no longer tolerate chemotherapy. This report provides evidence that aggressive local treatment with GKRS at the time of recurrence may be appropriate, depending on a patient’s individual clinical situation, and can lead to prolonged survival and improved quality of life.

  5. Glioblastoma

    Science.gov (United States)

    ... these tumors to contain cystic mineral, calcium deposits, blood vessels, or a mixed grade of cells. Glioblastomas are usually highly malignant—a large number of tumor cells are reproducing at any given time, and they are nourished by an ample blood supply. Dead cells may also be seen, especially ...

  6. Neural Stem Cells and Glioblastoma

    OpenAIRE

    Rispoli, Rossella; Conti, Carlo; Celli, Paolo; Caroli, Emanuela; Carletti, Sandro

    2014-01-01

    Glioblastoma multiforme represents one of the most common brain cancers with a rather heterogeneous cellular composition, as indicated by the term “multiforme". Recent reports have described the isolation and identification of cancer neural stem cells from human adult glioblastoma multiforme, which possess the capacity to establish, sustain, and expand these tumours, even under the challenging settings posed by serial transplantation experiments. Our study focused on the distribution of neura...

  7. GSVD comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival.

    Directory of Open Access Journals (Sweden)

    Cheng H Lee

    Full Text Available Despite recent large-scale profiling efforts, the best prognostic predictor of glioblastoma multiforme (GBM remains the patient's age at diagnosis. We describe a global pattern of tumor-exclusive co-occurring copy-number alterations (CNAs that is correlated, possibly coordinated with GBM patients' survival and response to chemotherapy. The pattern is revealed by GSVD comparison of patient-matched but probe-independent GBM and normal aCGH datasets from The Cancer Genome Atlas (TCGA. We find that, first, the GSVD, formulated as a framework for comparatively modeling two composite datasets, removes from the pattern copy-number variations (CNVs that occur in the normal human genome (e.g., female-specific X chromosome amplification and experimental variations (e.g., in tissue batch, genomic center, hybridization date and scanner, without a-priori knowledge of these variations. Second, the pattern includes most known GBM-associated changes in chromosome numbers and focal CNAs, as well as several previously unreported CNAs in >3% of the patients. These include the biochemically putative drug target, cell cycle-regulated serine/threonine kinase-encoding TLK2, the cyclin E1-encoding CCNE1, and the Rb-binding histone demethylase-encoding KDM5A. Third, the pattern provides a better prognostic predictor than the chromosome numbers or any one focal CNA that it identifies, suggesting that the GBM survival phenotype is an outcome of its global genotype. The pattern is independent of age, and combined with age, makes a better predictor than age alone. GSVD comparison of matched profiles of a larger set of TCGA patients, inclusive of the initial set, confirms the global pattern. GSVD classification of the GBM profiles of an independent set of patients validates the prognostic contribution of the pattern.

  8. 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.

  9. Phase II Study of Erlotinib Plus Temozolomide During and After Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

    Science.gov (United States)

    Prados, Michael D.; Chang, Susan M.; Butowski, Nicholas; DeBoer, Rebecca; Parvataneni, Rupa; Carliner, Hannah; Kabuubi, Paul; Ayers-Ringler, Jennifer; Rabbitt, Jane; Page, Margaretta; Fedoroff, Anne; Sneed, Penny K.; Berger, Mitchel S.; McDermott, Michael W.; Parsa, Andrew T.; Vandenberg, Scott; James, C. David; Lamborn, Kathleen R.; Stokoe, David; Haas-Kogan, Daphne A.

    2009-01-01

    Purpose This open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response. Patients and Methods Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials. Results Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival. Conclusion Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted. PMID:19075262

  10. Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma.

    Science.gov (United States)

    Butowski, Nicholas; Chang, Susan M; Lamborn, Kathleen R; Polley, Mei-Yin; Pieper, Russell; Costello, Joseph F; Vandenberg, Scott; Parvataneni, Rupa; Nicole, Angelina; Sneed, Patricia K; Clarke, Jennifer; Hsieh, Emily; Costa, Bruno M; Reis, Rui M; Hristova-Kazmierski, Maria; Nicol, Steven J; Thornton, Donald E; Prados, Michael D

    2011-12-01

    This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

  11. Peripheral blood-derived, γ9δ2 t cell-enriched cell lines from glioblastoma multiforme patients exert anti-tumoral effects in vitro.

    Science.gov (United States)

    Marcu-Malina, V; Garelick, D; Peshes-Yeloz, N; Wohl, A; Zach, L; Nagar, M; Amariglio, N; Besser, M J; Cohen, Z R; Bank, I

    2016-01-01

    The goal of this work was to assess the potential of T cells expressing Vγ9Vδ2+ T cell receptors (TCR, γ9δ2T cells) present in peripheral blood (PB) m ononuclear cells (MC, PBMC) of glioblastoma multiforme (GBM) patients to act as anti-tumoral agents. We found that γ9δ2T cell levels were decreased in patients' PB relative to a cohort of healthy donors (HD) (respectively 0.52±0.55%, n=16, vs 1.12±0.6%, n=14, p=0.008) but did not significantly correlate with postoperative survival (R=0.6, p=0.063). Importantly, however, the γ9δ2T cells could be expanded in vitro to consist 51±23% of the cultured lymphocytes (98% CD3+). This was achieved after 14 days of culture in medium containing the amino-bisphosphonate (ABP) Zoledronate (Zol) and interleukin (IL)-2, resulting in γ9δ2T cell-enriched lines (gdTCEL) similar to those of HD derived gdTCEL (54±19%). Moreover, gdTCEL from patients and HD mediated cytotoxicity to GBM-derived cell lines (GBMDCL), which was abrogated by immune-magnetic removal of the γ9δ2T cells. Furthermore, low level interferon (IFN) γ secretion was induced by gdTCEL briefly co-cultured with GBMDCL or autologous - tumor-derived cells, which was greatly amplified in the presence of Zol. Importantly, IFNγ secretion was inhibited by mevastatin but enhanced by cross-linking of butyrophilin 3A1 (CD277) on a CD277+ GBMDCL (U251MG) or by pretreatment of GBMDCL with temozolomide (TMZ). Taken together, these data suggest that γ9δ2T cells in PB of GBM patients can give rise to gdTCEL that mediate anti-tumoral activities. PMID:27049073

  12. Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptide.

    Science.gov (United States)

    Oji, Yusuke; Hashimoto, Naoya; Tsuboi, Akihiro; Murakami, Yui; Iwai, Miki; Kagawa, Naoki; Chiba, Yasuyoshi; Izumoto, Shuichi; Elisseeva, Olga; Ichinohasama, Ryo; Sakamoto, Junichi; Morita, Satoshi; Nakajima, Hiroko; Takashima, Satoshi; Nakae, Yoshiki; Nakata, Jun; Kawakami, Manabu; Nishida, Sumiyuki; Hosen, Naoki; Fujiki, Fumihiro; Morimoto, Soyoko; Adachi, Mayuko; Iwamoto, Masahiro; Oka, Yoshihiro; Yoshimine, Toshiki; Sugiyama, Haruo

    2016-09-15

    We previously evaluated Wilms' tumor gene 1 (WT1) peptide vaccination in a large number of patients with leukemia or solid tumors and have reported that HLA-A*24:02 restricted, 9-mer WT1-235 peptide (CYTWNQMNL) vaccine induces cellular immune responses and elicits WT1-235-specific cytotoxic T lymphocytes (CTLs). However, whether this vaccine induces humoral immune responses to produce WT1 antibody remains unknown. Thus, we measured IgG antibody levels against the WT1-235 peptide (WT1-235 IgG antibody) in patients with glioblastoma multiforme (GBM) receiving the WT1 peptide vaccine. The WT1-235 IgG antibody, which was undetectable before vaccination, became detectable in 30 (50.8%) of a total of 59 patients during 3 months of WT1 peptide vaccination. The dominant WT1-235 IgG antibody subclass was Th1-type, IgG1 and IgG3 . WT1-235 IgG antibody production was significantly and positively correlated with both progression-free survival (PFS) and overall survival (OS). Importantly, the combination of WT1-235 IgG antibody production and positive delayed type-hypersensitivity (DTH) to the WT1-235 peptide was a better prognostic marker for long-term OS than either parameter alone. These results suggested that WT1-235 peptide vaccination induces not only WT1-235-specific CTLs as previously described but also WT1-235-specific humoral immune responses associated with antitumor cellular immune response. Our results indicate that the WT1 IgG antibody against the WT1 peptide may be a useful predictive marker, with better predictive performance in combination with DTH to WT1 peptide, and provide a new insight into the antitumor immune response induction in WT1 peptide vaccine-treated patients. PMID:27170523

  13. Extended disease-free interval of 6 years in a recurrent glioblastoma multiforme patient treated with G207 oncolytic viral therapy

    Directory of Open Access Journals (Sweden)

    Whisenhunt Jr TR

    2015-01-01

    Full Text Available Thomas R Whisenhunt Jr, Kiran F Rajneesh, James R Hackney, James M Markert Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA Background: Glioblastoma multiforme (GBM is a relentless primary central nervous system malignancy that remains resistant to conventional therapy despite major advances in clinical neurooncology. This report details the case of a patient who had failed conventional treatment for recurrent GBM and was ultimately treated with a genetically engineered herpes simplex virus (HSV type 1 vector, G207. Methods: Case report detailing the outcomes of one patient enrolled into the gene therapy arm of the Neurovir G207 protocol whereby stereotactic injection of 120 µL G207 viral suspension containing 1×107 plaque-forming units (or active viral particles was made into the enhancing region of the tumor. Results: In this patient, despite aggressive surgical resection, adjuvant radiotherapy and chemotherapy, tumor progression occurred. However, with G207 oncolytic therapy and brief exposures to second and third treatments, this patient had an extended survival time of 7.5 years and a 6-year apparent disease-free interval, an extraordinarily unusual finding in the pretemozolomide era. Conclusion: With minimal adjunctive chemotherapy, including one course of temozolomide, one course of procarbazine, and four cycles of irinotecan, the patient survived over 7 years before the next recurrence. Addition of G207 to this patient’s traditional therapy may have been the critical treatment producing her prolonged survival. This report demonstrates the potential for long-term response to a one-time treatment with oncolytic HSV and encourages continued research on oncolytic viral therapy for GBM. Keywords: oncolytic virotherapy, malignant glioma, tumor, herpes simplex, HSV-1, immunotherapy

  14. Salvage fractionated Stereotactic Radiotherapy (fSRT with or without chemotherapy and immunotherapy for recurrent Glioblastoma Multiforme: A single institution experience

    Directory of Open Access Journals (Sweden)

    Shaakir eHasan

    2015-05-01

    Full Text Available Background: The current standard of care for salvage treatment of Glioblastoma Multiforme (GBM is gross total resection and adjuvant chemoradiation for operable patients. Limited evidence exists to suggest that any particular treatment modality improves survival for recurrent GBM, especially if inoperable. We report our experience with fractionated stereotactic radiotherapy (fSRT with and without chemo/immunotherapy, identifying prognostic factors associated with prolonged survival. Methods: From 2007 to 2014, 19 patients between 29 and 78 years old (median 55 with recurrent GBM following resection and chemoradiation for their initial tumor, received 18 – 35 Gy (median 25 in 3 – 5 fractions via Cyberknife fSRT. Clinical target volume (CTV ranged from 0.9 to 152 cc. Sixteen patients received adjuvant systemic therapy with bevacizumab (BEV, temozolomide (TMZ, anti-epidermal growth factor receptor (125I-mAb 425, or some combination thereof. Results: The median overall survival (OS from date of recurrence was 8 months (2.5 – 61 and 5.3 months (0.6 – 58 from the end of fSRT. The OS at 6 and 12 months was 47% and 32%, respectively. Three of 19 patients were alive at the time of this review at 20, 49 and 58 months from completion of fSRT. Hazard ratios for survival indicated that patients with a frontal lobe tumor, adjuvant treatment with either BEV or TMZ, time to first recurrence >16 months, CTV < 36 cc, Recursive Partitioning Analysis (RPA < 5, and ECOG (Eastern Cooperative Oncology Group performance status < 2 were all associated with improved survival (P <0.05. There was no evidence of radionecrosis for any patient.Conclusions: Radiation Therapy Oncology Group (RTOG 1205 will establish the role of reirradiation for recurrent GBM, however our study suggests that cyberknife with chemotherapy can be safely delivered, and is most effective in patients with smaller frontal lobe tumors, good performance status or long interval from diagnosis.

  15. Progression-free and overall survival in patients with recurrent Glioblastoma multiforme treated with last-line bevacizumab versus bevacizumab/lomustine.

    Science.gov (United States)

    Heiland, D H; Masalha, W; Franco, P; Machein, M R; Weyerbrock, A

    2016-02-01

    Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma multiforme (GBM). 1-(2-Chlorethyl)-cyclohexyl-nitrosourea (CCNU, lomustine) monotherapy is an approved chemotherapeutical option for recurrent GBM. Recent evidence demonstrated a survival benefit of combined treatment with BEV and CCNU in patients with a first recurrence of GBM. We examined the outcome of recurrent GBM patients with BEV monotherapy versus BEV/CCNU therapy when used as last-line therapy. 35 patients with recurrent GBM treated between 2010 and 2014 were included in this retrospective study. Progression-free and overall survival was determined with reference to the beginning of BEV or BEV/CCNU therapy and initial diagnosis. 17 patients received BEV monotherapy, 18 patients received combined BEV and CCNU therapy. The impact of parameters such as IDH mutation, MGMT promoter methylation, tumor localization, histology and the number of surgeries were included in a multivariate ANOVA analysis. Furthermore, Karnofsky performance score (KPS), neurological function and toxicity were assessed. BEV/CCNU treatment led to an extension of PFS (6.11 months; 95% CL 3.41-12.98 months; log-rank p = 0.00241) and OS (6.59 months; 95% CL 5.51-16.3 months; log-rank p = 0.0238) of 2 months compared to BEV monotherapy. This survival advantage was independent of histology, IDH mutation status or the number of previous surgeries. Neurological function, KPS and toxicity were not significantly different between both treatment groups. Last-line therapy with BEV/CCNU results in a longer PFS and OS compared to BEV monotherapy and is well-tolerated. These findings confirm the role of these agents in the treatment of recurrent GBM and are in line with other studies. PMID:26614518

  16. 复发难治多形性胶质母细胞瘤的综合治疗%Combined Modality Therapy of Recurrent and Refractory Glioblastoma Multiforme

    Institute of Scientific and Technical Information of China (English)

    杨群英; 沈冬; 赛克; 牟永告; 张湘衡; 陈忠平

    2010-01-01

    恶性脑胶质瘤是成人最常见的原发脑肿瘤,治疗困难,预后差.以手术治疗为主,放疗、化疗联合应用的综合治疗策略对生存的改善有一定帮助,但即使初次治疗有效者大多最终又复发.我们报道一例复发难治多形性胶质母细胞瘤(glioblastoma multiforme,GBM),患者经5次手术、放疗,以及包括替莫唑胺、伊立替康、替尼泊苷、顺铂、尼妥珠单抗、血管内皮抑素、干扰素β等在内的细胞毒药物及分子靶向药物等综合治疗,该患者随访至今,生存时间已超过33个月.本文结合此病例的治疗过程,对恶性胶质瘤的规范化治疗、复发恶性胶质瘤的挽救治疗以及恶性胶质瘤治疗新方法的探索进行讨论,并分析存在的不足和可以参考的经验.

  17. Patterns of Recurrence Analysis in Newly Diagnosed Glioblastoma Multiforme After Three-Dimensional Conformal Radiation Therapy With Respect to Pre-Radiation Therapy Magnetic Resonance Spectroscopic Findings

    International Nuclear Information System (INIS)

    Purpose: To determine whether the combined magnetic resonance imaging (MRI) and magnetic resonance spectroscopy imaging (MRSI) before radiation therapy (RT) is valuable for RT target definition, and to evaluate the feasibility of replacing the current definition of uniform margins by custom-shaped margins based on the information from MRI and MRSI. Methods and Materials: A total of 23 glioblastoma multiforme (GBM) patients underwent MRI and MRSI within 4 weeks after surgery but before the initiation of RT and at 2-month follow-up intervals thereafter. The MRSI data were quantified on the basis of a Choline-to-NAA Index (CNI) as a measure of spectroscopic abnormality. A combined anatomic and metabolic region of interest (MRI/S) consisting of T2-weighted hyperintensity, contrast enhancement (CE), resection cavity, and CNI2 (CNI ≥ 2) based on the pre-RT imaging was compared to the extent of CNI2 and the RT dose distribution. The spatial relationship of the pre-RT MRI/S and the RT dose volume was compared with the extent of CE at each follow-up. Results: Nine patients showed new or increased CE during follow-up, and 14 patients were either stable or had decreased CE. New or increased areas of CE occurred within CNI2 that was covered by 60 Gy in 6 patients and within the CNI2 that was not entirely covered by 60 Gy in 3 patients. New or increased CE resided within the pre-RT MRI/S lesion in 89% (8/9) of the patients with new or increased CE. Conclusion: These data indicate that the definition of RT target volumes according to the combined morphologic and metabolic abnormality may be sufficient for RT targeting

  18. SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells

    Science.gov (United States)

    Talarico, Cristina; Dattilo, Vincenzo; D'Antona, Lucia; Barone, Agnese; Amodio, Nicola; Belviso, Stefania; Musumeci, Francesca; Abbruzzese, Claudia; Bianco, Cataldo; Trapasso, Francesco; Schenone, Silvia; Alcaro, Stefano; Ortuso, Francesco; Florio, Tullio; Paggi, Marco G.; Perrotti, Nicola; Amato, Rosario

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive CNS tumor and is characterized by a very high frequency of clinical relapse after therapy and thus by a dismal prognosis, which strongly compromises patients survival. We have recently identified the small molecule SI113, as a potent and selective inhibitor of SGK1, a serine/threonine protein kinase, that modulates several oncogenic signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation and perturbs cell cycle progression by modulating SGK1-related substrates. SI113 is also able to strongly and consistently block, in vitro and in vivo, growth and survival of human hepatocellular-carcinomas, either used as a single agent or in combination with ionizing radiations. In the present paper we aim to study the effect of SI113 on human GBM cell lines with variable p53 expression. Cell viability, cell death, caspase activation and cell cycle progression were then analyzed by FACS and WB-based assays, after exposure to SI113, with or without oxidative stress and ionizing radiations. Moreover, autophagy and related reticulum stress response were evaluated. We show here, that i) SGK1 is over-expressed in highly malignant gliomas and that the treatment with SI113 leads to ii) significant increase in caspase-mediated apoptotic cell death in GBM cell lines but not in normal fibroblasts; iii)enhancement of the effects of ionizing radiations; iv) modulation of the response to oxidative reticulum stress; v) induction of cytotoxic autophagy. Evidence reported here underlines the therapeutic potential of SI113 in GBM, suggesting a new therapeutic strategy either alone or in combination with radiotherapy. PMID:26908461

  19. The effect of combining recombinant human tumor necrosis factor-alpha with local radiation on tumor control probability of a human glioblastoma multiforme xenograft in nude mice

    International Nuclear Information System (INIS)

    Purpose: To evaluate the antitumor activity of recombinant human tumor necrosis factor-alpha (rHuTNF-α) on a human glioblastoma multiforme (U87) xenograft in nude mice, and to study the effect of combining rHuTNF-α with local radiation on the tumor control probability of this tumor model. Methods and Materials: U87 xenograft was transplanted SC into the right hindleg of NCr/Sed nude mice (7-8 weeks old, male). When tumors reached a volume of about 110 mm3, mice were randomly assigned to treatment: rHuTNF-α alone compared with normal saline control; or local radiation plus rHuTNF-α vs. local radiation plus normal saline. Parameters of growth delay, volume doubling time, percentage of necrosis, and cell loss factor were used to assess the antitumor effects of rHuTNF-α on this tumor. The TCD50 (tumor control dose 50%) was used as an endpoint to determine the effect of combining rHuTNF-α with local radiation. Results: Tumor growth in mice treated with a dose of 150 μg/kg body weight rHuTNF-α, IP injection daily for 7 consecutive days, was delayed about 8 days compared to that in controls. Tumors in the treatment group had a significantly longer volume doubling time, and were smaller in volume and more necrotic than matched tumors in control group. rHuTNF-α also induced a 2.3 times increase of cell loss factor. The administration of the above-mentioned dose of rHuTNF-α starting 24 h after single doses of localized irradiation under hypoxic condition, resulted in a significant reduction in TCD50 from the control value of 60.9 Gy to 50.5 Gy (p 50 value in the treatment vs. the control groups

  20. Development and in vitro testing of liposomal gadolinium-formulations for neutron capture therapy of glioblastoma multiforme

    International Nuclear Information System (INIS)

    For the improvement of current neutron capture therapy, several liposomal formulations of neutron capture agent gadolinium were developed and tested in a glioma cell model. Formulations were analyzed regarding physicochemical and biological parameters, such as size, zeta potential, uptake into cancer cells and performance under neutron irradiation. The neutron and photon dose derived from intracellular as well as extracellular Gd was calculated via Monte Carlo simulations and set in correlation with the reduction of cell survival after irradiation. To investigate the suitability of Gd as a radiosensitizer for photon radiation, cells were also irradiated with synchrotron radiation in addition to clinically used photons generated by linear accelerator. Irradiation with neutrons led to significantly lower survival for Gd-liposome-treated F98 and LN229 cells, compared to irradiated control cells and cells treated with non-liposomal Gd-DTPA. Correlation between Gd-content and -dose and respective cell survival displayed proportional relationship for most of the applied formulations. Photon irradiation experiments showed the proof-of-principle for the radiosensitizer approach, although the photon spectra currently used have to be optimized for higher efficiency of the radiosensitizer. In conclusion, the newly developed Gd-liposomes show great potential for the improvement of radiation treatment options for highly malignant glioblastoma.

  1. Enhancing tumor apparent diffusion coefficient histogram skewness stratifies the postoperative survival in recurrent glioblastoma multiforme patients undergoing salvage surgery.

    Science.gov (United States)

    Zolal, Amir; Juratli, Tareq A; Linn, Jennifer; Podlesek, Dino; Sitoci Ficici, Kerim Hakan; Kitzler, Hagen H; Schackert, Gabriele; Sobottka, Stephan B; Rieger, Bernhard; Krex, Dietmar

    2016-05-01

    Objective To determine the value of apparent diffusion coefficient (ADC) histogram parameters for the prediction of individual survival in patients undergoing surgery for recurrent glioblastoma (GBM) in a retrospective cohort study. Methods Thirty-one patients who underwent surgery for first recurrence of a known GBM between 2008 and 2012 were included. The following parameters were collected: age, sex, enhancing tumor size, mean ADC, median ADC, ADC skewness, ADC kurtosis and fifth percentile of the ADC histogram, initial progression free survival (PFS), extent of second resection and further adjuvant treatment. The association of these parameters with survival and PFS after second surgery was analyzed using log-rank test and Cox regression. Results Using log-rank test, ADC histogram skewness of the enhancing tumor was significantly associated with both survival (p = 0.001) and PFS after second surgery (p = 0.005). Further parameters associated with prolonged survival after second surgery were: gross total resection at second surgery (p = 0.026), tumor size (0.040) and third surgery (p = 0.003). In the multivariate Cox analysis, ADC histogram skewness was shown to be an independent prognostic factor for survival after second surgery. Conclusion ADC histogram skewness of the enhancing lesion, enhancing lesion size, third surgery, as well as gross total resection have been shown to be associated with survival following the second surgery. ADC histogram skewness was an independent prognostic factor for survival in the multivariate analysis. PMID:26830088

  2. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy†

    Science.gov (United States)

    Raizer, Jeffrey J.; Abrey, Lauren E.; Lassman, Andrew B.; Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Yung, W.K. Alfred; Gilbert, Mark R.; Aldape, Kenneth A.; Wen, Patrick Y.; Fine, Howard A.; Mehta, Minesh; DeAngelis, Lisa M.; Lieberman, Frank; Cloughesy, Timothy F.; Robins, H. Ian; Dancey, Janet; Prados, Michael D.

    2010-01-01

    Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was not allowed. Patients received 150 mg/day erlotinib. Patients requiring surgery were treated 7 days prior to tumor removal for PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) and intracellular signaling pathways. Ninety-six patients were evaluable (53 recurrent MG and 43 NP GBM); 5 patients were not evaluable for response. PFS-6 in recurrent GBM was 3% with a median PFS of 2 months; PFS-6 in recurrent AG was 27% with a median PFS of 2 months. Twelve-month survival was 57% in NP GBMs post-RT. Primary toxicity was dermatologic. The tissue-to-plasma ratio normalized to nanograms per gram dry weight for erlotinib and OSI-420 ranged from 25% to 44% and 30% to 59%, respectively, for pretreated surgical patients. No effect on EGFR or intratumoral signaling was seen. Patients with NP GBM post-RT who developed rash in cycle 1 had improved survival (P < .001). Single-agent activity of erlotinib is minimal for recurrent MGs and marginally beneficial following RT for NP GBM patients. Development of rash in cycle 1 correlates with survival in patients with NP GBM after RT. PMID:20150372

  3. Volumetry of [{sup 11}C]-methionine PET uptake and MRI contrast enhancement in patients with recurrent glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Galldiks, Norbert; Schroeter, Michael; Fink, Gereon R. [University Hospital of Cologne, Department of Neurology, Cologne (Germany); Ullrich, Roland; Kracht, Lutz W. [Max Planck-Institute for Neurological Research, Cologne (Germany)

    2010-01-15

    We investigated the relationship between three-dimensional volumetric data of the metabolically active tumour volume assessed using [{sup 11}C]-methionine positron emission tomography (MET-PET) and the area of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) enhancement assessed using magnetic resonance imaging (MRI) in patients with recurrent glioblastoma (GBM). MET-PET and contrast-enhanced MRI with Gd-DTPA were performed in 12 uniformly pretreated patients with recurrent GBM. To calculate the volumes in cubic centimetres, a threshold-based volume-of-interest (VOI) analysis of the metabolically active tumour volume (MET uptake indexes of {>=}1.3 and {>=}1.5) and of the area of Gd-DTPA enhancement was performed after coregistration of all images. In all patients, the metabolically active tumour volume as shown using a MET uptake index of {>=}1.3 was larger than the volume of Gd-DTPA enhancement (30.2 {+-} 22.4 vs. 13.7 {+-} 10.6 cm{sup 3}; p = 0.04). Metabolically active tumour volumes as shown using MET uptake indexes of {>=}1.3 and {>=}1.5 and the volumes of Gd-DTPA enhancement showed a positive correlation (r = 0.76, p = 0.003, for an index of {>=}1.3, and r = 0.74, p = 0.005, for an index of {>=}1.5). The present data suggest that in patients with recurrent GBM the metabolically active tumour volume may be substantially underestimated by Gd-DTPA enhancement. The findings support the notion that complementary information derived from MET uptake and Gd-DTPA enhancement may be helpful in developing individualized, patient-tailored therapy strategies in patients with recurrent GBM. (orig.)

  4. The autotaxin-lysophosphatidic acid-lysophosphatidic acid receptor cascade: proposal of a novel potential therapeutic target for treating glioblastoma multiforme.

    Science.gov (United States)

    Tabuchi, Sadaharu

    2015-01-01

    Glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Its prognosis is one of the worst among all cancer types, and it is considered a fatal malignancy, incurable with conventional therapeutic strategies. As the bioactive multifunctional lipid mediator lysophosphatidic acid (LPA) is well recognized to be involved in the tumorigenesis of cancers by acting on G-protein-coupled receptors, LPA receptor (LPAR) antagonists and LPA synthesis inhibitors have been proposed as promising drugs for cancer treatment. Six LPARs, named LPA1-6, are currently recognized. Among them, LPA1 is the dominant LPAR in the CNS and is highly expressed in GBM in combination with the overexpression of autotaxin (ATX), the enzyme (a phosphodiesterase, which is a potent cell motility-stimulating factor) that produces LPA.Invasion is a defining hallmark of GBM. LPA is significantly related to cell adhesion, cell motility, and invasion through the Rho family GTPases Rho and Rac. LPA1 is responsible for LPA-driven cell motility, which is attenuated by LPA4. GBM is among the most vascular human tumors. Although anti-angiogenic therapy (through the inhibition of vascular endothelial growth factor (VEGF)) was established, sufficient results have not been obtained because of the increased invasiveness triggered by anti-angiogenesis. As both ATX and LPA play a significant role in angiogenesis, similar to VEGF, inhibition of the ATX/LPA axis may be beneficial as a two-pronged therapy that includes anti-angiogenic and anti-invasion therapy. Conventional approaches to GBM are predominantly directed at cell proliferation. Recurrent tumors regrow from cells that have invaded brain tissues and are less proliferative, and are thus quite resistant to conventional drugs and radiation, which preferentially kill rapidly proliferating cells. A novel approach that targets this invasive subpopulation of GBM cells may improve the prognosis of GBM. Patients with GBM that

  5. MiR-196a exerts its oncogenic effect in glioblastoma multiforme by inhibition of IκBα both in vitro and in vivo

    KAUST Repository

    Yang, Guang

    2014-01-23

    BackgroundRecent studies have revealed that miR-196a is upregulated in glioblastoma multiforme (GBM) and that it correlates with the clinical outcome of patients with GBM. However, its potential regulatory mechanisms in GBM have never been reported.MethodsWe used quantitative real-time PCR to assess miR-196a expression levels in 132 GBM specimens in a single institution. Oncogenic capability of miR-196a was detected by apoptosis and proliferation assays in U87MG and T98G cells. Immunohistochemistry was used to determine the expression of IκBα in GBM tissues, and a luciferase reporter assay was carried out to confirm whether IκBα is a direct target of miR-196a. In vivo, xenograft tumors were examined for an antiglioma effect of miR-196a inhibitors.ResultsWe present for the first time evidence that miR-196a could directly interact with IκBα 3′-UTR to suppress IκBα expression and subsequently promote activation of NF-κB, consequently promoting proliferation of and suppressing apoptosis in GBM cells both in vitro and in vivo. Our study confirmed that miR-196a was upregulated in GBM specimens and that high levels of miR-196a were significantly correlated with poor outcome in a large cohort of GBM patients. Our data from human tumor xenografts in nude mice treated with miR-196 inhibitors demonstrated that inhibition of miR-196a could ameliorate tumor growth in vivo.ConclusionsMiR-196a exerts its oncogenic effect in GBM by inhibiting IκBα both in vitro and in vivo. Our findings provide new insights into the pathogenesis of GBM and indicate that miR-196a may predict clinical outcome of GBM patients and serve as a new therapeutic target for GBM. © 2014 © 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.

  6. The Role of a Single Angiogenesis Inhibitor in the Treatment of Recurrent Glioblastoma Multiforme: A Meta-Analysis and Systematic Review.

    Directory of Open Access Journals (Sweden)

    Yawei Wang

    Full Text Available Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients.Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library. Demographic data, treatment regimens, objective response rate (ORR, median progression-free survival (PFS, median overall survival (OS, 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0.A total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR 2.93, 95% CI 1.38-6.21; p = 0.025; and RR 2.36 95% CI 1.46-3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07. when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64-17.6, p<0.001, but not for 6-months PFS (p = 0.07 and 1-year OS (p = 0.31. As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence of 12.1%, while high

  7. Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513

    Energy Technology Data Exchange (ETDEWEB)

    Brachman, David G., E-mail: david.brachman@dignityhealth.org [Arizona Oncology Services Foundation, Scottsdale, Arizona (United States); Barrow Neurological Institute, St. Joseph' s Hospital and Medical Center, Phoenix, Arizona (United States); Pugh, Stephanie L. [Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States); Ashby, Lynn S. [Barrow Neurological Institute, St. Joseph' s Hospital and Medical Center, Phoenix, Arizona (United States); Thomas, Theresa A. [Arizona Oncology Services Foundation, Scottsdale, Arizona (United States); Dunbar, Erin M. [University of Florida College of Medicine, Gainesville, Florida (United States); Narayan, Samir [St. Joseph Mercy Hospital, Ann Arbor, Michigan (United States); Robins, H. Ian [University of Wisconsin Hospital, Madison, Wisconsin (United States); Bovi, Joseph A. [Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Rockhill, Jason K. [University of Washington Medical Center, Seattle, Washington (United States); Won, Minhee [Barrow Neurological Institute, St. Joseph' s Hospital and Medical Center, Phoenix, Arizona (United States); Curran, Walter P. [Emory University, Atlanta, Georgia (United States)

    2015-04-01

    Purpose: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. Methods and Materials: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. Results: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. Conclusions: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

  8. Urticaria Multiforme

    OpenAIRE

    Emer, Jason J.; Bernardo, Sebastian G.; Kovalerchik, Olga; Ahmad, Moneeb

    2013-01-01

    Urticaria multiforme is a benign cutaneous hypersensitivity reaction seen in pediatric patients that is characterized by the acute and transient onset of blanchable, annular, polycyclic, erythematous wheals with dusky, ecchymotic centers in association with acral edema. It is most commonly misdiagnosed as erythema multiforme, a serum-sickness-like reaction, or urticarial vasculitis. Since these three diagnoses represent distinct clinical entities with unique prognoses and management strategie...

  9. Dioscin, a natural steroid saponin, induces apoptosis and DNA damage through reactive oxygen species: a potential new drug for treatment of glioblastoma multiforme.

