Operated low grade astrocytomas: a long term PET study on the effect of radiotherapy.
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The role of postoperative radiotherapy in patients with low grade gliomas is not established yet. PET with 11C methionine (MET) and 18F fluorodeoxyglucose (FDG) was used to perform cross sectional comparisons as well as within patient follow up studies in 30 operated patients with fibrillary astrocytoma WHO II. Uptake of tracer by tumour was quantified by radioactivity concentration ratios in tumour over contralateral brain (T/C). Comparing patients who did (n=13) or did not (n=17) receive external radiotherapy subsequent to first tumour resection, no differences in MET and FDG T/C between both groups were found during a postoperative period of 94 months (when recurrence and malignant progression of low grade astrocytomas are expected). Malignant progression occurred at a similar rate in both patient groups at a mean (SD) postoperative interval of 46 (26) months. Irrespective of whether radiotherapy was applied or not, malignant tumour recurrences showed higher T/C values (MET: 1.70 (0.64), FDG: 0.98 (0.23)) than recurrences without signs of malignancy (MET: 1.21 (0.21), FDG: 0.82 (0.08)) (Mann-Whitney: MET p=0.086, FDG p=0.035). The data show a relative lack of radiotherapy administered immediately after first tumour resection. In the course of disease, patients with tumours undergoing malignant progression may be identified with PET tracer methods. (+info)
Effect of radiotherapy on brain glucose metabolism in patients operated on for low grade astrocytoma.
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OBJECTIVE: To assess the effect of postoperative radiotherapy on brain glucose metabolism (CMRGlu) of operated patients with low grade astrocytomas. METHODS: PET and 18F-fluorodeoxyglucose was used to measure absolute CMRGlu in patients with fibrillary astrocytoma (WHO II) of the frontal lobe, who did (n=7) or did not (n=12) receive radiotherapy subsequent to first debulking tumour resection. In addition, statistical parametric mapping (SPM95) was applied to assess the pattern of relative CMRGlu associated with the frontal tumour. Data were compared with 12 healthy controls. RESULTS: A global reduction of absolute CMRGlu was found when either patients with or without radiotherapy were compared with controls (ROI analysis). Brain areas of relative CMRGlu reduction were found in the brain ipsilateral and contralateral to the tumour, comparing both patient groups with controls by SPM ("tumour diaschisis effect"). Superimposed, absolute CMRGlu in the contralateral frontal, parietal, occipital cortex as well as in the white matter was on average 17% lower in patients receiving radiotherapy than in patients who did not. CONCLUSIONS: The data discriminate a tumour effect from a radiotherapy effect, and support the view of adverse effects of radiotherapy on brain not directly involved by tumour. (+info)
Human chorionic gonadotrophin in CSF, not serum, predicts outcome in germinoma.
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OBJECTIVES: Some intracranial germinomas, which may contain syncytiotrophoblastic giant cells (STGCs), are associated with a mildly to moderately increased human chorionic gonadotropin (HCG) concentration in serum, and patients with such germinomas are thus treated more aggressively than those with "pure" germinoma. However, the patients with germinoma and detectable HCG in CSF but not in serum have been classified and treated similarly to those with "pure" germinomas. The outcome of these patients and the relevance of HCG in the CSF were analysed. METHODS: The outcomes of patients with germinoma and increased serum HCG concentration (n=7) were compared with those of patients having detectable HCG titre in the CSF but not in the serum (n=5). RESULTS: Both groups in our series received similar treatments and also showed similar recurrence rates. The 40% recurrence rate in the group with HCG only in CSF did not correspond to the rate typical for "pure" germinoma: these tumours would be expected to have a better outcome. An additional patient whose CSF HCG were raised without increased serum HCG at recurrence is presented. CONCLUSIONS: It is recommended that patients with an increased HCG concentration in CSF should be considered to have "HCG producing germinoma", and they should be treated and followed up accordingly. (+info)
Oncological applications of FDG PET imaging: brain tumors, colorectal cancer, lymphoma and melanoma.
