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The authors report a biopsy proven case of skin and subcutaneous tumour seeding three years after craniotomy for a supra-tentorial multiform glioblastoma in 42 y old male without intracranial recurrence.
Mongrel adult albino female rats with multiform glioblastoma transplanted to the right cerebellar hemisphere were given subcutaneous injections of 8 mg/kg of a serotonin-creatine sulphate solution beginning with the 3rd and to the 28th postoperative days. Rats with a tumor inoculated at the same periods and given injections of a physiological saline solution served as controls. The injection of serotonin leads to a significant increase in the survival of rats by 20% as compared to the survival of rats in the control group, but practically has no effect on the life span of sick animals. Consequently, serotonin either produces an antineoplastic effect in which case the animals do not contract the disease, or it has no effect on the tumor so that the animals die of the developing tumor. Study of the tryptophan content in the neoplasm and the 5-OIAA content in urine provides evidence of a disturbed serotonin synthesis and metabolism in these neoplasms.
On the basis of 4 observations, the formation of extracranial metastases of multiform glioblastomas is dealth with which complied with all the criteria established by Weiss (histological identification of a primary brain tumour, connection of clinical data between cerebral tumour and metastases, ruling out of another primary tumour not belonging to the neuraxis by a complete autopsy). All 4 patients were--in some cases several times--trephined, subjected to postoperative irradiation and some of them were also treated with chemotherapeutics. The postoperative survival time was between 16 and 24 months, the average age of the patients was 35 years which was strikingly low. 3 patients showed infiltrations of bones and neighbouring soft parts, in one case the tumour penetrated into the sinus, in one patient paranasal sinuses and orbitae were affected, two cases showed metastases in the vertebral column and in one case metastases were found in the cervical gland nodes. One glioblastoma accompanied by a fibrosarcoma showed a particularly extensive extracranial formation of metastases. As regards the reasons for the formation of extracranial metastases of intracranial tumors many hypotheses have been established which are critically discussed by the authors.
The authors evaluate therapeutic results in 31 patients with the diagnosis of multiform glioblastoma. The comprehensive therapeutic procedure used as a rule which involves surgery, radiotherapy and in some instances also chemotherapy still gives very unsatisfactory results. The mean survival period of patients after surgery was 26.7 weeks and the mortality of patients within one month was 22.6%. Even radical surgery does not produce more favourable therapeutic results. Contemporary trends of preclinical and clinical research are focused in particular on different immunotherapeutic methods.
Primary glioblastoma multiforme of cerebellar hemispheres in adults is a rare condition. Most of them result from dedifferentiation of astrocytoma to glioblastoma. We present two cases of unusual de novo cerebellar glioblastomas, one of which is the giant-cell variant. We review their clinical behaviour with conventional MR imaging features and discuss the key findings that can lead to the correct diagnosis in sight of new MR imaging technologies.
Glioblastoma multiforme (GBM), the most common and malignant central nervous system tumor in humans, is highly proliferative and resistant to apoptosis. Stat3, a latent transcription factor being activated by aberrant cytokine or growth factor signaling, acts as a suppressor of apoptosis in a number of cancer cells. Here we report that GBM tumors and cell lines contain high levels of constitutively activated Stat3 when compared with normal human astrocytes, white matter, and normal tissue adjacent to tumor. The persistent activation of Stat3 is in part, attributable to an autocrine action of interleukin-6 in the GBM cell line U251. Janus kinase inhibitor AG490 inhibits Stat3 activation with a concomitant reduction in steady-state levels of Bcl-X(L), Bcl-2 and Mcl-1 proteins and induces apoptosis in U251 cells as revealed by Poly (ADP-ribose) polymerase cleavage and Annexin-V staining. Expression of a dominant negative mutant Stat3 protein or treatment with AG490 markedly reduces the proliferation of U251 cells by inhibiting the constitutive activation of Stat3. These results provide evidence that constitutive activation of Stat3 contributes to the pathogenesis of glioblastoma by promoting both proliferation and survival of GBM cells. Therefore, targeting Stat3 signaling may provide a potential therapeutic intervention for GBM.