    Science.gov (United States)

    Lv, Linlin; Zheng, Lingli; Dong, Deshi; Xu, Lina; Yin, Lianhong; Xu, Youwei; Qi, Yan; Han, Xu; Peng, Jinyong

    2013-09-01

    Dioscin, a natural product obtained from medicinal plants shows lipid-lowering, anti-cancer and hepatoprotective effects. However, the effect of it on glioblastoma is unclear. In this study, dioscin significantly inhibited proliferation of C6 glioma cells and caused reactive oxygen species (ROS) generation and Ca²⁺ release. ROS accumulation affected levels of malondialdehyde, nitric oxide, glutathione disulfide and glutathione, and caused cell apoptosis. In addition, ROS generation caused mitochondrial damage including structural changes, increased mitochondrial permeability transition and decreased mitochondria membrane potential, which led to the release of cytochrome C, nuclear translation of programmed cell death-5 and increased activities of caspase-3,9. Simultaneously, dioscin down-regulated protein expression of Bcl-2, Bcl-xl, up-regulated expression of Bak, Bax, Bid and cleaved poly (ADP-ribose) polymerase. Also, oxygen stress induced S-phase arrest of cancer cells by way of regulating expression of DNA Topo I, p53, CDK2 and Cyclin A and caused DNA damage. In a rat allograft model, dioscin significantly inhibited tumor size and extended the life cycle of the rats. In conclusion, dioscin shows noteworthy anti-cancer activity on glioblastoma cells by promoting ROS accumulation, inducing DNA damage and activating mitochondrial signal pathways. Ultimately, we believe dioscin has promise as a new therapy for the treatment of glioblastoma. PMID:23871826

  10. 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

  11. 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

  12. Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme: an observational study of a cohort of consecutive non-selected patients from a single institution

    International Nuclear Information System (INIS)

    Although implementation of temozolomide (TMZ) as a part of primary therapy for glioblastoma multiforme (GBM) has resulted in improved patient survival, the disease is still incurable. Previous studies have correlated various parameters to survival, although no single parameter has yet been identified. More studies and new approaches to identify the best and worst performing patients are therefore in great demand. This study examined 225 consecutive, non-selected GBM patients with performance status (PS) 0–2 receiving postoperative radiotherapy with concomitant and adjuvant TMZ as primary therapy. At relapse, patients with PS 0–2 were mostly treated by reoperation and/or combination with bevacizumab/irinotecan (BEV/IRI), while a few received TMZ therapy if the recurrence-free period was >6 months. Median overall survival and time to progression were 14.3 and 8.0 months, respectively. Second-line therapy indicated that reoperation and/or BEV/IRI increased patient survival compared with untreated patients and that BEV/IRI was more effective than reoperation alone. Patient age, ECOG PS, and use of corticosteroid therapy were significantly correlated with patient survival and disease progression on univariate analysis, whereas p53, epidermal growth factor receptor, and O6-methylguanine-DNA methyltransferase expression (all detected by immunohistochemistry), tumor size or multifocality, and extent of primary operation were not. A model based on age, ECOG PS, and corticosteroids use was able to predict survival probability for an individual patient. The survival of RT/TMZ-treated GBM patients can be predicted based on patient age, ECOG PS, and corticosteroid therapy status

  13. 胶质母细胞瘤放射治疗靶区设计现状与思考%Target volume delineation for glioblastoma multiforme: current practice and advice

    Institute of Scientific and Technical Information of China (English)

    李明焕; 孔莉; 于金明

    2013-01-01

    胶质母细胞瘤(GBM)术后放疗大都采用MRI与CT融合影像来勾画靶区,但是否包含瘤周水肿区尚有争议.根据术后、放疗后的复发范围,不论靶区设计是否包含水肿区,大部分复发都发生在磁共振(MRI)显示增强原发肿瘤灶外2 cm之内,瘤周水肿程度与复发模式无必然关系.GBM的临床和病理特征对放化疗疗效预测和预后也有重要指导意义.GBM的靶区设计趋向于个体化,可在保证疗效的同时减少治疗毒性.%The use of adjuvant extemal-beam RT is well established in the postoperative treatment of glioblastoma multiforme (CBM).It is consensus that target volume should be determined based on the fusion images of MRI and CT,but the inclusion of peritumoural edematous is controversial.The vast majority of recurrences occur within 2 cm of the original tumor site or " in radiation field".There is no inevitable relation between the degree of peritumoral edema and recurrence model.The clinical and pathological characteristics may be as predictive and prognostic factors for the treatment of GBM.Target volume delineation for CBM tend to individual,which can maintain known outcomes and reduce treatment toxicity.

  14. Diagnostic examination performance by using microvascular leakage, cerebral blood volume, and blood flow derived from 3-T dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging in the differentiation of glioblastoma multiforme and brain metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Server, Andres; Nakstad, Per H. [Oslo University Hospital-Ullevaal, Section of Neuroradiology, Department of Radiology and Nuclear Medicine, Oslo (Norway); University of Oslo, Oslo (Norway); Orheim, Tone E.D. [Oslo University Hospital, Interventional Centre, Oslo (Norway); Graff, Bjoern A. [Oslo University Hospital-Ullevaal, Department of Radiology and Nuclear Medicine, Oslo (Norway); Josefsen, Roger [Oslo University Hospital-Ullevaal, Department of Neurosurgery, Oslo (Norway); Kumar, Theresa [Oslo University Hospital-Ullevaal, Department of Pathology, Oslo (Norway)

    2011-05-15

    Conventional magnetic resonance (MR) imaging has limited capacity to differentiate between glioblastoma multiforme (GBM) and metastasis. The purposes of this study were: (1) to compare microvascular leakage (MVL), cerebral blood volume (CBV), and blood flow (CBF) in the distinction of metastasis from GBM using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging (DSC-MRI), and (2) to estimate the diagnostic accuracy of perfusion and permeability MR imaging. A prospective study of 61 patients (40 GBMs and 21 metastases) was performed at 3 T using DSC-MRI. Normalized rCBV and rCBF from tumoral (rCBVt, rCBFt), peri-enhancing region (rCBVe, rCBFe), and by dividing the value in the tumor by the value in the peri-enhancing region (rCBVt/e, rCBFt/e), as well as MVL were calculated. Hemodynamic and histopathologic variables were analyzed statistically and Spearman/Pearson correlations. Receiver operating characteristic curve analysis was performed for each of the variables. The rCBVe, rCBFe, and MVL were significantly greater in GBMs compared with those of metastases. The optimal cutoff value for differentiating GBM from metastasis was 0.80 which implies a sensitivity of 95%, a specificity of 92%, a positive predictive value of 86%, and a negative predictive value of 97% for rCBVe ratio. We found a modest correlation between rCBVt and rCBFt ratios. MVL measurements in GBMs are significantly higher than those in metastases. Statistically, both rCBVe, rCBVt/e and rCBFe, rCBFt/e were useful in differentiating between GBMs and metastases, supporting the hypothesis that perfusion MR imaging can detect infiltration of tumor cells in the peri-enhancing region. (orig.)

  15. Simultaneous integrated boost by RapidArc therapy plus temozolomide for treatment of patients with glioblastoma multiform: A single institution experience

    Directory of Open Access Journals (Sweden)

    Mohamed Daoud

    2015-09-01

    Full Text Available Purpose: The aim of this study is to report the treatment outcomes, toxicities, and dosimetric feasibility of simultaneous integrated boost by RapidArc (RA-SIB compared with 3dimentional-conformal radiation therapy (3D-CRT for patients with glioblastoma. Methods: Eleven patients with unifocal glioblastoma (grade IV astrocytoma, WHO classification were treated during the period from April 2011 until February 2013 with postoperative irradiation and concomitant temozolomide 75 mg/m2 followed by 6-12 months of adjuvant temozolomide 200 mg/m2 for 5 days/4weeks. One patient received temozolomide for 12 months, 5patients for 6 months, and 5patients did not receive adjuvant temozolomide. RA-SIB technique was used and patients received 46 Gy per fraction of 2 Gy in 23 sessions on the planning target volume (PTV1 (contrast enhancement + per-focal edema as seen in T2 MR + 2.3 cm with concomitant daily superimposed boost (SIB on PTV2 corresponding to the contrast enhancement + 2.3 cm. The treatment outcomes and toxicity were assessed. Dose Volume Histogram DVH analysis was performed between SIB-RA and 3D-CRT plans of each patient. For the PTV, the comparison parameters included, the mean dose, the standard deviation, maximum dose, conformity index (CI, and homogeneity index (HI. Results: The median progression free survival (PFS and overall survival (OS were 13 months (95% CI, 8.2-17.8, and 16 months (95% CI, 2.1-29.9 respectively. Four of six patients (67% showed local progression (recurrence after initial response, all recurrences occurred at the site of PTV2. Seven patients experienced acute grade 1-2 toxicities during the treatment. Late post radiation brain edema was reported in 3 patients. Conclusion: The SIB-RA did not prove the superiority in survival outcomes compared with the historical data using 3D-CRT. From the dosimetric standpoint, SIB-RA is a superior technique with respect to 3D-CRT when there are overlaps between organs at risk (OARs and

  16. Recurrent Glioblastoma: Where we stand

    OpenAIRE

    Sanjoy Roy; Debarshi Lahiri; Tapas Maji; Jaydip Biswas

    2015-01-01

    Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM) treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment w...

  17. 复发前后多形性胶质母细胞瘤的等位基因谱分析%An allelotype study of primary and corresponding recurrent glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    胡杰; 江澄川; 吴浩强; 彭颂先; 唐婉君; 陈商群

    2003-01-01

    目的研究多形性胶质母细胞瘤(glioblastoma multiforme, GBM)复发前后的分子遗传学变化,了解基因组范围内哪些染色体区域可能与GBM复发有关. 方法应用聚合酶链反应技术为基础的杂合性丢失(loss of heterozygosity, LOH)分析法,采用荧光标记的引物和377型DNA序列自动分析仪,检测了1例复发前后GBM所有22对常染色体上多达382个微卫星位点.相邻2个微卫星位点之间的平均距离为10 cM. 结果对原发肿瘤标本的等位基因谱分析显示,染色体9p21上D9S157位点和10q21.3-26.3上D10S537、D10S185、D10S192、D10S597、D10S587、D10S217位点存在LOH.对复发肿瘤标本的研究显示,不但9p21和10q21.3-26.3上LOH的范围扩大,而且在其它多条染色体上也出现了LOH(包括1q、7p、7q、21q、20p、20q、10p、19p、19q).结论染色体9p和10q可能在该例GBM的发生中起着重要作用.尽管该病例复发前后的病理诊断相同,复发后GBM存在着更广泛的分子遗传学异常改变,可能伴随着更多肿瘤抑制基因的失活.

  18. Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

    Directory of Open Access Journals (Sweden)

    Geletneky Karsten

    2012-03-01

    Full Text Available Abstract Background The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM, the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01. ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. Methods ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD. Secondary objectives are proof of concept (PoC and Progression-free Survival (PFS up to 6 months. Discussion This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment

  19. Treatment of brain glioblastoma multiforme with pcDNA3.1-Egr. 1p-p16 combined with gamma knife radiation: An experimental study on nude mice

    Directory of Open Access Journals (Sweden)

    Liu Wenke

    2013-01-01

    Full Text Available Background: High post-operative recurrence and poor prognosis are likely to be related to the infiltrative growth of the glioblastoma multiforme (GBM. Objectives: The primary objective of this study is to investigate the possible synergistic effect of the combined treatment of gamma knife radio-surgery (GKRS and gene therapy for GBM and secondary objective is to explore the role of GKRS for the temporal and spatial regulation of the gene expression. Materials and Methods: The study performed on 70 nude mice and randomly divided into seven groups. Subcutaneous injection of human GBM tumor cells (T98G was carried out to establish the animal models. Various doses of liposome-mediated pcDNA3.1-Egr. 1p-p16 recombinant plasmid were transfected through intra-tumor injection. GKRS was scheduled following the plasmid transfection. Tumor volumes were measured every 4 days after the treatment. Subcutaneous tumor nodule specimens were collected to analyze the cell apoptosis and p16 gene expression using terminal-deoxynucleoitidyl transferase mediated nick end labeling staining and reverse transcription-polymerase chain reaction. Tumor volumes, levels of cell apoptosis and p16 gene expression were compared between groups. Results: Rates of tumor growth were significantly lower in the pcDNA3.1-Egr. 1p-p16 plasmid + GKRS groups than that in the remaining groups 28 days following the GKRS management. The p16mRNA expression was noted in both of the pcDNA3.1-Egr. 1p-p16 plasmid group and the pcDNA3.1-Egr. 1p-p16 plasmid + GKRS with marginal-dose of 20 Gy group. The level of messenger ribonucleic acid expression was higher in the pcDNA3.1-Egr. 1p-p16 plasmid + GKRS with the marginal-dose of 20 Gy group, with a markedly increased apoptotic and necrotic cells, than that in the pcDNA3.1-Egr. 1p-p16 plasmid group. Conclusions: In animal studies, pcDNA3.1-Egr. 1p-p16 in combination with GKRS is a preferable management option for the GBM to the sole use of GKRS or gene

  20. Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

    International Nuclear Information System (INIS)

    The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application

  1. Statin use and survival following glioblastoma multiforme

    DEFF Research Database (Denmark)

    Gaist, David; Hallas, Jesper; Friis, Søren;

    2014-01-01

    AIM: While some studies indicate a potential chemopreventive effect of statin use on the risk of glioma, the effect of statins on the prognosis of brain tumours has not yet been examined. We thus conducted a cohort study evaluating the influence of statin use on survival in patients with glioblas......AIM: While some studies indicate a potential chemopreventive effect of statin use on the risk of glioma, the effect of statins on the prognosis of brain tumours has not yet been examined. We thus conducted a cohort study evaluating the influence of statin use on survival in patients...... redeemed prescriptions) was matched to two statin non-users (models were used to compute hazard ratios (HRs) and 95% confidence intervals (CI) for all......: 0.63-1.01). CONCLUSION: Long-term prediagnostic statin use may improve survival following GBM....

  2. Transcription analysis of TIMP-1 and NM23-h1 genes in glioma cell invasion Análise transcricional dos genes TIMP-1 e NM23-H1 na invasão celular em astrocitoma difuso e glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    José Augusto Nasser

    2006-09-01

    Full Text Available PURPOSE: To evaluate using transcription analysis the presence and importance of two genes: NM23-H1 and TIMP-1 on control of tumor cell invasion in diffuse astrocytomas (WHO II and glioblastoma multiforme (WHO IV. METHOD: Northern blot analysis of NM23-H1 and TIMP-1 was performed. Eight diffuse astrocytomas and 19 glioblastomas (WHO IV were analyzed to determine if TIMP-1 and NM23-H1 were candidates to inhibition of tumor cell invasion quantitated RNA levels. The samples were collected directly from operating room. Total cellular RNA was extracted from frozen tissue samples using guanidinium-isothiocyanate and cesium chloride gradients. Total RNA (10 mg per sample from tumor tissue were size fractionated through 1% agarose-formaldehyde gel and transferred to nylon filters and then hybridized to 32P-labeled DNA probes and placed for autoradiography. Levels of specific RNAs were determined by computer-assisted laser densitometry. Blot filters were sequentially hybridized to nm23 and TIMP-1 probes in addition to GAPDH, as a control. Statistical analyses were carried out according to t-test for equality of means. RESULTS: NM23-H1 were detected in each sample, however it did not correlate with malignancy and invasiveness. On the other side TIMP-1 gene expression showed a clear correlation between low expression and invasiveness. CONCLUSION: The data suggest that TIMP-1 is an inhibitor of high grade gliomas invasion. NM23-H1 was present in the entire gliomas sample, but it did not vary in diffuse astrocytomas and glioblastomas.OBJETIVO: Comparar através da análise da expressão dos níveis de RNA, a presença e a relevância dos genes NM23-H1 e TIMP-1 no controle da invasão celular tumoral dentro do tecido cerebral normal em: astrocitoma difuso (OMS II e glioblastoma multiforme (OMS:IV. MÉTODO: Análise em "Northern blot" dos genes NM23-H1 e TIMP-1. Oito astrocitomas fibrilares difusos (OMS II e 19 glioblastomas multiformes foram analisados para

  3. Associations between polymorphisms in DNA repair genes and glioblastoma.

    Science.gov (United States)

    McKean-Cowdin, Roberta; Barnholtz-Sloan, Jill; Inskip, Peter D; Ruder, Avima M; Butler, Maryann; Rajaraman, Preetha; Razavi, Pedram; Patoka, Joe; Wiencke, John K; Bondy, Melissa L; Wrensch, Margaret

    2009-04-01

    A pooled analysis was conducted to examine the association between select variants in DNA repair genes and glioblastoma multiforme, the most common and deadliest form of adult brain tumors. Genetic data for approximately 1,000 glioblastoma multiforme cases and 2,000 controls were combined from four centers in the United States that have conducted case-control studies on adult glioblastoma multiforme, including the National Cancer Institute, the National Institute for Occupational Safety and Health, the University of Texas M. D. Anderson Cancer Center, and the University of California at San Francisco. Twelve DNA repair single-nucleotide polymorphisms were selected for investigation in the pilot collaborative project. The C allele of the PARP1 rs1136410 variant was associated with a 20% reduction in risk for glioblastoma multiforme (odds ratio(CT or CC), 0.80; 95% confidence interval, 0.67-0.95). A 44% increase in risk for glioblastoma multiforme was found for individuals homozygous for the G allele of the PRKDC rs7003908 variant (odds ratio(GG), 1.44; 95% confidence interval, 1.13-1.84); there was a statistically significant trend (P = 0.009) with increasing number of G alleles. A significant, protective effect was found when three single-nucleotide polymorphisms (ERCC2 rs13181, ERCC1 rs3212986, and GLTSCR1 rs1035938) located near each other on chromosome 19 were modeled as a haplotype. The most common haplotype (AGC) was associated with a 23% reduction in risk (P = 0.03) compared with all other haplotypes combined. Few studies have reported on the associations between variants in DNA repair genes and brain tumors, and few specifically have examined their impact on glioblastoma multiforme. Our results suggest that common variation in DNA repair genes may be associated with risk for glioblastoma multiforme. PMID:19318434

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

    OpenAIRE

    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 ...

  5. Establishment of human glioblastoma multiform multidrug resistant cell line in vitro and identification of its biological characteristics%人脑胶质瘤多药耐药细胞株的构建及生物学特性鉴定

    Institute of Scientific and Technical Information of China (English)

    白义凤; 廖红展; 刘天助; 郭洪波

    2011-01-01

    Objective To establish the imatinib (STI-571)-resistant subline in vitro and investigate its biological characteristics. Methods Human glioblastoma multiform drug-resistant cell line (named U251AR) was established in vitro by successively increasing the concentration of imatinib in a cell culture medium. The 50% inhibitory dose (IC50) values and the resistance indexes ([IC50U251/STI-571]/[IC50 U251]) for other chemotherapeutic agents were evaluated using cell counting kit-8 assays. Expressions of acquired multidrug resistance P-glycoprotein (MDR 1, ABCB 1; MDR3, ABCB4),breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance-associated protein 1 (MRP1,ABCC1) were detected by QRT-PCR. Flow cytometry was employed to detect the protein expression of ABCG2. Results The U251AR was developed after culture for 12 months and similar morphologies of U251 and U251/STI-571 cells were determined. The resistance coefficient of U251AR cells to imatinib was 20.41 times more than that of the parent cells, and U251AR cells showed cross-resistance to many anti-tumor agents (P<0.05). The resistance coefficients of U251AR cell line to doxorubicin and cisplatin were 5.06 and 10.28 times, respectively, more than those of U251 cells (P<0.05). QRT-PCR indicated that the mRNA levels of MDR1, MRP1, BCRPandABCB4 (P-g4) in the U251/STI571 resistant cells were significantly higher than those in the U251 cells (P<0.05). The protein expression of ABCG2 in U251AR cell line was significantly increased as compared with that in the parent cells (P<0.05).Conclusion We have successfully established multidrug resistant cell line U251AR, and the drug resistance of U251/STI571 is associated with over-expressions of ABCC1, ABCB1, ABCB4, and ABCG2 mRNA, and ABCG2 protein.%目的 体外构建胶质瘤耐甲磺酸伊玛替尼多药耐药细胞株,并研究其生物学特性。方法采用逐渐增加培养基中伊玛替尼药物浓度的方法诱导构建耐甲磺酸

  6. 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...

  7. An update on the epigenetics of glioblastomas.

    Science.gov (United States)

    Ferreira, Wallax Augusto Silva; Pinheiro, Danilo do Rosário; Costa Junior, Carlos Antonio da; Rodrigues-Antunes, Symara; Araújo, Mariana Diniz; Leão Barros, Mariceli Baia; Teixeira, Adriana Corrêa de Souza; Faro, Thamirys Aline Silva; Burbano, Rommel Rodriguez; Oliveira, Edivaldo Herculano Correa de; Harada, Maria Lúcia; Borges, Bárbara do Nascimento

    2016-09-01

    Glioblastomas, also known as glioblastoma multiforme (GBM), are the most aggressive and malignant type of primary brain tumor in adults, exhibiting notable variability at the histopathological, genetic and epigenetic levels. Recently, epigenetic alterations have emerged as a common hallmark of many tumors, including GBM. Considering that a deeper understanding of the epigenetic modifications that occur in GBM may increase the knowledge regarding the tumorigenesis, progression and recurrence of this disease, in this review we discuss the recent major advances in GBM epigenetics research involving histone modification, glioblastoma stem cells, DNA methylation, noncoding RNAs expression, including their main alterations and the use of epigenetic therapy as a valid option for GBM treatment. PMID:27585647

  8. Phase II clinical study of boron neutron capture therapy combined with X-ray radiotherapy/temozolomide in patients with newly diagnosed glioblastoma multiforme-Study design and current status report

    Energy Technology Data Exchange (ETDEWEB)

    Kawabata, Shinji, E-mail: neu046@poh.osaka-med.ac.jp [Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686 (Japan); Miyatake, Shin-Ichi; Hiramatsu, Ryo; Hirota, Yuki; Miyata, Shiro; Takekita, Yoko; Kuroiwa, Toshihiko [Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686 (Japan); Kirihata, Mitsunori [Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8931 (Japan); Sakurai, Yoshinori; Maruhashi, Akira; Ono, Koji [Kyoto University Research Reactor Institute, 2 Asashiro-Nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan)

    2011-12-15

    Recently, we reported our clinical experiences of boron neutron capture therapy (BNCT) for the newly diagnosed glioblastoma. The major differences of our protocol from the other past studies were simultaneous use of both sodium borocapate and boronophenylalanine, and combination with fractionated X-ray irradiation. These results showed the efficacy of combination therapy with external beam X-ray irradiation and BNCT. For our future study, we planned the multi-centric phase II clinical study for newly diagnosed glioblastoma patients in Japan (OSAKA-TRIBRAIN0902, NCT00974987).

  9. Brainstem disconnection

    OpenAIRE

    Duffield, Curtis; Jocson, Jennifer; Wootton-Gorges, Sandra L.

    2009-01-01

    Brainstem disconnection is a very rare neonatal abnormality, with only seven cases reported. We report a unique case of a neonate who presented at delivery with hypertonia, dysmorphic facial features, and respiratory distress, as well as numerous musculoskeletal and genitourinary abnormalities. MRI of the brain showed disconnection between the pons and medulla with cerebellar hypoplasia and absent cerebellar peduncles. It aided in the description of the neurological and vascular anomalies ass...

  10. Brainstem disconnection

    Energy Technology Data Exchange (ETDEWEB)

    Duffield, Curtis; Wootton-Gorges, Sandra L. [University of California Davis, Medical Center and UC Davis Children' s Hospital, Department of Radiology, Sacramento, CA (United States); Jocson, Jennifer [University of California Davis, Medical Center and UC Davis Children' s Hospital, Department of Pediatrics, Sacramento, CA (United States)

    2009-12-15

    Brainstem disconnection is a very rare neonatal abnormality, with only seven cases reported. We report a unique case of a neonate who presented at delivery with hypertonia, dysmorphic facial features, and respiratory distress, as well as numerous musculoskeletal and genitourinary abnormalities. MRI of the brain showed disconnection between the pons and medulla with cerebellar hypoplasia and absent cerebellar peduncles. It aided in the description of the neurological and vascular anomalies associated with this diagnosis. (orig.)

  11. 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)

    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 cm2; or Arm B, 70.4 Gy, TM ≤ 20 cm2. Both Arms A and B received BCNU (80 mg/m2, 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.

  12. Eritema Multiform Di Rongga Mulut

    OpenAIRE

    Siti Aminah

    2008-01-01

    Eritema multiform adalah suatu penyakit akut yang terdapat pada kulit dan membran mukosa, yang dapat menyebabkan beberapa jenis lesi kulit. Penyebab eritema multiform belum diketahui dengan pasti, banyak para peneliti menganggap bahwa etiologi dari penyakit eritema multiform ini disebabkan oleh beberapa faktor penunjang seperti reaksi alergi dari obatobatan, alergi dari makanan, reaksi terhadap mikro .orqanisme, efek radioterapi, penyakit sistemik, infeksi dan neoplasia. Gambaran klin...

  13. MRI texture features as biomarkers to predict MGMT methylation status in glioblastomas

    OpenAIRE

    Korfiatis, Panagiotis; Kline, Timothy L.; Coufalova, Lucie; Lachance, Daniel H.; Parney, Ian F.; Carter, Rickey E.; Buckner, Jan C.; Erickson, Bradley J

    2016-01-01

    Purpose: Imaging biomarker research focuses on discovering relationships between radiological features and histological findings. In glioblastoma patients, methylation of the O6-methylguanine methyltransferase (MGMT) gene promoter is positively correlated with an increased effectiveness of current standard of care. In this paper, the authors investigate texture features as potential imaging biomarkers for capturing the MGMT methylation status of glioblastoma multiforme (GBM) tumors when combi...

  14. Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression

    OpenAIRE

    Gloria Perazzoli; Jose Prados; Raul Ortiz; Octavio Caba; Laura Cabeza; Maria Berdasco; Beatriz Gónzalez; Consolación Melguizo

    2015-01-01

    Background The use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-gly...

  15. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    OpenAIRE

    Hayley Patricia Ellis; Kathreena Mary Kurian

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common primary intrinsic central nervous system tumor and has an extremely poor overall survival with only 10% patients being alive after 5 years. There has been interesting preliminary evidence suggesting that diabetic patients receiving peroxisome proliferator-activated receptor gamma (PPARγ) agonists, a group of anti-diabetic, thiazolidinedione drugs, have an increased median survival for glioblastoma. Although thiazolidinediones are effective oral...

  16. Identification of ZCCHC8 as fusion partner of ROS1 in a case of congenital glioblastoma multiforme with a t(6;12)(q21;q24.3).

    Science.gov (United States)

    Coccé, Mariela C; Mardin, Balca R; Bens, Susanne; Stütz, Adrian M; Lubieniecki, Fabiana; Vater, Inga; Korbel, Jan O; Siebert, Reiner; Alonso, Cristina N; Gallego, Marta S

    2016-09-01

    Congenital gliobastoma multiforme (GBM) is rare and little is known about the molecular defects underlying the initiation and progression of this tumor type. We present a case of congenital GBM analyzed by conventional cytogenetics, fluorescence in situ hybridization, array comparative genomic hybridization and next generation sequencing. On cytogenetic analysis we detected a reciprocal translocation t(6;12)(q21;q24.3). By sequencing, the translocation was shown to form a fusion between the 5' region of ZCCHC8 and the 3' region of ROS1. RT-PCR analyses confirmed the existence of an in-frame fusion transcript with ZCCHC8 exons 1-3 joined to ROS1 exons 36-43. In addition to the ZCCHC8-ROS1 fusion, we detected a deletion in the short arm of chromosome 9, including homozygous loss of the CDKN2A/2B locus in 9p21.3 and heterozygous deletion of the HAUS6 gene in 9p22.1. The latter encodes a protein involved in faithful chromosome segregation by regulating microtubule nucleation and its deletion might be associated with the marked subclonal changes of ploidy observed in the tumor. This report adds the ZCCHC8-ROS1 fusion as oncogenic driver in GBM and supports the role of ROS1 activation in the pathogenesis of a subset of GBM. © 2016 Wiley Periodicals, Inc. PMID:27121553

  17. P53表达对胶质母细胞瘤替莫唑胺疗效的影响%Impact of P53 smtus to response of temozolomide for multiform glioblastomas

    Institute of Scientific and Technical Information of China (English)

    李守巍; 陈宝师; 崔云; 李桂林; 江涛; 王忠诚

    2008-01-01

    目的 探讨突变型P53表达情况对胶质母细胞瘤替莫唑胺(蒂清胶囊)化疗临床预后的影响.方法 入选经手术、放疗和替莫唑胺联合治疗的伴O6-甲基鸟嘌呤-DNA转移酶(MGMT)低表达的胶质母细胞瘤患者,利用生存分析比较突变型P53高表达组患者与低表达组患者的临床预后是否存在统计学差异.结果 患者性别、年龄、Karnofsky生活状态(KPS)评分及肿瘤切除程度在两组患者问无统计学意义,突变型P53低表达组患者的肿瘤无进展生存时间明显长于高表达组(P<0.05),两组患者的生存时间无统计学意义.结论 P53可能参与多形性胶质母细胞瘤替莫唑胺化疗的耐药机制,是影响其临床预后的一种生物指标.%objective This study was designed to assess the clinical outcomes of MGMT low expression glioblastomas with different expression level of mutant P53 to the response of temozolomide chemotherapy.Method Glioblastomas with low MGMT expression were treated with surgical resection,radiotherapy and temozolomide capsule chemotherapy.They were divided into high and low mutant P53 expression groups.Patient age,gender,KPS score and extent of resection were anyalzed between the two groups.Correlation between P53 status and control of tumor growth were analyzed by survival analysis.Results No statistically significant difference in age,gender,KPS score or extent of resection existed between the two groups.Patients with both low mutant P53 expression and low MGMT had much longer progression-free survival time to temozolomide capsule than those with high mutant P53 expression and low MGMT(P<0.05).Overall survival time did not reach statistical significance between the two groups.Conclusions P53 plays a role in chemotherapy resistance to temozolomide.Glioblastoma patients with both low MGMT and low mutant P53 expression have higher progression-free survival time and may have longer term prognosis.

  18. Recurrent Glioblastoma: Where we stand

    Directory of Open Access Journals (Sweden)

    Sanjoy Roy

    2015-01-01

    Full Text Available Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment with targeted agents or cytotoxic chemotherapy, reirradiation, or radiosurgery. Research into novel therapies is investigating alternative temozolomide regimens, convection-enhanced delivery, immunotherapy, gene therapy, antiangiogenic agents, poly ADP ribose polymerase inhibitors, or cancer stem cell signaling pathways. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy.

  19. Recurrent Glioblastoma: Where we stand.

    Science.gov (United States)

    Roy, Sanjoy; Lahiri, Debarshi; Maji, Tapas; Biswas, Jaydip

    2015-01-01

    Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM) treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment with targeted agents or cytotoxic chemotherapy, reirradiation, or radiosurgery. Research into novel therapies is investigating alternative temozolomide regimens, convection-enhanced delivery, immunotherapy, gene therapy, antiangiogenic agents, poly ADP ribose polymerase inhibitors, or cancer stem cell signaling pathways. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy. PMID:26981507

  20. 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.

  1. Evaluation of the Lactate-to-N-Acetyl-aspartate Ratio Defined With Magnetic Resonance Spectroscopic Imaging Before Radiation Therapy as a New Predictive Marker of the Site of Relapse in Patients With Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Deviers, Alexandra [Département de Radiothérapie, Institut Claudius Regaud, Toulouse (France); UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse (France); INP (Institut National Polytechnique), ENVT (Ecole Nationale Vétérinaire de Toulouse), Unité d' Anatomie-Imagerie-Embryologie, Université de Toulouse, Toulouse (France); Ken, Soléakhéna [Département de Radiothérapie, Institut Claudius Regaud, Toulouse (France); UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse (France); Filleron, Thomas [Bureau des Etudes Cliniques, Institut Claudius Regaud, Toulouse (France); Rowland, Benjamin; Laruelo, Andrea [Département de Radiothérapie, Institut Claudius Regaud, Toulouse (France); Catalaa, Isabelle; Lubrano, Vincent [UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse (France); Hôpital de Rangueil, CHU (Centre Hospitalier Universitaire) de Toulouse, Toulouse (France); Celsis, Pierre [UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse (France); and others

    2014-10-01

    Purpose: Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-{sup 1}H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM). Methods and Materials: Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis of the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence. Results: A LNR of ≥0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm{sup 3}; range: 6-49 cm{sup 3}). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01). Conclusions: Pre-RT LNR-0.4 in GBM

  2. A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas

    Science.gov (United States)

    2016-07-08

    Pilomyxoid Astrocytoma; Pilocytic Astrocytoma; Glioma, Astrocytic; Optic Nerve Glioma; Pleomorphic Xanthoastrocytoma; Glioblastoma Multiforme; Anaplastic Astrocytoma; Gliosarcoma; Diffuse Intrinsic Pontine Glioma; DIPG; Low-grade Glioma; Brainstem Glioma

  3. Selective Lentiviral Gene Delivery to CD133-Expressing Human Glioblastoma Stem Cells

    OpenAIRE

    N Sumru Bayin; Aram S Modrek; August Dietrich; Jonathan Lebowitz; Tobias Abel; Hae-Ri Song; Markus Schober; David Zagzag; Christian J Buchholz; Chao, Moses V; Placantonakis, Dimitris G.

    2014-01-01

    Glioblastoma multiforme (GBM) is a deadly primary brain malignancy. Glioblastoma stem cells (GSC), which have the ability to self-renew and differentiate into tumor lineages, are believed to cause tumor recurrence due to their resistance to current therapies. A subset of GSCs is marked by cell surface expression of CD133, a glycosylated pentaspan transmembrane protein. The study of CD133-expressing GSCs has been limited by the relative paucity of genetic tools that specifically target them. H...

  4. Targeting EGFR for Treatment of Glioblastoma: Molecular Basis to Overcome Resistance

    OpenAIRE

    Taylor, Tiffany E.; Furnari, Frank B.; Cavenee, Webster K.

    2012-01-01

    Glioblastoma (glioblastoma multiforme; GBM; WHO Grade IV) accounts for the majority of primary malignant brain tumors in adults. Amplification and mutation of the epidermal growth factor receptor (EGFR) gene represent signature genetic abnormalities encountered in GBM. A range of potential therapies that target EGFR or its mutant constitutively active form, ΔEGFR, including tyrosine kinase inhibitors (TKIs), monoclonal antibodies, vaccines, and RNA-based agents, are currently in development o...

  5. Eosinophils in glioblastoma biology

    Directory of Open Access Journals (Sweden)

    Curran Colleen S

    2012-01-01

    Full Text Available Abstract Glioblastoma multiforme (GBM is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review.

