UZ Leuven

Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: sensitivity, interobserver variability and prognostic value.Van Laere K, Ceyssens S, Van Calenbergh F, de Groot T,Menten J, Flamen P, Bormans G, Mortelmans L.  Eur J Nucl Med Mol Imaging. 2005 Jan;32(1):39-51. Abstract: PURPOSE: 18F-fluorodeoxyglucose (FDG) and 11Cmethionine (MET) PET imaging studies allow the investigation of metabolism and amino acid transport in brain tumours. Their (relative) usefulness and prognostic value in suspected recurrence or progression of primary brain tumours after previous therapy is an issue of debate. The aim of this study was to compare directly both radioligands in this setting. METHODS: Cerebral uptake of FDG and MET was determined sequentially on the same day in 30 patients (21 males,nine females; age 40.4+/-15.6 years), on average 4.0 years (range 0.1-18) after therapy for a primary brain tumour (23 grade II-IV astrocytomas, four oligodendrogliomas and three mixed oligo-astrocytomas).Images were acquired on a Siemens HR+ dedicated PET camera. Two observers scored FDG and MET scans independently. Semi-quantitative indices defined by the tumour (maximum)-to-background ratio were calculated based on manual ROI delineation and by using MET ROIs for FDG after automated co-registration. Patient follow-up was conducted until the last contact with inconspicuous clinical findings (average 41 months, range 12-62 months after PET) [(n=10)] or until death (n=20). RESULTS: Overall median survival was 15.0 months. MET showed pathologically increased uptake in 28/30 scans, and FDG in 17/30. The inter-observer agreement was 100% for MET and 73% for FDG. Using Kaplan-Meier survival analysis, significant differences were found for both FDG (cut-off 0.8, log-rank p=0.007) and MET (cut-off 2.2, log-rank p=0.014). The combination of FDG and MET information resulted in the highest prognostic accuracy (p=0.003), while MET alone was the best prognostic predictor in the subgroup of patients with primary astrocytoma (n=23). CONCLUSION: FDG and MET PET studies provide complementary prognostic information in patients with suspected brain tumour recurrence or progression after primary therapy. MET is considered the single agent of choice in the evaluation of  these patients because of its sensitivity and clearer delineation of the suspected recurrence.

Surgery and adjuvant dendritic cellbased tumour vaccination for patients with relapsed malignant glioma, a feasibility study. De Vleeschouwer S, Rutkowski S, Kaempgen E, Wolff JE, Kuhl J, Demaerel P, Warmuth-Metz M, Flamen P, Van Calenbergh F, Plets C, Sorensen N, Opitz A, Van Gool SW.  Br J Cancer. 2004,91,1656-1662.Abstract: Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden.

Transient local response and persistent tumor control in a child with recurrent malignant glioma treated with combination therapy including dendritic cell therapy. De Vleeschouwer S, Van Calenbergh F, Demaerel P, Flamen P, Rutkowski, S, Kaempgen E, Wolff JEA, Plets C, Sciot R, Van Gool SW.  J Neurosurg (spine) 2004,100,492-497. Abstract: Treatment of malignant glioma is difficult and discouraging.Even after resection and maximal adjuvant therapy, the prognosis remains poor. The authors sought a novel form of treatment, such as stimulating the patient’s own immune response against the tumor, and developed a protocol of tumor vaccination in which autologous dendritic cells (DCs) were used in patients with recurrent malignant glioma. A 4- year-old girl was treated by means of biopsy sampling and radiotherapy for a rolandic low-grade glioma. Ten years later, a Grade III recurrence was discovered and treated with subtotal resection, interstitial radiation, six courses of oral  temozolomide, and 12 courses of oral VP 16. At the end of the chemotherapy cycle, a new rapidly growing recurrence was diagnosed. A macroscopically complete resection was performed. Afterward, the girl was vaccinated with autologous DCs that had been pulsed ex vivo with the homogenate of the resection specimen. She received six vaccines in total. The efficacy of immunization was checked by a positive delayed-type hypersensitivity skin  eaction after the second injection. After the fifth vaccine, a transient contrast enhancement without mass effect was visualized on magnetic resonance maging. Simultaneously, positron emission tomography imaging revealed a ransient increase of  metabolic activity around the resection cavity, but the metabolic uptake ratio remained below 1.8. The patient’s disease is still in complete remission 24 months after the last urgery. She is clinically well with minor and stable left hemiparesis. This case report illustrates the potential of vaccination with DCs loaded with crude tumor homogenate as adjuvant therapy to induce prolonged tumor control of malignant glioma and the objective noninvasively monitored immune response against infiltrating tumor cells.

Uptake and presentation of malignant glioma tumor cell lysates by monocyte-derived dendritic cells. De Vleeschouwer S, Arredouani M, Ade M, Cadot P, Vermassen E, Ceuppens JL, Van Gool SW.  Cancer Immunol Immunother 2005;54:372-82. Abstract: Malignant glioma of the CNS is a tumor with a very bad prognosis. Development of adjuvant immunotherapy is hampered by interindividual and intratumoral antigenic heterogeneity of gliomas. To evaluate feasibility of tumor vaccination with (autologous) tumor cells, we have studied uptake of tumor cell lysates by dendritic cells (DCs), and the T-cell stimulatory capacity of the loaded DCs. DCs are professional antigen-presenting cells, which have already been used as natural adjuvants to initiate immune responses in human cancer. An efficacious uptake of tumor cell proteins, followed by processing and presentation of tumor-associated antigens by the DCs, is indeed one of the prerequisites for a potent and specific stimulationof T lymphocytes. Human monocytes were differentiated in vitro to immature DCs, and these were loaded with FITC-labeled tumor cell proteins. Uptake of the tumor cell proteins and presentation of ntigens in the context of both MHC class I and II could be demonstrated using FACS analysis and confocal microscopy. After further maturation, the loaded DCs had the capacity to induce specific T-cell cytotoxic activity against tumor cells. We conclude that DCs loaded with crude tumor lysate are efficacious antigen-presenting cells able to initiate a T-cell response against malignant glioma tumor cells.

Lhermitte- Duclos disease: 11 C-methionine positron emission tomography data in 4 patients. Van Calenbergh F, Vantomme N, Flamen P, Demaerel P, Sciot R, Legius E, Mortelmans L, Plets C.  Surg. Neurol 2006;65:293-296. Abstract: BACKGROUND: Lhermitte-Duclos disease is a cerebellar lesion, characterized by an overgrowth of cerebellar ganglion cells, which replace granular cells and Purkinje cells. Lhermitte-Duclos disease may be a manifestation of Cowden syndrome (multiple hamartoma-neoplasia syndrome). The nature of LDD, whether neoplastic, dysplastic, or hamartomatous, is still not exactly understood. Metabolic imaging of the amino acid metabolism using PET could be useful for noninvasive characterization of these lesions. METHODS: To define the Meth-PET imaging characteristics of these lesions, we undertook a Meth-PET study in 4 patients with LDD after obtaining informed consent. All 4 patients had clinical signs of Cowden syndrome. In 2, the diagnosis was made with MRI; in 2, it was confirmed histologically. RESULTS: Using Meth-PET, the cerebellar lesions had a high methionine uptake, except in the subtotally resected lesion. The uptake of the lesions was markedly higher than that of the contralateral normal regions. The mean L/C ratio was 2.07. CONCLUSION: 11C-methionine positron emission tomography visualizes the lesion of Lhermitte-Duclos disease as a high uptake area. This amino acid hypermetabolism may be related to the slow growth of the lesions, and is an argument to suggest that patients with LDD should be followed up carefully to detect progression of the cerebellar lesion.

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