Glioblastoma multiforme (GBM) cells frequently harbor amplification and/or gain-of-function mutation of the EGFR gene leading to the activation of multiple signaling pathways. Blockade of EGFR activation inhibited the activation of both AKT and Stat3 in U87 and D54 GBM cells and induced spontaneous apoptosis, which were associated with reduction in the steady-state level of Mcl-1. Surprisingly, inhibition of PI3 kinase (PI3K) activity, which in turn inhibited AKT activation, significantly increased the DNA-binding activity of Stat3 in U87 and D54 cells. This was not due to an increase in the level of tyrosine-phosphorylated Stat3. Conversely, ectopic expression of constitutively activated AKT significantly decreased the DNA-binding activity of Stat3 in 293T cells. Interestingly, blockade of protein phosphatase 2A activity in GBM or 293T cells by calyculin A, which activated AKT, stabilized the phosphorylation of multiple Ser/Thr residues that were located in the transactivation domain (TAD) of Stat3 and this in turn completely ablated the DNA-binding activity of Stat3. Collectively, these results suggest that both Stat3 and AKT provide survival signals in U87 and D54 cells, and Ser/Thr phosphorylation of Stat3-TAD by the PI3K-AKT pathway negatively controls the DNA-binding function of Stat3.
OBJECT: Glioblastoma multiforme (GBM) remains incurable by conventional treatments, although some patients experience long-term survival. A younger age, a higher Karnofsky Performance Scale (KPS) score, more aggressive treatment, and long progression-free intervals have been reported to be positively associated with long-term postoperative patient survival. The aim of this retrospective study was the identification of additional favorable prognostic factors affecting long-term survival in surgically treated adult patients with supratentorial GBM. METHODS: Of 113 adult patients newly diagnosed with histologically verified supratentorial GBM who were enrolled in Phase III trials during the period between 1987 and 1998, six (5.3%) who survived for longer than 5 years were defined as long-term survivors, whereas the remaining 107 patients served as controls. All six were women and were compared with the controls; they were younger (mean age 44.2 years, range 31-60 years), and their preoperative KPS scores were higher (mean 85, range 60-100). Four of the six patients underwent gross-total resection. In five patients (83.3%) the progression-free interval was longer than 5 years and in three a histopathological diagnosis of giant cell GBM was made. This diagnosis was not made in the other 107 patients. CONCLUSIONS: Among adult patients with supratentorial GBM, female sex and histopathological characteristics consistent with giant cell GBM may be predictive of a better survival rate, as may traditional factors (that is, younger age, good KPS score, more aggressive resection, and a long progression-free interval).
AIM: Glioblastoma multiforme (GBM) is an incurable disease that can only be managed in a palliative way. The GBM accounts for approximately half of all newly diagnosed primary brain tumors with an incidence of 2-3 cases per 100,000 people each year. Surgery and radiation are the standard options for palliation, and whether there is a place for chemotherapy is still discussed. Boron neutron capture therapy (BNCT) is a promising and possibly curative method of treating GBM. The purpose of this article is to provide an updated review on the current management and future possibilities of treating GBM with BNCT. METHOD: Use was made of computerized searches and of checking cross-references of articles and book chapters. RESULTS: The principle of BNCT uses the high ability of 10B to capture thermal neutrons and to disintegrate immediately into a He nucleus (alpha-particle) and a Li nucleus. To reach a sufficient concentration of 10B in the malignant cells compared to the surrounding healthy tissue, 10B-carriers must be highly tumor-selective. At present, the 10B carriers boronophenylalanine (BPA) and sodium borocaptate (BSH) are used in clinical trials to perform BNCT. CONCLUSION: The BNCT is a promising and possibly curative method of treating GBM, but at present this procedure is far from perfect. Because of the lack of selectivity of the boron carriers, it appears so far that radiation toxicity limits the radiation dose, so that tumor damage is modest. Current investigations and developments are aimed at targeting the boron carriers to the tumor, in order to limit the damage to the healthy, surrounding tissue.
Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavours, with low response rates and survival rarely exceeding 6 months. There are no standard chemotherapeutic regimens and new therapeutic approaches have to be found. We report an open-label, uncontrolled, multicentre phase II trial of lonidamine (LND) and diazepam in 16 patients with GBM at first relapse and a Karnofsky performance status > or = 70. The treatment regimen consisted of LND 450 mg/day and diazepam 15 mg/day orally of every 28-day cycle until progression or unacceptable toxicity. Patients received a median of three cycles (range, 1-12). No complete or partial response was observed. Therefore, according to the design of the study, no additional patients were enrolled and the trial was closed. Nevertheless, seven stabilizations (50%) were observed. Median time to progression was 8 weeks (range, 5-19 weeks). Median overall survival from recurrence was 15 weeks (range, 14-61 weeks). No grade 3-4 toxicity, except somnolence, was observed and there were no therapy-related deaths. Dose reduction for diazepam due to somnolence (grade III) was performed in 9 patients. The combination of LND and diazepam is well tolerated. LND and diazepam, acting on two distinct mitochondrial sites involved in cellular energy metabolism, may exert a cytostatic effect on tumour growth as shown by the high percentage of stable patients. The LND-diazepam at the used dosing schedule did not show a complete or partial response. LND plus diazepam may be interesting in the adjuvant setting or associated to chemotherapy to act on different targets and increase the therapeutic index.
