Kaoru Tamura, Masaru Aoyagi, Noboru Ando, Takahiro Ogishima, Hiroaki Wakimoto, Masaaki Yamamoto and Kikuo Ohno
Recent evidence suggests that a glioma stem cell subpopulation may determine the biological behavior of tumors, including resistance to therapy. To investigate this hypothesis, the authors examined varying grades of gliomas for stem cell marker expressions and histopathological changes between primary and recurrent tumors.
Tumor samples were collected during surgery from 70 patients with varying grades of gliomas (Grade II in 12 patients, Grade III in 16, and Grade IV in 42) prior to any adjuvant treatment. The samples were subjected to immunohistochemistry for MIB-1, factor VIII, GFAP, and stem cell markers (CD133 and nestin). Histopathological changes were compared between primary and recurrent tumors in 31 patients after radiation treatment and chemotherapy, including high-dose irradiation with additional stereotactic radiosurgery.
CD133 expression on glioma cells was confined to de novo glioblastomas but was not observed in lower-grade gliomas. In de novo glioblastomas, the mean percentage of CD133-positive glioma cells in sections obtained at recurrence was 12.2% ± 10.3%, which was significantly higher than that obtained at the primary surgery (1.08% ± 1.78%). CD133 and Ki 67 dual-positive glioma cells were significantly increased in recurrent de novo glioblastomas as compared with those in primary tumors (14.5% ± 6.67% vs 2.16% ± 2.60%, respectively). In contrast, secondary glioblastomas rarely expressed CD133 antigen even after malignant progression following radiotherapy and chemotherapy.
The authors' results indicate that CD133-positive glioma stem cells could survive, change to a proliferative cancer stem cell phenotype, and cause recurrence in cases with de novo glioblastomas after radiotherapy and chemotherapy.
Kaoru Tamura, Masaru Aoyagi, Hiroaki Wakimoto, Noboru Ando, Tadashi Nariai, Masaaki Yamamoto and Kikuo Ohno
Recent evidence suggests that a glioma stem cell subpopulation might contribute to radioresistance in malignant gliomas. To investigate this hypothesis, the authors examined recurrent malignant gliomas for histopathological changes after high-dose irradiation with Gamma Knife surgery (GKS) and external beam radiation therapy (EBRT).
Thirty-two patients with malignant gliomas (Grade 3 in 8 patients, Grade 4 in 24) underwent GKS in combination with EBRT. Serial MR and L-[methyl-11C] methionine PET images were employed to assess remnant or recurrent tumors after GKS. Twelve patients underwent surgical removal after GKS and EBRT. Histological sections were subjected to immunohistochemistry for MIB-1, factor VIII, and stem cell markers, nestin and CD133.
The site of GKS treatment failure was local in 16 (76.2%) of 21 patients with glioblastomas showing progression; in 9 of these 16 patients, the recurrence clearly arose within the target lesion of GKS. Histopathological examination after GKS and EBRT showed variable mixtures of viable tumor tissues and necrosis. Viable tumor tissues exhibited high MIB-1 indices but reduced numbers of tumor blood vessels. There was marked accumulation of CD133-positive glioma cells, particularly in remnant tumors within the necrotic areas, in sections obtained after GKS plus EBRT, whereas CD133-positive cells appeared very infrequently in primary sections prior to adjuvant treatment.
The results indicate that CD133-positive glioma stemlike cells can survive high-dose irradiation, leading to recurrence, despite prolonged damage to tumor blood vessels. This could be an essential factor limiting the effectiveness of GKS plus EBRT for malignant gliomas.
Tadashi Nariai, Yoji Tanaka, Hiroaki Wakimoto, Masaru Aoyagi, Masashi Tamaki, Kiichi Ishiwata, Michio Senda, Kenji Ishii, Kimiyoshi Hirakawa and Kikuo Ohno
The authors retrospectively analyzed the data obtained in patients who had undergone l-[methyl-11C] methionine (MET)—positron emission tomography (PET) studies to clarify the relationship between MET uptake and tumor biological features and to discuss the clinical usefulness of MET-PET studies.
One hundred ninety-four patients with cerebral glioma or suspected glioma underwent PET scanning 20 minutes after injection of MET, whose uptake into the tumor was expressed as a ratio to contralateral healthy brain tissue (T/N ratio). Analyses were performed to determine how MET uptake correlated with tumor pathological features and prognosis. The T/N ratios before and after various treatments were also examined.
There were significant differences in the T/N ratio among the nonneoplastic lesions, low-grade gliomas, and malignant gliomas. Furthermore, there were significant correlations between patient survival and pretreatment T/N ratios. Among patients with malignant gliomas, a significant difference in survival was observed between cases with and without postoperative tumor remnant based on elevated MET uptake. The MET uptake was heterogeneous even among the homogeneous tumor areas demonstrated on MR imaging. Malignant pathological features were detected in the areas with the highest MET uptake. The effectiveness of radiotherapy or chemotherapy was expressed as a significantly decreased T/N ratio in some of the tumor types.
The ability of MET-PET to reflect the biological nature of gliomas makes it an excellent method for monitoring active tumor tissue, and treatments based on its findings should provide a powerful clinical protocol in the course of glioma therapy.