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A fatal case of glioblastoma multiforme, initially appearing as orofacial pain of unknown cause, is reported. The report of case illustrates the multidisciplinary approach that, at times, is required to diagnose elusive orofacial pain.
Primary glioblastoma multiforme (GBM) commonly overexpresses the epidermal growth factor receptor (EGFR) gene and its ligand-independent mutant, EGFRvIII. Amplification of the EGFR gene has been implicated in the pathogenesis of primary GBM, in particular the small cell phenotype, and this finding may contribute to its aggressive clinical behavior. Anti-EGFR clinical trials for GBM are being conducted, and it would be useful to identify a rapid technique to determine whether EGFR expression and the small cell phenotype are associated with a response to therapy. In the present study we examined 56 cases of GBM using chromogenic in situ hybridization (CISH). CISH analysis and morphology identified 22 small cell (SCGBM) and 22 non-small cell glioblastoma (NSCGBM), and 12 cases of a mixed phenotype. Fourteen cases of SCGBM (14/22) showed EGFR amplification, while only 5 NSCGBM (5/22) cases showed amplification. We have therefore used CISH as an efficient, economic and reliable means for routinely assessing EGFR amplification in GBM, including the small cell variant.
Outgrowth of tumor-infiltrating lymphocytes (TIL) from the human primary brain tumor glioblastoma multiforme was achieved by OKT3 initiation (10 ng/ml), followed by sustained expansion by interleukin-2 (IL-2; 200 U/ml). Tumor-infiltrating lymphocyte (TIL) initiation by this process was performed in parallel with the standard "IL-2-only" method. Of ten tumors, seven yielded TIL in response to OKT3/IL-2, whereas only three of these seven grew after initiation with IL-2 alone. On the basis of cell doubling times, at least 60 doublings, resulting in (hypothetically) up to 10(23) TIL from as few as 2 x 10(5) cells in tumor suspensions, could be achieved using OKT3/IL-2. OKT3-initiated TIL proliferated in culture for as long as 288 days, although senescence of some cultures occurred at as early as 73 days. Significant heterogeneity of lymphocytes infiltrating the fresh tumors and heterogeneity of resultant TIL phenotype and function were apparent, yet several common trends were noted. In all cases after OKT3 initiation, significant net growth was not apparent until approximately 14 days. In contrast, in the three samples that grew in response to IL-2 alone, log-phase growth was always observed earlier. During the early phase of the cultures, all TIL expressed some killing activity toward a broad spectrum of tumors, including the autologous tumor. No consistent preference of TIL for lysis of autologous tumor was observed. Glioblastoma multiforme TIL cultures contained a mixture of CD8+ and CD4+ cells, with few CD16+ or NKH-1+. Of the six TIL examined in detail for population phenotype in relationship to time in culture, four eventually became exclusively CD4+. Further analysis of these CD4+ TIL indicated that all were of the helper-inducer class, 4B4+ and 2H4-. Concurrent with the decline in CD8+ cells, a decline in the cytolytic activity of these TIL cultures occurred. Furthermore, in two TIL that remained CD8+, a decline in the cytolytic activity also occurred. Therefore, loss of killing activity was not merely a reflection of the major cell phenotype changes. These results indicate that the OKT3/IL-2 process provides an alternative to IL-2 alone for TIL initiation and growth, as well as providing a novel system for further analysis of tumor-derived lymphocyte and accessory cell functional potential.
The present report describes two patients with glioblastoma multiforme with the tumour demonstrating low central apparent diffusion coefficient values similar to those found in cerebral abscesses. Although conventional MR images were fairly specific for tumour, the cases illustrate the need for exercising caution when using diffusion-weighted (DW) MR images for the differentiation of necrotic brain tumours from abscesses. The DW MR imaging information should always be integrated with the conventional spin-echo MR images.
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.
Intraventricular neoplasms of the third ventricle represent a small minority of intracranial tumors. Furthermore, few cases of solitary, third ventricular glioblastoma multiforme were reported in the literature. The authors report a case of a fifty-nine year old man who presented with progressive gait disturbance, disorientation, diffuse headache, and vomiting. Computed tomography and magnetic resonance imaging (MRI) confirmed a solitary third ventricular ring-enhancing lesion and obstructive hydrocephalus. The final pathology of the lesion upon permanent section was glioblastoma multiforme (GBM). The clinical course, radiologic findings, the possible origin of this lesion, as well as possible treatment regimen are discussed.
