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Journal of Neuro-Oncology

, Volume 137, Issue 2, pp 417–427 | Cite as

Tumor microenvironment after biodegradable BCNU wafer implantation: special consideration of immune system

  • Ichiyo ShibaharaEmail author
  • Mitsuto Hanihara
  • Takashi Watanabe
  • Mitsuru Dan
  • Sumito Sato
  • Hiroki Kuroda
  • Akinori Inamura
  • Madoka Inukai
  • Atsuko Hara
  • Yoshie Yasui
  • Toshihiro Kumabe
Clinical Study

Abstract

Biomaterials to treat cancers hold therapeutic potential; however, their translation to bedside treatment requires further study. The carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea; BCNU) wafer, a biodegradable polymer, currently is the only drug that is able to be placed at the surgical site to treat malignant tumors. However, how this wafer affects the surrounding tumor microenvironment is not well understood to date. We retrospectively reviewed all patients with glioblastoma treated with and without BCNU wafers who underwent repeat resection at tumor recurrence. We investigated radiological imaging; the interval between the two surgeries; and immunohistochemistry of CD3, CD4, CD8, CD20, CD68, FOXP3, and PD1. We implanted BCNU wafers in 41 newly diagnosed glioblastoma patients after approval of the wafer in Japan. Of them, 14 underwent surgery at recurrence and tissue was obtained from around the wafers. The interval between the first and second surgeries ranged from 63 to 421 days. The wafer could be observed on magnetic resonance imaging at up to 226 days, whereas intraoperatively the biodegraded material of the wafer could be found at up to 421 days after the initial surgery. Immunohistochemical analysis demonstrated that CD8+ and CD68+ cells were significantly increased, but FOXP3+ cells did not increase, after wafer implantation compared to tissue from cases without wafer implantation. MRI data and immune cells, as well as interval between surgeries and immune cells, demonstrated positive correlation. These results helped us to understand the bioactivity of bioengineered materials and to establish a new approach for immunotherapy.

Keywords

BCNU wafer Gliadel Bioengineering CD8 FOXP3 

Notes

Acknowledgements

We would like to thank Enago (http://www.enago.jp) for the English language review. This study was founded by Japan Brain Foundation.

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflict of interest.

Supplementary material

11060_2017_2733_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 23 KB)
11060_2017_2733_MOESM2_ESM.pptx (10.4 mb)
Supplementary material 2: Supplementary Figure S1. Representative MRI for Volumetric analysis. T1Gd and FLAIR from initial and pre-second surgery of Case 9 were demonstrated. The area of high intensity in FLAIR and T1Gd was measured using axial imaging by OsiriX software (Pixmeo SARL, Bernex, Switzerland). FLAIR volume and T1Gd volume were quantified based on the sum of axial area, and the ratio of FLAIR volume/T1Gd volume (F/G ratio) was used for the analysis. Supplementary Figure S2. MRI and intraoperative findings of the BCNU wafer group (Cases 1–8, 10–14). Supplementary Figure S3. The number of CD8+ VIL, CD8+ TIL, and FOXP3+ cells obtained from immunohistochemical staining of Case 17. This case underwent BCNU wafer implantation at the second surgery, but there was no increase of CD8+ VIL, and TIL at the third surgery. (PPTX 10604 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ichiyo Shibahara
    • 1
    Email author return OK on get
  • Mitsuto Hanihara
    • 1
  • Takashi Watanabe
    • 2
  • Mitsuru Dan
    • 1
  • Sumito Sato
    • 1
  • Hiroki Kuroda
    • 1
  • Akinori Inamura
    • 1
  • Madoka Inukai
    • 3
  • Atsuko Hara
    • 3
  • Yoshie Yasui
    • 1
  • Toshihiro Kumabe
    • 1
  1. 1.Department of NeurosurgeryKitasato University School of MedicineSagamiharaJapan
  2. 2.Department of General Internal MedicineJCHO Sendai HospitalSendaiJapan
  3. 3.Department of PathologyKitasato University School of MedicineSagamiharaJapan

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