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This article will focus primarily on body oncology diagnosis, staging and therapy monitoring using fluorodeoxyglucose (FDG) PET imaging. Common pitfalls and artifacts in body FDG imaging will be covered. Examples of diagnosis, staging and therapy monitoring of brain tumor, colorectal cancer, lymphoma and melanoma will be given. Importance of correlation with anatomic imaging and practical use of FDG imaging in patient management will be stressed. (+info)
Dosimetry of 131I-labeled 81C6 monoclonal antibody administered into surgically created resection cavities in patients with malignant brain tumors.
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The objective of this study was to perform the dosimetry of 131I-labeled 81C6 monoclonal antibody (MAb) in patients with recurrent malignant brain tumors, treated by direct injections of MAb into surgically created resection cavities (SCRCs). METHODS: Absorbed dose estimates were performed for nine patients. Dosimetry was performed retrospectively using probe counts (during patient isolation) and whole-body and SPECT images thereafter. Absorbed doses were calculated for the SCRC interface and for regions of interest (ROIs) 1 and 2 cm thick, measured from the margins of cavity interface. Also, mean absorbed doses were calculated for normal brain, liver, spleen, thyroid gland, stomach, bone marrow and whole body. The average residence time for the SCRC was 111 h (65-200h). RESULTS: The average absorbed dose per unit injected activity (range) to the SCRC interface and ROIs 1 and 2 cm thick from the cavity interface were 31.9 (7.8-84.2), 1.9 (0.7-3.6) and 1.0 (0.4-1.8) cGy/MBq, respectively. Average absorbed doses per unit administered activity to brain, liver, spleen, thyroid, stomach, bone marrow and whole body were 0.18, 0.03, 0.08, 0.05, 0.02, 0.02 and 0.01 cGy/MBq, respectively. The high absorbed dose delivered to the SCRC interface may have produced an increase in cavity volume independent of tumor progression. CONCLUSION: At the maximum tolerated dose of 3700 MBq 131I-labeled 81C6 MAb, the absorbed doses to the SCRC interface and ROIs of 1 and 2 cm thickness were estimated to be 1180, 71 and 39 Gy, respectively. The estimated average absorbed dose to the brain was 6.5 Gy. There was no neurological toxicity and minimal hematologic toxicity at this maximum tolerated administration level. (+info)
O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy.
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The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) contributes to the resistance of human brain tumor cell lines and xenografts to methylating and chloroethylating agents. We assayed MGMT in 174 newly diagnosed or recurrent gliomas to (a) quantitate changes in MGMT activity associated with alkylating agent-based chemotherapy; and (b) assess the contribution of MGMT to clinical outcome. Glioma MGMT activity ranged 300-fold, averaging 3,800+/-7,200 molecules/cell. Twenty-four percent of tumors lacked detectable activity [Methyl repair-deficient (Mer-) phenotype, defined here as <151 molecules/cell or <0.25 fmol/10(6) cells]. Tumors treated with surgery alone and tumors recurring after surgery and radiotherapy did not differ significantly in frequency of the Mer- phenotype (29% versus 24%). However, the frequency of the Mer- phenotype among tumors recurring after surgery, radiation, and alkylating agent-based chemotherapy was 7-fold lower than in tumors treated with surgery alone (4.3% versus 29%; P < or = 0.02) and 6-fold lower than in tumors recurring after surgery and radiation (4.3% versus 24%; P < or = 0.05). In contrast to gliomas, there was no relationship of alkylating agent-based therapy with the frequency of the Mer- phenotype in paired histologically normal brain. These data suggest that alkylating agents, either alone or synergistically with radiotherapy, selectively kill Mer- glioma cells in situ. Importantly, Mer- and Mer+ tumors did not differ in time to tumor progression following treatment with alkylating agents, indicating that although Mer- glioma cells may be differentially killed by alkylators, factors other than Mer phenotype were the principal determinants of time to clinical progression. Nonetheless, our results support the possibility that complete ablation of glioma MGMT with substrate analogue inhibitors could improve the efficacy of alkylating agent-based chemotherapy. (+info)
Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340.