Glioblastoma multiforme (GBM) is the most common and aggressive primary human brain tumour in adults with an average survival of 11 months. The 2-year survival is less than 10%, and only a small proportion of patients are alive at 3 years. Despite improved treatment strategies and aggressive therapy, the prognosis of GBM has changed little in past decades. Thus, any test that can reliably and rapidly diagnose the tumour and predict patient survival could be a valuable tool. Herein we report the use of quantitative real-time polymerase chain reaction (PCR) to quantify five glycosyltransferase transcripts in gliomas. Our results indicate that measuring GM1 synthase (beta-1,3 galactosyltransferase) mRNA may provide a useful method for segregating GBMs from other types of gliomas. In these studies, 97% of gliomas (36/37 tumours) below a threshold value had a diagnosis of GBM compared with 49% (52/106 tumours) above the threshold. More importantly, the increased expression of GD3 synthase mRNA in combination with decreased GalNAcT message correlated with increased survival in 79 GBM patients (proportional hazards model controlling for age, P = 0.02). These data were further corroborated by a data analysis from one of our previous studies on gangliosides of 80 GBMs, in which increased amounts of GM3 and GD3 (which accumulate in the absence of GalNAcT) correlated with a longer survival (P < 0.01). Thus, measuring GalNAcT and GD3 transcripts may provide a rapid method to assess prognosis in GBM patients. In summary, the data indicate that measuring glycosyltransferase mRNA levels by real-time PCR may be clinically useful for determining both diagnosis and prognosis in GBM patients.
OBJECTIVE: Glioblastoma multiforme (GBM) is a major cause of morbidity and mortality in neurosurgical patients. Despite the overall poor prognosis a range in survival times exists. Many approaches have been undertaken to define patient subgroups based on molecular changes. The aim of this study was to assess a possible correlation between the immunohistochemical p53, Mdm2, EGFR and Msh2 expression and age. METHOD: 143 patients (77 male, 66 female) were included in this retrospective study who underwent craniotomy for newly-diagnosed GBM between May 1994 and February 2000. For statistical analysis, patients were separated into three age groups: 1. < 40 years, 2. 40-60 years, 3. > 60 years. Immunohistochemical staining (IHC) was performed using anti-p53 (clone DO-1), anti-Mdm2 (clone IF-2), anti-EGFR (clone H11) and anti-Msh2 antibodies (clone AB-1). The results were compared with the Ki67/MIB-1 proliferation index (Ki67 PI) and patient survival. FINDINGS: P53 protein expression was significantly decreasing with advanced age (p < 0.05) whereas EGFR and Mdm2 expression was increasing (p < 0.05; p=0.01). Msh2 expression was unrelated to age. Multivariate analysis revealed Msh2 protein expression as a significant predictor of prolonged survival (p=0.004) whereas p53, Mdm2 and EGFR were not associated with patient survival. P53, Mdm2, EGFR and Msh2 expression was not associated with the Ki67 PI. INTERPRETATION: Our results support the hypothesis that in GBM patients a complex relationship exists between the p53, Mdm2 and EGFR expression and age. Msh2 expression is not related to age. Notably, nuclear Msh2 expression turned out to be an independent prognostic indicator.