  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. A Flexible Semi-Automatic Approach for Glioblastoma multiforme Segmentation

    CERN Document Server

    Egger, Jan; Kuhnt, Daniela; Kappus, Christoph; Carl, Barbara; Freisleben, Bernd; Nimsky, Christopher

    2011-01-01

    Gliomas are the most common primary brain tumors, evolving from the cerebral supportive cells. For clinical follow-up, the evaluation of the preoperative tumor volume is essential. Volumetric assessment of tumor volume with manual segmentation of its outlines is a time-consuming process that can be overcome with the help of segmentation methods. In this paper, a flexible semi-automatic approach for grade IV glioma segmentation is presented. The approach uses a novel segmentation scheme for spherical objects that creates a directed 3D graph. Thereafter, the minimal cost closed set on the graph is computed via a polynomial time s-t cut, creating an optimal segmentation of the tumor. The user can improve the results by specifying an arbitrary number of additional seed points to support the algorithm with grey value information and geometrical constraints. The presented method is tested on 12 magnetic resonance imaging datasets. The ground truth of the tumor boundaries are manually extracted by neurosurgeons. The...

  8. Urticaria multiforme er en variant af urticaria, som imiterer erythema multiforme

    DEFF Research Database (Denmark)

    Authried, Georg; Bracher, Linda; Bygum, Anette

    2013-01-01

    A 21-month-old boy developed urticaria multiforme during the course of a presumed pneumonia, which was treated with imacillin. At admission to hospital he was initially considered to have erythema multiforme, but the correct diagnosis was soon established as urticaria multiforme. He had a good re...... response to antihistamines. The diagnostic differences between urticaria multiforme and erythema multiforme are presented in this case report....

  9. Brainstem Cavernous Angioma

    Science.gov (United States)

    ... in significant, and potentially life-threatening, symptoms. The nerves that transverse the brainstem control basic, involuntary functions such as respiration, gag reflex, heartbeat regulation, body temperature, pain and heat sensation, ...

  10. Glioblastoma and intracranial aneurysms: Case report and review of literature

    OpenAIRE

    Rushna Ali; Aqueel Pabaney; Adam Robin; Horia Marin; Mark Rosenblum

    2015-01-01

    Background: There is a paucity of data on the association of glioblastoma multiforme (GBM) with intracranial aneurysms. It is an important clinical entity for physicians to be aware of and its presence illustrates several critical features of the pathophysiology of malignant glioma. In this article we present a case of a middle cerebral artery (MCA) pseudoaneurysm that occurred in a patient with recurrent GBM as well discuss the current literature relating to this unique combination of pathol...

  11. An integrative characterization of recurrent molecular aberrations in glioblastoma genomes

    OpenAIRE

    Sintupisut, Nardnisa; Liu, Pei-Ling; Yeang, Chen-Hsiang

    2013-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Decades of investigations and the recent effort of the Cancer Genome Atlas (TCGA) project have mapped many molecular alterations in GBM cells. Alterations on DNAs may dysregulate gene expressions and drive malignancy of tumors. It is thus important to uncover causal and statistical dependency between ‘effector’ molecular aberrations and ‘target’ gene expressions in GBMs. A rich collection of prior st...

  12. Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma

    OpenAIRE

    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...

  13. ASSOCIATIONS BETWEEN POLYMORPHISMS IN DNA REPAIR GENES AND GLIOBLASTOMA

    OpenAIRE

    McKean-Cowdin, Roberta; Barnholtz-Sloan, Jill; Inskip, Peter; Ruder, Avima; Butler, MaryAnn; Rajaraman, Preetha; Razavi, Pedram; Patoka, Joe; Wiencke, John; Bondy, Melissa; Wrensch, Margaret

    2009-01-01

    A pooled analysis was conducted to examine the association between select variants in DNA repair genes and glioblastoma multiforme (GBM), the most common and deadliest form of adult brain tumors. Genetic data for approximately 1,000 GBM cases and 2,000 controls were combined from four centers in the United States that have conducted case-control studies of adult GBM including the National Cancer Institute, the National Institute for Occupational Safety and Health, the University of Texas M.D....

  14. Primary spinal glioblastoma treated with adjuvant radiation and temozolomide: Report of two cases

    Directory of Open Access Journals (Sweden)

    Supriya Mallick

    2015-01-01

    Full Text Available Primary spinal glioblastoma multiforme (GBM is a rare entity, which is invariably associated with poor outcome. Standard treatment is surgery followed by post-operative radiotherapy. Due to paucity of cases role of chemotherapy is investigational. We intend to report two cases of primary spinal GBM treated with radiation and adjuvant temozolomide.

  15. Cellular immunotherapy directed against human cytomegalovirus as a novel approach for glioblastoma treatment

    OpenAIRE

    Schuessler, Andrea; Walker, David G.; Khanna, Rajiv

    2014-01-01

    Glioblastoma multiforme (GBM) has a very poor prognosis, despite multimodal therapy including surgery, radiation and chemotherapy. A novel adoptive immunotherapy that exploits the presence of cytomegalovirus antigens in malignant brain cancer cells has been shown to be safe and elicit potential clinical benefit for the treatment of recurrent GBM.

  16. 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 apoptosis-induci

  17. Paediatric brain-stem gliomas: MRI, FDG-PET and histological grading correlation

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Jong Won; Kim, In-One; Cheon, Jung-Eun; Kim, Woo Sun; Moon, Sung Gyu; Kim, Tae Jung; Yeon, Kyung Mo [Seoul National University Hospital, Department of Radiology, Seoul (Korea); Chi, Je Geun [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea); Wang, Kyu-Chang [Seoul National University College of Medicine, Department of Neurosurgery, Seoul (Korea); Chung, June Key [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea)

    2006-09-15

    MRI and FDG-PET may predict the histological grading of paediatric brain-stem gliomas. To assess MRI findings and metabolic imaging using FDG-PET of brain-stem gliomas based on histological grading. Included in the study were 20 paediatric patients (age 3-14 years, mean 8.2 years) with brain-stem glioma (five glioblastomas, ten anaplastic astrocytomas and five low-grade astrocytomas). MR images were assessed for the anatomical site of tumour origin, focality, pattern of tumour growth, and enhancement. All glioblastomas were located in the pons and showed diffuse pontine enlargement with focally exophytic features. Eight anaplastic astrocytomas were located in the pons and demonstrated diffuse pontine enlargement without exophytic features. Low-grade astrocytomas were located in the pons, midbrain or medulla and showed focally exophytic growth features and peripheral enhancement. In 12 patients in whom FDG-PET was undertaken, glioblastomas showed hypermetabolic or hypometabolic lesions, anaplastic astrocytomas showed no metabolic change or hypometabolic lesions and low-grade astrocytomas showed hypometabolism compared with the cerebellum. MRI findings correlated well with histological grading of brain-stem gliomas and MRI may therefore predict the histological grading. FDG-PET may be helpful in differentiating between anaplastic astrocytoma and glioblastomas among high-grade tumours. (orig.)

  18. Pediatric brainstem oligodendroglioma

    Directory of Open Access Journals (Sweden)

    Sandeep Mohindra

    2012-01-01

    Full Text Available The authors present the first report of pediatric brainstem oligodendroglioma, infiltrating midbrain, and medulla oblongata. The report details clinical features, radiological findings, and surgical steps. As this entity is exceedingly uncommon, the overall epidemiology, prognosis, and long-term outcome remain far from established.

  19. AMISULPIRIDE INDUCED ERYTHEMA MULTIFORME: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Arun

    2014-08-01

    Full Text Available Antipsychotic agents being used for schizophrenia accounts to cause adverse cutaneous reactions in approximately 5% of the individuals. Erythema multiforme caused by amisulpride therapy in a schizophrenic patient is not a commonly seen side effect. Reversal of lesion was seen after stopping the amisulpride which emphasized the cause of Erythema Multiforme.

  20. Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma.

    Science.gov (United States)

    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.

  1. Erythema multiforme following vaccination in an infant

    Directory of Open Access Journals (Sweden)

    Kaur Sarvjit

    2008-01-01

    Full Text Available Erythema multiforme is a cutaneous reaction pattern precipitated by varied agents, notably herpes simplex and drugs. It predominantly occurs in adolescents and young adults but may be seen at other ages also. While vaccination is rarely a precipitating factor for erythema multiforme, it may occasionally be seen in infants and children. We report here a case of a two month-old infant with lesions of erythema multiforme minor appearing after two weeks following vaccination for DPT, Hepatitis B and influenza.

  2. NETRIN-4 protects glioblastoma cells FROM temozolomide induced senescence.

    Directory of Open Access Journals (Sweden)

    Li Li

    Full Text Available Glioblastoma multiforme is the most common primary tumor of the central nervous system. The drug temozolomide (TMZ prolongs lifespan in many glioblastoma patients. The sensitivity of glioblastoma cells to TMZ is interfered by many factors, such as the expression of O-6-methylguanine-DNA methyltransferase (MGMT and activation of AKT signaling. We have recently identified the interaction between netrin-4 (NTN4 and integrin beta-4 (ITGB4, which promotes glioblastoma cell proliferation via activating AKT-mTOR signaling pathway. In the current work we have explored the effect of NTN4/ITGB4 interaction on TMZ induced glioblastoma cell senescence. We report here that the suppression of either ITGB4 or NTN4 in glioblastoma cell lines significantly enhances cellular senescence. The sensitivity of GBM cells to TMZ was primarily determined by the expression of MGMT. To omit the effect of MGMT, we concentrated on the cell lines devoid of expression of MGMT. NTN4 partially inhibited TMZ induced cell senescence and rescued AKT from dephosphorylation in U251MG cells, a cell line bearing decent levels of ITGB4. However, addition of exogenous NTN4 displayed no significant effect on TMZ induced senescence rescue or AKT activation in U87MG cells, which expressed ITGB4 at low levels. Furthermore, overexpression of ITGB4 combined with exogenous NTN4 significantly attenuated U87MG cell senescence induced by TMZ. These data suggest that NTN4 protects glioblastoma cells from TMZ induced senescence, probably via rescuing TMZ triggered ITGB4 dependent AKT dephosphorylation. This suggests that interfering the interaction between NTN4 and ITGB4 or concomitant use of the inhibitors of the AKT pathway may improve the therapeutic efficiency of TMZ.

  3. Spatiotemporal Evolution of the Primary Glioblastoma Genome.

    Science.gov (United States)

    Kim, Jinkuk; Lee, In-Hee; Cho, Hee Jin; Park, Chul-Kee; Jung, Yang-Soon; Kim, Yanghee; Nam, So Hee; Kim, Byung Sup; Johnson, Mark D; Kong, Doo-Sik; Seol, Ho Jun; Lee, Jung-Il; Joo, Kyeung Min; Yoon, Yeup; Park, Woong-Yang; Lee, Jeongwu; Park, Peter J; Nam, Do-Hyun

    2015-09-14

    Tumor recurrence following treatment is the major cause of mortality for glioblastoma multiforme (GBM) patients. Thus, insights on the evolutionary process at recurrence are critical for improved patient care. Here, we describe our genomic analyses of the initial and recurrent tumor specimens from each of 38 GBM patients. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor. In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk for TMZ-induced hypermutation for these tumors under the standard regimen. PMID:26373279

  4. Applicable advances in the molecular pathology of glioblastoma.

    Science.gov (United States)

    Ranjit, Melissa; Motomura, Kazuya; Ohka, Fumiharu; Wakabayashi, Toshihiko; Natsume, Atsushi

    2015-07-01

    Comprising more than 80% of malignant brain tumors, glioma has proven to be a daunting cause of mortality in a vast majority of the human population. Progressive and extensive research on malignant glioma has substantially enhanced our understanding of glioma cell biology and molecular pathology. Subtypes of glioma such as astrocytoma and oligodendroglioma are currently grouped together into one pathological class, where they show many differences in histology and molecular etiology. This indicates that it may be beneficial to consider a new and radical subclassification. Thus, we summarize recent developments in glioblastoma multiforme (GBM) subtypes, immunohistochemical analyses useful for diagnoses and the biological evaluation and therapeutic implications of gliomas in this review.

  5. Role of Nitric Oxide in Glioblastoma Therapy: Another Step to Resolve the Terrible Puzzle ?

    Science.gov (United States)

    Altieri, R; Fontanella, M; Agnoletti, A; Panciani, P P; Spena, G; Crobeddu, E; Pilloni, G; Tardivo, V; Lanotte, M; Zenga, F; Ducati, A; Garbossa, D

    2015-01-01

    Glioblastoma Multiforme, the most common and aggressive primary brain tumor, remains incurable despite of the advent of modern surgical and medical treatments. This poor prognosis depends by the recurrence after surgery and intrinsic or acquired resistance to chemotherapy and radiotherapy. Nitric oxide is a small molecule that plays a key roles in glioma pathophysiology. Many researches showing that NO is involved in induction of apoptosis, radiosensitization and chemosensitization. Therefore, NO role, if clarified, may improve the knowledge about this unsolved puzzle called GBM.

  6. A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells

    OpenAIRE

    Visnyei, Koppany; Onodera, Hideyuki; Damoiseaux, Robert; Saigusa, Kuniyasu; Petrosyan, Syuzanna; De Vries, David; Ferrari, Denise; Saxe, Jonathan; Panosyan, Eduard H.; Masterman-Smith, Michael; Mottahedeh, Jack; Bradley, Kenneth A.; Huang, Jing; Sabatti, Chiara; Nakano, Ichiro

    2011-01-01

    Glioblastoma multiforme (GBM) is amongst the most lethal of all cancers. GBM consist of a heterogeneous population of tumor cells amongst which a tumor initiating and treatment-resistant subpopulation, here termed GBM stem cells (GSC), have been identified as primary therapeutic targets. Here, we describe a high-throughput small molecule screening approach that enables the identification and characterization of chemical compounds that are effective against GSC. The paradigm uses a tissue cult...

  7. Evaluation of MGMT Promoter Methylation Status and Correlation with Temozolomide Response in Orthotopic Glioblastoma Xenograft Model

    OpenAIRE

    Kitange, Gaspar J.; Carlson, Brett L.; Mladek, Ann C.; Decker, Paul A.; Schroeder, Mark A.; Wu, Wenting; Grogan, Patrick T.; Giannini, Caterina; Ballman, Karla V.; Buckner, Jan C.; James, C. David; Sarkaria, Jann N.

    2008-01-01

    CpG methylation within the O6-methylguanine-DNA-methyltransferase (MGMT) promoter is associated with enhanced survival of glioblastoma multiforme (GBM) patients treated with temozolomide (TMZ). Although MGMT promoter is methylated in ~50% of GBM, several studies have reported a lack of correlation between MGMT methylation and protein expression levels and consequently inaccurate discrimination of TMZ sensitive and resistant patients. To understand the limitations of currently used assays, TMZ...

  8. Real-time multi-modality imaging of Glioblastoma tumor resection and recurrence

    OpenAIRE

    Hingtgen, Shawn; Figueiredo, Jose-Luiz; Farrar, Christian; Duebgen, Matthias; Martinez-Quintanilla, Jordi; Bhere, Deepak; Shah, Khalid

    2012-01-01

    The lack of relevant pre-clinical animal models incorporating the clinical scenario of GBM resection and recurrence has contributed significantly to the inability to successfully treat the devastating brain tumor Glioblastoma multiforme (GBM). A multi-modality imaging approach that allows real-time assessment of tumor resection during surgery and non-invasive detection of post-operative tumor volumes is urgently needed. In this study, we report the development and implementation of an optical...

  9. Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma

    OpenAIRE

    Yamaki, Tomohiro; Suenaga, Yusuke; Iuchi, Toshihiko; Alagu, Jennifer; Takatori, Atsushi; Itami, Makiko; Araki, Akinobu; Ohira, Miki; Inoue, Masahiro; Kageyama, Hajime; Yokoi, Sana; Saeki, Naokatsu; Nakagawara, Akira

    2013-01-01

    Glioblastoma multiforme (GBM) is a highly invasive and chemoradioresistant brain malignancy. Temozolomide (TMZ), a DNA-alkylating agent, is effective against GBM and has become the standard first-line drug. However, the mechanism by which TMZ regulates the progression of GBM remains elusive. Here, we demonstrate that TMZ targets TAp63, a p53 family member, inducing its expression to suppress the progression of human GBM. High levels of TAp63 expression in GBM tissues after TMZ treatment was a...

  10. Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab

    OpenAIRE

    Prados, Michael; Cloughesy, Timothy; Samant, Meghna; Fang, Liang; Wen, Patrick Y.; Mikkelsen, Tom; Schiff, David; Abrey, Lauren E; Yung, W.K. Alfred; Paleologos, Nina; Nicholas, Martin K.; Jensen, Randy; Vredenburgh, James; Das, Asha; Friedman, Henry S.

    2010-01-01

    Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, ...

  11. Valganciclovir and bevacizumab for recurrent glioblastoma: A single-institution experience

    OpenAIRE

    Peng, Chengwei; Wang, Jialing; Tanksley, Jarred P.; Mobley, Bret C.; Gregory D. Ayers; Moots, Paul L.; Clark, Stephen W.

    2015-01-01

    Prolonged treatment with adjuvant valganciclovir has been shown in one retrospective study to exert a significant effect on overall survival (OS) in newly diagnosed patients with glioblastoma multiforme (GBM). However, studies evaluating the effectiveness of valganciclovir in the treatment of recurrent GBM have not been performed. We evaluated the effect of valganciclovir in the recurrent setting in combination with bevacizumab therapy. A retrospective analysis was performed on patients treat...

  12. Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors

    OpenAIRE

    Liu, Qinghai; Nguyen, David H.; DONG, QINGHUA; Shitaku, Peter; Chung, Kenneth; Liu, On Ying; Jonathan L Tso; Liu, Jason Y; Konkankit, Veerauo; Cloughesy, Timothy F.; Mischel, Paul S; Lane, Timothy F.; Liau, Linda M.; Stanley F Nelson; Tso, Cho-Lea

    2009-01-01

    Glioblastoma multiforme (GBM) remains refractory to conventional therapy. CD133+ GBM cells have been recently isolated and characterized as chemo-/radio-resistant tumor-initiating cells and are hypothesized to be responsible for post-treatment recurrence. In order to explore the molecular properties of tumorigenic CD133+ GBM cells that resist treatment, we isolated CD133+ GBM cells from tumors that are recurrent and have previously received chemo-/radio-therapy. We found that the purified CD1...

  13. Continuous Low-Dose Temozolomide Chemotherapy and Microvessel Density in Recurrent Glioblastoma

    OpenAIRE

    Woo, Jong-Yun; Yang, Seung Ho; Lee, Youn Soo; Lee, Su Youn; Kim, Jeana; Hong, Yong Kil

    2015-01-01

    Objective The purpose of this study was to evaluate the clinical efficacy of continuous low-dose temozolomide (TMZ) chemotherapy for recurrent and TMZ-refractory glioblastoma multiforme (GBM) and to study the relationship between its efficacy and microvessel density within the tumor. Methods Thirty patients who had recurrent GBM following Stupp's regimen received TMZ daily at 50 mg/m2/day until tumor progression between 2007 and 2013. The median duration of continuous low-dose TMZ administrat...

  14. Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts

    OpenAIRE

    Kitange, Gaspar J.; Carlson, Brett L.; Schroeder, Mark A.; Grogan, Patrick T.; Lamont, Jeff D.; Decker, Paul A.; Wu, Wenting; James, C. David; Sarkaria, Jann N.

    2009-01-01

    Temozolomide (TMZ)-based therapy is the standard of care for patients with glioblastoma multiforme (GBM), and resistance to this drug in GBM is modulated by the DNA repair protein O6-methylguanine-DNA methyl-transferase (MGMT). Expression of MGMT is silenced by promoter methylation in approximately half of GBM tumors, and clinical studies have shown that elevated MGMT protein levels or lack of MGMT promoter methylation is associated with TMZ resistance in some, but not all, GBM tumors. In thi...

  15. Optical Touch Pointer for Fluorescence Guided Glioblastoma Resection Using 5-Aminolevulinic Acid

    OpenAIRE

    Haj-Hosseini, Neda; Richter, Johan; Andersson-Engels, Stefan; Wårdell, Karin

    2010-01-01

    Background and Objective Total tumor resection in patients with glioblastoma multiforme (GBM) is difficult to achieve due to the tumor's infiltrative way of growing and morphological similarity to the surrounding functioning brain tissue. The diagnosis is usually subjectively performed using a surgical microscope. The objective of this study was to develop and evaluate a hand-held optical touch pointer using a fluorescence spectroscopy system to quantitatively distinguish healthy from maligna...

  16. Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide

    DEFF Research Database (Denmark)

    Dresemann, G.; Weller, M.; Ostenfeld-Rosenthal, Ann Maria;

    2010-01-01

    A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitum...

  17. Case Report: Pregnancy in a patient with recurrent glioblastoma [v1; ref status: indexed, http://f1000r.es/27s

    Directory of Open Access Journals (Sweden)

    Birgit Flechl

    2013-11-01

    Full Text Available We report the case of a woman with relapsed glioblastoma multiforme (GBM who recently gave birth. She announced her pregnancy shortly after the sixth cycle of a dense regimen of temozolomide, prescribed for treating the first recurrence of glioblastoma. Three years ago, in April 2008, she had undergone gross total resection of a glioblastoma multiforme in the postcentral region of the right hemisphere and had subsequently received treatment according to the actual standard therapy consisting of radiotherapy up to 60 Gy with concomitant and adjuvant temozolomide. The complete amount of temozolomide given before this pregnancy was 20.9 mg/m2. Nevertheless, she delivered a 1890 g child by caesarean section in the 32/6 week of pregnancy. The child showed no anomalies and is developing normally under close surveillance by paediatricians.

  18. Inhibition of Autophagy by Chloroquine Enhances the Antitumor Efficacy of Sorafenib in Glioblastoma.

    Science.gov (United States)

    Liu, Xiangyu; Sun, Kangjian; Wang, Handong; Dai, Yuyuan

    2016-10-01

    Glioblastoma multiforme (GBM) is the most aggressive and common brain tumor in adults. Sorafenib, a multi-kinase inhibitor, has been shown to inhibit cell proliferation and induce apoptosis through inhibition of STAT3 signaling in glioblastoma cells and in intracranial gliomas. However, sorafenib also induces cell autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the therapeutic effect of sorafenib on glioblastoma is uncertain. Here, we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM. PMID:26971793

  19. Yes and PI3K bind CD95 to signal invasion of glioblastoma.

    Science.gov (United States)

    Kleber, Susanne; Sancho-Martinez, Ignacio; Wiestler, Benedict; Beisel, Alexandra; Gieffers, Christian; Hill, Oliver; Thiemann, Meinolf; Mueller, Wolf; Sykora, Jaromir; Kuhn, Andreas; Schreglmann, Nina; Letellier, Elisabeth; Zuliani, Cecilia; Klussmann, Stefan; Teodorczyk, Marcin; Gröne, Hermann-Josef; Ganten, Tom M; Sültmann, Holger; Tüttenberg, Jochen; von Deimling, Andreas; Regnier-Vigouroux, Anne; Herold-Mende, Christel; Martin-Villalba, Ana

    2008-03-01

    Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo. PMID:18328427

  20. 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.

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

    International Nuclear Information System (INIS)

    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

  2. miR-155 is up-regulated in primary and secondary glioblastoma and promotes tumour growth by inhibiting GABA receptors.

    Science.gov (United States)

    D'Urso, Pietro I; D'Urso, Oscar F; Storelli, Carlo; Mallardo, Massimo; Gianfreda, Cosimo Damiano; Montinaro, Antonio; Cimmino, Antonia; Pietro, Caliandro; Marsigliante, Santo

    2012-07-01

    An altered expression of microRNAs (miRNAs) contributes both to the development of cancer and to the progression of the disease. Malignant tumours and tumour cell lines have widespread deregulated expressions of miRNAs compared to normal tissues. In this study, we investigated the expression profiles of 340 mammalian miRNAs in 93 cases of multiform glioblastoma (primary and secondary glioblastoma tumours), by means of DNA microarrays. We show that the expression profiles of 10 miRNAs can distinguish primary from secondary glioblastoma types. Moreover, we found elevated miR-155 levels in primary and secondary glioblastoma tissues as well as in glioblastoma primary cultures. We hypothesised that γ-aminobutyric acid A receptor 1 (GABRA1) is a miR-155 target, and studied the correlation between miR-155 up-regulation and the GABRA1 protein in cultured glioblastoma cells by miRNA silencing. We show that a decrease in miR-155 expression to normal levels restores the expression of GABRA1, making glioblastoma cells sensitive to signals that inhibit cell proliferation mediated by GABRA1. In conclusion, the expression patterns of different miRNAs characterise primary and secondary glioblastomas. The aberrant overexpression of miR-155 contributes to the malignant phenotype of glioblastoma cells removing growth inhibition. PMID:22470130

  3. Sildenafil: A rare cause of erythema multiforme.

    Science.gov (United States)

    Sharma, Nidhi Raghunandan; Sharma, Sudhanshu; Ahmad, Javid; Nadkarni, Nitin; Rana, Shweta; Kalhan, Shivani

    2016-01-01

    Erythema multiforme (EM) is an acute self-limiting mucocutaneous condition of uncertain etiopathogenesis. The most common precipitating factors are herpes simplex virus infection, mycoplasma infection, drugs, and vaccination. We report a case of EM following sildenafil used for loss of libido. EM induced by sildenafil has not been reported so far. PMID:27190421

  4. BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression

    OpenAIRE

    Persano, L; Pistollato, F; Rampazzo, E; Della Puppa, A; Abbadi, S; Frasson, C; Volpin, F; S. Indraccolo; Scienza, R; G. Basso

    2012-01-01

    Glioblastoma multiforme (GBM) is the most common brain tumour, characterized by a central and partially necrotic (i.e., hypoxic) core enriched in cancer stem cells (CSCs). We previously showed that the most hypoxic and immature (i.e., CSCs) GBM cells were resistant to Temozolomide (TMZ) in vitro, owing to a particularly high expression of O6-methylguanine-DNA-methyltransferase (MGMT), the most important factor associated to therapy resistance in GBM. Bone morphogenetic proteins (BMPs), and in...

  5. RM-05CASE OF GLIOBLASTOMA PATIENT TREATED WITH NovoTTF THERAPY AT RECURRENCE DEGENERATING TO SARCOMA

    OpenAIRE

    Majd, Pejman; O'Connell, Daniel; Kim, Ronald; Bota, Daniela; Carrillo, Jose

    2014-01-01

    NovoTTF treatment is an FDA approved treatment strategy for recurrent Glioblastoma multiforme (GBM) management which employs alternating electric fields to the region of the malignant tumor through probes on the patient's head which is thought to improve time to disease progression of GBM via cell cycle mitosis disruption. A patient is described with recurrent GBM who had disease progression following initial standard surgical treatment and concomitant chemo-radiotherapy and was found to have...

  6. CS-04STAT3 INVOLVEMENT IN AN EMT-LIKE PROCESS IN GLIOBLASTOMA BRAIN TUMOR INITIATING CELLS

    OpenAIRE

    Chesnelong, Charles; Luchman, Artee; Gregory Cairncross, J.; Weiss, Samuel

    2014-01-01

    Glioblastoma Multiforme (GBM) is the most aggressive subtype of brain tumour with a median survival of 15 months. Currently, GBM is managed by a combination of maximal safe resection followed by radiation and chemotherapy. However, GBM invariably recurs, highlighting the need to better delineate the basis of recurrent disease and develop novel more effective and targeted therapies. The Signal Transducer and Activator of Transcription 3 (STAT3) is abnormally active in GBM. A growing body of ev...

  7. Afatinib, an irreversible ErbB family blocker, with protracted temozolomide in recurrent glioblastoma: A case report

    OpenAIRE

    Alshami, Jad; Guiot, Marie-Christine; Owen, Scott; Kavan, Petr; Gibson, Neil; Solca, Flavio; Cseh, Agnieszka; Reardon, David A.; Muanza, Thierry

    2015-01-01

    There are few effective treatments for recurrent glioblastoma multiforme (GBM). We present a patient with recurrent GBM who achieved a prolonged response to treatment with afatinib, an irreversible ErbB family blocker, plus temozolomide. A 58-year-old female patient was diagnosed with multifocal primary GBM. After surgical resection, first-line therapy comprised radiotherapy and temozolomide. Following disease progression after 3 temozolomide cycles, the patient entered a phase I/II clinical ...

  8. O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients

    OpenAIRE

    Spiegl-Kreinecker, Sabine; Pirker, Christine; Filipits, Martin; Lötsch, Daniela; Buchroithner, Johanna; Pichler, Josef; Silye, Rene; Weis,Serge; Micksche, Michael; Fischer, Johannes; Berger, Walter

    2009-01-01

    O6-Methylguanine DNA methyltransferase (MGMT) is implicated as a major predictive factor for treatment response to alkylating agents including temozolomide (TMZ) of glioblastoma multiforme (GBM) patients. However, whether the MGMT status in GBM patients should be detected at the level of promoter methylation or protein expression is still a matter of debate. Here, we compared promoter methylation (by methylation-specific polymerase chain reaction) and protein expression (by Western blot) in t...

  9. Cystic hemangioblastoma of the brainstem

    Directory of Open Access Journals (Sweden)

    Amit Agrawal

    2010-01-01

    Full Text Available Hemangioblastomas are very highly vascular neoplasm with benign characteristics and; in comparison to cerebellar hemangioblastoma; cases of cystic hemangioblastoma of the brain stem are rare with only a few case reports available in the literature. We report the case of a 43-year-old-female with cystic hemagioblastoma of the brainstem managed successfully and review the relevant literature.

  10. Cystic hemangioblastoma of the brainstem

    OpenAIRE

    Amit Agrawal; Anand Kakani; Vagh, Sunita J; Hiwale, Kishore M; Gaurav Kolte

    2010-01-01

    Hemangioblastomas are very highly vascular neoplasm with benign characteristics and; in comparison to cerebellar hemangioblastoma; cases of cystic hemangioblastoma of the brain stem are rare with only a few case reports available in the literature. We report the case of a 43-year-old-female with cystic hemagioblastoma of the brainstem managed successfully and review the relevant literature.

  11. Brainstem reflexes and brainstem auditory evoked responses in Huntington's chorea.

    OpenAIRE

    Bollen, E; Arts, R.J.; Roos, R A; van der Velde, E A; Buruma, O J

    1986-01-01

    Blink reflex, corneal reflex, jaw reflex, exteroceptive suppression in masseter muscles and brainstem auditory evoked potentials were measured in 20 patients with Huntington's chorea and 12 controls. A significantly increased latency of the second component of the homolateral and heterolateral blink reflex was found in the patient group as compared with the controls. The other investigations revealed no significant differences between patients and controls except for some facilitation of the ...

  12. Erythema Multiforme Following Application of Hair Dye

    OpenAIRE

    Sankha Koley; Jyotirindranath Sarkar; Sanjiv Choudhary; Suparna Dhara; Manoj Choudhury

    2012-01-01

    Erythema multiforme (EM) is an acute mucocutaneous hypersensitivity reaction with varying degrees of blistering and ulceration. Common causes of EM are herpes simplex virus infection, mycoplasma infection, drug hypersensitivity, vaccination and drug-virus interaction. EM induced by contact dermatitis is rare. Paraphenylene diamine, a common ingredient in many hair dyes, is well known to produce allergic contact dermatitis. We report a 35-year-old lady presenting with EM following severe conta...

  13. Rapamycin-mediated mTOR inhibition attenuates survivin and sensitizes glioblastoma cells to radiation therapy

    Institute of Scientific and Technical Information of China (English)

    Arunkumar Anandharaj; Senthilkumar Cinghu; Woo-Yoon Park

    2011-01-01

    Survivin, an antiapoptotic protein, is elevated in most malignancies and attributes to radiation resistance in tumors including glioblastoma multiforme. The downregulation of survivin could sensitize glioblastoma ceils to radiation therapy. In this study, we investigated the effect of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), in attenuating survivin and enhancing the therapeutic efficacy for glioblastoma cells, and elucidated the underlying mechanisms. Here we tested various concentrations of rapamycin (1-8 nM) in combination with radiation dose 4 Gy. Rapamycin effectively modulated the protein kinase B (Akt)/mTOR pathway by inhibiting the phosphorylation of Akt and mTOR proteins, and this inhibition was further enhanced by radiation. The expression level of survivin was decreased in rapamycin pre-treatment glioblastoma ceils followed by radiation; meanwhile, the phosphorylation of H2A histone family member X (H2AX) at serine-139 (γ-H2AX) was increased, p21 protein was also induce on radiation with rapamycin pre-treatment, which enhanced G1 arrest and the accumulation of cells at G0/subG1 phase. Furthermore, the clonogenic cell survival assay revealed a significant dose-dependent decrease in the surviving fraction for all three cell lines pre-treated with rapamycin. Our studies demonstrated that targeting survivin may be an effective approach for radiosensitization of malignant glioblastoma.

  14. Evaluation of a Novel Approach for Automatic Volume Determination of Glioblastomas Based on Several Manual Expert Segmentations

    CERN Document Server

    Egger, Jan; Kuhnt, Daniela; Carl, Barbara; Kappus, Christoph; Freisleben, Bernd; Nimsky, Christopher

    2011-01-01

    The glioblastoma multiforme is the most common malignant primary brain tumor and is one of the highest malignant human neoplasms. During the course of disease, the evaluation of tumor volume is an essential part of the clinical follow-up. However, manual segmentation for acquisition of tumor volume is a time-consuming process. In this paper, a new approach for the automatic segmentation and volume determination of glioblastomas (glioblastoma multiforme) is presented and evaluated. The approach uses a user-defined seed point inside the glioma to set up a directed 3D graph. The nodes of the graph are obtained by sampling along rays that are sent through the surface points of a polyhedron. After the graph has been constructed, the minimal s-t cut is calculated to separate the glioblastoma from the background. For evaluation, 12 Magnetic Resonance Imaging (MRI) data sets were manually segmented slice by slice, by neurosurgeons with several years of experience in the resection of gliomas. Afterwards, the manual se...