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Synthetic matrix metalloproteinase (MMP) inhibitors have activity against a variety of tumors in preclinical models but have not been studied in gliomas. We determined the effect of AG3340, a novel synthetic MMP inhibitor with Ki values against gelatinases in the low picomolar range, on the growth of a human malignant glioma cell line (U87) in SCID-NOD mice. Mice were injected s.c. with U87 cells. Tumors were allowed to grow to a size of approximately 0.5 x 0.5 cm (after about 3 weeks), and the mice were randomized to receive either: (a) 100 mg/kg AG3340 in vehicle; or (b) vehicle control (0.5% carboxymethyl cellulose, 0.1% pluronic F68), both given daily i.p. Tumor area was measured twice weekly, and animals were sacrificed when moribund, or earlier if premorbid histology was examined. In vivo inhibition of tumor growth was profound, with AG3340 decreasing tumor size by 78% compared with controls after 31 days (when controls were sacrificed; P < 0.01, Wilcoxon test). Control animals survived 31 days after the i.p. injections began, and AG3340 mice survived 71 days, representing a >2-fold increase in survival associated with tumor growth delay. Histological examination found that AG3340-treated tumors were smaller, had lower rates of proliferation, and significantly less invasion than control-treated tumors. Hepatic or pulmonary metastases were not seen in either group. In a separate experiment, the tumors were smaller and sampled after a shorter duration of treatment; the changes in proliferation were more marked and occurred earlier than differences in tumor invasion between the two groups. Furthermore, in vitro cell growth was not inhibited at AG3340 concentrations of <1 mM. AG3340 plasma concentrations in vivo, 1 h after administration, ranged from 67 to 365 nM. Thus, AG3340 produced a profound inhibition of glioma tumor growth and invasion. AG3340 markedly increased survival in this in vivo glioma model. Treatment with AG3340 may be potentially useful in patients with malignant gliomas. (+info)
Increased oncogenicity of subclones of SV40 large T-induced neuroectodermal tumor cell lines after loss of large T expression and concomitant mutation in p53.
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A model for medulloblastoma-like primitive neuroectodermal tumors was established in rat using retrovirally transduced SV40 large T antigen (LT) as an inducing agent (O. D. Wiestler et al., Brain Pathol., 2: 47-59, 1992). A cell line isolated from such a tumor and clonal derivatives thereof were biologically and molecularly characterized. In the parental tumor cell line, TZ870, which had been selected for G418 resistance, virtually all cells expressed LT and wild-type p53, which were complexed to each other. When plated in soft agar, these cells grew relatively slowly and formed disperse colonies. However, when grown without selection pressure, these cells reproducibly gave rise to LT-negative and G418-sensitive derivatives, LT-0 cells. Surprisingly, these latter cells exhibited a higher degree of malignancy both in vitro, growing readily to large colonies in soft agar, and in vivo, where they gave rise to a rapidly growing malignant tumor. Clonal selection from TZ870 cells revealed two types of clones: in one type, LT expression was stably maintained, even without selection pressure, whereas the other type lost the LT coding sequences. All LT-negative clones exhibited the same phenotype as the LT-0 cells. Reexpression of LT had no effect. However, LT no longer formed complexes with p53, and p53 was metabolically stable, suggesting that it had been mutated. Sequence analyses and diagnostic restriction digests of the p53 gene revealed that (a) both the parental LT-transformed cells and their derivatives contained only one complete p53 allele and (b) all LT-positive clones expressed wild-type p53, whereas all LT-negative clones expressed a mutant allele with a common mutation at Cys-174-->Tyr, indicating their clonal origin. We assume that the loss of LT coding sequences is the consequence of the p53 mutation, perhaps by inducing genomic instability, and that both the p53 mutation and additional genetic alterations that accompany the loss of LT coding sequences might contribute to enhanced malignancy. (+info)