PURPOSE: Glioblastoma multiforme (GBM) represents the prototype of an angiogenic tumor. Recently, the continuous low-dose scheduling of chemotherapeutic drugs in combination with an inhibition of cyclooxygenase-2 (COX-2) has been suggested as a novel anti-angiogenic approach. The aim of this study was to evaluate the safety and activity of continuous low-dose temozolomide (TMZ) plus the COX-2 inhibitor rofecoxib in patients with newly diagnosed GBM. METHODS: In vitro, endothelial cells were characterized by a tenfold higher sensitivity to TMZ than glioma cells. Consequently, a subgroup of patients with incompletely resected GBM (n=13) was divided into three groups aiming at a dose escalation to 1/10 of the daily MTD for TMZ: (A) TMZ 10 mg/m2 every third day and rofecoxib 25 mg/d; (B) TMZ 10 mg/m2/d and rofecoxib 25 mg/d; (C) TMZ 5 mg/m2 twice a day and rofecoxib 12.5 mg twice a day. COX-2, VEGF, VEGF Receptor-2, and CD34 were assessed immunohistochemically, in the clinical setting. RESULTS: The mean follow-up period was 15 months. We observed no severe toxicity attributable to the therapy. Quality of life was not impaired. For the whole study population, median time to progression and overall survival were 8 months and 16 months, respectively. Immunohistochemistry suggested that tumors with higher vessel densities were characterized by a significantly better control than those with lower vessel densities. CONCLUSIONS: Continuous low-dose TMZ plus rofecoxib is feasible, safe, and maintains good quality of life. This study is indicative of an anti-angiogenic efficacy of continuous low-dose TMZ plus rofecoxib in GBMs, especially in those tumors that are characterized by a high angiogenic activity.
Cerebral glioblastomas multiforme (GMs), the most malignant human primary brain tumor, molecular genetically comprise two subsets characterized by p53 tumor suppressor gene status. One is characterized by p53 mutation and another is with wild-type p53 and overexpression of epidermal growth factor receptor (EGFR). We analyzed the p53 status by a highly reliable yeast-based assay, overexpression of EGFR by immunohistochemistry, and their relations to clinical outcome along with other several clinical parameters, in a total of 42 patients with GMs. We found p53 mutations in 18 cases (43%) of 42 GMs and overexpression of EGFR in 16 cases (43%) of 37 GMs. The tumors with p53 mutation were associated with younger onset ages and longer survival. We also analyzed their survival and radiation sensitivity relative to p53 status, EGFR and other prognostic factors, including onset age, extent of surgery, post-operative Karnofsky performance score (KPS), and location of tumor. Log-rank tests showed that younger onset ages (below 50 years; p < 0.0111), p53 mutation (p < 0.0005), superficial tumor location (p < 0.0026) and post operatives KPS (over 80%; p < 0.0147) correlated with longer survival. Multivariate Cox regression analysis identified the absence of p53 mutation (p < 0.0335) and the deep tumor location (p < 0.0297) as the independent, adverse prognostic factors. Tumor response to radiation was assessed by progression-free period (time to progression; TTP). A significant correlation was found between TTP and survival (p < 0.0001). Log-rank tests and multivariate Cox regression analysis showed that younger onset ages (below 50 years; p < 0.0145), p53 mutation (p < 0.0001), radical resection (p < 0.0198) and post operative KPS (over 80%; p < 0.0001) correlated with radiation sensitivity, and identified the absence of p53 mutation (p < 0.0146) as the sole independent hazard for radiation response. In conclusion, p53 mutation confers radiation sensitivity in GMs, which results in patients' longer survival.
BACKGROUND: Glioblastoma multiforme (GBM) is a hypervascularized and locally infiltrating brain tumor of astroglial origin with a very poor prognosis. An X-linked c-fos oncogene-inducible mitogenic, morphogenic, and angiogenic factor, endothelial growth factor-D (VEGF-D), is the newest mammalian member of VEGF family. We analyzed VEGF-D in GBM because of its high angiogenic potential and its linkage to the X chromosome. MATERIALS AND METHODS: Nonmalignant brain and GBM tissue sections as well as GBM cell lines were analyzed by immunofluorescence for the expression of VEGF-D, factor VIII (endothelial cell marker), glial-fibrillary acidic protein (GFAP) (astrocytic cell lineage cytoplasmic marker), and several Fos family transcription factors, including c-Fos and Fra-1. The proteins were also detected by Western blots. The differences between genotypes of normal brain and GBM cells were examined by cDNA microarrays. RESULTS AND CONCLUSIONS: GBM expressed ubiquitously VEGF-D, which colocalized with GFAP. Contrary to our expectations, low levels of c-Fos were detected in GBM cells. However, we identified another Fos family member, Fra-1, together with its transcriptional activation partner, c-Jun, as being stably up-regulated in GBM cells. Furthermore, we demonstrated that a fra-1 transgene induced VEGF-D expression in cultured cells and GBM cell stimulation evoked a sustained increase in both Fra-1 and VEGF-D levels. This study reveals that an up-regulation of AP-1 factors may be a hallmark of GBM. Because VEGF-D activates VEGF receptor 2 and 3, receptors important for tumor angiogenesis, it may represent an X-linked/AP-1-regulated onco-angiogen in human GBM. The VEGF-D system and AP-1 activity appear to be very attractive targets for new molecular diagnostics and rational molecular anti-cancer therapies.