  15. Lyme disease of the brainstem

    Energy Technology Data Exchange (ETDEWEB)

    Kalina, Peter [Mayo Clinic, Department of Radiology, Rochester, MN (United States); Decker, Andrew [Northern Westchester Hospital Center, Department of Neurology, Mt. Kisco, NY (United States); Kornel, Ezriel [Northern Westchester Hospital Center, Division of Neurosurgery, Mt. Kisco, NY (United States); Halperin, John J. [North Shore University Hospital, Department of Neurology, Manhasset, NY (United States)

    2005-12-01

    Lyme disease is a multisystem infectious disease caused by the tick-borne spirochete, Borrelia burgdorferi. Central nervous system (CNS) involvement typically causes local inflammation, most commonly meningitis, but rarely parenchymal brain involvement. We describe a patient who presented with clinical findings suggesting a brainstem process. Magnetic resonance imaging (MRI) and positron emission tomography (PET) suggested a brainstem neoplasm. Prior to biopsy, laboratory evaluation led to the diagnosis of Lyme disease. Clinical and imaging abnormalities improved markedly following antimicrobial therapy. We describe Lyme disease involvement of the cerebellar peduncles with hypermetabolism on PET. Although MRI is the primary imaging modality for most suspected CNS pathology, the practical applications of PET continue to expand. (orig.)

  16. Lyme disease of the brainstem

    International Nuclear Information System (INIS)

    Lyme disease is a multisystem infectious disease caused by the tick-borne spirochete, Borrelia burgdorferi. Central nervous system (CNS) involvement typically causes local inflammation, most commonly meningitis, but rarely parenchymal brain involvement. We describe a patient who presented with clinical findings suggesting a brainstem process. Magnetic resonance imaging (MRI) and positron emission tomography (PET) suggested a brainstem neoplasm. Prior to biopsy, laboratory evaluation led to the diagnosis of Lyme disease. Clinical and imaging abnormalities improved markedly following antimicrobial therapy. We describe Lyme disease involvement of the cerebellar peduncles with hypermetabolism on PET. Although MRI is the primary imaging modality for most suspected CNS pathology, the practical applications of PET continue to expand. (orig.)

  17. Pilomyxoid astrocytoma of the brainstem.

    Science.gov (United States)

    Pereira, Francisco Otavio; Lombardi, Ismael Augusto; Mello, Adriana Yuki; Romero, Flavio Ramalho; Ducati, Luis Gustavo; Gabarra, Roberto Colichio; Zanini, Marco Antonio

    2013-04-15

    A pilomyxoid astrocytoma is a recently described tumor that occurs predominantly in the hypothalamic-chiasmatic region and is rarely found elsewhere. It has similar features as pilocytic astrocytomas, but has distinct histological characteristics and a poorer prognosis. A pilomyxoid astrocytoma is an aggressive tumor, and increased awareness is necessary with a suspect case. We present the first case of a pilomyxoid astrocytoma of the brainstem described after the newest World Health Organization classification of central nervous system tumors.

  18. Pilomyxoid astrocytoma of the brainstem

    Directory of Open Access Journals (Sweden)

    Marco Antonio Zanini

    2013-04-01

    Full Text Available A pilomyxoid astrocytoma is a recently described tumor that occurs predominantly in the hypothalamic-chiasmatic region and is rarely found elsewhere. It has similar features as pilocytic astrocytomas, but has distinct histological characteristics and a poorer prognosis. A pilomyxoid astrocytoma is an aggressive tumor, and increased awareness is necessary with a suspect case. We present the first case of a pilomyxoid astrocytoma of the brainstem described after the newest World Health Organization classification of central nervous system tumors.

  19. Pilomyxoid astrocytoma of the brainstem

    OpenAIRE

    Marco Antonio Zanini; Ducati Gustavo Luis; Roberto Colichio Gabarra; Adriana Yuki Mello; Ismael Augusto Lombardi; Flavio Ramalho Romero; Francisco Otavio Pereira

    2013-01-01

    Abstract A pilomyxoid astrocytoma is a recently described tumor that occurs predominantly in the hypothalamic-chiasmatic region and is rarely found elsewhere. It has similar features as pilocytic astrocytomas, but has distinct histological characteristics and a poorer prognosis. A pilomyxoid astrocytoma is an aggressive tumor, and increased awareness is necessary with a suspect case. We present the first case of a pilomyxoid astrocytoma of the brainstem described after the newest World Health...

  20. Canine Butterfly Glioblastomas: A Neuroradiological Review

    Science.gov (United States)

    Rossmeisl, John H.; Clapp, Kemba; Pancotto, Theresa E.; Emch, Samantha; Robertson, John L.; Debinski, Waldemar

    2016-01-01

    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 for 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 that were associated with extensive perilesional edema, and involvement of the corpus callosum. The masses displayed heterogeneous T1, T2, and fluid-attenuated inversion recovery signal intensities, variable contrast enhancement (2/3), and mass effect. All tumors demonstrated classical histopathological features of glioblastoma multiforme (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 an MRI evidence of asymmetric or symmetric bilateral, intra-axial cerebral mass lesions with signal characteristics compatible with glioma.

  1. 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.

  2. Repurposing antipsychotics as glioblastoma therapeutics: Potentials and challenges

    Science.gov (United States)

    LEE, JIN-KU; NAM, DO-HYUN; LEE, JEONGWU

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and most lethal primary brain tumor, with tragically little therapeutic progress over the last 30 years. Surgery provides a modest benefit, and GBM cells are resistant to radiation and chemotherapy. Despite significant development of the molecularly targeting strategies, the clinical outcome of GBM patients remains dismal. The challenges inherent in developing effective GBM treatments have become increasingly clear, and include resistance to standard treatments, the blood-brain barrier, resistance of GBM stem-like cells, and the genetic complexity and molecular adaptability of GBM. Recent studies have collectively suggested that certain antipsychotics harbor antitumor effects and have potential utilities as anti-GBM therapeutics. In the present review, the anti-tumorigenic effects and putative mechanisms of antipsychotics, and the challenges for the potential use of antipsychotic drugs as anti-GBM therapeutics are reviewed. PMID:26893731

  3. Gamma Knife Treatment of Brainstem Metastases

    OpenAIRE

    Peterson, Halloran E.; Larson, Erik W.; Fairbanks, Robert K; Mackay, Alexander R.; Lamoreaux, Wayne T.; Call, Jason A.; Carlson, Jonathan D.; Ling, Benjamin C; Demakas, John J.; Cooke, Barton S; Ben Peressini; Lee, Christopher M

    2014-01-01

    The management of brainstem metastases is challenging. Surgical treatment is usually not an option, and chemotherapy is of limited utility. Stereotactic radiosurgery has emerged as a promising palliative treatment modality in these cases. The goal of this study is to assess our single institution experience treating brainstem metastases with Gamma Knife radiosurgery (GKRS). This retrospective chart review studied 41 patients with brainstem metastases treated with GKRS. The most common primary...

  4. Brainstem haematoma due to presumed cryptic telangiectasia.

    OpenAIRE

    Howard, R S

    1986-01-01

    Three patients with primary brainstem haematoma are reported. The clinical presentation suggested an initial diagnosis of pontine tumour in two and demyelination in one patient. The subacute course is characteristic of brainstem haematoma due to presumed cryptic telangiectasia, the abnormal vessels being destroyed by the haemorrhage. These findings emphasise the importance of considering haematoma due to cryptic telangiectasia in the differential diagnosis of subacute brainstem lesions.

  5. NHERF-1: Modulator of Glioblastoma Cell Migration and Invasion

    Directory of Open Access Journals (Sweden)

    Kerri L. Kislin

    2009-04-01

    Full Text Available The invasive nature of malignant gliomas is a clinical problem rendering tumors incurable by conventional treatment modalities such as surgery, ionizing radiation, and temozolomide. Na+/H+ exchanger regulatory factor 1 (NHERF-1 is a multifunctional adaptor protein, recruiting cytoplasmic signaling proteins and membrane receptors/transporters into functional complexes. This study revealed that NHERF-1 expression is increased in highly invasive cells that reside in the rim of glioblastoma multiforme (GBM tumors and that NHERF-1 sustains glioma migration and invasion. Gene expression profiles were evaluated from laser capture-microdissected human GBM cells isolated from patient tumor cores and corresponding invaded white matter regions. The role of NHERF-1 in the migration and dispersion of GBM cell lines was examined by reducing its expression with small-interfering RNA followed by radial migration, three-dimensional collagen dispersion, immunofluorescence, and survival assays. The in situ expression of NHERF-1 protein was restricted to glioma cells and the vascular endothelium, with minimal to no detection in adjacent normal brain tissue. Depletion of NHERF-1 arrested migration and dispersion of glioma cell lines and caused an increase in cell-cell cohesiveness. Glioblastoma multiforme cells with depleted NHERF-1 evidenced a marked decrease in stress fibers, a larger cell size, and a more rounded shape with fewer cellular processes. When NHERF-1 expression was reduced, glioma cells became sensitized to temozolomide treatment resulting in increased apoptosis. Taken together, these results provide the first evidence for NHERF-1 as a participant in the highly invasive phenotype of malignant gliomas and implicate NHERF-1 as a possible therapeutic target for treatment of GBM.

  6. Assessment of temozolomide action encapsulated in chitosan and polymer nanostructures on glioblastoma cell lines

    Directory of Open Access Journals (Sweden)

    Abrudan C.

    2014-03-01

    Full Text Available Purpose : Glioblastoma multiforme (GBM remains one of the most devastating diseases known to mankind and affects more than 17,000 patients in the United States alone every year. This malignancy infiltrates the brain early in its course and makes complete neurosurgical resection almost impossible. Recent years have brought significant advances in tumor biology. Many cancers, including gliomas, appear to be supported by cells with stemlike properties. Nanoparticles are excellent candidates to serve as delivery vectors of drugs or biologically active molecules because of their unique chemical and physical properties that result in specific transportation and deposition of such agents in specific organs and tissues..

  7. EG-02CORRELATION OF MGMT PROMOTER METHYLATION STATUS ANALYSIS USING 6 MS-MLPA PROBES AND CLINICAL RESPONSE OF TEMOZOLOMIDE IN GLIOBLASTOMA PATIENTS

    OpenAIRE

    Fakkert, Michelle; de Leng, Wendy; de Weger, Roel; Willems, Stefan; Spliet, Wim; Van Hecke, Wim; De Vos, Filip

    2014-01-01

    INTRODUCTION: For patients diagnosed with Glioblastoma Multiforme (GBM) O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is an important predictive factor for treatment with temozolomide (TMZ). MGMT reverses the toxic effect of alkylating chemotherapies like TMZ, therefore absence of the MGMT protein, due to promoter hypermethylation, results in greater tumor response and prolonged survival. MGMT methylation status can be determined using Methylation Specific Multiplex Ligat...

  8. Treatment with Tumor-Treating Fields Therapy and Pulse Dose Bevacizumab in Patients with Bevacizumab-Refractory Recurrent Glioblastoma: A Case Series

    OpenAIRE

    Ansstas, George; Tran, David D.

    2016-01-01

    Patients with bevacizumab-refractory recurrent glioblastoma multiforme (GBM) have a poor prognosis. We propose that instead of continuing on bevacizumab, patients should switch to treatment with Optune™, a novel antimitotic Tumor-Treating Fields (TTFields) therapy approved in the United States for newly diagnosed and recurrent GBM. This would reserve bevacizumab for subsequent disease progression. In this case series, we describe 8 patients with recurrent GBM who had disease progression on be...

  9. Erythema multiforme following application of hair dye

    Directory of Open Access Journals (Sweden)

    Sankha Koley

    2012-01-01

    Full Text Available Erythema multiforme (EM is an acute mucocutaneous hypersensitivity reaction with varying degrees of blistering and ulceration. Common causes of EM are herpes simplex virus infection, mycoplasma infection, drug hypersensitivity, vaccination and drug-virus interaction. EM induced by contact dermatitis is rare. Paraphenylene diamine, a common ingredient in many hair dyes, is well known to produce allergic contact dermatitis. We report a 35-year-old lady presenting with EM following severe contact dermatitis to hair dye. So far as we know, this is the first report from India describing EM following contact dermatitis.

  10. Bayesian segmentation of brainstem structures in MRI

    DEFF Research Database (Denmark)

    Iglesias, Juan Eugenio; Van Leemput, Koen; Bhatt, Priyanka;

    2015-01-01

    In this paper we present a method to segment four brainstem structures (midbrain, pons, medulla oblongata and superior cerebellar peduncle) from 3D brain MRI scans. The segmentation method relies on a probabilistic atlas of the brainstem and its neighboring brain structures. To build the atlas, we...... combined a dataset of 39 scans with already existing manual delineations of the whole brainstem and a dataset of 10 scans in which the brainstem structures were manually labeled with a protocol that was specifically designed for this study. The resulting atlas can be used in a Bayesian framework to segment...... the brainstem structures in novel scans. Thanks to the generative nature of the scheme, the segmentation method is robust to changes in MRI contrast or acquisition hardware. Using cross validation, we show that the algorithm can segment the structures in previously unseen T1 and FLAIR scans with great accuracy...

  11. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Hayley Patricia Ellis

    2014-03-01

    Full Text Available Glioblastoma Multiforme (GBM is the most common primary intrinsic CNS tumour and has an extremely poor overall survival, despite advances in neurosurgery, chemotherapy and radiation therapy. There has been interesting preliminary evidence suggesting that patients receiving the group of anti-diabetic drugs known as PPARγ (Peroxisome proliferator-activated receptor gamma agonists have a lower incidence of glioma. The nuclear hormone receptor PPARγ has been found to be expressed in high grade gliomas, and its activation has been shown to have several antineoplastic effects on human and rat glioma cell lines, and in some instances an additional protective increase in antioxidant enzymes has been observed in normal astrocytes. At present, no clinical trials are underway with regards to treating glioma patients using PPARγ agonists, as Pioglitazone and Rosiglitazone are only FDA-approved for use in treatment of type-2 diabetes. This review presents the case for evaluating the potential of PPARγ agonists as novel adjuvants in the treatment of high grade glioma. We introduce the PPARγ pathway, PPARγ gene and its products and examine recent research in glioblastoma.

  12. Wnt inhibitory factor-1 regulates glioblastoma cell cycle and proliferation.

    Science.gov (United States)

    Wu, Jun; Fang, Jiasheng; Yang, Zhuanyi; Chen, Fenghua; Liu, Jingfang; Wang, Yanjin

    2012-10-01

    Wnt proteins are powerful regulators of cell proliferation and differentiation, and activation of the Wnt signalling pathway is involved in the pathogenesis of several types of human tumours. Wnt inhibitory factor-1 (WIF-1) acts as a Wnt antagonist and tumour suppressor. Previous studies have shown that reducing expression of the WIF-1 gene aberrantly activates Wnt signalling and induces the development of certain types of cancers. In the present study, we examined the expression of WIF-1 in human primary glioblastoma multiforme (GBM) tumours. Studies using semiquantitative reverse transcription-polymerase chain reaction and immunohistochemical analysis revealed that WIF-1 expression is lower in human GBM than in normal brain tissue. To clarify the role of WIF-1, we transfected U251 human glioblastoma-derived cells, which do not express WIF-1, with the pcDNA3.1-WIF1 vector to restore WIF-1 expression. The results of cell proliferation, colony formation and apoptosis assays, as well as flow cytometry, indicate that exogenous WIF-1 has no effect on U251 cell apoptosis, but does arrest cells at the G(0)/G(1) phase and inhibit cell growth. Collectively, our data suggest that WIF-1 is a potent inhibitor of GBM growth. PMID:22901505

  13. Glioblastoma cancer stem cells: Biomarker and therapeutic advances.

    Science.gov (United States)

    Pointer, Kelli B; Clark, Paul A; Zorniak, Michael; Alrfaei, Bahauddeen M; Kuo, John S

    2014-05-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans. It accounts for fifty-two percent of primary brain malignancies in the United States and twenty percent of all primary intracranial tumors. Despite the current standard therapies of maximal safe surgical resection followed by temozolomide and radiotherapy, the median patient survival is still less than 2 years due to inevitable tumor recurrence. Glioblastoma cancer stem cells (GSCs) are a subgroup of tumor cells that are radiation and chemotherapy resistant and likely contribute to rapid tumor recurrence. In order to gain a better understanding of the many GBM-associated mutations, analysis of the GBM cancer genome is on-going; however, innovative strategies to target GSCs and overcome tumor resistance are needed to improve patient survival. Cancer stem cell biology studies reveal basic understandings of GSC resistance patterns and therapeutic responses. Membrane proteomics using phage and yeast display libraries provides a method to identify novel antibodies and surface antigens to better recognize, isolate, and target GSCs. Altogether, basic GBM and GSC genetics and proteomics studies combined with strategies to discover GSC-targeting agents could lead to novel treatments that significantly improve patient survival and quality of life.

  14. Overexpression of miR-100 inhibits cell proliferation, migration, and chemosensitivity in human glioblastoma through FGFR3

    Directory of Open Access Journals (Sweden)

    Luan YX

    2015-11-01

    Full Text Available Yongxin Luan,1 Shuyan Zhang,1 Ling Zuo,2 Lixiang Zhou1 1Department of Neurosurgery, First Bethune Hospital of Jilin University, 2Department of Ophthalmology, Second Bethune Hospital of Jilin University, Changchun, People’s Republic of China Background: Glioblastoma multiforme is one of the most deadly forms of brain cancer. We investigated the regulatory effects of microRNA-100 (miR-100 on cell proliferation, migration, and chemosensitivity in human glioblastoma. Methods: miR-100 expression was assessed by quantitative real-time polymerase chain reaction in both glioblastoma cells and human tumors. Lentiviruses of miR-100 mimics and inhibitors were transfected into U251 and T98G cells. The regulatory effects of either overexpressing or downregulating miR-100 on glioblastoma were evaluated by a viability assay, growth assay, migration assay, chemosensitivity assay, and an in vivo tumor transplantation assay. Expression of fibroblast growth factor receptor 3 (FGFR3, the bioinformatically predicted target of miR-100, was examined by Western blot in glioblastoma. FGFR3 was then ectopically overexpressed in U251 and T98G cells, and its effects on miR-100-mediated cancer regulation were evaluated by growth, migration, and chemosensitivity assays. Results: MiR-100 was markedly downregulated in both glioblastoma cell lines and human tumors. Overexpressing miR-100 through lentiviral transfection in U251 and T98G cells significantly inhibited cancer growth (both in vitro and in vivo and migration and increased chemosensitivity to cisplatin and 1, 3-bis (2-chloroethyl-l-nitrosourea, whereas downregulation of miR-100 had no effects on development of cancer. FGFR3 was directly regulated by miR-100 in glioblastoma. Ectopically overexpressing FGFR3 was able to ameliorate the anticancer effects of upregulation of miR-100 on glioblastoma growth, migration, and chemosensitivity. Conclusion: MiR-100 was generally downregulated in glioblastoma. Overexpressing mi

  15. Suppression of the Eag1 potassium channel sensitizes glioblastoma cells to injury caused by temozolomide

    Science.gov (United States)

    Sales, Thais Torquato; Resende, Fernando Francisco Borges; Chaves, Natália Lemos; Titze-De-Almeida, Simoneide Souza; Báo, Sônia Nair; Brettas, Marcella Lemos; Titze-De-Almeida, Ricardo

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma.

  16. Microarray Analysis in Glioblastomas

    Science.gov (United States)

    Bhawe, Kaumudi M.; Aghi, Manish K.

    2016-01-01

    Microarray analysis in glioblastomas is done using either cell lines or patient samples as starting material. A survey of the current literature points to transcript-based microarrays and immunohistochemistry (IHC)-based tissue microarrays as being the preferred methods of choice in cancers of neurological origin. Microarray analysis may be carried out for various purposes including the following: To correlate gene expression signatures of glioblastoma cell lines or tumors with response to chemotherapy (DeLay et al., Clin Cancer Res 18(10):2930–2942, 2012)To correlate gene expression patterns with biological features like proliferation or invasiveness of the glioblastoma cells (Jiang et al., PLoS One 8(6):e66008, 2013)To discover new tumor classificatory systems based on gene expression signature, and to correlate therapeutic response and prognosis with these signatures (Huse et al., Annu Rev Med 64(1):59–70, 2013; Verhaak et al., Cancer Cell 17(1):98–110, 2010) While investigators can sometimes use archived tumor gene expression data available from repositories such as the NCBI Gene Expression Omnibus to answer their questions, new arrays must often be run to adequately answer specific questions. Here, we provide a detailed description of microarray methodologies, how to select the appropriate methodology for a given question, and analytical strategies that can be used. Experimental methodology for protein microarrays is outside the scope of this chapter, but basic sample preparation techniques for transcript-based microarrays are included here. PMID:26113463

  17. Imaging of adult brainstem gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Purohit, Bela, E-mail: purohitbela@yahoo.co.in; Kamli, Ali A.; Kollias, Spyros S.

    2015-04-15

    Highlights: •BSG are classified on MRI into diffuse low-grade, malignant, focal tectal and exophytic subtypes. •Their prognosis and treatment is variable and is almost similar to adult supratentorial gliomas. •This article illustrates the imaging of adult BSGs on MRI and FET-PET. •We also describe prognostic factors and the treatment options of these tumours. -- Abstract: Brainstem gliomas (BSGs) are uncommon in adults accounting for about 2% of all intracranial neoplasms. They are often phenotypically low-grade as compared to their more common paediatric counterparts. Since brainstem biopsies are rarely performed, these tumours are commonly classified according to their MR imaging characteristics into 4 subgroups: (a) diffuse intrinsic low-grade gliomas, (b) enhancing malignant gliomas, (c) focal tectal gliomas and (d) exophytic gliomas/other subtypes. The prognosis and treatment is variable for the different types and is almost similar to adult supratentorial gliomas. Radiotherapy (RT) with adjuvant chemotherapy is the standard treatment of diffuse low-grade and malignant BSGs, whereas, surgical resection is limited to the exophytic subtypes. Review of previous literature shows that the detailed imaging of adult BSGs has not received significant attention. This review illustrates in detail the imaging features of adult BSGs using conventional and advanced MR techniques like diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), MR perfusion weighted imaging (PWI), MR spectroscopy (MRS), as well as {sup 18}F-fluoro-ethyl-tyrosine positron emission tomography ({sup 18}F-FET/PET). We have discussed the pertinent differences between childhood and adult BSGs, imaging mimics, prognostic factors and briefly reviewed the treatment options of these tumours.

  18. Chlamydia pneumoniae infection-associated erythema multiforme

    Directory of Open Access Journals (Sweden)

    Shinsaku Imashuku

    2013-06-01

    Full Text Available There is a well-known correlation between Herpes simplex (HSV infection and erythema multiforme (EM. More recently, in Japan, it was found that Chlamydia pneumoniae (Cp may promote the development of EM. All cases of Cp infection-associated EM that had been diagnosed in our clinic over the past two years (from 2011 to 2012 were analyzed. Cp infection was diagnosed on the basis of a significant increase (>2.00 in anti-Cp IgM titers, as measured by the HITAZYME-ELISA test. There were 7 cases of Cp-EM, one male and 6 females. Median age was 13 years (range 3-29 years. It is recommended that the possible involvement of Cp infection, besides HSV or Mycoplasma pneumoniae infections, should be considered in all cases of EM.

  19. Erythema Multiforme Major Following Treatment with Infliximab

    Science.gov (United States)

    Edwards, Dean; Boritz, Eli; Cowen, Edward W.; Brown, Ronald S.

    2012-01-01

    Background The growth in the use of anti-TNF-α agents for treatment of inflammatory conditions has led to increased recognition of the side effects associated with this class of drugs. Case Description We report a case of a patient who developed erythema multiforme (EM) major with characteristic oral and cutaneous lesions following treatment with the anti-TNF-α medication infliximab therapy for Crohn’s Disease (CD). Clinical Implications To our knowledge, this is the first reported case of infliximab-induced EM secondary to the treatment of CD. It is important for dental clinicians evaluating patients using anti-TNF-α agents to be aware of this possible complication. PMID:23036796

  20. Intracerebral neurocysticercosis mimicking glioblastoma multiforme: a rare differential diagnosis in Central Europe

    Energy Technology Data Exchange (ETDEWEB)

    Sabel, M.; Weber, F. [Dept. of Neurosurgery, Heinrich-Heine Univ. Duesseldorf (Germany); Neuen-Jacob, E. [Dept. of Neuropathology, Heinrich-Heine Univ. Duesseldorf (Germany); Vogt, C. [Dept. of Internal Medicine, Heinrich-Heine Univ. Duesseldorf (Germany)

    2001-03-01

    A 47-year-old Greek man presented with a 4-week history of speech difficulties. CT and MRI revealed a low-density multilobulated cystic frontal mass with peripheral ring contrast enhancement adjacent to the sylvian fissure. Examination was normal. Blood tests revealed leucocytosis (16,000 cells/{mu}l) and an elevated erythrocyte sedimentation rate (30/52). A malignant brain tumour was suspected and surgically removed. Histological examination disclosed intracerebral neurocysticercosis. (orig.)

  1. VEGF-dependent mechanism of anti-angiogenic action of diamond nanoparticles in Glioblastoma Multiforme tumor

    DEFF Research Database (Denmark)

    Grodzik, M.; Sawosz, E.; Wierzbicki, M.;

    2012-01-01

    of diamond nanoparticle on VEGF level and inhibition of the brain tumor angiogenesis. We evaluated interaction of VEGF-A and VEGF-receptor proteins with diamond nanoparticles (TEM), visualized lower the permeability of blood vessels after diamond nanoparticles treatment and determined localization...

  2. Synthetic Nano-Low Density Lipoprotein as Targeted Drug DeliveryVehicle for Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Nikanjam, Mina; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Shu,Xiao; Budinger, Thomas F.; Forte, Trudy M.

    2006-06-14

    This paper discribes a synthetic low density lipoprotein(LDL) made by complexing a 29 amino acid that consists of a lipid bindingdomain and the LDL receptor binding domain with a lipid microemulsion.The nano-LDL particles were intermdiate in size between LDL and HDL andbound to LDL receptors on GBM brain tumor cells. Synthetic nano-LDLuptake by GBM cells was LDL receptor specific and dependent on cellreceptor number. It is suggested that these synthetic particles can serveas a delivery vehicle for hydophobic anti-tumor drugs by targeting theLDL receptor.

  3. Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound

    Directory of Open Access Journals (Sweden)

    Yang FY

    2012-02-01

    Full Text Available Feng-Yi Yang1, Ming-Che Teng1, Maggie Lu2, Hsiang-Fa Liang2, Yan-Ru Lee1, Chueh-Chuan Yen3, Muh-Lii Liang4,5, Tai-Tong Wong51Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 2Drug Delivery Laboratory, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 3Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 4Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, 5Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, TaiwanBackground: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1-conjugated liposomes selectively to brain tumors.Methods: Firefly luciferase (Fluc-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice.Results: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug ratio (P < 0.001. Combining repeated pulsed HIFU with AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin has similar antitumor effects.Conclusion: This study demonstrates that targeted or untargeted liposomal doxorubicin, followed by repeated pulsed HIFU, is a promising high-dose chemotherapy method that allows the desired brain tumor region to be targeted specifically.Keywords: repeated focused ultrasound, interleukin-4 receptor, blood-brain barrier, brain tumor, target drug delivery

  4. Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme

    DEFF Research Database (Denmark)

    Lassen, Ulrik; Sorensen, Morten; Gaziel, Tine Bernhardtsen;

    2013-01-01

    Kinase B (AKT), and the mammalian target of rapamycin (mTOR) and is associated with unfavorable prognosis. Temsirolimus, an mTOR inhibitor, has been well-tolerated in monotherapy, but with limited effects. The combination of temsirolimus and antibodies to vascular endothelial factor (VEGF) has not yet...

  5. Glioblastoma multiforme of the optic chiasm: A rare case of common pathology

    Directory of Open Access Journals (Sweden)

    Kirill A Lyapichev

    2016-01-01

    Conclusion: Chiasmal GBM is an extremely rare condition where a biopsy is necessary for accurate diagnosis and optimal treatment. Differential diagnosis for such lesions can be very difficult and include demyelinating optic neuritis and non-demyelinating inflammatory optic neuropathy (e.g., sarcoid, vascular lesions (e.g., cavernoma, compressive lesions of the optic apparatus, metastatic malignancy, and primary tumors of the anterior optic pathway. The role of chemotherapy and radiotherapy including novel stereotaxic radiosurgery methods is still unclear and will need to be evaluated.

  6. LIN28 Is Involved in Glioma Carcinogenesis and Predicts Outcomes of Glioblastoma Multiforme Patients

    OpenAIRE

    Qin, Rong; ZHOU, JINGXU; Chen, Chao; Xu, Tao; Yan, Yong; Ma, Yushui; Zheng, Zongli; Shen, Yiping; Lu, Yicheng; Fu, Da; Chen, Juxiang

    2014-01-01

    LIN28, an evolutionarily conversed RNA binding protein which can bind to the terminal loops of let-7 family microRNA precursors and block their processing to maturation, is highly expressed in several subsets of tumors that carry poor prognoses, such as ovarian carcinoma, hepatocellular carcinoma, colon carcinoma and germ cell carcinoma. However, there has been no study on the expression of LIN28 in glioma tissues or their importance as a prognostic predictor of glioma patients. This study ai...

  7. LIN28 is involved in glioma carcinogenesis and predicts outcomes of glioblastoma multiforme patients.

    Directory of Open Access Journals (Sweden)

    Rong Qin

    Full Text Available LIN28, an evolutionarily conversed RNA binding protein which can bind to the terminal loops of let-7 family microRNA precursors and block their processing to maturation, is highly expressed in several subsets of tumors that carry poor prognoses, such as ovarian carcinoma, hepatocellular carcinoma, colon carcinoma and germ cell carcinoma. However, there has been no study on the expression of LIN28 in glioma tissues or their importance as a prognostic predictor of glioma patients. This study aimed to examine the expression of LIN28 in glioma and correlate the results to patient outcome. We found that LIN28 expression was significantly higher in the group of patients with a poor prognosis compared to patients with a good prognosis by gene microarray. Log-rank analysis showed patients with higher LIN28 expression level in tumor had a shorter progression-free survival and overall survival times compared to those with lower LIN28 expression level. Similar results were also obtained from the tissue microarray analysis. Univariate and multivariate analyses showed high LIN28 expression was an independent prognostic factor for a shorter progression-free survival and overall survival in GBM patients. Furthermore in vitro experiments showed that down-regulation of LIN28 in U251 and U373 cells caused cell cycle arrest in the G1 phase, delayed cell proliferation, increased apoptosis, and resulted in fewer colonies compared to controls. Summarily, our data provides a potential target for cancer therapy as an approach to overcome the poor options currently available for GBM patients.

  8. P17.47COMPREHENSIVE PROTEOMIC PROFILING OF BEVACIZUMAB-RESISTANT GLIOBLASTOMA MULTIFORME

    OpenAIRE

    Kaufman, K.L.; Ly, L.; McKay, M.; Mallawaaratchy, D.M.; Mactier, S.; Crossett, B.; Molloy, M; Buckland, M.E.; McDonald, K. L.; Christopherson, R. I.

    2014-01-01

    Drugs that impair tumour angiogenesis, i.e. therapeutic antibody anti-vascular endothelial growth factor, bevacizumab (BEV), are becoming standard therapy for recurrent GBM, despite having no impact on overall survival times. Resistance to BEV is fatal, and mechanisms are largely unexplored. With access to exceedingly rare fresh-frozen serial GBM tumours, we performed comprehensive quantitative proteome analyses to identify important mechanisms of BEV escape and tumour recurrence. Tumour tiss...

  9. Glioblastoma Multiforme Segmentation in MRI Data with a Balloon Inflation Approach

    CERN Document Server

    Zukić, Dženan; Bauer, Miriam H A; Kuhnt, Daniela; Carl, Barbara; Freisleben, Bernd; Kolb, Andreas; Nimsky, Christopher

    2011-01-01

    Gliomas are the most common primary brain tumors, evolving from the cerebral supportive cells. For clinical follow-up, the evaluation of the preoperative tumor volume is essential. Volumetric assessment of tumor volume with manual segmentation of its outlines is a time-consuming process that can be overcome with the help of computer-assisted segmentation methods. In this paper, a semi-automatic approach for World Health Organization (WHO) grade IV glioma segmentation is introduced that uses balloon inflation forces, and relies on the detection of high-intensity tumor boundaries that are coupled by using contrast agent gadolinium. The presented method is evaluated on 27 magnetic resonance imaging (MRI) data sets and the ground truth data of the tumor boundaries - for evaluation of the results - are manually extracted by neurosurgeons.

  10. Nanoparticles containing allotropes of carbon have genotoxic effects on glioblastoma multiforme cells

    DEFF Research Database (Denmark)

    Hinzmann, Mateusz; Jaworski, Sławomir; Kutwin, Marta;

    2014-01-01

    The carbon-based nanomaterial family consists of nanoparticles containing allotropes of carbon, which may have a number of interactions with biological systems. The objective of this study was to evaluate the toxicity of nanoparticles comprised evaluation of cell morphology, and assessment of cel...

  11. In vitro evaluation of the effects of graphene platelets on glioblastoma multiforme cells

    DEFF Research Database (Denmark)

    Jaworski, Slawomir; Sawosz, Ewa; Grodzik, Marta;

    2013-01-01

    Graphene is a single atom-thick material with exciting potential. It can be used in many fields, from electronics to biomedicine. However, little is known about its toxicity and biocompatibility. Herein, we report a study on the toxicity of graphene platelets (GPs) by examining the influence of G...

