Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-six recurrent Glioblastoma (rGBM) patients sequentially treated at the National Neurological Institute 'C Besta' were enrolled for a second surgery in order to remove recurrent tumor and to place an Ommaya reservoire to allow local delivery of chemotherapy and local pre-targeted radio-immunotherapy (RIT). All patients had partial tumor resection and 75% of them had a residual tumor mass after exeresis larger than 2 cm. After surgery all patients were managed with a second line systemic chemotherapy (PCV). Moreover the protocol scheduled two cycles of local RIT (90 Yttrium 5- 25 mCi per cycle) with a 10 week interval. Locoregional mitoxantrone chemotherapy was locally delivered as a single dose of 4 mg every 20 days. Responses to treatment were assessed by monthly neurological examination and by MRI or contrast-enhanced CT scan performed every 2 months. For the whole group of patients the PFS after second surgery at 6 and 12 months was 61% and 22%, respectively and survival after recurrence at 6, 12 and 18 months was 80%, 53% and 42%, respectively. Neither major side effects occurred systemically nor related on the place of local injections. The percentage of long-term survivors was very high: 42% of patients were still alive at 18 months. We stress the concept that the combined treatments could be more effective if delivered into a smaller residual tumor mass and probably in an adjuvant setting, before tumour recurrence.
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PMID:Intratumoral delivery of mitoxantrone in association with 90-Y radioimmunotherapy (RIT) in recurrent glioblastoma. 1592 92

Patients with supratentorial high-grade glioma underwent surgery within a vertically open 0.5-T magnetic resonance (MR) system to evaluate the efficacy of intraoperative MR guidance in achieving gross-total resection. For 31 patients, preoperative clinical data and MR findings were consistent with the putative diagnosis of a high-grade glioma, in 23 cases in eloquent regions. Tumor resections were carried out within a 0.5-T MR SIGNA SP/i (GE Medical Systems, USA). The resection of the lesion was carried out using fully MR compatible neurosurgical equipment and was stopped at the point when the operation was considered complete by the surgeon viewing the operation field with the microscope. We repeated imaging to determine the residual tumor volume only visible with MRI. Areas of tissue that were abnormal on these images were localized in the bed of resection by using interactive MR guidance. The procedure of resection, imaging control and interactive image guidance was repeated where necessary. Almost all tissue with abnormal characteristics was resected, with the exception of tissue localized in eloquent brain areas. The diagnosis of glioblastoma was confirmed in all 31 cases. When comparing the tumor volume before resection and at the point where the neurosurgeon would otherwise have terminated surgery ("first control"), residual tumor tissue was detectable in 29/31 patients; the mean residual tumor volume was 30.7 +/- 24%. After repeated resections under interactive image guidance the mean residual tumor volume was 15.1%. At this step we found tumor remnants only in 20/31 patients. The perioperative morbidity (12.9%) was low. Twenty-seven patients underwent sufficient postoperative radiotherapy. We found a significant difference (log(rank)p = 0.0037) in the mean survival times of the two groups with complete resection (n = 10, median survival time 537 days) and incomplete resection (n = 17, median survival time 237 days). The resection of primary glioblastoma multiforme under intraoperative MR guidance as demonstrated is a possibility to achieve a more complete removal of the tumor than with conventional techniques. In our small but homogeneous patient group we found an increase in the median survival time in patients with MRI for complete tumor resection, and the overall surgical morbidity was low.
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PMID:Intraoperative MRI to guide the resection of primary supratentorial glioblastoma multiforme--a quantitative radiological analysis. 1595 97

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is a major determinant of methylating anticancer drug resistance. Inactivation of MGMT by pseudosubstrate inhibitors, such as O(6)-benzylguanine (O(6)BG), sensitizes tumor cells to O(6)-alkylating agents. However, systemic administration of O(6)BG causes depletion of MGMT in all tissues of the body. Therefore, dose reduction of O(6)-alkylating drugs administered together with O(6)BG is required in order to avoid unwished toxic side effects. To attenuate the increased systemic toxicity caused by MGMT inhibitors, local MGMT inactivation would be desirable. Here, we report on intracerebral treatment with O(6)BG of a patient suffering from glioblastoma. O(6)BG was administered weekly in the tumor cavity by means of an Ommaya reservoir. This application was well tolerated. Concomitant treatment with temozolomide (Temodal) was associated with transient tumor stabilization without detectable side effects. Although evidence is still lacking that local O(6)BG administration caused MGMT to be depleted in the residual tumor, the trial shows that intracerebral treatment with O(6)BG is feasible. It might be a safe strategy for improving glioma therapy by treatment with temozolomide (and presumably also other O(6)-alkylating drugs) concomitant with O(6)BG without augmenting drug-induced systemic side effects.
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PMID:Local intracerebral administration of O(6)-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma. 1703 55