OBJECTIVES: Glioblastoma multiforme (GBM) may potentially be responsive to antiangiogenic therapies as these tumors are highly vascularized and overexpress angiogenic factors. Thalidomide exhibits antiangiogenic activity and may provide additive or synergistic antitumor effects when given concurrently with temozolomide, an alkylating agent. To further evaluate this new concept of combining an antiangiogenic with an alkylating agent, efficacy and tolerability of thalidomide alone and in combination with temozolomide were explored in a single-institution, nonrandomized open-label phase II study. PATIENTS AND METHODS: Forty-four patients with GBMs, who received thalidomide for a period of at least three months, were evaluated for survival, time to tumor progression (TTP), and side effects. Microsurgical tumor extirpation and radiotherapy preceded chemotherapy. Nineteen patients (43%) received thalidomide only (T), and 25 patients (57%) had a combined chemotherapy of thalidomide and temozolomide (TT). Median thalidomide dosage was 200 mg/day. Median temozolomide dosage was 200 mg/m2/day for five days, in monthly cycles. Neuroradiological outcomes were assessed by a semiquantitative grading system. RESULTS: Median survival was 103 weeks (95% CI, 65-141 weeks) for TT-patients and 63 weeks (95% CI, 49-77 weeks) for T-patients (p < 0.01). Median TTP for the TT-group was 36 weeks (95% CI, 20-52 weeks) and 17 weeks (95% CI, 13-21 weeks) for the T-group (p < 0.06). Neuroradiologically, 14 patients (56%) of the TT-group and six (32%) of the T-group had evidence of stable disease on at least two successive neuroradiological follow-ups. Progressive disease was found in nine patients (36%) of the TT-group and in 13 (68%) of the T-group. In two patients (8%) of the TT-group, a response with tumor regression was found. Thalidomide and concurrent temozolomide were safe and well tolerated with mild to moderate toxicities. CONCLUSIONS: The combination of thalidomide and temozolomide in the treatment of GBM appears to be more effective than that of thalidomide alone with respect to survival, TTP, and neuroradiological documentation of progression, stable disease or response. Further concurrent prospective studies of these agents in a larger group of patients with GBM will be required to establish the soundness of these intriguing observations.
Glioblastoma multiforme is characterized as highly invasive and rapidly growing astrocytomas, and scientists have sought for efficient treatment against malignant gliomas for a long time. Therefore, we compared the respond of rat glioma (C6) and glioblastoma multiforme cells derived from two patients to vitamins K1, K2 and K3. The cells were exposed to 100, 250, 500, 750 and 1000 microM of vitamins K1 and K2, and 1, 10, 25, 50, 75 and 100 microM of vitamin K3 for 24 hours in an incubator atmosphere of 5% CO2, 37 degrees C and 100% humidity. Cell viability was estimated by MTT assay. Vitamin K1 showed no growth effect on all the glioma cells examined. Vitamin K2 did not cause any change in number of C6, however induced growth inhibition in a dose-dependent manner on glioblastoma multiforme. The IC50 values of vitamin K2 were 960 microM and 970 microM for glioblastoma multiforme, respectively. Vitamin K3 had also growth inhibitory effect in a dose-dependent manner on both C6 and glioblastoma multiforme. The IC50 values were 41 microM, 24 microM and 23 microM for vitamin K3, respectively. We concluded that vitamin K3 is more effective than vitamin K2 for inhibition of cancer cell growth, and might have an alternative value as an anticancer drug against glioblastoma multiforme.
Glioblastoma multiforme is invariably associated with intracranial failure following conventional therapy. Extracranial as well as metastatic failure are rarely seen. Subtle extracranial abnormalities in most patients with glioblastoma multiforme are not indicative of convexity failure. However, in patients with high p53 and Ki67 immunoreactivity and in whom the dura was not closed at the time of craniotomy, the possibility of early extradural failure should be considered.