  12. Nanoparticles containing allotropes of carbon have genotoxic effects on glioblastoma multiforme cells.

    Science.gov (United States)

    Hinzmann, Mateusz; Jaworski, Sławomir; Kutwin, Marta; Jagiełło, Joanna; Koziński, Rafał; Wierzbicki, Mateusz; Grodzik, Marta; Lipińska, Ludwika; Sawosz, Ewa; Chwalibog, Andrè

    2014-01-01

    The carbon-based nanomaterial family consists of nanoparticles containing allotropes of carbon, which may have a number of interactions with biological systems. The objective of this study was to evaluate the toxicity of nanoparticles comprised of pristine graphene, reduced graphene oxide, graphene oxide, graphite, and ultradispersed detonation diamond in a U87 cell line. The scope of the work consisted of structural analysis of the nanoparticles using transmission electron microscopy, evaluation of cell morphology, and assessment of cell viability by Trypan blue assay and level of DNA fragmentation of U87 cells after 24 hours of incubation with 50 μg/mL carbon nanoparticles. DNA fragmentation was studied using single-cell gel electrophoresis. Incubation with nanoparticles containing the allotropes of carbon did not alter the morphology of the U87 cancer cells. However, incubation with pristine graphene and reduced graphene oxide led to a significant decrease in cell viability, whereas incubation with graphene oxide, graphite, and ultradispersed detonation diamond led to a smaller decrease in cell viability. The results of a comet assay demonstrated that pristine graphene, reduced graphene oxide, graphite, and ultradispersed detonation diamond caused DNA damage and were therefore genotoxic in U87 cells, whereas graphene oxide was not. PMID:24876774

  13. SU-C-BRE-03: Dual Compartment Mathematical Modeling of Glioblastoma Multiforme (GBM)

    Energy Technology Data Exchange (ETDEWEB)

    Yu, V; Nguyen, D; Kupelian, P; Kaprealian, T; Selch, M; Low, D; Pajonk, F; Sheng, K [UCLA, Los Angeles, CA (United States)

    2014-06-15

    Purpose: To explore the aggressive recurrence and radioresistence of GBM with a dual compartment tumor survival mathematical model based on intrinsic tumor heterogeneity, cancer stem cells (CSC) and differentiated cancer cells (DCC). Methods: The repopulation and differentiation responses to radiotherapy of a solid tumor were simulated using an Ordinary Differential Equation (ODE). To obtain the tumor radiobiological parameters, we assumed that a tumor consists of two subpopulations, each with its distinctive linear quadratic parameters. The dual compartment cell survival model was constructed as SF(D)=F × exp(-α{sub 1} D-β{sub 1}D{sup 2}) + (1-F) × exp(-α{sub 2}D-β{sub 2}D{sup 2}) for a single fraction of treatment, with F as the fraction of CSC, and α and β describing the radiological properties of each population. Robust least square fitting was performed on clonogenic survival data from one GBM (U373MG) and one NSCLC (H460) cell line. The fit parameters were then used in the ODE model to predict treatment outcome of various treatment schemes. Results: The fit parameters from GBM cell survival data were (F, α{sub 1}, β{sub 1}, α{sub 2}, β{sub 2})=(0.0396, 0.0801, 0.0006, 0.1363, 0.0279), exhibiting two populations with distinctive radiological properties, CSC more radioresistant than DCC. The GBM cell line exhibited significantly poorer tumor control than its single compartment model prediction and NSCLC, which responded well to hypofrationation. The increased radioresistance was due to rapid regrowth of the DCC compartment triggered by its depletion while maintaining a viable CSC population. The rapid regrowth can be reduced by treating dose fractions ≤ 2 Gy with a prolonged treatment period. Conclusion: The interaction between a radioresistant CSC compartment and DCC compartment can explain the poor clinical outcome of GBM after radiotherapy despite dose escalation and hypofractionation attempts. Lower dose fractions result in better treatment outcome but still eventually recurs. Dose escalation beyond 100 Gy and/or differentiation therapy will be vital in achieving GBM tumor control.

  14. Predicting the growth of glioblastoma multiforme spheroids using a multiphase porous media model.

    Science.gov (United States)

    Mascheroni, Pietro; Stigliano, Cinzia; Carfagna, Melania; Boso, Daniela P; Preziosi, Luigi; Decuzzi, Paolo; Schrefler, Bernhard A

    2016-10-01

    Tumor spheroids constitute an effective in vitro tool to investigate the avascular stage of tumor growth. These three-dimensional cell aggregates reproduce the nutrient and proliferation gradients found in the early stages of cancer and can be grown with a strict control of their environmental conditions. In the last years, new experimental techniques have been developed to determine the effect of mechanical stress on the growth of tumor spheroids. These studies report a reduction in cell proliferation as a function of increasingly applied stress on the surface of the spheroids. This work presents a specialization for tumor spheroid growth of a previous more general multiphase model. The equations of the model are derived in the framework of porous media theory, and constitutive relations for the mass transfer terms and the stress are formulated on the basis of experimental observations. A set of experiments is performed, investigating the growth of U-87MG spheroids both freely growing in the culture medium and subjected to an external mechanical pressure induced by a Dextran solution. The growth curves of the model are compared to the experimental data, with good agreement for both the experimental settings. A new mathematical law regulating the inhibitory effect of mechanical compression on cancer cell proliferation is presented at the end of the paper. This new law is validated against experimental data and provides better results compared to other expressions in the literature.

  15. Early clinical experience of boron neutron capture therapy for glioblastoma multiforme

    International Nuclear Information System (INIS)

    Boron neutron capture therapy (BNCT) is a binary treatment modality that can selectively irradiate tumor tissue. BNCT uses drugs containing a stable isotope of boron. 10B, to sensitize tumor cells to irradiation by low energy (thermal) neutrons. The interaction of the 10B with a thermal neutron (neutron capture) causes the 10B nucleus to split, releasing an alpha particle and a lithium nucleus. These products of the 10B(n, α)7Li reaction are very damaging to cells but have a combined path length in tissue of approximately 14 μm, or roughly the diameter of one or two cells. Thus, most of the ionizing energy imparted to tissue is localized to 10B-loaded cells

  16. Distinct molecular signatures in pediatric infratentorial glioblastomas defined by aCGH.

    Science.gov (United States)

    Sharma, S; Free, A; Mei, Y; Peiper, S C; Wang, Z; Cowell, J K

    2010-10-01

    Glioblastomas (GBM) are rare in children, but reportedly have more varied outcome which suggests differences in tumor etiology compared to typical GBM of adults. To investigate this we performed high resolution array comparative genomic hybridization (aCGH) analysis on three pediatric infratentorial GBM, ages 3.5, 7 and 14 years. Two of these tumors occurred in the brainstem and one in the spinal cord. While histologically typical, one brainstem tumor showed mainly pleomorphic astrocytic cells, whereas the other brainstem and spinal tumors showed a GFAP positive small cell component. Whole chromosomal gains (#1 and #2) and loss (#20) were seen only in the pleomorphic brainstem GBM, which also showed a high level of segmental genomic copy number changes. Segmental loss involving chromosome 8 was seen in all three tumors (Chr8;133039446-136869494, Chr8;pter-3581577, and Chr8;pter-30480019 respectively), whereas loss involving chromosome 16 was seen in only 2 cases with small cell components (Chr16;31827239-qter and Chr16;pter-29754532). Segmental gain of chromosome 7 was shared only between the 2 brainstem cases (Chr7;17187166-qter and Chr7;69824947-qter). Chromosome 17 showed segmental gain of 17q in the backdrop of loss of 17p only in case 1. Segmental gain of chromosome 1q was seen only in case 2. The spinal GBM showed a relatively stable karyotype with a unique loss of Chr19;32848902-qter. None of the frequent losses, gains and amplifications known to occur in adult GBM were identified, suggesting that pediatric infratentorial glioblastomas show a molecular karyotype that was more characteristic of pediatric embryonal tumors than adult GBM.

  17. Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis.

    Science.gov (United States)

    Lamborn, Kathleen R; Chang, Susan M; Prados, Michael D

    2004-07-01

    Survival for patients with glioblastoma multiforme is short, and current treatments provide limited benefit. Therefore, there is interest in conducting phase 2 trials of experimental treatments in newly diagnosed patients. However, this requires historical data with which to compare the experimental therapies. Knowledge of prognostic markers would also allow stratification into risk groups for phase 3 randomized trials. In this retrospective study of 832 glioblastoma multiforme patients enrolled into prospective clinical trials at the time of initial diagnosis, we evaluated several potential prognostic markers for survival to establish risk groups. Analyses were done using both Cox proportional hazards modeling and recursive partitioning analyses. Initially, patients from 8 clinical trials, 6 of which included adjuvant chemotherapy, were included. Subsequent analyses excluded trials with interstitial brachytherapy, and finally included only nonbrachytherapy trials with planned adjuvant chemotherapy. The initial analysis defined 4 risk groups. The 2 lower risk groups included patients under the age of 40, the lowest risk group being young patients with tumor in the frontal lobe only. An intermediate-risk group included patients with Karnofsky performance status (KPS) >70, subtotal or total resection, and age between 40 and 65. The highest risk group included all patients over 65 and patients between 40 and 65 with either KPS<80 or biopsy only. Subgroup analyses indicated that inclusion of adjuvant chemotherapy provides an increase in survival, although that improvement tends to be minimal for patients over age 65, for patients over age 40 with KPS less than 80, and for those treated with brachytherapy.

  18. Air pollution is associated with brainstem auditory nuclei pathology and delayed brainstem auditory evoked potentials

    OpenAIRE

    Calderón-Garcidueñas, Lilian; D’Angiulli, Amedeo; Kulesza, Randy J.; Torres-Jardón, Ricardo; Osnaya, Norma; Romero, Lina; Keefe, Sheyla; Herritt, Lou; Brooks, Diane M.; Avila-Ramirez, Jose; Delgado-Chávez, Ricardo; Medina-Cortina, Humberto; González-González, Luis Oscar

    2011-01-01

    We assessed brainstem inflammation in children exposed to air pollutants by comparing brainstem auditory evoked potentials (BAEPs) and blood inflammatory markers in children age 96.3± 8.5 months from highly polluted (n=34) versus a low polluted city (n=17). The brainstems of nine children with accidental deaths were also examined. Children from the highly polluted environment had significant delays in wave III (t(50)=17.038; p

  19. Brainstem involvement in subacute sclerosing panencephalitis

    Directory of Open Access Journals (Sweden)

    Pawan Sharma

    2011-01-01

    Full Text Available The parieto-occipital region of the brain is most frequently and severely affected in subacute sclerosing panencephalitis (SSPE. The basal ganglia, cerebellum and corpus callosum are less commonly involved. Brainstem involvement is rarely described in SSPE, and usually there is involvement of other regions of the brain. We describe a patient with subacute sclerosing panencephalitis with brain magnetic resonance imaging showing extensive brainstem involvement without significant involvement of other cortical structures. Though rarely described in SSPE, one should be aware of such brainstem and cerebellum involvement, and SSPE should be kept in mind when brainstem signal changes are seen in brain MRI with or without involvement of other regions of brain to avoid erroneous reporting.

  20. Detection of brainstem involvemetn in multiple sclerosis

    International Nuclear Information System (INIS)

    The Gradient Refocusing Technique, which seppresses the influence of cerebrospinal fluis (GSF) and vascular motion artifact on MRI sensitivity, is applied combined with Brainstem Auditory Evoked Potentials (BAEPs) and median Somatosensory Evoked Potentials (SEPs) in the evaluation of the brainstem in 30 MS patients with clinical signs of involvement of this structure in order to reevaluate the sensitivity of these techniques. (Author). 2 refs.; 1 tab

  1. Brainstem Circuits Regulating Gastric Function

    Science.gov (United States)

    Travagli, R. Alberto; Hermann, Gerlinda E.; Browning, Kirsteen N.; Rogers, Richard C.

    2011-01-01

    Brainstem parasympathetic circuits that modulate digestive functions of the stomach are comprised of afferent vagal fibers, neurons of the nucleus tractus solitarius (NTS), and the efferent fibers originating in the dorsal motor nucleus of the vagus (DMV). A large body of evidence has shown that neuronal communications between the NTS and the DMV are plastic and are regulated by the presence of a variety of neurotransmitters and circulating hormones as well as the presence, or absence, of afferent input to the NTS. These data suggest that descending central nervous system inputs as well as hormonal and afferent feedback resulting from the digestive process can powerfully regulate vago-vagal reflex sensitivity. This paper first reviews the essential “static” organization and function of vago-vagal gastric control neurocircuitry. We then present data on the opioidergic modulation of NTS connections with the DMV as an example of the “gating” of these reflexes, i.e., how neurotransmitters, hormones, and vagal afferent traffic can make an otherwise static autonomic reflex highly plastic. PMID:16460274

  2. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53.

    OpenAIRE

    Mercer, W E; Shields, M T; Amin, M; Sauve, G J; Appella, E; Romano, J W; Ullrich, S J

    1990-01-01

    To investigate the effect that human wild-type p53 (wt-p53) expression has on cell proliferation we constructed a recombinant plasmid, pM47, in which wt-p53 cDNA is under transcriptional control of the hormone-inducible mouse mammary tumor virus promoter linked to the dominant biochemical selection marker gene Eco gpt. The pM47 plasmid was introduced into T98G cells derived from a human glioblastoma multiforme tumor, and a stable clonal cell line, GM47.23, was derived that conditionally expre...

  3. Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1, independent of sonic hedgehog level

    OpenAIRE

    Munoz, Jessian L.; Rodriguez-Cruz, Vivian; Ramkissoon, Shakti H.; Ligon, Keith L.; Greco, Steven J.; Rameshwar, Pranela

    2015-01-01

    Glioblastoma Multiforme (GBM), the most common and lethal adult primary tumor of the brain, showed a link between Sonic Hedgehog (SHH) pathway in the resistance to temozolomide (TMZ). PTCH1, the SHH receptor, can tonically represses signaling by endocytosis. We asked how the decrease in PTCH1 in GBM cells could lead to TMZ-resistance. TMZ resistant GBM cells have increased PTCH1 mRNA and reduced protein. Knockdown of Dicer, a Type III RNAase, indicated that miRNAs can explain the decreased PT...

  4. Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression.

    Directory of Open Access Journals (Sweden)

    Gloria Perazzoli

    Full Text Available The use of temozolomide (TMZ has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated.Four nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2'-deoxycytidine was used to demethylate the MGMT promoter and O(6-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed.Our results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229 and high (SF268 and SK-N-SH basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC50 showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC50 did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC50, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines.These results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma multiforme patients.

  5. Science Letters: Dendritic cell therapy with improved outcome in glioma multiforme--a case report

    Institute of Scientific and Technical Information of China (English)

    KHAN Jamal A.; YAQIN Sharmin

    2006-01-01

    Malignant gliomas are the most devastating tumors in clinical practice and have poorest survival. Immunological treatment of such patients may likely increase the survival and quality of life. Dendritic cells (DCs), most potent antigen presenting cells in combination with oral chemotherapeutic agents may be tried for patients giving consent to such treatment. We have successfully combined the two therapies in an adult male patient who was on downhill course after being operated on once with post operation chemotherapy and radiotherapy for glioma in the left parietal area. He received five dendritic cell therapy vaccines in combination with oral chemotherapy and responded dramatically having near normal quality of life for an additional five months with this regime, increasing the survival after operation to 11 months. This therapy is continuing with radiological betterment of the lesion. The DCs are matured with antigen extracted from wax embedded tissue at 6th day of culture. We feel that the treatment can be given to more number of patients to establish its efficacy for the dreaded cancer glioblastoma multiforme.

  6. Glioblastoma with oligodendroglial components: glioblastoma or anaplastic oligodendroglial tumors.

    Science.gov (United States)

    Takeuchi, Hiroaki; Hosoda, Tetsuya; Kitai, Ryuhei; Kodera, Toshiaki; Arishima, Hidetaka; Tsunetoshi, Kenzo; Neishi, Hiroyuki; Yamauchi, Takahiro; Sato, Kazufumi; Imamura, Yoshiyuki; Itoh, Hiroshi; Kubota, Toshihiko; Kikuta, Ken-ichiro

    2012-07-01

    There have been some recent reports about glioblastoma with oligodendroglial (OG) components and malignant glioma with primitive neuroectodermal tumor (PNET)-like components. We investigated whether the presence and extent of OG components and PNET-like components influenced the prognosis in patients with glioblastoma. Eighty-six patients with glioblastoma were divided into an OG group (28 %), which revealed areas with a honeycomb appearance, and a non-OG group (72 %) without a honeycomb appearance. Patients with glioblastoma were also divided into a PNET group (27 %), which revealed areas with PNET-like features defined as neoplastic cells with high N/C ratios and hyperchromatic oval-carrot-shaped nuclei, and lacked the typical honeycomb appearance, and a non-PNET group (73 %) without PNET features. There were no significant differences in overall survival among the OG, the non-OG, the PNET, and the non-PNET groups. Two patients who survived longer than 36 months had both OG and PNET components with 1p or 19q loss of heterozygosity. Perinuclear halo, which is a characteristic feature of oligodendrogliomas, is an artifact of tissue fixation. Therefore, we should not readily use the term glioblastoma with OG components. PNET-like components, which are considered rare in malignant gliomas, may be frequently identified in glioblastomas. PMID:22527749

  7. The transcriptome and miRNome profiling of glioblastoma tissues and peritumoral regions highlights molecular pathways shared by tumors and surrounding areas and reveals differences between short-term and long-term survivors

    OpenAIRE

    Fazi, Barbara; Felsani, Armando; Grassi, Luigi; Moles, Anna; D'Andrea, Daniel; Toschi, Nicola; Sicari, Daria; De Bonis, Pasquale; Anile, Carmelo; Guerrisi, Maria Giovanna; Luca, Emilia; Farace, Maria Giulia; Maira, Giulio; Ciafré, Silvia Anna; Mangiola, Annunziato

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor, driving patients to death within 15 months after diagnosis (short term survivors, ST), with the exception of a small fraction of patients (long term survivors, LT) surviving longer than 36 months. Here we present deep sequencing data showing that peritumoral (P) areas differ from healthy white matter, but share with their respective frankly tumoral (C) samples, a number of mRNAs and microRNAs representative of...

  8. Characterization of radioresistant variant from U251 human glioblastoma cell line and the role of antioxdant enzymes in its radioresistancy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hyung Chahn; Park, In Chul; Park, Myung Jin; Woo, Sang Hyeok; Rhee, Chang Hum; Hong, Seok-II [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2004-07-01

    To investigate the radioresistant mechanism in glioblastoma multiforme(GBM), we isolated the radioresistant clone (RRC) from U251 human glioblastoma cell line by exposing to repeated fractions of 3 Gy {gamma}-radiation for six months. RRC had higher radioresistance than the parent cell line as measured by clonogenic survival assay. FACS analysis showed that RRC had a delayed G2 arrest after radiation. Antioxidant enzymes, such as SOD, catalase, glutathione peroxidase (GPX), glutathione reductase (GR), were activated up to 5 folds in RRC after radiation. Erk 1/2 activation was higher in RRC than in the parent cell. Therefore, radioresistancy in RRC might be due to the delayed cell cycle, the coordinated high activation of antioxidant enzyme rather than a single enzyme alone,and higher activation of Erk 1/2.

  9. Bullous Lupus Erythematosus Manifesting As Erythema Multiforme

    Directory of Open Access Journals (Sweden)

    Dhurat Rachita

    2004-01-01

    Full Text Available Bullous SLE has a distinctive clinical, histopathologic and immunopathologic features that together constitute a unique bullous disease phenotype. We report a 33 year old female presenting with multiple tense vesicles and bullae on normal and erythematous skin over the body and oral erosions. Palms and extremities showed typical target lesions. She had consumed NSAIDs intermittently for joint pains. She was diagnosed as bullous erythema multiforme and started on oral prednisolone but lesions failed to heal. Patient recollected a history of low grade fever and a photosensitive rash in the past. Investigations revealed positive ANA with a peripheral pattern. A skin biopsy of a vesicle showed a subepidemal blisher. Perilesional direct immunofluorescence studies showed a linear deposition of IgG, IgA and fibrin along the basement membrane zone and perivascular deposition of IgG. Lapus band test showed a linear deposition of IgG, C3, IgM and fibrin at BMZ clinching the diagnosis of bullous lupus erythematosus.

  10. IMAGING WHITE MATTER IN HUMAN BRAINSTEM

    Directory of Open Access Journals (Sweden)

    Anastasia A Ford

    2013-07-01

    Full Text Available The human brainstem is critical for the control of many life-sustaining functions, such as consciousness, respiration, sleep, and transfer of sensory and motor information between the brain and the spinal cord. Most of our knowledge about structure and organization of white and gray matter within the brainstem is derived from ex vivo dissection and histology studies. However, these methods cannot be applied to study structural architecture in live human participants. Tractography from diffusion-weighted MRI may provide valuable insights about white matter organization within the brainstem in vivo. However, this method presents technical challenges in vivo due to susceptibility artifacts, functionally dense anatomy, as well as pulsatile and respiratory motion. To investigate the limits of MR tractography, we present results from high angular resolution diffusion imaging (HARDI of an intact excised human brainstem performed at 11.1T using isotropic resolution of 0.333, 1, and 2 mm, with the latter reflecting resolution currently used clinically. At the highest resolution, the dense fiber architecture of the brainstem is evident, but the definition of structures degrades as resolution decreases. In particular, the inferred corticopontine/corticospinal tracts (CPT/CST, superior (SCP and middle cerebellar peduncle (MCP, and medial lemniscus (ML pathways are clearly discernable and follow known anatomical trajectories at the highest spatial resolution. At lower resolutions, the CST/CPT, SCP, and MCP pathways are artificially enlarged due to inclusion of collinear and crossing fibers not inherent to these three pathways. The inferred ML pathways appear smaller at lower resolutions, indicating insufficient spatial information to successfully resolve smaller fiber pathways. Our results suggest that white matter tractography maps derived from the excised brainstem can be used to guide the study of the brainstem architecture using diffusion MRI in vivo.

  11. [Palliative care for glioblastoma].

    Science.gov (United States)

    Dieudonné, Nathalie; De Micheli, Rita; Hottinger, Andreas

    2016-04-27

    Patients with glioblastoma have a limited life expectancy and an impaired quality of life and they should be offered palliative care soon after the diagnosis is established. Still, only a quarter of patients aged over 65 return home or medical institution after completing treatments. Home care must be promoted by coordinating assistance and care, combining disciplines such as physiotherapy and ergotherapy, medical and nursing care and psychosocial support. Patients are at risk of mood, personality and behavioural disorders. Limited awareness of these troubles and their physical limitations alter their capacity of rehabilitation and social relationships. Isolation of relatives, exhaustion and misunderstandings should be prevented. The therapeutic goals should be discussed and determined upstream to anticipate difficulties and questions concerning end of life. PMID:27281945

  12. Expression of the neurotrophin receptors Trk A and Trk B in adult human astrocytoma and glioblastoma

    Indian Academy of Sciences (India)

    Shashi Wadhwa; Tapas C Nag; Anupam Jindal; Rahul Kushwaha; Ashok K Mahapatra; Chitra Sarkar

    2003-03-01

    Neurotrophins and their receptors of the Trk family play a critical role in proliferation, differentiation and survival of the developing neurons. There are reports on their expression in neoplasms too, namely, the primitive neuroectodermal tumours of childhood, and in adult astrocytic gliomas. The involvement of Trk receptors in tumour pathogenesis, if any, is not known. With this end in view, the present study has examined 10 tumour biopsy samples (identified as astrocytoma, pilocytic astrocytoma and glioblastoma) and peritumoral brain tissue of adult patients, for the presence of Trk A and Trk B receptors, by immunohistochemistry. The nature of the tumour samples was also confirmed by their immunoreactivity (IR) to glial fibrillary acidic protein. In the peritumoral brain tissue, only neurons showed IR for Trk A and Trk B. On the contrary, in the tumour sections, the IR to both receptors was localized in the vast majority of glia and capillary endothelium. There was an obvious pattern of IR in these gliomas: high levels of IR were present in the low-grade (type I and II) astrocytoma; whereas in the advanced malignant forms (WHO grade IV giant cell glioblastoma and glioblastoma multiforme) the IR was very weak. These findings suggest that Trk A and Trk B are involved in tumour pathogenesis, especially in the early stage, and may respond to signals that elicit glial proliferation, and thus contribute to progression towards malignancy.

  13. Glioblastoma, brain metastases and soft tissue sarcoma of extremities: Candidate tumors for BNCT

    International Nuclear Information System (INIS)

    10B-concentration ratios between human glioblastoma multiforme (U87MG), sarcoma (S3) and melanoma (MV3) xenografted in nu/nu mice and selected normal tissues were investigated to test for preferential 10B-accumulation. Animals received BSH, BPA or both compounds sequentially. Mean 10B-concentration ratios between tumor and normal tissues above 2 were found indicating therapeutic ratios. In addition to glioblastoma, brain metastases and soft tissue sarcoma appear to be promising targets for future BNCT research. - Highlights: • BSH leads to high 10B concentration ratios between sarcoma, muscle and brain as well as between glioblastoma and brain. • The 10B concentration in tumors is quite low as is the 10B concentration ratio between tumors and blood. • BPA-f leads to 10B accumulation in tumors relative to blood and advantageous absolute 10B concentrations in tumors. • The 10B concentration ratios between tumors and brain and sarcoma and muscle, are modest. • The advantage of the sequential injection of both compounds is an enhanced intratumoral 10B concentration

  14. A murine model of xenotransplantation of human glioblastoma with imunosupression by orogastric cyclosporin

    Directory of Open Access Journals (Sweden)

    Alexandre M. Cunha

    2011-02-01

    Full Text Available Several animal experimental models have been used in the study of malignant gliomas. The objective of the study was to test the efficacy of a simple, reproducible and low cost animal model, using human cells of glioblastoma multiforme (GBM xenotransplantated in subcutaneous tissue of Wistar rats, immunosuppressed with cyclosporin given by orogastric administration, controlled by nonimunosuppressed rats. The animals were sacrificed at weekly intervals and we have observed gradual growth of tumor in the immunosuppressed group. The average tumor volume throughout the experiment was 4.38 cm³ in the immunosuppressed group, and 0.27 cm³ in the control one (p<0.001. Tumors showed histopathological hallmarks of GBM and retained its glial identity verified by GFAP and vimentin immunoreaction. Immunosuppression of rats with cyclosporin was efficient in allowing the development of human glioblastoma cells in subcutaneous tissues. The model has demonstrated the maintenance of most of the histopathological characteristics of human glioblastoma in an heterotopic site and might by considered in research of molecular and proliferative pathways of malignant gliomas.

  15. A Novel Molecular Diagnostic of Glioblastomas: Detection of an Extracellular Fragment of Protein Tyrosine Phosphatase μ

    Directory of Open Access Journals (Sweden)

    Susan M. Burden-Gulley

    2010-04-01

    Full Text Available We recently found that normal human brain and low-grade astrocytomas express the receptor protein tyrosine phosphatase mu (PTPμ and that the more invasive astrocytomas, glioblastoma multiforme (GBM, downregulate full-length PTPμ expression. Loss of PTPμ expression in GBMs is due to proteolytic cleavage that generates an intracellular and potentially a cleaved and released extracellular fragment of PTPμ. Here, we identify that a cleaved extracellular fragment containing the domains required for PTPμ-mediated adhesion remains associated with GBM tumor tissue. We hypothesized that detection of this fragment would make an excellent diagnostic tool for the localization of tumor tissue within the brain. To this end, we generated a series of fluorescently tagged peptide probes that bind the PTPμ fragment. The peptide probes specifically recognize GBM cells in tissue sections of surgically resected human tumors. To test whether the peptide probes are able to detect GBM tumors in vivo, the PTPμ peptide probes were tested in both mouse flank and intracranial xenograft human glioblastoma tumor model systems. The glial tumors were molecularly labeled with the PTPμ peptide probes within minutes of tail vein injection using the Maestro FLEX In Vivo Imaging System. The label was stable for at least 3 hours. Together, these results indicate that peptide recognition of the PTPμ extracellular fragment provides a novel molecular diagnostic tool for detection of human glioblastomas. Such a tool has clear translational applications and may lead to improved surgical resections and prognosis for patients with this devastating disease.

  16. Clinical characteristics and pathogenesis of cerebellar glioblastoma.

    Science.gov (United States)

    Takahashi, Yoshinobu; Makino, Keishi; Nakamura, Hideo; Hide, Takuichiro; Yano, Shigetoshi; Kamada, Hajime; Kuratsu, Jun-Ichi

    2014-11-01

    Cerebellar glioblastomas (GBMs) are rare, with neither their pathogenesis nor prognosis being completely understood. The present study aimed to clarify the clinical characteristics of cerebellar GBMs by comparison with supratentorial GBMs, focusing particularly on the pathogenesis. The clinical factors between cerebellar (n=10) and supratentorial (n=216) GBMs were compared. Additionally, p53 and epidermal growth factor receptor (EGFR) levels were investigated in six patients by immunostaining as well as the isocitrate dehydrogenase 1 (IDH1) status of five patients by direct sequencing. Eight males and two females participated in the present study, the mean age at diagnosis was 56.6 years and the range 37-75 years. Four patients presented with hydrocephalus and one with brainstem involvement, and two patients were diagnosed with neurofibromatosis type 1. Two patients had previously received radiotherapy, eight patients received postoperative radiotherapy and seven chemotherapy. The mean Karnofsky performance status (KPS) score was lower in patients with cerebellar GBMs compared to those with supratentorial GBM; however, the survival times did not differ between the two groups. All of the cases of six cerebellar GBMs were p53‑positive and EGFR‑negative, as detected by immunostaining, consistent with secondary GBM. However, no IDH1 mutations were detected in any of the five cases of cerebellar GBMs analyzed, indicating that these tumors were not of the secondary type. The KPS score with cerebellar GBMs may be lower due to hydrocephalus, which was ameliorated by surgery but may have impacted the survival rate. It was confirmed that cerebellar GBMs were identical to supratentorial GBMs with respect to its clinical features, with the possible exception of the KPS score. The present study's genetic analyses indicated that cerebellar GBMs may develop via a pathway different from that of either primary or secondary GBM. PMID:25199771

  17. Calcium signaling orchestrates glioblastoma development: Facts and conjunctures.

    Science.gov (United States)

    Leclerc, Catherine; Haeich, Jacques; Aulestia, Francisco J; Kilhoffer, Marie-Claude; Miller, Andrew L; Néant, Isabelle; Webb, Sarah E; Schaeffer, Etienne; Junier, Marie-Pierre; Chneiweiss, Hervé; Moreau, Marc

    2016-06-01

    While it is a relatively rare disease, glioblastoma multiform (GBM) is one of the more deadly adult cancers. Following current interventions, the tumor is never eliminated whatever the treatment performed; whether it is radiotherapy, chemotherapy, or surgery. One hypothesis to explain this poor outcome is the "cancer stem cell" hypothesis. This concept proposes that a minority of cells within the tumor mass share many of the properties of adult neural stem cells and it is these that are responsible for the growth of the tumor and its resistance to existing therapies. Accumulating evidence suggests that Ca(2+) might also be an important positive regulator of tumorigenesis in GBM, in processes involving quiescence, maintenance, proliferation, or migration. Glioblastoma tumors are generally thought to develop by co-opting pathways that are involved in the formation of an organ. We propose that the cells initiating the tumor, and subsequently the cells of the tumor mass, must hijack the different checkpoints that evolution has selected in order to prevent the pathological development of an organ. In this article, two main points are discussed. (i) The first is the establishment of a so-called "cellular society," which is required to create a favorable microenvironment. (ii) The second is that GBM can be considered to be an organism, which fights to survive and develop. Since GBM evolves in a limited space, its only chance of development is to overcome the evolutionary checkpoints. For example, the deregulation of the normal Ca(2+) signaling elements contributes to the progression of the disease. Thus, by manipulating the Ca(2+) signaling, the GBM cells might not be killed, but might be reprogrammed toward a new fate that is either easy to cure or that has no aberrant functioning. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.

  18. Calcium signaling orchestrates glioblastoma development: Facts and conjunctures.

    Science.gov (United States)

    Leclerc, Catherine; Haeich, Jacques; Aulestia, Francisco J; Kilhoffer, Marie-Claude; Miller, Andrew L; Néant, Isabelle; Webb, Sarah E; Schaeffer, Etienne; Junier, Marie-Pierre; Chneiweiss, Hervé; Moreau, Marc

    2016-06-01

    While it is a relatively rare disease, glioblastoma multiform (GBM) is one of the more deadly adult cancers. Following current interventions, the tumor is never eliminated whatever the treatment performed; whether it is radiotherapy, chemotherapy, or surgery. One hypothesis to explain this poor outcome is the "cancer stem cell" hypothesis. This concept proposes that a minority of cells within the tumor mass share many of the properties of adult neural stem cells and it is these that are responsible for the growth of the tumor and its resistance to existing therapies. Accumulating evidence suggests that Ca(2+) might also be an important positive regulator of tumorigenesis in GBM, in processes involving quiescence, maintenance, proliferation, or migration. Glioblastoma tumors are generally thought to develop by co-opting pathways that are involved in the formation of an organ. We propose that the cells initiating the tumor, and subsequently the cells of the tumor mass, must hijack the different checkpoints that evolution has selected in order to prevent the pathological development of an organ. In this article, two main points are discussed. (i) The first is the establishment of a so-called "cellular society," which is required to create a favorable microenvironment. (ii) The second is that GBM can be considered to be an organism, which fights to survive and develop. Since GBM evolves in a limited space, its only chance of development is to overcome the evolutionary checkpoints. For example, the deregulation of the normal Ca(2+) signaling elements contributes to the progression of the disease. Thus, by manipulating the Ca(2+) signaling, the GBM cells might not be killed, but might be reprogrammed toward a new fate that is either easy to cure or that has no aberrant functioning. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. PMID:26826650

  19. BC3EE2,9B, a synthetic carbazole derivative, upregulates autophagy and synergistically sensitizes human GBM8901 glioblastoma cells to temozolomide.

    Science.gov (United States)

    Chen, Chien-Min; Syu, Jhih-Pu; Way, Tzong-Der; Huang, Li-Jiau; Kuo, Sheng-Chu; Lin, Chung-Tien; Lin, Chih-Li

    2015-11-01

    Glioblastoma multiforme (GBM) is the most fatal form of human brain cancer. Although temozolomide (TMZ), an oral alkylating chemotherapeutic agent, improves the survival rate, the prognosis of patients with GBM remains poor. Naturally occurring carbazole alkaloids isolated from curry leaves (Murraya koenigii Spreng.) have been shown to possess a wide range of anticancer properties. However, the effects of carbazole derivatives on glioblastoma cells remain poorly understood. In the present study, anti‑glioblastoma profiles of a series of synthetic carbazole derivatives were evaluated in vitro. The most promising derivative in this series was BC3EE2,9B, which showed significant anti‑proliferative effects in GBM8401 and GBM8901 cells. BC3EE2,9B also triggered cell‑cycle arrest, most prominently at the G1 stage, and suppressed glioblastoma cell invasion and migration. Furthermore, BC3EE2,9B induced autophagy‑mediated cell death and synergistically sensitized GBM cells to TMZ cytotoxicity. The possible mechanism underlying BC3EE2,9B‑induced autophagy may involve activation of adenosine monophosphate-activated protein kinase and the attenuation of the Akt and mammalian target of the rapamycin downstream signaling pathway. Taken together, the present results provide molecular evidence for the mode of action governing the ability of BC3EE2,9B to sensitize drug‑resistant glioblastoma cells to the chemotherapeutic agent TMZ.