PURPOSE: To evaluate the efficacy of 9-amino [20s] camptothecin (9-AC) given before radiation therapy to patients with newly diagnosed glioblastoma multiforme (GBM). METHODS: Eligible patients had newly diagnosed GBM who had residual measurable contrast-enhancing tumor. The trial was a phase 2 trial of 9-AC at 1100 microg/m2 /24 h infused over 72 h every two weeks for up to six cycles in patients with newly diagnosed GBM before radiation therapy. RESULTS: Fourteen patients entered the study and all were evaluable. All of the patients had progressive disease by imaging criteria after at least two cycles of 9-AC (1 month). The median overall survival was 7.5 months (range 1.5-18 months). The most common adverse event was transient lymphopenia (grade 3-4). One patient developed grade 4 neutropenic fever that resolved after three days of diagnosis. CONCLUSIONS: 9-AC lacks activity against glioblastoma multiforme (GBM). Further studies looking at the efficacy of 9-AC in GBM may be futile.
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.
A 62-year-old male presented with glioblastoma multiforme in the left frontal lobe manifesting as motor aphasia, subsequent to a malignant lymphoma in the right orbit. He underwent subtotal removal of the right orbital mass presenting as right exophthalmos which was shown by histological examination to be non-Hodgkin's lymphoma. He received 30 Gy Lineac irradiation to the right orbit. His post-operative course was satisfactory. Magnetic resonance (MR) imaging with gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) 7 months later demonstrated a small spotty enhanced lesion in the left frontal lobe. He developed motor aphasia 1 year after irradiation. MR imaging disclosed an enhanced mass in the left frontal lobe, which was totally removed. Histological examination revealed glioblastoma multiforme. Patients with malignant lymphoma may develop a subsequent second malignant tumor. MR imaging with Gd-DTPA is quite useful for early detection of a second brain tumor.
UNLABELLED: 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).
Primary brain tumors including anaplastic astrocytomas and glioblastoma multiforme are difficult to treat because of their locally invasive nature and chemoradioresistance. Novel therapies are needed. One class of therapeutics is fusion proteins consisting of peptide toxins fused to brain tumor selective ligands. DAB389EGF is a fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor (EGF). DAB389EGF is selectively toxic to EGF receptor (EGFR) overexpressing cells. Close to half of all high-grade primary brain tumors have EGFR gene amplification and EGFR overexpression. With the use of convection-enhanced delivery (CED), DAB389EGF may be delivered locally at high concentrations to the brain tumor. CED would avoid many of the pharmacologic and toxicologic barriers which have limited effective use of this agent including rapid clearance from the circulation, high anti-diphtheria toxin antibody titers in the blood and toxicities to the liver and kidney. Both cell lines and animal models are available to assess the potential of this agent for brain tumor therapy. Since significant amounts of clinical grade DAB389EGF are available, some careful additional preclinical efficacy work should lead to testing of this agent in patients within the next few years.
This postmortem study of 12 patients with glioblastoma multiforme (GBM) treated with boron neutron capture therapy (BNCT) employing an epithermal neutron beam and p-boronophenylalanine describes the neuropathological findings in patients receiving a relatively high radiation dose to the tumor, but a relatively low radiation dose to the normal brain. In addition to a standardized neuropathology panel of sections, we used individual treatment dosimetry maps to select sections along the projected maximum radiation beam pathway. We found that the normal neuroparenchyma exposed to the highest radiation dose exhibited a single instance of radiation-induced focal venular fibrinoid necrosis and a single instance of multifocal demyelination. Semiquantitative analysis of pretreatment neurosurgical and postmortem tumor samples revealed only two radiation ascribed histopathological findings to be particular to therapy, fibrinoid necrosis and vascular hyalinization. In this relatively small series of cases we found an unexpectedly high frequency of cases (3 of 12) with neurodegenerative histopathology (Lewy bodies, neurofibrillary tangles, and neuritic senile plaques), which appeared, by distribution, to be independent of the radiation beam. Two of these patients were over 70 yr of age. One was only 41. Our findings suggest an acceptable radiation-induced level of neurotoxicity at the lower doses employed, but raise the possibility of unexpected boron neurodegenerative toxicity.
