Met-PET uptake index for total tumor resection: identification of 11C-methionine uptake index as a goal for total tumor resection including infiltrating tumor cells in glioblastoma


Glioblastoma multiforme (GBM) is largely due to glioma stem cells (GSCs) that escape from total resection of gadolinium (Gd)-enhanced tumor on MRI. The aim of this study is to identify the imaging requirements for maximum resection of GBM with infiltrating GSCs. We investigated the relationship of tumor imaging volume between MRI and 11C-methionine (Met)-PET and also the relationship between Met uptake index and tumor activity. In ten patients, tumor-to-contralateral normal brain tissue ratio (TNR) was calculated to evaluate metabolic activity of Met uptake areas which were divided into five subareas by the degrees of TNR. In each GBM, tumor tissue was obtained from subareas showing the positive Met uptake. Immunohistochemistry was performed to examine the tumor proliferative activity and existence of GSCs. In all patients, the volume of Met uptake area at TNR ≦ 1.4 was larger than that of the Gd-enhanced area. The Met uptake area at TNR 1.4 beyond the Gd-enhanced tumor was much wider in high invasiveness–type GBMs than in those of low invasiveness type, and survival was much shorter in the former than the latter types. Immunohistochemistry revealed the existence of GSCs in the area showing Met uptake at TNR 1.4 and no Gd enhancement. Areas at TNR > 1.4 included active tumor cells with relatively high Ki-67 labeling index. In addition, it was demonstrated that GSCs could exist beyond the border of Gd-enhanced tumor. Therefore, to obtain maximum resection of GBMs, including infiltrating GSCs, aggressive surgical excision that includes the Met-positive area at TNR 1.4 should be considered.

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The authors would like to express their gratitude to Taichi Furumochi and Yasuhiro Shiraishi of the Department of Neurology, Ehime University Hospital, Japan; and Satsuki Myoga of the Department of Pathology, Ehime University Hospital, Japan, for their help in obtaining the pathologic and radiologic findings.

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Correspondence to Akihiro Inoue.

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This study was approved by the Ethics Committee for Clinical Research of Ehime University Hospital (no. 1703011) prior to initiation and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

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Informed consent was obtained from all individual participants included in the study.

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Representative images of volumetric analysis of GBM. Volumetric analysis of the relationship among the Gd-enhanced area, Met-uptake area, and the area of high intensity on T2WI. The Met-uptake area that was superimposed on the Gd-enhanced image was divided into five subareas according to Met-uptake index, at TNRs of 1.2, 1.4, 1.6, 1.8, and ≧2.0, which are drawn as iso-contour lines as the borderlines of each subarea. (PNG 1027 kb).


Bar graph showing volumetric ratios of Met-uptake area in the 12 patients. In all patients, the Met-uptake area at TNR ≤1.4 was larger than the Gd-enhanced area. (PNG 307 kb).


Immunohistochemical and mRNA expression of glioma stem cell markers, CD133 and nestin in GBMs. Immunohistochemical expression in C-type of GBMs (a). Bar graph showing expression of CD133 in each type of GBMs (b). mRNA expression of CD133 in the tumor core and periphery was determined with qRT-PCR. The values are the relative expression of mRNA of CD133 normalized to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH). In the high-invasiveness type (A- and C-type), the expression of CD133 is higher at the periphery of the tumor than at its core. However, in the low-invasiveness type (B-type), the level of CD133 is lower at the periphery of the tumor than at the core. (PNG 2587 kb).

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Inoue, A., Ohnishi, T., Kohno, S. et al. Met-PET uptake index for total tumor resection: identification of 11C-methionine uptake index as a goal for total tumor resection including infiltrating tumor cells in glioblastoma. Neurosurg Rev 44, 587–597 (2021).

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  • Glioblastoma
  • Positron emission tomography
  • Methionine
  • Total resection
  • Surgical planning