  20. Ciprofloxacin induced erythema multiforme: a case report

    Directory of Open Access Journals (Sweden)

    K. M. Narasimhamurthy

    2015-06-01

    Full Text Available Erythema multiforme (EM is an acute, self-limited, and sometimes recurring skin condition that is considered to be a type IV hypersensitivity reaction associated with certain infections, medications, and other various triggers like flavorings and preservatives, such as benzoic acid and cinnamon, immunologic disorders, such as transient selective C4 deficiency of infancy, collagen diseases, vasculitides, sarcoidosis, non-Hodgkin lymphoma, leukemia, multiple myeloma, myeloid metaplasia, and polycythemia, physical or mechanical factors, such as tattooing, radiotherapy, cold, and sunlight, foods, including salmon berries and margarine, malignancy, and hormonal. EM may be present within a wide spectrum of severity. EM minor represents a localized eruption of the skin with minimal or no mucosal involvement. According to a consensus definition, Stevens-Johnson syndrome (SJS was separated from the EM spectrum and added to toxic epidermal necrolysis (TEN. The two spectra are now divided into the following: (1 EM consisting of erythema minor and major and (2 SJS/TEN. Ciprofloxacin is a second generation fluoroquinolone. Fluoroquinolones are rapidly bactericidal in vitro and are considerably potent against Escherichia coli and various species of Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria. Mainly used in urinary tract infections, prostatitis, sexually transmitted diseases, gastrointestinal and abdominal infections, respiratory tract infections, bone-joint and soft tissue infections. Metronidazole is a nitroimidazole antimicrobial medication used particularly for anaerobic bacteria and protozoa. It is on the World Health Organizations list of essential medicines, a list of the most important medications needed in a basic health system. Here we report the case of a 39-year-old male patient who presented with EM to the dermatology outpatient department, Adichunchanagiri Hospital and Research Centre. The patient gave a history of taking

  1. 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

  2. Stereotactic Radiosurgery for Glioblastoma.

    Science.gov (United States)

    Redmond, Kristin J; Mehta, Minesh

    2015-01-01

    Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and one of the most aggressive of all human cancers. GBM tumors are highly infiltrative and relatively resistant to conventional therapies. Aggressive management of GBM using a combination of surgical resection, followed by fractionated radiotherapy and chemotherapy has been shown to improve overall survival; however, GBM tumors recur in the majority of patients and the disease is most often fatal. There is a need to develop new treatment regimens and technological innovations to improve the overall survival of GBM patients. The role of stereotactic radiosurgery (SRS) for the treatment of GBM has been explored and is controversial. SRS utilizes highly precise radiation techniques to allow dose escalation and delivery of ablative radiation doses to the tumor while minimizing dose to the adjacent normal structures. In some studies, SRS with concurrent chemotherapy has shown improved local control with acceptable toxicities in select GBM patients. However, because GBM is a highly infiltrative disease, skeptics argue that local therapies, such as SRS, do not improve overall survival. The purpose of this article is to review the literature regarding SRS in both newly diagnosed and recurrent GBM, to describe SRS techniques, potential eligible SRS candidates, and treatment-related toxicities. In addition, this article will propose promising areas for future research for SRS in the treatment of GBM. PMID:26848407

  3. Emerging Biomarkers in Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    McNamara, Mairéad G.; Sahebjam, Solmaz; Mason, Warren P., E-mail: warren.mason@uhn.ca [Pencer Brain Tumor Centre, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9 (Canada)

    2013-08-22

    Glioblastoma, the most common primary brain tumor, has few available therapies providing significant improvement in survival. Molecular signatures associated with tumor aggressiveness as well as with disease progression and their relation to differences in signaling pathways implicated in gliomagenesis have recently been described. A number of biomarkers which have potential in diagnosis, prognosis and prediction of response to therapy have been identified and along with imaging modalities could contribute to the clinical management of GBM. Molecular biomarkers including O(6)-methlyguanine-DNA-methyltransferase (MGMT) promoter and deoxyribonucleic acid (DNA) methylation, loss of heterozygosity (LOH) of chromosomes 1p and 19q, loss of heterozygosity 10q, isocitrate dehydrogenase (IDH) mutations, epidermal growth factor receptor (EGFR), epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, phosphatase and tensin homolog (PTEN), p16INK4a gene, cytochrome c oxidase (CcO), phospholipid metabolites, telomerase messenger expression (hTERT messenger ribonucleic acid [mRNA]), microRNAs (miRNAs), cancer stem cell markers and imaging modalities as potential biomarkers are discussed. Inclusion of emerging biomarkers in prospective clinical trials is warranted in an effort for more effective personalized therapy in the future.

  4. Central mechanisms II: pharmacology of brainstem pathways.

    Science.gov (United States)

    Bolser, D C

    2009-01-01

    Following systemic administration, centrally acting antitussive drugs are generally assumed to act in the brainstem to inhibit cough. However, recent work in humans has raised the possibility of suprapontine sites of action for cough suppressants. For drugs that may act in the brainstem, the specific locations, types of neurones affected, and receptor specificities of the compounds represent important issues regarding their cough-suppressant actions. Two medullary areas that have received the most attention regarding the actions of antitussive drugs are the nucleus of the tractus solitarius (NTS) and the caudal ventrolateral respiratory column. Studies that have implicated these two medullary areas have employed both microinjection and in vitro recording methods to control the location of action of the antitussive drugs. Other brainstem regions contain neurones that participate in the production of cough and could represent potential sites of action of antitussive drugs. These regions include the raphe nuclei, pontine nuclei, and rostral ventrolateral medulla. Specific receptor subtypes have been associated with the suppression of cough at central sites, including 5-HT1A, opioid (mu, kappa, and delta), GABA-B, tachykinin neurokinin-1 (NK-1) and neurokinin-2, non-opioid (NOP-1), cannabinoid, dopaminergic, and sigma receptors. Aside from tachykinin NK-1 receptors in the NTS, relatively little is known regarding the receptor specificity of putative antitussive drugs in particular brainstem regions. Our understanding of the mechanisms of action of antitussive drugs would be significantly advanced by further work in this area. PMID:18825342

  5. Brainstem Encephalitis and ADEM Following Mumps

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2004-03-01

    Full Text Available Clinical manifestations of brainstem encephalitis (BSE with fever, decreased level of consciousness, and left facial and abducens paralysis developed 1 week after bilateral parotitis and mumps in a 4 year-old female child and were followed by symptoms of acute disseminated encephalomyelitis (ADEM within 20 days of recovery from BSE.

  6. Neuromyelitis Optica Lesion Mimicking Brainstem Glioma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2007-12-01

    Full Text Available A 12-year-old girl who presented with weakness of the left extremities and right sided sixth cranial nerve palsy had neuromyelitis optica (NMO mistaken for brainstem glioma on MRI, in a report from Brain Research Institute, Yonsei University College of Medicine,Seoul, Republic of KoreaNeuromyelitis Optica, Optic-Spinal Syndrome, Spectroscopy.

  7. Ondine′s curse after brainstem infarction

    OpenAIRE

    Pedroso Jose; Baiense Robson; Scalzaretto Ana; Neto Pedro; Teixeira de Gois Aecio; Ferraz Maria

    2009-01-01

    This report describes a rare case of acquired Ondine′s curse. The patient developed central sleep apnea syndrome named Ondine′s curse after a brainstem infarction. Lesions involving the descending medullocervical pathways that subserve automatic breathing can result in this syndrome.

  8. Erythema multiforme as the result of taking carbamazepine

    Directory of Open Access Journals (Sweden)

    Maharani Laillyza Apriasari

    2010-06-01

    Full Text Available Background: Erythema multiforme is an acute mucocutaneus disease which is caused by the hypersensitivity reaction. It is characterized by target lesions on the skin or ulcerative oral lesion. Etiology of the disease is unknown, it is currently considered as immunologic disease. The triggering factors is the use of certain type of drugs like antibiotics, anticonvulsant, and NSAID. Most of the dentists do not know about it is mechanism, so a lot of people consider it as a malpractice. Purpose: This paper reported a case of a man, 46 years old which had ulcerative oral mucous, peeled and pain lips after taking carbamazepine drugs. Case: The clinical diagnosis of this case was erythema multiforme because of the hypersensitivity reaction as the result of taking carbamazepine. Case management: The final diagnosis based on anamnesis history of taking systemic drugs and clinical manifestation of erythema multiforme in the oral cavity. The drugs therapy that had been given were antihistamine, oral corticosteroid, gargle liquid contained of topical anesthetic, corticosteroid, and antibiotic. Conclusion: In this case, it can be concluded that erythema multiforme appeared was triggered by taking carbamazepine as the drug of choice for trigeminal neuralgia therapy. These drugs can cause type III hypersensitivity reaction. The final diagnosis based on anamnesis history of taking carbamazepine before lesions erupted and the characterized clinical manifestation.Latar belakang: Erythema multiforme adalah penyakit mukokutaneus akut yang menyerang kulit dan mukosa sebagai akibat dari reaksi hipersensitivitas. Secara karakteristik ditandai oleh lesi target pada kulit atau lesi ulserasi pada mukosa rongga mulut. Etiologi penyakit ini belum jelas, diduga karena adanya reaksi imunologi. Pencetusnya dikarenakan adanya pemakaian obat-obatan tertentu seperti antibiotik, antikonvulsan dan NSAID. Banyak dokter gigi kurang memahami mekanisme timbulnya penyakit ini, sehingga

  9. 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.

  10. Targeting NF-κB in glioblastoma: A therapeutic approach.

    Science.gov (United States)

    Friedmann-Morvinski, Dinorah; Narasimamurthy, Rajesh; Xia, Yifeng; Myskiw, Chad; Soda, Yasushi; Verma, Inder M

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-κB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-κB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-κB activity or targeting of inducible NF-κB genes is an attractive therapeutic approach for GBM. PMID:26824076

  11. Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence.

    Directory of Open Access Journals (Sweden)

    Gabrielle C Nickel

    Full Text Available Human cancers are driven by the acquisition of somatic mutations. Separating the driving mutations from those that are random consequences of general genomic instability remains a challenge. New sequencing technology makes it possible to detect mutations that are present in only a minority of cells in a heterogeneous tumor population. We sought to leverage the power of ultra-deep sequencing to study various levels of tumor heterogeneity in the serial recurrences of a single glioblastoma multiforme patient. Our goal was to gain insight into the temporal succession of DNA base-level lesions by querying intra- and inter-tumoral cell populations in the same patient over time. We performed targeted "next-generation" sequencing on seven samples from the same patient: two foci within the primary tumor, two foci within an initial recurrence, two foci within a second recurrence, and normal blood. Our study reveals multiple levels of mutational heterogeneity. We found variable frequencies of specific EGFR, PIK3CA, PTEN, and TP53 base substitutions within individual tumor regions and across distinct regions within the same tumor. In addition, specific mutations emerge and disappear along the temporal spectrum from tumor at the time of diagnosis to second recurrence, demonstrating evolution during tumor progression. Our results shed light on the spatial and temporal complexity of brain tumors. As sequencing costs continue to decline and deep sequencing technology eventually moves into the clinic, this approach may provide guidance for treatment choices as we embark on the path to personalized cancer medicine.

  12. Decitabine nanoconjugate sensitizes human glioblastoma cells to temozolomide.

    Science.gov (United States)

    Cui, Yi; Naz, Asia; Thompson, David H; Irudayaraj, Joseph

    2015-04-01

    In this study, we developed and characterized a delivery system for the epigenetic demethylating drug, decitabine, to sensitize temozolomide-resistant human glioblastoma multiforme (GBM) cells to alkylating chemotherapy. A poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) based nanoconjugate was fabricated to encapsulate decitabine and achieved a better therapeutic response in GBM cells than that with the free drug. After synthesis, the highly efficient uptake process and intracellular dynamics of this nanoconjugate were monitored by single-molecule fluorescence tools. Our experiments demonstrated that, under an acidic pH due to active glycolysis in cancer cells, the PLGA-PEG nanovector could release the conjugated decitabine at a faster rate, after which the hydrolyzed lactic acid and glycolic acid would further acidify the intracellular microenvironment, thus providing positive feedback to increase the effective drug concentration and realize growth inhibition. In temozolomide-resistant GBM cells, decitabine can potentiate the cytotoxic DNA alkylation by counteracting cytosine methylation and reactivating tumor suppressor genes, such as p53 and p21. Owing to the excellent internalization and endolysosomal escape enabled by the PLGA-PEG backbone, the encapsulated decitabine exhibited a better anti-GBM potential than that of free drug molecules. Hence, the synthesized nanoconjugate and temozolomide could act in synergy to deliver a more potent and long-term antiproliferative effect against malignant GBM cells.

  13. Pediatric spinal glioblastoma ofthe conus medullaris:a case report oflong survival

    Institute of Scientific and Technical Information of China (English)

    AntonellaCacchione; AngelaMastronuzzi; MariaGiuseppinaCefalo; GiovannaStefaniaColafati; FrancescaDiomediCamassei; MicheleRizzi; AlessandroDeBenedictis; AndreaCarai

    2016-01-01

    High‑grade gliomas of the spinal cord represent a rare entity in children. Their biology, behavior, and controversial treatment options have been discussed in a few pediatric cases. These tumors are associated with severe disability and poor prognosis. We report a case of a 4‑year‑old child diagnosed with an isolated glioblastoma multiforme of the conus medullaris. The patient underwent subtotal surgical excision, followed by adjuvant radiotherapy and oral chem‑otherapy. He is alive with mild neurologic deifcits at 52months after diagnosis. We describe the peculiar characteris‑tics of this rare condition in pediatric oncology. We also provide an overview of current multidisciplinary therapeutic approaches and prognostic factors for this disease.

  14. Stopping cancer in its tracks: using small molecular inhibitors to target glioblastoma migrating cells.

    Science.gov (United States)

    Mattox, Austin K; Li, Jing; Adamson, David C

    2012-12-01

    Glioblastoma multiforme (GBM) represents one of the most common aggressive types of primary brain tumors. Despite advances in surgical resection, novel neuroimaging procedures, and the most recent adjuvant radiotherapy and chemotherapy, the median survival after diagnosis is about 12-14 months. Targeting migrating GBM cells is a key research strategy in the fight against this devastating cancer. Though the vast majority of the primary tumor focus can be surgically resected, these migrating cells are responsible for its universal recurrence. Numerous strategies and technologies are being explored to target migrating glioma cells, with small molecular inhibitors as one of the most commonly studied. Small molecule inhibitors, such as protein kinase inhibitors, phosphorylation site inhibitors, protease inhibitors, and antisense oligonucleotides show promise in slowing the progression of this disease. A better understanding of these small molecule inhibitors and how they target various extra- and intracellular signaling pathways may eventually lead to a cure for GBM.

  15. 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

    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...

  16. Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth.

    Directory of Open Access Journals (Sweden)

    Tae Hyong Kim

    Full Text Available Glioblastoma multiforme (GBM, the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4 is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future.

  17. Sodium ion channel mutations in glioblastoma patients correlate with shorter survival

    Directory of Open Access Journals (Sweden)

    Velculescu Victor E

    2011-02-01

    Full Text Available Abstract Background Glioblastoma Multiforme (GBM is the most common and invasive astrocytic tumor associated with dismal prognosis. Treatment for GBM patients has advanced, but the median survival remains a meager 15 months. In a recent study, 20,000 genes from 21 GBM patients were sequenced that identified frequent mutations in ion channel genes. The goal of this study was to determine whether ion channel mutations have a role in disease progression and whether molecular targeting of ion channels is a promising therapeutic strategy for GBM patients. Therefore, we compared GBM patient survival on the basis of presence or absence of mutations in calcium, potassium and sodium ion transport genes. Cardiac glycosides, known sodium channel inhibitors, were then tested for their ability to inhibit GBM cell proliferation. Results Nearly 90% of patients showed at least one mutation in ion transport genes. GBM patients with mutations in sodium channels showed a significantly shorter survival compared to patients with no sodium channel mutations, whereas a similar comparison based on mutational status of calcium or potassium ion channel mutations showed no survival differences. Experimentally, targeting GBM cells with cardiac glycosides such as digoxin and ouabain demonstrated preferential cytotoxicity against U-87 and D54 GBM cells compared to non-tumor astrocytes (NTAs. Conclusions These pilot studies of GBM patients with sodium channel mutations indicate an association with a more aggressive disease and significantly shorter survival. Moreover, inhibition of GBM cells by ion channel inhibitors such as cardiac glycosides suggest a therapeutic strategy with relatively safe drugs for targeting GBM ion channel mutations. Key Words: glioblastoma multiforme, ion channels, mutations, small molecule inhibitors, cardiac glycosides.

  18. Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma

    OpenAIRE

    Sayour, Elias J.; McLendon, Pat; Mclendon, Roger; Leon, Gabriel; Reynolds, Renee; Kresak, Jesse; Sampson, John H; Mitchell, Duane A

    2015-01-01

    Glioblastoma multiforme (GBM) is an aggressive malignancy associated with profound host immunosuppression mediated in part by FoxP3 expressing regulatory CD4+ T lymphocytes (Tregs) that down-regulate anti-tumor immunity. In order to assess whether FoxP3 was an independent driver differentially expressed in primary versus recurrent GBMs, we stained resected primary and recurrent GBM tumors for CD3, CD4, CD8 and FoxP3 expression using standard immunohistochemistry. Slides were scanned with a hi...

  19. A Novel Extracellular Hsp90 Mediated Co-Receptor Function for LRP1 Regulates EphA2 Dependent Glioblastoma Cell Invasion

    OpenAIRE

    Udhayakumar Gopal; Bohonowych, Jessica E.; Carla Lema-Tome; Angen Liu; Elizabeth Garrett-Mayer; Bingcheng Wang; Isaacs, Jennifer S.

    2011-01-01

    BACKGROUND: Extracellular Hsp90 protein (eHsp90) potentiates cancer cell motility and invasion through a poorly understood mechanism involving ligand mediated function with its cognate receptor LRP1. Glioblastoma multiforme (GBM) represents one of the most aggressive and lethal brain cancers. The receptor tyrosine kinase EphA2 is overexpressed in the majority of GBM specimens and is a critical mediator of GBM invasiveness through its AKT dependent activation of EphA2 at S897 (P-EphA2(S897)). ...

  20. Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo

    OpenAIRE

    Onken, J.; Torka, R.; Korsing, S; J Radke; Krementeskaia, I.; M. Nieminen; Bai, X.; A. Ullrich; Heppner, F.; Vajkoczy, P.

    2016-01-01

    Purpose: Receptor tyrosine kinase AXL (RTK-AXL) is regarded as suitable target in glioma therapy. Here we evaluate the anti-tumoral effect of small molecule inhibitor BMS-777607 targeting RTK-AXL in a preclinical glioma model and provide evidence that RTK-AXL is expressed and phosphorylated in primary and recurrent glioblastoma multiforme (GBM). Experimental design: We studied the impact of BMS-777607 targeting RTK-AXL in GBM models in vitro and in vivo utilizing glioma cells SF126 and U118MG...

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

    International Nuclear Information System (INIS)

    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-JunS73 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

  2. Corticosteroids compromise survival in glioblastoma.

    Science.gov (United States)

    Pitter, Kenneth L; Tamagno, Ilaria; Alikhanyan, Kristina; Hosni-Ahmed, Amira; Pattwell, Siobhan S; Donnola, Shannon; Dai, Charles; Ozawa, Tatsuya; Chang, Maria; Chan, Timothy A; Beal, Kathryn; Bishop, Andrew J; Barker, Christopher A; Jones, Terreia S; Hentschel, Bettina; Gorlia, Thierry; Schlegel, Uwe; Stupp, Roger; Weller, Michael; Holland, Eric C; Hambardzumyan, Dolores

    2016-05-01

    Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten

  3. Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy

    Science.gov (United States)

    Verlut, Clotilde; Mouillet, Guillaume; Magnin, Eloi; Buffet-Miny, Joëlle; Viennet, Gabriel; Cattin, Françoise; Billon-Grand, Nora Clelia; Bonnet, Emilie; Servagi-Vernat, Stéphanie; Godard, Joël; Billon-Grand, Romain; Petit, Antoine; Moulin, Thierry; Cals, Laurent; Pivot, Xavier; Curtit, Elsa

    2016-01-01

    INTRODUCTION Temozolomide and concomitant radiotherapy followed by temozolomide has been used as a standard therapy for the treatment of newly diagnosed glioblastoma multiform since 2005. A search for prognostic factors was conducted in patients with glioblastoma routinely treated by this strategy in our institution. METHODS This retrospective study included all patients with histologically proven glioblastoma diagnosed between June 1, 2005, and January 1, 2012, in the Franche-Comté region and treated by radiotherapy (daily fractions of 2 Gy for a total of 60 Gy) combined with temozolomide at a dose of 75 mg/m2 per day, followed by six cycles of maintenance temozolomide (150–200 mg/m2, five consecutive days per month). The primary aim was to identify prognostic factors associated with overall survival (OS) in this cohort of patients. RESULTS One hundred three patients were included in this study. The median age was 64 years. The median OS was 13.7 months (95% confidence interval, 12.5–15.9 months). In multivariate analysis, age over 65 years (hazard ratio [HR] = 1.88; P = 0.01), Medical Research Council (MRC) scale 3–4 (HR = 1.62; P = 0.038), and occurrence of postoperative complications (HR = 2.15; P = 0.028) were associated with unfavorable OS. CONCLUSIONS This study identified three prognostic factors in patients with glioblastoma eligible to the standard chemotherapy and radiotherapy treatment. Age over 65 years, MRC scale 3–4, and occurrence of postoperative complications were associated with unfavorable OS. A simple clinical evaluation including these three factors enables to estimate the patient prognosis. MRC neurological scale could be a useful, quick, and simple measure to assess neurological status in glioblastoma patients.

  4. Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy

    Science.gov (United States)

    Verlut, Clotilde; Mouillet, Guillaume; Magnin, Eloi; Buffet-Miny, Joëlle; Viennet, Gabriel; Cattin, Françoise; Billon-Grand, Nora Clelia; Bonnet, Emilie; Servagi-Vernat, Stéphanie; Godard, Joël; Billon-Grand, Romain; Petit, Antoine; Moulin, Thierry; Cals, Laurent; Pivot, Xavier; Curtit, Elsa

    2016-01-01

    INTRODUCTION Temozolomide and concomitant radiotherapy followed by temozolomide has been used as a standard therapy for the treatment of newly diagnosed glioblastoma multiform since 2005. A search for prognostic factors was conducted in patients with glioblastoma routinely treated by this strategy in our institution. METHODS This retrospective study included all patients with histologically proven glioblastoma diagnosed between June 1, 2005, and January 1, 2012, in the Franche-Comté region and treated by radiotherapy (daily fractions of 2 Gy for a total of 60 Gy) combined with temozolomide at a dose of 75 mg/m2 per day, followed by six cycles of maintenance temozolomide (150–200 mg/m2, five consecutive days per month). The primary aim was to identify prognostic factors associated with overall survival (OS) in this cohort of patients. RESULTS One hundred three patients were included in this study. The median age was 64 years. The median OS was 13.7 months (95% confidence interval, 12.5–15.9 months). In multivariate analysis, age over 65 years (hazard ratio [HR] = 1.88; P = 0.01), Medical Research Council (MRC) scale 3–4 (HR = 1.62; P = 0.038), and occurrence of postoperative complications (HR = 2.15; P = 0.028) were associated with unfavorable OS. CONCLUSIONS This study identified three prognostic factors in patients with glioblastoma eligible to the standard chemotherapy and radiotherapy treatment. Age over 65 years, MRC scale 3–4, and occurrence of postoperative complications were associated with unfavorable OS. A simple clinical evaluation including these three factors enables to estimate the patient prognosis. MRC neurological scale could be a useful, quick, and simple measure to assess neurological status in glioblastoma patients. PMID:27559302

  5. Auditory brain-stem responses in syphilis.

    OpenAIRE

    Rosenhall, U; Roupe, G

    1981-01-01

    Analysis of auditory brain-stem electrical responses (BSER) provides an effective means of detecting lesions in the auditory pathways. In the present study the wave patterns were analysed in 11 patients with secondary or latent syphilis with no clinical symptoms referrable to the central nervous system and in two patients with congenital syphilis and general paralysis. Decreased amplitudes and prolonged latencies occurred frequently in patients with secondary and with advanced syphilis. This ...

  6. Pro-apoptotic and anti-angiogenic properties of the α /β-thujone fraction from Thuja occidentalis on glioblastoma cells.

    Science.gov (United States)

    Torres, Angelo; Vargas, Yosselyn; Uribe, Daniel; Carrasco, Cristian; Torres, Cristian; Rocha, René; Oyarzún, Carlos; San Martín, Rody; Quezada, Claudia

    2016-05-01

    The most aggressive type of brain tumor is glioblastoma multiforme, which to date remains incurable. Thuja occidentalis is used in homeopathy for the treatment of cancer, however, its mechanism of action remains unknown. We set out to study the effects of thujone fractions of Thuja on glioblastoma using in vitro and in vivo models. We found that the α/ β-thujone fraction decrease the cell viability and exhibit a potent anti-proliferative, pro-apoptotic and anti-angiogenic effects in vitro. In vivo assays showed that α /β-thujone promotes the regression of neoplasia and inhibits the angiogenic markers VEGF, Ang-4 and CD31 into the tumor. PMID:26900077

  7. Effects of Caffeine on Auditory Brainstem Response

    Directory of Open Access Journals (Sweden)

    Saleheh Soleimanian

    2008-06-01

    Full Text Available Background and Aim: Blocking of the adenosine receptor in central nervous system by caffeine can lead to increasing the level of neurotransmitters like glutamate. As the adenosine receptors are present in almost all brain areas like central auditory pathway, it seems caffeine can change conduction in this way. The purpose of this study was to evaluate the effects of caffeine on latency and amplitude of auditory brainstem response(ABR.Materials and Methods: In this clinical trial study 43 normal 18-25 years old male students were participated. The subjects consumed 0, 2 and 3 mg/kg BW caffeine in three different sessions. Auditory brainstem responses were recorded before and 30 minute after caffeine consumption. The results were analyzed by Friedman and Wilcoxone test to assess the effects of caffeine on auditory brainstem response.Results: Compared to control group the latencies of waves III,V and I-V interpeak interval of the cases decreased significantly after 2 and 3mg/kg BW caffeine consumption. Wave I latency significantly decreased after 3mg/kg BW caffeine consumption(p<0.01. Conclusion: Increasing of the glutamate level resulted from the adenosine receptor blocking brings about changes in conduction in the central auditory pathway.

  8. The Study of Glioblastoma Differentiation Possibility

    Directory of Open Access Journals (Sweden)

    Medyanik I.A.

    2014-06-01

    Full Text Available The aim of the investigation was to assess the possibility of glioblastoma differentiation using infrared spectroscopy, proton magnetic resonance spectroscopy and immunohistochemistry. Materials and Methods. 22 patients with glioblastomas and 21 patients with anaplastic astrocytomas were examined. All the patients underwent infrared spectroscopy of blood serum. 16 patients with glioblastomas were examined preoperatively and postoperatively, and in both cases 7 of them underwent proton magnetic resonance spectroscopy of tumors and identical peritumoral areas. All diagnoses were morphologically confirmed, and 10 cases with glioblastomas and 15 cases with anaplastic astrocytomas were confirmed by immunohistochemistry. Results. Glioblastoma differentiation (Grade IV into anaplastic astrocytomas (Grade III was revealed postoperatively, in total glioblastoma resection and confirmed by the findings of infrared spectroscopy in blood serum, proton magnetic resonance spectroscopy of identical peritumoral areas performed preoperatively and postoperatively, as well as by immunohistochemical investigation of peritumoral area. Conclusion. The complex of the techniques applied (infrared spectroscopy, proton magnetic resonance spectroscopy, immunohistochemistry enables to assess how effective and total the surgery was, and if it promoted glioblastoma differentiation postoperatively, and determine how the tumor will develop after the surgery: as glioblastoma — with early continuous tumor growth, or as anaplastic astrocytoma — with the longer recurrence-free period. The findings are in agreement with tissue theory of tumor genesis; and change the understanding of the role and significance of surgical resection of glioblastomas in tumor differentiation.

  9. Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

    Directory of Open Access Journals (Sweden)

    Nicolas Goffart

    2013-08-01

    Full Text Available Glioblastoma multiforme (GBM, WHO grade IV is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This “seed-and-soil” relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their “stem cell” properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology.

  10. MRI texture features as biomarkers to predict MGMT methylation status in glioblastomas

    Science.gov (United States)

    Korfiatis, Panagiotis; Kline, Timothy L.; Coufalova, Lucie; Lachance, Daniel H.; Parney, Ian F.; Carter, Rickey E.; Buckner, Jan C.; Erickson, Bradley J.

    2016-01-01

    Purpose: Imaging biomarker research focuses on discovering relationships between radiological features and histological findings. In glioblastoma patients, methylation of the O6-methylguanine methyltransferase (MGMT) gene promoter is positively correlated with an increased effectiveness of current standard of care. In this paper, the authors investigate texture features as potential imaging biomarkers for capturing the MGMT methylation status of glioblastoma multiforme (GBM) tumors when combined with supervised classification schemes. Methods: A retrospective study of 155 GBM patients with known MGMT methylation status was conducted. Co-occurrence and run length texture features were calculated, and both support vector machines (SVMs) and random forest classifiers were used to predict MGMT methylation status. Results: The best classification system (an SVM-based classifier) had a maximum area under the receiver-operating characteristic (ROC) curve of 0.85 (95% CI: 0.78–0.91) using four texture features (correlation, energy, entropy, and local intensity) originating from the T2-weighted images, yielding at the optimal threshold of the ROC curve, a sensitivity of 0.803 and a specificity of 0.813. Conclusions: Results show that supervised machine learning of MRI texture features can predict MGMT methylation status in preoperative GBM tumors, thus providing a new noninvasive imaging biomarker. PMID:27277032

  11. Endoscopy-verified occult subependymal dissemination of glioblastoma and brain metastasis undetected by MRI: prognostic significance

    Directory of Open Access Journals (Sweden)

    Iacoangeli M

    2012-12-01

    Full Text Available Maurizio Iacoangeli,1 Alessandro Di Rienzo,1 Roberto Colasanti,1 Antonio Zizzi,2 Maurizio Gladi,1 Lorenzo Alvaro,1 Niccolò Nocchi,1 Lucia Giovanna Maria Di Somma,1 Marina Scarpelli,2 Massimo Scerrati11Department of Neurosurgery, 2Department of Pathology, Università Politecnica delle Marche, Umberto I General Hospital, Ancona, ItalyAbstract: Although various prognostic indices exist for patients with malignant brain tumors, the prognostic significance of the subependymal spread of intracranial tumors is still a matter of debate. In this paper, we report the cases of two intraventricular lesions, a recurrent glioblastoma multiforme (GBM and a brain metastasis, each successfully treated with a neuroendoscopic approach. Thanks to this minimally invasive approach, we achieved good therapeutic results: we obtained a histological diagnosis; we controlled intracranial hypertension by treating the associated hydrocephalus and, above all, compared with a microsurgical approach, we reduced the risks related to dissection and brain retraction. Moreover, in both cases, neuroendoscopy enabled us to identify an initial, precocious subependymal tumor spreading below the threshold of magnetic resonance imaging (MRI detection. This finding, undetected in pre-operative MRI scans, was then evident during follow-up neuroimaging studies. In light of these data, a neuroendoscopic approach might play a leading role in better defining the prognosis and optimally tailored management protocols for GBM and brain metastasis.Keywords: subependymal spreading, glioblastoma, brain metastasis, endoscopy, minimally invasive surgery, prognosis

  12. The role of intra-arterial chemotherapy as an adjuvant treatment for glioblastoma.

    Science.gov (United States)

    Theodotou, Christian; Shah, Ashish H; Hayes, Seth; Bregy, Amade; Johnson, Jeremiah N; Aziz-Sultan, Mohammad A; Komotar, Ricardo J

    2014-08-01

    Glioblastoma multiforme (GBM) is an aggressive tumor with poor survival outcomes and limited treatment options. We conducted a literature review to compare the survival outcomes of intra-arterial (IA) and intravenous (IV) chemotherapy delivery for GBM. Nine studies of IA chemotherapy infusion with 301 total patients met our criteria for inclusion and three studies contained IV treatment groups for comparison (n = 230 for IA, n = 71 for IV). The studies were grouped by either using newly diagnosed or recurrent GBM patients. In the newly diagnosed group, IV chemotherapy produced a statistically higher median overall survival (MOS; 16.3 months) compared with IA treatment (14.02 months). However, the total number of adverse events in IA chemotherapy was 1.08 per patient whereas for IV it was higher at 1.54 events per patient. Our recurrent GBM group includes only patients treated with IA chemotherapy which resulted in an average MOS of 10.84 months. This group had 2.7 adverse events per patient but no IV group is available for comparison. Historically, the survival of patients with recurrent GBM ranges from 3 to 9 months (Gil-Gil et al. Bevacizumab for the treatment of glioblastoma. Clin Med Insights Oncol 2013;7:123-35). For this reason, we believe IA chemotherapy to be a viable methodology in recurrent GBM patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications. PMID:24432794

  13. Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

    Energy Technology Data Exchange (ETDEWEB)

    Goffart, Nicolas [Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège 4000 (Belgium); Kroonen, Jérôme [Human Genetics, CHU and University of Liège, Liège 4000 (Belgium); The T& P Bohnenn Laboratory for Neuro-Oncology, Department of Neurology and Neurosurgery, UMC Utrecht, Utrecht 3556 (Netherlands); Rogister, Bernard, E-mail: Bernard.Register@ulg.ac.be [Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège 4000 (Belgium); Department of Neurology, CHU and University of Liège, Liège 4000 (Belgium); GIGA-Development, Stem Cells and Regenerative Medicine, University of Liège, Liège 4000 (Belgium)

    2013-08-14

    Glioblastoma multiforme (GBM, WHO grade IV) is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs) play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This “seed-and-soil” relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their “stem cell” properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology.