We investigated glioblastoma multiforme (GBM) for a pattern of consistent alterations in cell adhesion molecules (CAM) expression that might distinguish tumor from normal autologous brain tissue. We used frozen section immunohistochemistry with anti-CAM and computerized image analysis to quantify staining intensity which we expressed as relative intensity units (RIU). Our results showed that normal brain tissue generally did not express alpha 1 beta 1, intercellular CAM-1 (ICAM-1), and sialylated Lewisx, slightly expressed alpha 2, alpha 4, alpha 5, alpha 6 beta 1, alpha v beta 3, lymphocyte function-associated antigen-3 (LFA-3), Lewisx, sialylated LewisLewisx, had a good expression of alpha 3 beta 1 and CD44, and strongly expressed neural CAM (NCAM). GBM expressed alpha 2, alpha 3, alpha 5, alpha 6 beta 1, alpha v beta 3, ICAM-1, LFA-3, CD44, Lewisx, sialylated Lewisx, and sialylated LewisLewisx significantly higher (2-11-fold RIU) than normal brain tissue. ICAM-1 and LFA-3 were the most distinctive markers of GBM. The small blood vessel endothelial cells of the normal brain and the GBM showed a few differences. The tumor endothelium expression of alpha 2 beta 1, alpha 4 beta 1, and LFA-3 RIU appeared twice higher than in normal endothelium and alpha 6 beta 1 showed an average of 40% RIU decrease in comparison to normal. These results show that the expression of several CAM is consistently altered in GBM and its microvasculature when compared with autologous normal brain tissue.
OBJECT: Because the prognosis for patients with glioblastoma multiforme (GBM) remains poor, investigators have focused on developing new and more effective treatment modalities. Targeted toxins represent a new class of compounds composed of a potent protein toxin and a carrier ligand that will recognize cell surface antigens located on target tissue. A recombinant fusion protein was created that contains the translocation and catalytic portions of diphtheria toxin that are responsible for cell entry and killing, respectively, fused to the noninternalizing aminoterminal fragment portion of human plasminogen activator. This diptheria toxin-uPA fusion protein (DTAT) has the advantage over other fusion proteins of targeting malignant glioma cells and the endothelial cells of the neovasculature that express the urokinase-type plasminogen activator receptor (uPAR). Another protein, DTAT13, was synthesized to target uPAR on the neovasculature and the uPAR and interleukin-13 receptor-expressing GBM cells. The authors describe the in vitro and in vivo efficacy of DTAT and DTAT13 against GBM. METHODS: The in vitro cytotoxicity of DTAT and DTAT13 was measured using cell proliferation assays. In vivo studies were performed in which DTAT, DTAT13, or a control protein was injected directly into GBM flank tumors in athymic nude mice. Tumor volume was assessed over time and analyzed using the Student t-test. The systemic organ effects of DTAT and DTAT13 were examined functionally and histologically in tumor-free C57BL/6 mice. In vitro, DTAT and DTAT13 were found to be highly potent and selective against U118MG, U87MG, and U373MG GBM cell lines and human umbilical vein endothelial cells. In vivo, DTAT and DTAT13 both caused a statistically significant (p < 0.05) regression of U87MG GBM flank tumors when administered every other day at 10 mg/day for five doses. No tumor regression was seen in control animals. Both DTAT and DTAT13 had little effect on histological findings in the liver, kidney, spleen, and lungs. Serum analysis did not demonstrate an effect on blood urea nitrogen levels, but liver alanine aminotransferase levels rose to statistically significant (p = 0.046) but not life-threatening levels. Also, DTAT13 was less toxic than DTAT in studies of mortality rates. CONCLUSIONS: Both DTAT and DTAT13 might have potential for clinical application against GBM because of their ability to target both the tumor cells and neovasculature simultaneously with an absence of serious systemic side effects. The discovery that DTAT13 was less toxic than DTAT indicated that the bispecific fusion protein might target a broader subset of antigenetically diverse patients with tumors while reducing the systemic exposure to toxin that would be necessary if two agents were administered separately.
