Abstract
Purpose
Lower grade gliomas with 1p/19q codeletion are often responsive to chemotherapy, and several of these have been treated using upfront chemotherapy and subsequent resection following tumor volume decrease. This study aimed to elucidate the histological changes and the mechanism of recurrence after alkylating agent chemotherapy in 1p/19-codeleted gliomas.
Methods
Fourteen 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agent chemotherapy were included and compared with their pre-chemotherapy specimens. Histological changes were investigated using hematoxylin–eosin staining, and changes in proliferative activity, status of glioma stem cells (GSCs), and tumor-infiltrating macrophages were assessed using immunohistochemistry for Ki-67/MIB-1, CD68 as a pan-macrophage/monocyte marker, CD163 as a presumed marker of M2 polarity, and nestin and CD133 as markers of GSCs.
Results
The most frequent histological findings following chemotherapy included a sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 index decreased and the number of CD68 + cells increased after chemotherapy. The increasing rate of CD68 + cells in the post-/pre-chemotherapy specimens was inversely correlated with patient prognosis but not tumor response. The number of CD163 + cells, M2/M1 + M2 ratio, and the ratio of GSCs to total tumor cells increased after chemotherapy, and those in the post-chemotherapy specimens were negatively correlated with patient prognosis. There was a correlation between the M2/M1 + M2 ratio and the ratio of GSCs in both pre- and post-chemotherapy specimens.
Conclusion
GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agent chemotherapy in 1p/19q-codeleted gliomas.
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Data availability
Raw data of the findings of the study are available in Table S1.
Code availability
The code is available from the corresponding author, upon reasonable request.
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Acknowledgements
We thank Ms. Naoko Tsuzaki at the Department of Neurosurgery, Keio University School of Medicine for her technical assistance with laboratory work.
Funding
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science [15K10343, 19K09490 to H.S.].
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Conception, design, and development of methodology: T.K. and H.S. Data acquisition, experiment, analysis, and interpretation: T.K., K.O., Y.K., M.N., and H.S. Writing of the manuscript: T.K., K.O., and H.S. Study supervision: K.Y. and H.S.
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The study was approved by the Institutional Review Board of the Keio University School of Medicine (Approval Numbers 20050002, 20130250).
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Kanazawa, T., Ohara, K., Kitamura, Y. et al. Histopathological investigation of the 1p/19q-codeleted gliomas resected following alkylating agent chemotherapy. J Neurooncol 155, 235–246 (2021). https://doi.org/10.1007/s11060-021-03855-y
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DOI: https://doi.org/10.1007/s11060-021-03855-y