  14. Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM, WHO grade IV) is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs) play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This “seed-and-soil” relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their “stem cell” properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology

  15. Brainstem: neglected locus in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Lea T Grinberg

    2011-07-01

    Full Text Available The most frequent neurodegenerative diseases (NDs are Alzheimer’s disease (AD, Parkinson’s disease (PD, and frontotemporal lobar degeneration associated with protein TDP-43 (FTLD-TDP. Neuropathologically, NDs are characterized by abnormal intracellular and extracellular protein deposits and by disease-specific neuronal death. Practically all terminal stages of NDs are clinically associated with dementia. Therefore, major attention was directed to protein deposits and neuron loss in supratentorial (telencephalic brain regions in the course of NDs. This was also true for PD, although the pathological hallmark of PD is degeneration of pigmented neurons of the brainstem’s substantia nigra. However, PD pathophysiology was explained by dopamine depletion in the telencephalic basal ganglia due to insufficiency and degeneration of the projection neurons located in substantia nigra. In a similar line of argumentation AD- and FTLD-related clinical deficits were exclusively explained by supratentorial allo- and neocortical laminar neuronal necrosis. Recent comprehensive studies in AD and PD early stages found considerable and unexpected involvement of brainstem nuclei, which could have the potential to profoundly change our present concepts on origin, spread, and early clinical diagnosis of these diseases. In contrast with PD and AD, few studies addressed brainstem involvement in the course of the different types of FTLD-TDP. Some of the results, including ours, disclosed a higher and more widespread pathology than anticipated. The present review will focus mainly on the impact of brainstem changes during the course of the most frequent NDs including PD, AD, and FTLD-TDP, with special emphasis on the need for more comprehensive research on FTLDs.

  16. Case comparison and literature review of glioblastoma: A tale of two tumors

    Directory of Open Access Journals (Sweden)

    Gustavo Mendez

    2014-01-01

    Full Text Available Background: Diagnosis of glioblastoma multiforme (GBM includes a heterogeneous group of tumors. We describe two cases with histopathologically and molecularly similar tumors, but very different outcomes. We attempt to illustrate the need for improved prognostic markers for GBM. Case Description: Two patients with similar molecular profiles were retrospectively identified. The following markers were assessed: O6 -methylguanine DNA methyltransferase (MGMT methylation, isocitrate dehydrogenase (IDH 1 and 2 status, epidermal growth factor receptor (EGFR amplification, phosphatase and tensin homolog (PTEN status, Ki-67, p53, and 1p/19q status. Each patient was assigned a Karnofsky performance score at presentation. Case 1 (62-year-old male was a right temporal lobe glioblastoma with a molecular profile of amplified EGFR, normal PTEN, no IDH1/2 mutation, 28.7% MGMT promoter methylation, 5-20% Ki-67, 1p deletion, and 19q intact. The patient underwent resection followed by radiation therapy and 2 years of chemotherapy, and was asymptomatic and tumor free 5 years post diagnosis. Tumor eventually recurred and the patient expired 72 months after initial diagnosis. Case 2 (63-year-old male was a right frontal white matter mass consistent with glioblastoma with a molecular profile of amplified EGFR, absent PTEN, no IDH1/2 mutation, 9.9% MGMT promoter methylation, 5-10% Ki-67, and 1p/19q status inconclusive. A radical subtotal resection was performed; however, 2 weeks later symptoms had returned. Subsequent imaging revealed a tumor larger than at diagnosis. The patient expired 3 months after initial diagnosis. Conclusion: The need for formulating more robust means to classify GBM tumor subtypes is paramount. Standard histopathologic and molecular analyses are costly and did not provide either of these patients with a realistic appraisal of their prognosis. Individualized whole genome testing similar to that being reported for medulloblastoma and other tumors

  17. Cardamonin induces apoptosis by suppressing STAT3 signaling pathway in glioblastoma stem cells.

    Science.gov (United States)

    Wu, Ning; Liu, Jia; Zhao, Xiangzhong; Yan, Zhiyong; Jiang, Bo; Wang, Lijun; Cao, Shousong; Shi, Dayong; Lin, Xiukun

    2015-12-01

    Glioblastoma stem cells (GSCs) are the initiating cells in glioblastoma multiforme (GBM) and contribute to the resistance of GBM to chemotherapy and radiation. In the present study, we investigated the effects of cardamonin (3,4,2,4-tetrahydroxychalcone) on the self-renewal and apoptosis of GSCs, and if its action is associated with signal transducer and activator of transcription 3 (STAT3) pathway. CD133(+) GSCs, a kind of GSCs line, was established from human glioblastoma tissues. Cardamonin inhibited the proliferation and induced apoptosis in CD133+ GSCs. The proapoptotic effects of temozolomide (TMZ) were further enhanced by cardamonin in CD133+ GSCs and U87 cells in vitro. For in vivo study, injection of 5 × 10(5) cells of CD133+ GSCs subcutaneously (s.c.) into nude mice, 100 % of large tumors were developed within 8 weeks in all mice; in contrast, only one out of five mice developed a small tumor when 5 × 10(5) cells of CD133(-) GMBs cells were injected. Cardamonin also inhibited STAT3 activation by luciferase assay and suppressed the expression of the downstream genes of STAT3, such as Bcl-XL, Bcl-2, Mcl-1, survivin, and VEGF. Furthermore, cardamonin locked nuclear translocation and dimerization of STAT3 in CD133(+) GSCs. Docking analysis confirmed that cardamonin molecule was successfully docked into the active sites of STAT3 with a highly favorable binding energy of -10.78 kcal/mol. The study provides evidence that cardamonin is a novel inhibitor of STAT3 and has the potential to be developed as a new anticancer agent targeting GSCs. This study also reveals that targeting STAT3 signal pathway is an important strategy for the treatment of human GBM. PMID:26150336

  18. Erythema multiforme and persistent erythema as early cutaneous manifestations of Lyme disease

    NARCIS (Netherlands)

    Schuttelaar, M L; Laeijendecker, R; Heinhuis, R J; Van Joost, T

    1997-01-01

    We report two cases of borreliosis (Lyme disease) with unusual cutaneous manifestations, erythema multiforme, and persistent erythema. The lesions in both of our patients had distinctive histopathologic features. To our knowledge, this is the first report of erythema multiforme and persistent erythe

  19. A reproducible brain tumour model established from human glioblastoma biopsies

    Directory of Open Access Journals (Sweden)

    Li Xingang

    2009-12-01

    Full Text Available Abstract Background Establishing clinically relevant animal models of glioblastoma multiforme (GBM remains a challenge, and many commonly used cell line-based models do not recapitulate the invasive growth patterns of patient GBMs. Previously, we have reported the formation of highly invasive tumour xenografts in nude rats from human GBMs. However, implementing tumour models based on primary tissue requires that these models can be sufficiently standardised with consistently high take rates. Methods In this work, we collected data on growth kinetics from a material of 29 biopsies xenografted in nude rats, and characterised this model with an emphasis on neuropathological and radiological features. Results The tumour take rate for xenografted GBM biopsies were 96% and remained close to 100% at subsequent passages in vivo, whereas only one of four lower grade tumours engrafted. Average time from transplantation to the onset of symptoms was 125 days ± 11.5 SEM. Histologically, the primary xenografts recapitulated the invasive features of the parent tumours while endothelial cell proliferations and necrosis were mostly absent. After 4-5 in vivo passages, the tumours became more vascular with necrotic areas, but also appeared more circumscribed. MRI typically revealed changes related to tumour growth, several months prior to the onset of symptoms. Conclusions In vivo passaging of patient GBM biopsies produced tumours representative of the patient tumours, with high take rates and a reproducible disease course. The model provides combinations of angiogenic and invasive phenotypes and represents a good alternative to in vitro propagated cell lines for dissecting mechanisms of brain tumour progression.

  20. Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma.

    Science.gov (United States)

    Ahmad, F; Dixit, D; Sharma, V; Kumar, A; Joshi, S D; Sarkar, C; Sen, E

    2016-05-05

    Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) - two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the in vitro findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells.

  1. 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.

  2. Evaluation of tyrosine kinase inhibitor combinations for glioblastoma therapy.

    Directory of Open Access Journals (Sweden)

    Avadhut D Joshi

    Full Text Available Glioblastoma multiforme (GBM is the most common intracranial cancer but despite recent advances in therapy the overall survival remains about 20 months. Whole genome exon sequencing studies implicate mutations in the receptor tyrosine kinase pathways (RTK for driving tumor growth in over 80% of GBMs. In spite of various RTKs being mutated or altered in the majority of GBMs, clinical studies have not been able to demonstrate efficacy of molecular targeted therapies using tyrosine kinase inhibitors in GBMs. Activation of multiple downstream signaling pathways has been implicated as a possible means by which inhibition of a single RTK has been ineffective in GBM. In this study, we sought a combination of approved drugs that would inhibit in vitro and in vivo growth of GBM oncospheres. A combination consisting of gefitinib and sunitinib acted synergistically in inhibiting growth of GBM oncospheres in vitro. Sunitinib was the only RTK inhibitor that could induce apoptosis in GBM cells. However, the in vivo efficacy testing of the gefitinib and sunitinib combination in an EGFR amplified/PTEN wild type GBM xenograft model revealed that gefitinib alone could significantly improve survival in animals whereas sunitinib did not show any survival benefit. Subsequent testing of the same drug combination in a different syngeneic glioma model that lacked EGFR amplification but was more susceptible to sunitinib in vitro demonstrated no survival benefit when treated with gefitinib or sunitinib or the gefitinib and sunitinib combination. Although a modest survival benefit was obtained in one of two animal models with EGFR amplification due to gefitinib alone, the addition of sunitinib, to test our best in vitro combination therapy, did not translate to any additional in vivo benefit. Improved targeted therapies, with drug properties favorable to intracranial tumors, are likely required to form effective drug combinations for GBM.

  3. Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity

    International Nuclear Information System (INIS)

    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

  4. Erythema multiforme possibly triggered by food substances in a dog.

    Science.gov (United States)

    Itoh, Teruo; Nibe, Kazumi; Kojimoto, Atsuko; Mikawa, Mayumi; Mikawa, Kazuhiro; Uchida, Kazuyuki; Shii, Hiroki

    2006-08-01

    A 5-year-old female border collie presented with erythematous skin lesions at the axillae, groin, mucocutaneous junctions, and pinnae. Biopsy revealed lymphocytic interface dermatitis with hydropic degeneration of basal cells and keratinocyte apoptosis. Based on gross and histological features, diagnosis of erythema multiforme was made. The disease was resolved by treatment with azathioprine, prednisolone, and a hypoallergenic diet. Finally, the skin lesion was controlled without drug therapy but recurred easily every time commercial foods except the hypoallergenic diet were used, suggesting that food substances triggered this outbreak. PMID:16953090

  5. MRI findings of multiple sclerosis involving the brainstem

    International Nuclear Information System (INIS)

    To describe MRI findings of multiple sclerosis involving the brainstem. Among 35 cases of clinically definite multiple sclerosis, the authors retrospectively analysed 20 in which the brainstem was involved. MR images were analysed with regard to involvement sites in the brainstem or other locations, signal intensity, multiplicity, shape, enhancement pattern, and contiguity of brainstem lesions with cisternal or ventricular CSF space. The brainstem was the only site of involvement in five cases (25%), while simultaneous involvement of the brainstem and other sites was observed in 15 cases (75%). No case involved only the midbrain or medulla oblongata, and simultaneous involvement of the midbrain, pons and medulla oblongata was noted in 12 cases (60%). The most frequently involved region of the brainstem was the medulla oblongata (n=13; 90%), followed by the pons (n=17; 85%) and the midbrain (n=16; 80%). Compared with normal white matter, brainstem lesions showed low signal intensity on T1 weighted images, and high signal intensity on T2 weighted, proton density weighted, and FLAIR images. In 17 cases (85%), multiple intensity was observed, and the shape of lesions varied: oval, round, elliptical, patchy, crescentic, confluent or amorphous were seen on axial MR images, and in 14 cases (82%), coronal or sagittal scanning showed that lesions were long and tubular. Contiguity between brainstem lesions and cisternal or ventricular CSF space was seen in all cases (100%) involving midbrain (16/16) and medulla oblongata (18/18) and in 15 of 17 (88%) involving the pons. Contrast enhancement was apparent in 7 of 12 cases (58%). In the brainstem, MRI demonstrated partial or total contiguity between lesions and cisternal or ventricular CSF space, and coronal or sagittal images showed that lesions were long and tubuler

  6. Current concepts in glioblastoma imaging

    Institute of Scientific and Technical Information of China (English)

    George Alexiou; Spyridon Tsiouris; Haralabos Bougias; Spyridon Voulgaris; Andreas Fotopoulos

    2012-01-01

    Glioblastoma (GBM, WHO grade Ⅳ) is the most common and the most malignant primary brain tumor occurring during adulthood, with an annual incidence of 5 cases per 100 000. Treatment involves surgical resection, followed by radiotherapy and concomitant and adjuvant temozolomide. Despite multimodality treatment, the median survival time is 15 months. Herewith we discuss the value of neuroimaging in differentiating GBM from other types of brain tumors, in guiding tumor biopsy, in making non-invasive assessment of tumor's aggressiveness, in estimating overall prognosis, in differentiating treatment -induced brain necrosis from tumor recurrence and in assessing response to treatment.

  7. Evolving Molecular Genetics of Glioblastoma

    OpenAIRE

    Qiu-Ju Li; Jin-Quan Cai; Cheng-Yin Liu

    2016-01-01

    Objective: To summary the recent advances in molecular research of glioblastoma (GBM) and current trends in personalized therapy of this disease. Data Sources: Data cited in this review were obtained mainly from PubMed in English up to 2015, with keywords “molecular”, “genetics”, “GBM”, “isocitrate dehydrogenase”, “telomerase reverse transcriptase”, “epidermal growth factor receptor”, “PTPRZ1-MET”, and “clinical treatment”. Study Selection: Articles regarding the morphological pathology of GB...

  8. Inhibition of Glioblastoma Cell Growth In Vitro and In Vivo by Brucine, a Component of Chinese Medicine.

    Science.gov (United States)

    Ruijun, Wang; Wenbin, Meng; Yumin, Wang; Ruijian, Zhang; Puweizhong, Huang; Yulin, Li

    2014-01-01

    Glioblastoma multiforme (GBM) is one of the most common glial cell tumors and has drawn more and more attention in the clinic in recent years. Brucine has been reported to significantly suppress gastric cancer, lung cancer, and prostate cancer growth in vivo by inducing cell apoptosis. Here, the effects of brucine on U251 human glioma cell growth were investigated in vitro by cell proliferation assay, FACs, and qPCR in a xenograft tumor model. Treatment with brucine reduced the expression of BCL-2 and cyclooxygenase-2 (COX-2), while upregulated BAX expression in U251 human glioma cells resulted in reduced glioma cell survival rate and inhibited the growth of xenograft tumors. We concluded that brucine has a suppressive effect on U251 human glioma cells in vitro and in vivo, which could help in understanding the role of brucine in glioma cells and guiding drug use in the clinic. PMID:26629939

  9. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

    Energy Technology Data Exchange (ETDEWEB)

    Verhaak, Roel GW; Hoadley, Katherine A; Purdom, Elizabeth; Wang, Victoria; Qi, Yuan; Wilkerson, Matthew D; Miller, C Ryan; Ding, Li; Golub, Todd; Mesirov, Jill P; Alexe, Gabriele; Lawrence, Michael; O' Kelly, Michael; Tamayo, Pablo; Weir, Barbara A; Gabriel, Stacey; Winckler, Wendy; Gupta, Supriya; Jakkula, Lakshmi; Feiler, Heidi S; Hodgson, J Graeme; James, C David; Sarkaria, Jann N; Brennan, Cameron; Kahn, Ari; Spellman, Paul T; Wilson, Richard K; Speed, Terence P; Gray, Joe W; Meyerson, Matthew; Getz, Gad; Perou, Charles M; Hayes, D Neil; Network, The Cancer Genome Atlas Research

    2009-09-03

    The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.

  10. Changes of brainstem auditory and somatosensory evoked

    Institute of Scientific and Technical Information of China (English)

    Yang Jian

    2000-01-01

    Objective: to investigate the characteristics and clinical value of evoked potentials in late infantile form of metachromatic leukodystrophy. Methods: Brainstem auditory, and somatosensory evoked potentials were recorded in 6 patients, and compared with the results of CT scan. Results: All of the 6 patients had abnormal results of BAEP and MNSEP. The main abnormal parameters in BAEP were latency prolongation in wave I, inter-peak latency prolongation in Ⅰ-Ⅲ and Ⅰ-Ⅴ. The abnormal features of MNSEP were low amplitude and absence of wave N9, inter-Peak latency prolongation in Ng-N13 and N13-N20, but no significant change of N20 amplitude. The results also revealed that abnormal changes in BAEP and MNSEP were earlier than that in CT. Conclusion: The detection of BAEP and MNSEP in late infantile form of metachromatic leukodystrophy might early reveal the abnormality of conductive function in nervous system and might be a useful method in diagnosis.

  11. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Dolores Hernán Pérez de la Ossa

    Full Text Available Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9-Tetrahydrocannabinol (THC and Cannabidiol (CBD - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

  12. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

    Science.gov (United States)

    Hernán Pérez de la Ossa, Dolores; Lorente, Mar; Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María Del Rosario; Molpeceres, Jesús; Velasco, Guillermo; Torres-Suárez, Ana Isabel

    2013-01-01

    Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies. PMID:23349970

  13. Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme

    OpenAIRE

    Dolores Hernán Pérez de la Ossa; Mar Lorente; Maria Esther Gil-Alegre; Sofía Torres; Elena García-Taboada; María Del Rosario Aberturas; Jesús Molpeceres; Guillermo Velasco; Ana Isabel Torres-Suárez

    2013-01-01

    Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral a...

  14. Impact of therapy on quality of life, neurocognitive function and their correlates in glioblastoma multiforme: a review

    DEFF Research Database (Denmark)

    Henriksson, Roger; Asklund, Thomas; Poulsen, Hans Skovgaard

    2011-01-01

    that extend survival in patients with recurrent GBM, so one of the primary aims of new therapies is to reduce morbidity, restore or preserve neurologic functions, and the capacity to perform daily activities. Apart from temozolomide, cytotoxic chemotherapeutic agents do not appear to significantly impact...

  15. A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas†

    Science.gov (United States)

    Raizer, Jeffrey J.; Abrey, Lauren E.; Lassman, Andrew B.; Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Yung, W.K. Alfred; Gilbert, Mark R.; Aldape, Kenneth D.; Wen, Patrick Y.; Fine, Howard A.; Mehta, Minesh; DeAngelis, Lisa M.; Lieberman, Frank; Cloughesy, Timothy F.; Robins, H. Ian; Dancey, Janet; Prados, Michael D.

    2010-01-01

    The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 × 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where ≤1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs. PMID:20150371

  16. Treatment of glioblastoma multiforme cells with temozolomide-BioShuttle ligated by the inverse Diels-Alder ligation chemistry

    OpenAIRE

    Klaus Braun, Klaus

    2009-01-01

    Klaus Braun1, Manfred Wiessler1, Volker Ehemann2, Ruediger Pipkorn3, Herbert Spring4, Juergen Debus5, Bernd Didinger5, Mario Koch3, Gabriele Muller6, Waldemar Waldeck61German Cancer Research Center, Dept of Imaging and Radiooncology, Heidelberg, Germany; 2University of Heidelberg, Institute of Pathology, Heidelberg, Germany; 3German Cancer Research Center, Central Peptide Synthesis Unit, Heidelberg, Germany; 4German Cancer Research Center, Dept of Structural Analysis of Gene Structure and Fun...

  17. Quantitative proteomics reveals the novel co-expression signatures in early brain development for prognosis of glioblastoma multiforme

    OpenAIRE

    Yu, Xuexin; Feng, Lin; Liu, Dianming; Zhang, Lianfeng; Wu, Bo; Jiang, Wei; Han, Zujing; Cheng, Shujun

    2016-01-01

    Although several researches have explored the similarity across development and tumorigenesis in cellular behavior and underlying molecular mechanisms, not many have investigated the developmental characteristics at proteomic level and further extended to cancer clinical outcome. In this study, we used iTRAQ to quantify the protein expression changes during macaque rhesus brain development from fetuses at gestation 70 days to after born 5 years. Then, we performed weighted gene co-expression ...

  18. Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme

    DEFF Research Database (Denmark)

    Hofland, Kenneth F; Hansen, Steinbjørn; Sorensen, Morten;

    2014-01-01

    -free survival (PFS) and toxicity. RESULTS: The response rate was 32% (95% CI 17-51%) for Bev-Tem (n = 32) and 23% (95% CI 9-44%) for Bev-Iri (n = 31) (p = 0.56). Median PFS was 7.7 and 7.3 months for Bev-Tem and Bev-Iri, respectively. Hematological toxicity was more frequent with Bev-Tem including one death...... from febrile neutropenia whereas non-hematological toxicity was manageable. CONCLUSIONS: Only the Bev-Tem arm met the pre-specified level of activity of interest. Our results did not indicate any benefit from Bev-Iri in first-line therapy as opposed to Bev-Tem in terms of response and PFS....

  19. Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma.

    Science.gov (United States)

    Oh, Ji Eun; Ohta, Takashi; Nonoguchi, Naosuke; Satomi, Kaishi; Capper, David; Pierscianek, Daniela; Sure, Ulrich; Vital, Anne; Paulus, Werner; Mittelbronn, Michel; Antonelli, Manila; Kleihues, Paul; Giangaspero, Felice; Ohgaki, Hiroko

    2016-07-01

    The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas. PMID:26443480

  20. Isolated Brainstem Involvement in Posterior Reversible Encephalopathy Syndrome

    Directory of Open Access Journals (Sweden)

    Tarkan Ergün

    2013-09-01

    Full Text Available Posterior reversible encephalopathy syndrome (PRES is a clinical and radiologic entity characterized by headache, variable mental status, epilepsy, visual disturbances, and typical transient changes in the posterior cerebral perfusion. Parieto-occipital region the most commonly involved site. Less commonly, brainstem, basal ganglia, and cerebellum are involved besides the supratentorial white matter areas. However, isolated brainstem involvement is very rare. We here present a case of isolated brainstem involvement in posterior reversible encephalopathy syndrome which was diagnosed by diffusion-weighted MR imaging.

  1. Molecular heterogeneity in glioblastoma: potential clinical implications

    Directory of Open Access Journals (Sweden)

    Nicole Renee Parker

    2015-03-01

    Full Text Available Glioblastomas, (grade 4 astrocytomas, are aggressive primary brain tumors characterized by histopathological heterogeneity. High resolution sequencing technologies have shown that these tumors also feature significant inter-tumoral molecular heterogeneity. Molecular subtyping of these tumors has revealed several predictive and prognostic biomarkers. However, intra-tumoral heterogeneity may undermine the use of single biopsy analysis for determining tumor genotype and has implications for potential targeted therapies. The clinical relevance and theories of tumoral molecular heterogeneity in glioblastoma are discussed.

  2. Bevacizumab for the Treatment of Recurrent Glioblastoma

    OpenAIRE

    Chamberlain, Marc C.

    2011-01-01

    Despite advances in upfront therapy, the prognosis in the great majority of patients with glioblastoma (GBM) is poor as almost all recur and result in disease-related death. Glioblastoma are highly vascularized cancers with elevated expression levels of vascular endothelial growth factor (VEGF), the dominant mediator of angiogenesis. A compelling biologic rationale, a need for improved therapy, and positive results from studies of bevacizumab in other cancers led to the evaluation of bevacizu...

  3. Enterovirus 71 Brainstem Encephalitis and Cognitive and Motor Deficits

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-12-01

    Full Text Available Follow-up studies were conducted in 63 previously healthy children with enterovirus 71 brainstem encephalitis (49 stage II, 7 stage Ilia, and 7 stage Illb at National Cheng Kung University Hospital, Tainan, Taiwan.

  4. Brainstem cysticercose simulating cystic tumor lesion: a case report

    Directory of Open Access Journals (Sweden)

    Walter O. Arruda

    1994-09-01

    Full Text Available The authors report the case of a 37 year-old man with a solitary cysticercus cyst in the brainstem (pons successfully removed through a suboccipital craniectomy. Surgery in neurocysticercosis has been indicated in patients with hydrocephalus and/or large cystic lesions. Cystic lesions in the brainstem and spinal cord may have indication for surgery for two reasons: (1 diagnosis; and (2 treatment. Aspects related to differential diagnosis and therapeutic alternatives are discussed.

  5. Brainstem variant of posterior reversible encephalopathy syndrome: A case report.

    Science.gov (United States)

    Tortora, Fabio; Caranci, Ferdinando; Belfiore, Maria Paola; Manzi, Francesca; Pagliano, Pasquale; Cirillo, Sossio

    2015-12-01

    Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological condition, generally observed in conjunction with severe and acute hypertension, that involves mainly the posterior head areas (occipital and temporal lobes) and anterior "watershed" areas. In this syndrome it is rare to observe a predominant involvement of the brainstem. We describe the clinical and radiological findings in a patient with brainstem involvement, discussing its pathophysiological features and possible differential diagnosis.

  6. Panic and the brainstem: clues from neuroimaging studies.

    Science.gov (United States)

    Perna, Giampaolo; Guerriero, Giuseppe; Brambilla, Paolo; Caldirola, Daniela

    2014-01-01

    One of the most influential theories has conceived unexpected panic attack (PA) as a primal defensive reaction to threat within the internal milieu of the body. This theory is based on findings suggesting the involvement of dysfunctional respiratory regulation and/or abnormally sensitive central neural network of carbon dioxide (CO2)/hydrogen ion (H+) chemoreception in PA. Thus, unexpected PA may be related to phylogenetically older brain structures, including the brainstem areas, which process basic functions related to the organism's internal milieu. The brainstem represents a crucial area for homeostatic regulation, including chemoreception and cardio-respiratory control. In addition, the midbrain dorsal periaqueductal gray may be involved in the unconditioned defense reactions to proximal threats, including internal physical stimuli. Our aim was to specifically consider the potential involvement of the brainstem in panic disorder (PD) by a comprehensive review of the available neuroimaging studies. Available data are limited and potentially affected by several limitations. However, preliminary evidence of a role of the brainstem in PD can be found and, secondly, the brainstem serotonergic system seems to be involved in panic modulation with indications of both altered serotonergic receptors and 5-HT transporter bindings. In conclusion, our review suggests that the brainstem may be involved in psychopathology of PD and supports the relevant role of subcortical serotonergic system in panic pathogenesis. PMID:24923341

  7. The management of oral erythema multiforme in juvenile patient

    Directory of Open Access Journals (Sweden)

    Diah Savitri Ernawati

    2007-12-01

    Full Text Available Erythema multiforme is an acute inflammatory disease of the skin and mucous membranes that causes a variety of the skin lesionhence the name ‘multiforme’.The oral mucosa looks severely inflamed, but the feature are non specific and usually a biopsy is required in order to confirm the diagnosis. Cracked, bleeding, Crusted, swollen and ulcers of the lips is very characteristic of erythema multiforme, and lip involvement may cause significant morbidity. EM is assumed as an immune complex disorder which rises as a result of an immune response to an external agent such as herpes simplex virus or various drugs. We reported: 14-year girl, complained she suffered from painful oral ulceration for one week. One weeks advance the patient received a treatment of paracetamol and paramex for febris, headache and cough. Clinical examination of the skin showed no signs of cutaneous involvement. Other site such as the conjunctival, and genital were also free of lesions. The patients had several red-based superficial erosions on the upper and lower lips accompanied by crusting and bleeding. Intra oral findings showed multiple irregular erosions, ulcers and intense erythematous areas, mainly on the labial mucosa. The clinical diagnosis of EM was concluded by anamnesis and clinical appearance, with differential diagnosis of secondary herpes infection (herpes labialis and pemphigus vulgaris. Systemic and topical corticosteroid therapy is frequently used to treat EM Although it may partially suppress the disease. Objective: This report explains and describes the management of patients with EM which may help dentists to determine an accurate diagnosis to avoid further complication and to give medical intervention to the disease. Conclusion: Early recognition of this disease may prevent delayed diagnosis and incorrect treatment.

  8. Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future direction

    Directory of Open Access Journals (Sweden)

    Supriya Mallick

    2015-01-01

    Full Text Available Glioblastoma multiforme (GBM is the most aggressive form of primary brain tumor. Maximal safe surgical resection followed by adjuvant partial brain radiation with concurrent and adjuvant temozolomide (TMZ (oral alkylating agent is the standard of care. Five years survival in TMZ treated patient reaches 9.8%. We aimed to summarize the changes in the management of GBM beyond conventional temozolomide based adjuvant treatment. We searched the PUBMED with the following key words: Glioblastoma, phase III trial, Phase II trial, adjuvant treatment in GBM. Clinical research has found a wide range of molecular aberrations in GBM and attempts are being made to further improve survival with the addition of different classes of drugs. Angiogenesis inhibitors, oncolytic vaccines, dose dense TMZ, and anti-epidermal growth factor receptor monoclonal antibody in phase III trials have failed to improve survival. Recent studies have also shown that the management strategies might be different and needs to be customized as per the age of patients such as pediatric and elderly patients. In addition, treatments should be personalized depending on the molecular aberrations. We reviewed all published phase III trials for newly diagnosed GBM as well as also looked into possible future directions in this review. Limited progress has happed beyond conventional TMZ in the adjuvant treatment of GBM. Newer insights are emerging about treatment intensification and introduction of newer molecular targeted drugs with more information about molecular aberrations.

  9. New insights into the anticancer activity of carnosol: p53 reactivation in the U87MG human glioblastoma cell line.

    Science.gov (United States)

    Giacomelli, Chiara; Natali, Letizia; Trincavelli, Maria Letizia; Daniele, Simona; Bertoli, Alessandra; Flamini, Guido; Braca, Alessandra; Martini, Claudia

    2016-05-01

    Glioblastoma multiforme (GBM) is an aggressive brain tumour with high resistance to radio- and chemotherapy. As such, increasing attention has focused on developing new therapeutic strategies to improve treatment responses. Recently, attention has been shifted to natural compounds that are able to halt tumour development. Among them, carnosol (CAR), a phenolic diterpene present in rosemary, has become a promising molecule that is able to prevent certain types of solid cancer. However, no data are available on the effects of CAR in GBM. Here, CAR activity decreased the proliferation of different human glioblastoma cell lines, particularly cells that express wild type p53. The p53 pathway is involved in the control of apoptosis and is often impaired in GBM. Notably, CAR, through the dissociation of p53 from its endogenous inhibitor MDM2, was able to increase the intracellular p53 levels in GBM cells. Accordingly, functional reactivation of p53 was demonstrated by the stimulation of p53 target genes' transcription, the induction of apoptosis and cell cycle blockade. Most importantly, CAR produced synergistic effects with temozolomide (TMZ) and reduced the restoration of the tumour cells' proliferation after drug removal. Thus, for the first time, these data highlighted the potential use of the diterpene in the sensitization of GBM cells to chemotherapy through a direct re-activation of p53 pathway. Furthermore, progress has been made in delineating the biochemical mechanisms underlying the pro-apoptotic effects of this molecule. PMID:26939786

  10. PACAP and VIP inhibit the invasiveness of glioblastoma cells exposed to hypoxia through the regulation of HIFs and EGFR expression

    Directory of Open Access Journals (Sweden)

    Grazia eMaugeri

    2016-05-01

    Full Text Available Pituitary adenylate cyclase-activating polypeptide (PACAP and vasoactive intestinal peptide (VIP through the binding of vasoactive intestinal peptide receptors (VIPRs, perform a wide variety of effects in human cancers, including glioblastoma multiforme (GBM. This tumor is characterized by extensive areas of hypoxia, which triggers the expression of hypoxia-inducible factors (HIFs. HIFs not only mediate angiogenesis but also tumor cell migration and invasion. Furthermore, HIFs activation is linked to epidermal growth factor receptor (EGFR overexpression. Previous studies have shown that VIP interferes with the invasive nature of gliomas by regulating cell migration. However, the role of VIP family members in GBM infiltration under low oxygen tension has not been clarified yet. Therefore, in the present study we have investigated, for the first time, the molecular mechanisms involved in the anti-invasive effect of PACAP or VIP in U87MG glioblastoma cells exposed to hypoxia induced by treatment with desferrioxamine (DFX. The results suggest that either PACAP or VIP exert an anti-infiltrative effect under low oxygen tension by modulating HIFs and EGFR expression, key elements involved in cell migration and angiogenesis. These peptides act through the inhibition of PI3K/Akt and MAPK/ERK signaling pathways, which are known to have a crucial role in HIFs regulation. In conclusion, the modulation of hypoxic event and the anti-invasive effect exerted by some VIP family members might open new insights in the therapeutic approach to GBM.

  11. PACAP and VIP Inhibit the Invasiveness of Glioblastoma Cells Exposed to Hypoxia through the Regulation of HIFs and EGFR Expression.