On March 15, 2005, the U.S. Food and Drug Administration approved temozolomide (Temodar capsules, Schering-Plough Research Institute) for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. Five hundred seventy-three glioblastoma multiforme patients were randomized to receive either temozolomide + radiotherapy (n = 287) or radiotherapy alone (n = 286). Patients in the temozolomide + radiotherapy arm received concomitant temozolomide (75 mg/m2) once daily for the duration of radiation therapy (42-49 days). This was followed, 4 weeks later, by six cycles of temozolomide, 150 or 200 mg/m2 daily for 5 days, every 4 weeks. Patients in the control arm received radiotherapy only. In both arms, radiotherapy was delivered as 60 Gy/30 fractions to the tumor site with a 2 to 3 cm margin. Pneumocystis carinii pneumonia prophylaxis was required during temozolomide + radiotherapy treatment and was continued until recovery of lymphocytopenia (Common Toxicity Criteria grade <1). At disease progression, temozolomide salvage treatment was given to 161 of 282 patients (57%) in the radiotherapy alone arm, and to 62 of 277 patients (22%) in the temozolomide + radiotherapy arm. Patients receiving concomitant and maintenance temozolomide + radiotherapy had significantly improved overall survival. The hazard ratio was 0.63 (95% confidence interval, 0.52-0.75; log-rank, P < 0.0001). Median survival was 14.6 months (temozolomide + radiotherapy) versus 12.1 months (radiotherapy alone). Adverse events during temozolomide treatment included thrombocytopenia, nausea, vomiting, anorexia, constipation, alopecia, headache, fatigue, and convulsions.
BACKGROUND: The presence of an oligodendroglial component within a glioblastoma multiforme (GBM) is considered a prognostically favorable factor, but the clinical outcome of patients with glioblastoma multiforme with oligodendroglial component (GBMO) after combined post-operative radiotherapy and chemotherapy has rarely been reported. METHODS: We analyzed overall and progression-free survival in a group of ten consecutive patients initially diagnosed with GBMO between 1996 and 2004 (4.2% of all GBM patients). Median (range) age was 54 (34-73) years, 90% were resected and median radiotherapy dose was 54 (45-60.6) Gy. 80% of patients received post-operative chemotherapy with nimustine (ACNU) and VM26 (teniposide) for a median of 3.5 (1-6) cycles, the remainder were treated with post-operative radiotherapy alone. All specimens were reviewed by an experienced neuropathologist. RESULTS: Neuropathological re-evaluation revealed GBM with an oligodendroglial component of 30% or less in five cases, predominant oligoastrocytic tumors with focal areas of GBM in four patients and WHO grade III oligoastrocytoma with questionable transition to GBM in one patient. Four of ten patients were alive at at 40, 41, 41 and 82 months. The median overall survival (Kaplan-Meier) was 26 months, the 2-year survival rate was 60% (progression-free survival: 9.8 months and 40%, respectively). CONCLUSION: In conclusion, patients with GBMO treated with post-operative radiotherapy and chemotherapy with ACNU/VM26 had a better prognosis than reported for GBM in modern chemoradiation series.
The authors present a case of a very unusual clinical presentation of an intra-axial supratentorial glioblastoma multiforme (GBM) in a 63 year old diabetic female patient presenting with a three week history of left progressive complete oculomotor nerve palsy. CT scan and magnetic resonance imaging of the head revealed a left intra-axial mesial temporal glioblastoma multiforme. Operative resection and microscopic examination of a tissue specimen confirmed the diagnosis. The nature of the tumor, the pattern of spread and the postulated mechanisms of such a presentation are discussed. The authors suggest including the diagnosis of GBM in the differential diagnosis of patients with isolated complete oculomotor nerve palsy at the appropriate age group.
The authors report a case of an unusual progression of glioblastoma multiforme in the temporal lobe associated with the first onset of nonconvulsive simple partial status epilepticus (SPSE), a rare form of status epilepticus. The patient underwent a left temporal craniotomy and the tumor was removed. Concurrently, the hippocampus was removed as well. The pathological diagnosis of the tumor and the hippocampus were glioblastoma multiforme and hippocampal sclerosis. The patient's postoperative course was uneventful.