Poor chemosensitivity and the development of chemoresistance remain major obstacles to successful chemotherapy of malignant gliomas. GRP78 is a key regulator of the unfolded protein response (UPR). As a Ca2+-binding molecular chaperone in the endoplasmic reticulum (ER), GRP78 maintains ER homeostasis, suppresses stress-induced apoptosis, and controls UPR signaling. We report here that GRP78 is expressed at low levels in normal adult brain, but is significantly elevated in malignant glioma specimens and human malignant glioma cell lines, correlating with their rate of proliferation. Down-regulation of GRP78 by small interfering RNA leads to a slowdown in glioma cell growth. Our studies further reveal that temozolomide, the chemotherapeutic agent of choice for treatment of malignant gliomas, leads to induction of CHOP, a major proapoptotic arm of the UPR. Knockdown of GRP78 in glioblastoma cell lines induces CHOP and activates caspase-7 in temozolomide-treated cells. Colony survival assays further establish that knockdown of GRP78 lowers resistance of glioma cells to temozolomide, and, conversely, overexpression of GRP78 confers higher resistance. Knockdown of GRP78 also sensitizes glioma cells to 5-fluorouracil and CPT-11. Treatment of glioma cells with (-)-epigallocatechin gallate, which targets the ATP-binding domain of GRP78 and blocks its protective function, sensitizes glioma cells to temozolomide. These results identify a novel chemoresistance mechanism in malignant gliomas and show that combination of drugs capable of suppressing GRP78 with conventional agents such as temozolomide might represent a novel approach to eliminate residual tumor cells after surgery and increase the effectiveness of malignant glioma chemotherapy.
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PMID:The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. 1794 11

Reliable data on large cohorts of patients with glioblastoma are needed because such studies differ importantly from trials that have a strong bias toward the recruitment of younger patients with a higher performance status. We analyzed the outcome of 676 patients with histologically confirmed newly diagnosed glioblastoma who were treated consecutively at a single institution over a 7-year period (1997-2003) with follow-up to April 30, 2006. Survival probabilities were 57% at 1 year, 16% at 2 years, and 7% at 3 years. Progression-free survival was 15% at 1 year. Prolongation of survival was significantly associated with surgery in patients with a good performance status, whatever the patient's age, with an adjusted hazard ratio of 0.55 (p < 0.001) or a 45% relative decrease in the risk of death. Radiotherapy and chemotherapy improved survival, with adjusted hazard ratios of 0.61 (p = 0.001) and 0.89 (p = 0.04), respectively, regardless of age, performance status, or residual tumor volume. Recurrence occurred in 99% of patients throughout the follow-up. Reoperation was performed in one-fourth of these patients but was not effective, whether performed within 9 months (hazard ratio, 0.86; p = 0.256) or after 9 months (hazard ratio, 0.98; p = 0.860) of initial surgery, whereas second-line chemotherapy with procarbazine, lomustine, and vincristine (PCV) or with temozolomide improved survival (hazard ratio, 0.77; p = 0.008). Surgery followed by radiotherapy and chemotherapy should be considered in all patients with glioblastoma, and these treatments should not be withheld because of increasing age alone. The benefit of second surgery at recurrence is uncertain, and new trials are needed to assess its effectiveness. Chemotherapy with PCV or temozolomide seems to be a reasonable option at tumor recurrence.
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PMID:Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma. 1799 34

We present a case of de novo fibrosarcoma in a 43-year-old male, with MRI documented evolution from a 5 mm hyperintense area to 5 cm tumor mass in a 12-month period. The diagnosis of low-grade fibrosarcoma was established by three experienced neuropathologists. The patient underwent gross total resection with adjuvant fractionated conformal radiotherapy. Following first recurrence 3 months later, the patient was reoperated and stereotactic radiosurgery of a residual tumor was performed thereafter. The pathological diagnosis was similar, but with additional extensive radiation effects. Six months later the patient underwent aggressive surgical resection for second recurrence. The pathological diagnosis was WHO grade IV glioblastoma. The etiology of this highly unusual progression from primary mesenchymal neoplasm to high-grade glioma is discussed.
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PMID:Rapid growth of primary cerebral fibrosarcoma with conversion to glioblastoma at second recurrence. 1908 30