    Science.gov (United States)

    Maugeri, Grazia; Grazia D'Amico, Agata; Reitano, Rita; Magro, Gaetano; Cavallaro, Sebastiano; Salomone, Salvatore; D'Agata, Velia

    2016-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) through the binding of vasoactive intestinal peptide receptors (VIPRs), perform a wide variety of effects in human cancers, including glioblastoma multiforme (GBM). This tumor is characterized by extensive areas of hypoxia, which triggers the expression of hypoxia-inducible factors (HIFs). HIFs not only mediate angiogenesis but also tumor cell migration and invasion. Furthermore, HIFs activation is linked to epidermal growth factor receptor (EGFR) overexpression. Previous studies have shown that VIP interferes with the invasive nature of gliomas by regulating cell migration. However, the role of VIP family members in GBM infiltration under low oxygen tension has not been clarified yet. Therefore, in the present study we have investigated, for the first time, the molecular mechanisms involved in the anti-invasive effect of PACAP or VIP in U87MG glioblastoma cells exposed to hypoxia induced by treatment with desferrioxamine (DFX). The results suggest that either PACAP or VIP exert an anti-infiltrative effect under low oxygen tension by modulating HIFs and EGFR expression, key elements involved in cell migration and angiogenesis. These peptides act through the inhibition of PI3K/Akt and MAPK/ERK signaling pathways, which are known to have a crucial role in HIFs regulation. PMID:27303300

  12. Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B

    Energy Technology Data Exchange (ETDEWEB)

    Hamm, Rebecca; Zeino, Maen [Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany); Frewert, Simon [Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken (Germany); Efferth, Thomas, E-mail: efferth@uni-mainz.de [Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany)

    2014-11-15

    Treatment of glioblastoma multiforme (GBM), the most common and aggressive lethal brain tumor, represents a great challenge. Despite decades of research, the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B, a potent vacuolar H{sup +}-ATPase inhibitor influencing cellular pH values, is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol, a main component of cellular membranes, is known to be essential for GBM growth and cells bearing EGFRvIII mutation are highly dependent on exogenous cholesterol. Archazolid B caused excessive accumulation of free cholesterol within intracellular compartments thus depleting cellular cholesterol and leading to up-regulation of SREBP targeted genes, including LDLR and HMGCR, the key enzyme of cholesterol biosynthesis. This cholesterol response is considered to be a novel resistance mechanism induced by archazolid B. We surmise that re-elevation of cholesterol levels in archazolid B treated cells may be mediated by newly synthesized cholesterol, since the drug leads to endosomal/lysosomal malfunction and cholesterol accumulation.

  13. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma.

    Science.gov (United States)

    Scholz, Alexander; Harter, Patrick N; Cremer, Sebastian; Yalcin, Burak H; Gurnik, Stefanie; Yamaji, Maiko; Di Tacchio, Mariangela; Sommer, Kathleen; Baumgarten, Peter; Bähr, Oliver; Steinbach, Joachim P; Trojan, Jörg; Glas, Martin; Herrlinger, Ulrich; Krex, Dietmar; Meinhardt, Matthias; Weyerbrock, Astrid; Timmer, Marco; Goldbrunner, Roland; Deckert, Martina; Braun, Christian; Schittenhelm, Jens; Frueh, Jochen T; Ullrich, Evelyn; Mittelbronn, Michel; Plate, Karl H; Reiss, Yvonne

    2016-01-01

    Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti-angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin-2 (Ang-2) as a potential target in both naive and bevacizumab-treated glioblastoma. Ang-2 expression was absent in normal human brain endothelium, while the highest Ang-2 levels were observed in bevacizumab-treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang-2, whereas the combined inhibition of VEGF and Ang-2 leads to extended survival, decreased vascular permeability, depletion of tumor-associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206(+) (M2-like) macrophages were identified as potential novel targets following anti-angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang-2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang-2 may potentially overcome resistance to bevacizumab therapy. PMID:26666269

  14. Rindopepimut: an evidence-based review of its therapeutic potential in the treatment of EGFRvIII-positive glioblastoma

    Directory of Open Access Journals (Sweden)

    Babu R

    2012-09-01

    Full Text Available Ranjith Babu, D Cory AdamsonDivision of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC, USAAbstract: Glioblastoma multiforme (GBM is the most common primary brain tumor in adults and is universally fatal. Despite surgical resection, radiotherapy, and systemic chemotherapy, the median overall survival is less than 15 months. As current therapies are not tumor-specific, treatment commonly results in toxicity. The epidermal growth factor receptor variant III (EGFRvIII is a naturally occurring mutant of EGFR and is expressed on approximately 20% to 30% of GBMs. As it is not expressed on normal cells, it is an ideal therapeutic target. Rindopepimut is a peptide vaccine which elicits EGFRvIII-specific humoral and cellular immune responses. Phase I and II clinical trials have demonstrated significantly higher progression-free and overall survival times in vaccinated patients with EGFRvIII-expressing GBM tumors. Side effects are minimal and mainly consist of hypersensitivity reactions. Due to the efficacy and safety of rindopepimut, it is a promising therapy for patients with GBM. Currently, rindopepimut is undergoing clinical testing in an international Phase III trial for newly diagnosed GBM and a Phase II trial for relapsed GBM.Keywords: CDX-110, EGFRvIII, glioblastoma, immunotherapy, PEPvIII

  15. Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B

    International Nuclear Information System (INIS)

    Treatment of glioblastoma multiforme (GBM), the most common and aggressive lethal brain tumor, represents a great challenge. Despite decades of research, the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B, a potent vacuolar H+-ATPase inhibitor influencing cellular pH values, is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol, a main component of cellular membranes, is known to be essential for GBM growth and cells bearing EGFRvIII mutation are highly dependent on exogenous cholesterol. Archazolid B caused excessive accumulation of free cholesterol within intracellular compartments thus depleting cellular cholesterol and leading to up-regulation of SREBP targeted genes, including LDLR and HMGCR, the key enzyme of cholesterol biosynthesis. This cholesterol response is considered to be a novel resistance mechanism induced by archazolid B. We surmise that re-elevation of cholesterol levels in archazolid B treated cells may be mediated by newly synthesized cholesterol, since the drug leads to endosomal/lysosomal malfunction and cholesterol accumulation

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

    International Nuclear Information System (INIS)

    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

  17. Auditory Brainstem Response Improvements in Hyperbillirubinemic Infants

    Science.gov (United States)

    Abdollahi, Farzaneh Zamiri; Manchaiah, Vinaya; Lotfi, Yones

    2016-01-01

    Background and Objectives Hyperbillirubinemia in infants have been associated with neuronal damage including in the auditory system. Some researchers have suggested that the bilirubin-induced auditory neuronal damages may be temporary and reversible. This study was aimed at investigating the auditory neuropathy and reversibility of auditory abnormalities in hyperbillirubinemic infants. Subjects and Methods The study participants included 41 full term hyperbilirubinemic infants (mean age 39.24 days) with normal birth weight (3,200-3,700 grams) that admitted in hospital for hyperbillirubinemia and 39 normal infants (mean age 35.54 days) without any hyperbillirubinemia or other hearing loss risk factors for ruling out maturational changes. All infants in hyperbilirubinemic group had serum bilirubin level more than 20 milligram per deciliter and undergone one blood exchange transfusion. Hearing evaluation for each infant was conducted twice: the first one after hyperbilirubinemia treatment and before leaving hospital and the second one three months after the first hearing evaluation. Hearing evaluations included transient evoked otoacoustic emission (TEOAE) screening and auditory brainstem response (ABR) threshold tracing. Results The TEOAE and ABR results of control group and TEOAE results of the hyperbilirubinemic group did not change significantly from the first to the second evaluation. However, the ABR results of the hyperbilirubinemic group improved significantly from the first to the second assessment (p=0.025). Conclusions The results suggest that the bilirubin induced auditory neuronal damage can be reversible over time so we suggest that infants with hyperbilirubinemia who fail the first hearing tests should be reevaluated after 3 months of treatment. PMID:27144228

  18. Evolving Molecular Genetics of Glioblastoma

    Institute of Scientific and Technical Information of China (English)

    Qiu-Ju Li; Jin-Quan Cai; Cheng-Yin Liu

    2016-01-01

    Objective: To summary the recent advances in molecular research of glioblastoma (GBM) and current trends in personalized therapy of this disease.Data Sources: Data cited in this review were obtained mainly from PubMed in English up to 2015, with keywords "molecular", "genetics", "GBM", "isocitrate dehydrogenase", "telomerase reverse transcriptase", "epidermal growth factor receptor", "PTPRZ1-MET", and "clinical treatment".Study Selection: Articles regarding the morphological pathology of GBM, the epidemiology of GBM, genetic alteration of GBM, and the development of treatment for GBM patients were identified, retrieved, and reviewed.Results: There is a large amount of data supporting the view that these recurrent genetic aberrations occur in a specific context of cellular origin, co-oncogenic hits and are present in distinct patient populations.Primary and secondary GBMs are distinct disease entities that affect different age groups of patients and develop through distinct genetic aberrations.These differences are important, especially because they may affect sensitivity to radio-and chemo-therapy and should thus be considered in the identification of targets for novel therapeutic approaches.Conclusion: This review highlights the molecular and genetic alterations of GBM, indicating that they are of potential value in the diagnosis and treatment for patients with GBM.

  19. EGFR as a therapeutic target in glioblastoma

    Directory of Open Access Journals (Sweden)

    David M Siebert

    2012-01-01

    Full Text Available The tyrosine kinase receptor epidermal growth factor receptor (EGFR can be activated by several ligands, thus triggering downstream pathways regulating cell growth and survival. Its dysregula­tion is particularly important for the development and progression of astrocytomas. After the description of its role in glioblastomas (WHO grade IV astrocytomas, an overview on the therapeutic strategies target­ing EGFR is provided. It analyzes the past and ongoing trials concerning the small molecule tyro­sine kinase inhibitors, i.e. gefitinib, erlotinib and the combination therapies, the EGFR vaccina­tion strategies, the antibodies directed against EGFR and finally the intracranially administered EGFR-targeted therapies. As our understanding of the underlying molecular aberrancies in glioblastoma grows, our ability to better target specific subtypes of glioblastoma should improve. Molecular biomarker enriched clinical trials may lead to improved patient outcomes.

  20. Mesenchymal Migration as a Therapeutic Target in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Jessie Zhong

    2010-01-01

    Full Text Available Extensive infiltration of the surrounding healthy brain tissue is a cardinal feature of glioblastomas, highly lethal brain tumors. Deep infiltration by the glioblastoma cells renders complete surgical excision difficult and contemporary adjuvant therapies have had little impact on long-term survival. Thus, deep infiltration and resistance to irradiation and chemotherapy remain a major cause of patient mortality. Modern therapies specifically targeted to this unique aspect of glioblastoma cell biology hold significant promise to substantially improve survival rates for glioblastoma patients. In the present paper, we focus on the role of adhesion signaling molecules and the actin cytoskeleton in the mesenchymal mode of motility that characterizes invading glioblastoma cells. We then review current approaches to targeting these elements of the glioblastoma cell migration machinery and discuss other aspects of cell migration that may improve the treatment of infiltrating glioblastoma.

  1. 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

  2. Glioblastoma stem cells: radiobiological response to ionising radiations of different qualities

    International Nuclear Information System (INIS)

    Glioblastoma multiform (GBM) is the most common and malignant primary brain tumour, with very poor prognosis. The high recurrence rate and failure of conventional treatments are expected to be related to the presence of radio-resistant cancer stem cells (CSCs) inside the tumour mass. CSCs can both self-renew and differentiate into the heterogeneous lineages of cancer cells. Recent evidence showed a higher effectiveness of C-ions and protons in inactivating CSCs, suggesting a potential advantage of Hadrontherapy compared with conventional radiotherapy for GBM treatment. To investigate the mechanisms involved in the molecular and cellular responses of CSCs to ionising radiations, two GBM stem cell (GSC) lines, named lines 1 and 83, which were derived from patients with different clinical outcomes and having different metabolic profiles (as shown by NMR spectroscopy), were irradiated with 137Cs photons and with protons or C-ions of 62 MeV u-1 in the dose range of 5- 40 Gy. The biological effects investigated were: cell death, cell cycle progression, and DNA damage induction and repair. Preliminary results show a different response to ionising radiation between the two GSC lines for the different end points investigated. Further experiments are in progress to consolidate the data and to get more insights on the influence of radiation quality. (authors)

  3. Glioblastoma stem cells: radiobiological response to ionising radiations of different qualities.

    Science.gov (United States)

    Pecchia, I; Dini, V; Ricci-Vitiani, L; Biffoni, M; Balduzzi, M; Fratini, E; Belli, M; Campa, A; Esposito, G; Cirrone, G; Romano, F; Stancampiano, C; Pelacchi, F; Pallini, R; Tabocchini, M A

    2015-09-01

    Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour, with very poor prognosis. The high recurrence rate and failure of conventional treatments are expected to be related to the presence of radio-resistant cancer stem cells (CSCs) inside the tumour mass. CSCs can both self-renew and differentiate into the heterogeneous lineages of cancer cells. Recent evidence showed a higher effectiveness of C-ions and protons in inactivating CSCs, suggesting a potential advantage of Hadrontherapy compared with conventional radiotherapy for GBM treatment. To investigate the mechanisms involved in the molecular and cellular responses of CSCs to ionising radiations, two GBM stem cell (GSC) lines, named lines 1 and 83, which were derived from patients with different clinical outcomes and having different metabolic profiles (as shown by NMR spectroscopy), were irradiated with (137)Cs photons and with protons or C-ions of 62 MeV u(-1) in the dose range of 5-40 Gy. The biological effects investigated were: cell death, cell cycle progression, and DNA damage induction and repair. Preliminary results show a different response to ionising radiation between the two GSC lines for the different end points investigated. Further experiments are in progress to consolidate the data and to get more insights on the influence of radiation quality. PMID:25969527

  4. The potential of polymeric micelles in the context of glioblastoma therapy

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    Ramin eMorshed

    2013-12-01

    Full Text Available Glioblastoma multiforme (GBM, a type of malignant glioma, is the most common form of brain cancer found in adults. The current standard of care for GBM involves adjuvant temozolomide-based chemotherapy in conjunction with radiotherapy, yet patients still suffer from poor outcomes with a median survival of 14.6 months. Many novel therapeutic agents that are toxic to GBM cells in vitro cannot sufficiently accumulate at the site of an intracranial tumor after systemic administration. Thus, new delivery strategies must be developed to allow for adequate intratumoral accumulation of such therapeutic agents. Polymeric micelles offer the potential to improve delivery to brain tumors as they have demonstrated the capacity to be effective carriers of chemotherapy drugs, genes, and proteins in various preclinical GBM studies. In addition to this, targeting moieties and trigger-dependent release mechanisms incorporated into the design of these particles can promote more specific delivery of a therapeutic agent to a tumor site. Despite these advantages however, there are currently no micelle formulations targeting brain cancer in clinical trials. Here, we highlight key aspects of the design of polymeric micelles as therapeutic delivery systems with a review of their clinical applications in several non-brain tumor cancer types. We also discuss their potential to serve as nanocarriers targeting GBM, the major barriers preventing their clinical implementation in this disease context, as well as current approaches to overcome these limitations.

  5. REST controls self-renewal and tumorigenic competence of human glioblastoma cells.

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    Luciano Conti

    Full Text Available The Repressor Element 1 Silencing Transcription factor (REST/NRSF is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets.

  6. Epidermal to Mesenchymal Transition and Failure of EGFR-Targeted Therapy in Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Pala, Andrej; Karpel-Massler, Georg [Department of Neurosurgery, University of Ulm School of Medicine, Steinhövelstrasse 9, Ulm D-89077 (Germany); Kast, Richard Eric [Department of Psychiatry, University of Vermont, 22 Church Street, Burlington, VT 05401 (United States); Wirtz, Christian Rainer; Halatsch, Marc-Eric, E-mail: marc-eric.halatsch@uniklinik-ulm.de [Department of Neurosurgery, University of Ulm School of Medicine, Steinhövelstrasse 9, Ulm D-89077 (Germany)

    2012-05-08

    Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is almost never curable with the current standard treatment consisting of surgical resection, irradiation and temozolomide. The prognosis remains poor despite undisputable advances in the understanding of this tumor’s molecular biology and pathophysiology, which unfortunately has so far failed to translate into a meaningful clinical benefit. Dysregulation and a resulting prominent pathophysiological role of the epidermal growth factor receptor (EGFR) have been identified in several different malignant tumor entities, GBM among them. The EGFR is overexpressed in about 40% of GBM cases, and half of these coexpress a mutant, constitutively activated subtype, EGFRvIII. Unfortunately, recent trials studying with therapeutic approaches targeted against the EGFR and EGFRvIII have failed to meet expectations, with only a minority of patients responding despite evidence of good in vitro and rodent model activity. Having potentially high relevance within this context, epithelial to mesenchymal transition (EMT) is a phenomenon associated with early stages of carcinogenesis, cancer invasion and recurrence. During EMT, epithelial cells lose many of their epithelial characteristics, prominently E-cadherin expression, and acquire properties that are typical for mesenchymal cells such as the expression of vimentin. Epithelial to mesenchymal transition has been specifically demonstrated in GBM. In this review, we summarize the evidence that EMT may precipitate GBM resistance to EGFR-targeted therapy, and may thus be among the principal factors contributing to the clinical failure of targeted therapy against EGFR and EGFRvIII.

  7. Glioblastoma formation from cell population depleted of Prominin1-expressing cells.

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    Kenji Nishide

    Full Text Available Prominin1 (Prom1, also known as CD133 in human has been widely used as a marker for cancer stem cells (CSCs, which self-renew and are tumorigenic, in malignant tumors including glioblastoma multiforme (GBM. However, there is other evidence showing that Prom1-negative cancer cells also form tumors in vivo. Thus it remains controversial whether Prom1 is a bona fide marker for CSCs. To verify if Prom1-expressing cells are essential for tumorigenesis, we established a mouse line, whose Prom1-expressing cells can be eliminated conditionally by a Cre-inducible DTA gene on the Prom1 locus together with a tamoxifen-inducible CreER(TM, and generated glioma-initiating cells (GICs-LD by overexpressing both the SV40 Large T antigen and an oncogenic H-Ras(L61 in neural stem cells of the mouse line. We show here that the tamoxifen-treated GICs-LD (GICs-DTA form tumor-spheres in culture and transplantable GBM in vivo. Thus, our studies demonstrate that Prom1-expressing cells are dispensable for gliomagenesis in this mouse model.

  8. mTOR Promotes Survival and Astrocytic Characteristics Induced by Pten/Akt Signaling in Glioblastoma

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    Xiaoyi Hu

    2005-04-01

    Full Text Available Combined activation of Ras and Akt leads to the formation of astrocytic glioblastoma multiforme (GBM in mice. In human GBMs, AKT is not mutated but is activated in approximately 70% of these tumors, in association with loss of PTEN and/or activation of receptor tyrosine kinases. Mechanistic justification for the therapeutic blockade of targets downstream of AKT, such as mTOR, in these cancers requires demonstration that the oncogenic effect of PTEN loss is through elevated AKT activity. We demonstrate here that loss of Pten is similar to Akt activation in the context of glioma formation in mice. We further delineate the role of mTOR activity downstream of Akt in the maintenance of Akt+KRas-induced GBMs. Blockade of mTOR results in regional apoptosis in these tumors and conversion in the character of surviving tumor cells from astrocytoma to oligodendroglioma. These data suggest that mTOR activity is required for the survival of some cells within these GBMs, and mTOR appears required for the maintenance of astrocytic character in the surviving cells. Furthermore, our study provides the first example of conversion between two distinct tumor types usually thought of as belonging to specific lineages, and provides evidence for signal transduction-mediated transdifferentiation between glioma subtypes.

  9. Are neurosurgeons prepared to electively resample glioblastoma in patients without symptomatic relapse? A qualitative study.

    Science.gov (United States)

    Mir, Tasika; Bernstein, Mark

    2016-06-01

    Background This is a qualitative study designed to examine neurosurgeons' and neuro-oncologists' perceptions of resampling surgery for glioblastoma multiforme electively, post-therapy or at asymptomatic relapse. Methods Twenty-six neurosurgeons, three radiation oncologists and one neuro-oncologist were selected using convenience sampling and interviewed. Participants were presented with hypothetical scenarios in which resampling surgery was offered within a clinical trial and another in which the surgery was offered on a routine basis. Results Over half of the participants were interested in doing this within a clinical trial. About a quarter of the participants would be willing to consider routine resampling surgery if: (1) a resection were done rather than a simple biopsy; (2) they could wait until the patient becomes symptomatic and (3) there was a preliminary in vitro study with existing tumour samples to be able to offer patients some trial drugs. The remaining quarter of participants was entirely against the trial. Participants also expressed concerns about resource allocation, financial barriers, possibilities of patient coercion and the fear of patients' inability to offer true informed consent. Conclusion Overall, if surgeons are convinced of the benefits of the trial from their information from scientists, and they feel that patients are providing truly informed consent, then the majority would be willing to consider performing the surgery. Many surgeons would still feel uncomfortable with the procedure unless they are able to offer the patient some benefit from the procedure such that the risk to benefit ratio is balanced. PMID:26760112

  10. Amplified and homozygously deleted genes in glioblastoma: impact on gene expression levels.

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    Inês Crespo

    Full Text Available BACKGROUND: Glioblastoma multiforme (GBM displays multiple amplicons and homozygous deletions that involve relevant pathogenic genes and other genes whose role remains unknown. METHODOLOGY: Single-nucleotide polymorphism (SNP-arrays were used to determine the frequency of recurrent amplicons and homozygous deletions in GBM (n = 46, and to evaluate the impact of copy number alterations (CNA on mRNA levels of the genes involved. PRINCIPAL FINDINGS: Recurrent amplicons were detected for chromosomes 7 (50%, 12 (22%, 1 (11%, 4 (9%, 11 (4%, and 17 (4%, whereas homozygous deletions involved chromosomes 9p21 (52% and 10q (22%. Most genes that displayed a high correlation between DNA CNA and mRNA levels were coded in the amplified chromosomes. For some amplicons the impact of DNA CNA on mRNA expression was restricted to a single gene (e.g., EGFR at 7p11.2, while for others it involved multiple genes (e.g., 11 and 5 genes at 12q14.1-q15 and 4q12, respectively. Despite homozygous del(9p21 and del(10q23.31 included multiple genes, association between these DNA CNA and RNA expression was restricted to the MTAP gene. CONCLUSIONS: Overall, our results showed a high frequency of amplicons and homozygous deletions in GBM with variable impact on the expression of the genes involved, and they contributed to the identification of other potentially relevant genes.

  11. Hyaluronic acid-conjugated liposome nanoparticles for targeted delivery to CD44 overexpressing glioblastoma cells

    Science.gov (United States)

    Hayward, Stephen L.; Wilson, Christina L.; Kidambi, Srivatsan

    2016-01-01

    Glioblastoma Multiforme (GBM) is a highly prevalent and deadly brain malignancy characterized by poor prognosis and restricted disease management potential. Despite the success of nanocarrier systems to improve drug/gene therapy for cancer, active targeting specificity remains a major hurdle for GBM. Additionally, since the brain is a multi-cell type organ, there is a critical need to develop an approach to distinguish between GBM cells and healthy brain cells for safe and successful treatment. In this report, we have incorporated hyaluronic acid (HA) as an active targeting ligand for GBM. To do so, we employed HA conjugated liposomes (HALNPs) to study the uptake pathway in key cells in the brain including primary astrocytes, microglia, and human GBM cells. We observed that the HALNPs specifically target GBM cells over other brain cells due to higher expression of CD44 in tumor cells. Furthermore, CD44 driven HALNP uptake into GBM cells resulted in lysosomal evasion and increased efficacy of Doxorubicin, a model anti-neoplastic agent, while the astrocytes and microglia cells exhibited extensive HALNP-lysosome co-localization and decreased antineoplastic potency. In summary, novel CD44 targeted lipid based nanocarriers appear to be proficient in mediating site-specific delivery of drugs via CD44 receptors in GBM cells, with an improved therapeutic margin and safety. PMID:27120809

  12. Glioblastoma: Análisis molecular y sus implicancias clínicas

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    Carlos A Castañeda

    2015-04-01

    Full Text Available El glioblastoma multiforme (GB es el tumor cerebral primario del sistema nervioso central (SNC más frecuente y más letal en la edad adulta. La evidencia epidemiológica indica que su incidencia es menor en la raza hispana. El tratamiento quirúrgico es la opción terapéutica preferente. Recientemente se han introducido nuevas estrategias que incrementan el volumen de resección. El uso de quimioterapia y radioterapia concurrentes mejora la supervivencia de los pacientes, aunque se asocia a toxicidad. La mejora en la comprensión de la biología molecular del GB ha permitido la identificación de biomarcadores predictivos de respuesta terapéutica y pronóstico, así como la identificación de dianas terapéuticas que han permitido el desarrollo de nuevas estrategias en el tratamiento de estos tumores. Entre los biomarcadores actualmente disponibles se encuentran la codelección 1p/19q, la mutación de IDH y la metilación del promotor O6- metilguanina DNA-metiltransferasa. La identificación de dianas terapéuticas permite el desarrollo de nuevas drogas y su evaluación posterior en ensayos clínicos, aunque ninguna de ellas ha sido validada prospectivamente en ensayos clínicos de fase III

  13. Glioblastoma: Análisis molecular y sus implicancias clínicas

    Directory of Open Access Journals (Sweden)

    Carlos A Castañeda

    2015-06-01

    Full Text Available El glioblastoma multiforme (GB es el tumor cerebral primario del sistema nervioso central (SNC más frecuente y más letal en la edad adulta. La evidencia epidemiológica indica que su incidencia es menor en la raza hispana. El tratamiento quirúrgico es la opción terapéutica preferente. Recientemente se han introducido nuevas estrategias que incrementan el volumen de resección. El uso de quimioterapia y radioterapia concurrentes mejora la supervivencia de los pacientes, aunque se asocia a toxicidad. La mejora en la comprensión de la biología molecular del GB ha permitido la identificación de biomarcadores predictivos de respuesta terapéutica y pronóstico, así como la identificación de dianas terapéuticas que han permitido el desarrollo de nuevas estrategias en el tratamiento de estos tumores. Entre los biomarcadores actualmente disponibles se encuentran la codelección 1p/19q, la mutación de IDH y la metilación del promotor O6- metilguanina DNA-metiltransferasa. La identificación de dianas terapéuticas permite el desarrollo de nuevas drogas y su evaluación posterior en ensayos clínicos, aunque ninguna de ellas ha sido validada prospectivamente en ensayos clínicos de fase III

  14. Vestibular myogenic and acoustical brainstem evoked potentials in neurological practice

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    O. S. Korepina

    2012-01-01

    Full Text Available Along with the inspection of acoustical cortex and brainstem EP in neurologic, otoneurologic and audiologic practice recently start to use so-called vestibular evoked myogenic potentials (VEMP. It is shown, that at ear stimulation by a loud sound and record of sterno-cleidomastoid contraction is possible to estimate function of the inferior vestibular nerve and vestibulospinal pathways, a sacculo-cervical reflex. In article some methodical and clinical questions of application of these kinds are presented. Combine research acoustic brainstem EP and VEMP allows to confirm effectively lesions of acoustical and vestibular ways at brainstem. The conclusion becomes, that this kind of inspection is important for revealing demielinisation and defeats in vestibulospinal tract, that quite often happens at MS, and at estimation of efficiency of treatment

  15. P17.69FOTEMUSTINE TRATMENT: WHAT ABOUT GLIOBLASTOMA PATIENTS' QUALITY OF LIFE?

    Science.gov (United States)

    Petruzzi, A.; Finocchiaro, C.Y.; Simonetti, G.; Gaviani, P.; Casali, C.; Silvani, A.; Lamperti, E.

    2014-01-01

    Glioblastoma Multiforme (GBM) is the most common and aggressive type of adult primary central nervous system tumor. The median survival in GBM patients is about 14 months. The prognosis of GBM is poor and in addition there is a very high probability of recurrence. For most patients with newly diagnosed GBM, the gold standard first-line treatment is represented by postoperative radiotherapy plus temozolomide (TMZ). There is not yet a standard of care for treatment of recurrent GBM. Recent phase II studies have demonstrated the efficacy of fotemustine (FTM) in the treatment of recurrent gliomas. To the best of our knowledge, however, no studies have investigated the quality of life in GBM patients treated with FTM as second-line treatment. We therefore sought to assess the quality of life of recurrent glioblastoma patients treated with FTM standard schedule as proposed by Addeo et al. (a dose of 80 mg/sqm every 2 weeks for five consecutive administrations as the induction phase and every 4 weeks at 80 mg/sqm as the maintenance phase). We approached 54 recurrent glioblastoma patients treated with FTM. Of these 54 eligible patients, we excluded 4 patients because they were not willing to participate in the research study and 10 because they did not meet one of the inclusion criteria, i.e. Mini Mental State Examination ≥ 25. We evaluated overall patients' quality of life through various tools: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC brain cancer module (QLQ-BN20), Beck Depression Inventory (BDI), State-Trait Anxiety Inventory form Y (STAI-Y), Hospital Anxiety and Depression Scale (HADS), Psychological Distress Inventory (PDI). Of the total of 40 patients, 18 patients completed the battery of tests both at the beginning of therapy and 2 months after the start of therapy. We found that patients reported higher levels of distress at two months after the start of therapy (mean value = 22.4) as compared to those experienced at the

  16. Annular bullous lesions with atypical erythema multiforme in leprosy.

    Science.gov (United States)

    Shah, Aishani; Mahajan, Rashmi; Ninama, Kishan; Bilimoria, Freny

    2014-09-01

    Erythema nodosum leprosum (ENL) is an immune complex-mediated reaction that may complicate the course of multibacillary leprosy. Bullous lesions in Type II reaction, though reported, are exceedingly rare. We report the case of a 32 year old female patient who presented initially at our OPD with erythema nodosum. Cutaneous examination revealed impaired sensation over dorsum of right foot and thickened right lateral popliteal nerve. Slit skin smear (SSS) from ear lobes revealed AFB with a bacteriological index of 2+. She was started on MDT, tablet ofloxacin 200 mg twice a day, and 30 mg oral prednisolone. Two months later, she presented with generalised pruritus, large target lesions over the back, and hemorrhagic bullae over lower extremities and annular pattern of bullae, over both arms. A SSS was repeated which was positive for AFB. Histopathology from bullous lesions was consistent with ENL. Direct Immunofluorescence (DIF) study was negative. Our patient improved rapidly after she was started on thalidomide 100 mg twice daily, with withdrawal of ofloxacin. Erythema Multiforme (EMF) and annular bullous lesions have been reported in patients on treatment with ofloxacin. This case is being presented due to the unusual and varied manifestation of Type II lepra reaction in a 34 year old female patient.

  17. Development, characterization, and in vitro trials of chloroaluminum phthalocyanine-magnetic nanoemulsion to hyperthermia and photodynamic therapies on glioblastoma as a biological model

    Science.gov (United States)

    de Paula, L. B.; Primo, F. L.; Jardim, D. R.; Morais, P. C.; Tedesco, A. C.

    2012-04-01

    A glioblastoma multiforme (GBM) is the highest grade glioma tumor (grade IV) and is the most malignant form of astrocytomas. Grade IV tumors, which are the most malignant and aggressive, affect people between the ages of 45 and 70 years. A GBM exhibits remarkable characteristics that include excessive proliferation, necrosis, genetic instability, and chemoresistance. Because of these characteristics, GBMs are difficult to treat and have a poor prognosis with a median survival of less than one year. New methods to achieve widespread distribution of therapeutic agents across infiltrative gliomas significantly improve brain tumor therapy. Photodynamic therapy (PDT) and hyperthermia (HPT) are well-established tumor therapies with minimal side effects while acting synergistically. This study introduces a new promising nanocarrier for the synergistic application of PDT and magnetic hyperthermia therapy against human glioma cell line T98 G, with cellular viability reduction down to as low as 17% compared with the control.

  18. Precursor States of Brain Tumor Initiating Cell Lines Are Predictive of Survival in Xenografts and Associated with Glioblastoma Subtypes

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    Carlo Cusulin

    2015-07-01

    Full Text Available In glioblastoma multiforme (GBM, brain-tumor-initiating cells (BTICs with cancer stem cell characteristics have been identified and proposed as primordial cells responsible for disease initiation, recurrence, and therapeutic resistance. However, the extent to which individual, patient-derived BTIC lines reflect the heterogeneity of GBM remains poorly understood. Here we applied a stem cell biology approach and compared self-renewal, marker expression, label retention, and asymmetric cell division in 20 BTIC lines. Through cluster analysis, we identified two subgroups of BTIC lines with distinct precursor states, stem- or progenitor-like, predictive of survival after xenograft. Moreover, stem and progenitor transcriptomic signatures were identified, which showed a strong association with the proneural and mesenchymal subtypes, respectively, in the TCGA cohort. This study proposes a different framework for the study and use of BTIC lines and provides precursor biology insights into GBM.

  19. Does gender matter in glioblastoma?

    Science.gov (United States)

    Verger, E; Valduvieco, I; Caral, Ll; Pujol, T; Ribalta, T; Viñolas, N; Boget, T; Oleaga, L; Blanco, Y; Graus, F

    2011-10-01

    BACKGROUND The clinical outcome of glioblastoma (GBM) patients who receive radiotherapy alone or with chemotherapy is well established. However, little is known about how many patients do not receive this treatment. We consider it is important to investigate why a proportion of operated patients do not receive further treatment after surgery. METHODS We reviewed all consecutive GBM patients operated on in our hospital between January 2000 and December 2008. RESULTS A total of 216 patients with GBM were identified. Fifty-five (25%) did not receive any treatment after surgery. Univariate analysis showed that factors associated with no further treatment after surgery were older than 60 years (p=0.002), of female gender (p=0.03), had a KPS<70 (p<0.001) and had had a biopsy (p<0.001). Multivariate analysis indicated that age =60 years and KPS <70 were independent predictors of no further treatment after surgery. Gender was not an independent variable. However, women in the whole series were older than 60 years (p=0.01), and they had a worse KPS (p=0.02) and more biopsies (p=0.04) than men. In the whole group, median survival time was 10.4 months for men (n=125) vs. 7.2 months for women (n=91), log rank p<0.04. This difference was not observed in the group that was treated after surgery. CONCLUSIONS One out of four patients could not be treated after surgery. Independent predictors were older age and low KPS. These poor risk variables were more frequent in women and their survival was therefore lower than men in our series. PMID:21975336

  20. Brainstem Auditory Evoked Potentials Suggest a Role for the Ventral Cochlear Nucleus in Tinnitus

    OpenAIRE

    Gu, Jianwen Wendy; Herrmann, Barbara S.; Levine, Robert A.; Melcher, Jennifer R.

    2012-01-01

    Numerous studies have demonstrated elevated spontaneous and sound-evoked brainstem activity in animal models of tinnitus, but data on brainstem function in people with this common clinical condition are sparse. Here, auditory nerve and brainstem function in response to sound was assessed via auditory brainstem responses (ABR) in humans with tinnitus and without. Tinnitus subjects showed reduced wave I amplitude (indicating reduced auditory nerve activity) but enhanced wave V (reflecting eleva...