Experimental therapies for glioma are mostly based on the insights into the cell biology of the tumors studied by modern methods including genomics and metabolomics. In surgery, intraoperative visualization of residual tumor by fluorescence has helped with the radicality of resection. Although temozolamide has become an important agent in the combined radiochemotherapy of newly diagnosed glioblastoma, understanding the underlying mechanisms of action and resistance has led to alterations in dosing schemes, which may be more beneficial than the introduction of new agents. Targeted therapies that have been highly promising in other solid tumors have been rather disappointing in gliomas, not for the lack of promising targets but most likely due to inefficacy of the reagents to reach their target. Direct delivery of reagents with interstitial infusion via convection-enhanced delivery has proven to be safe and effective, but the potential of that technology has not been exploited because many technicalities are still to be worked out, and better, more selective reagents are needed. Gene therapy has been reactivated with direct adeno-viral application to transfer HSV-Tk into tumor cells by adenoviral vectors, still awaiting final analysis. Oncolytic viruses are also under long-term refinement and await definitive pivotal clinical trials. Immunotherapy is currently focusing on vaccination strategies using either specifically pulsed dendritic cells or immunization with a specific peptide, which is unique to the vIII variant of the epidemal growth factor receptor. An area attracting immense attention for basic research as well as translation into clinical use is the characterization of neural stem cells and their theraputic potential when appropriately manipulated.In general, there is a wide spectrum of specific neuro-oncological therapy developments, which are not only extrapolated from general oncology but also based on translational research in the field of glioma biology.
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PMID:Other experimental therapies for glioma. 1932 43

Brain abscesses by Propioni-bacterium acnes are rare. The rapid identification of this pathogen is important in order to choice the appropriate antibiotic therapy. We describe the case of a patient with excision of a multiform glioblastoma who 9 months later presented a tumor recurrence. A subtotal tumor excision was made and implants chemotherapy were placed in the residual tumor. After one month of surgery the patient presented a brain abscess. A craniotomy for drainage was performed. P. acnes was isolated from the biopsy and from purulent material. Identification was made by conventional biochemical tests and by the API system 20 A. The Minimum Inhibitory Concentration (MIC) to clindamycin, penicillin, amoxicillin and metronidazole was determined. The values of MIC (microg/ml) obtained were: 0.250, 0.040, 0.023 and 256, respectively. The patient received cefepime and metronidazole intravenously during 30 days and completed treatment with oral clindamycin for 60 days, considering the possibility of adjacent bone involvement. Eight months after the drainage the patient had no evidence of infection or tumor recurrence. Although P. acnes is a rare cause of post-neurosurgical infection, it should be considered as a possible pathogen in postoperative brain abscesses.
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PMID:[Post-surgery cerebral abscess due to Propionibacterium acnes]. 1941 1

Residual tumor cells remain beyond the margins of every glioblastoma (GBM) resection. Their resistance to postsurgical therapy is considered a major driving force of mortality, but their biology remains largely uncharacterized. In this study, residual tumor cells were derived via experimental biopsy of the resection margin after standard neurosurgery for direct comparison with samples from the routinely resected tumor tissue. In vitro analysis of proliferation, invasion, stem cell qualities, GBM-typical antigens, genotypes, and in vitro drug and irradiation challenge studies revealed these cells as unique entities. Our findings suggest a need for characterization of residual tumor cells to optimize diagnosis and treatment of GBM.
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PMID:Residual tumor cells are unique cellular targets in glioblastoma. 2069 20

Glioblastoma is found preferentially in men (1.5/1), nearing age 60, but all ages can be concerned. Clinical symptoms are intracranial mass without specificity, intracranial hypertension and localization signs. From the clinical history, the essential prognosis factors are: age, Karnofsky score and cognitive dysfunction. Conventional MRI sequences, including T1-FSE with and without contrast injection and T2-FSE or Flair-weighted sequences, provide the diagnosis in most cases, showing an intraparenchymal mass with a heterogeneous, irregularly enhanced signal. Other sequences define the tumor more precisely. Diffusion sequences provide the differential diagnosis with an abscess or a highly cellular tumor such as lymphoma. Perfusion sequences allow appreciation of tumor microvascularization outlining the tumor's most active areas. Magnetic resonance spectroscopy (SRM) sequences allow noninvasive exploration of tumor metabolism. Beyond its diagnostic role, imagery assists the surgical procedure itself, particularly with functional MRI, allowing a precise preoperative mapping of functional cortical areas. Biopsy can also be guided toward the most active areas of the tumor. In the postoperative period, MRI completes the surgeon's impression on whether or not there is residual tumor. Finally, this exam has become essential in follow-up to diagnose recurrence, radionecrosis, or pseudoprogression.
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PMID:[Clinical factors in glioblastoma and neuroradiology]. 2087 Feb 53


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