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Ventricular opening and cerebrospinal fluid circulation accelerate the biodegradation process of carmustine wafers suggesting their immunomodulation potential in the human brain

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Abstract

Purpose

Opening the ventricular system during glioblastoma surgery is often necessary, but the consequent effect on the tumor microenvironment of glioblastoma remains unknown. Implantation of carmustine wafer enables direct drug delivery to the tumor site; however, the exact mechanism of the wafer’s biodegradation process is unclear, and the available data is limited to in vivo non-human mammalian studies. We hypothesized that the ventricular opening affects the degradation process of the wafer and the glioblastoma tumor microenvironment.

Methods

This study included 30 glioblastoma patients. 21 patients underwent carmustine wafer implantation during initial surgery. All patients underwent repeated surgical resection upon recurrence, allowing for pathological comparison of changes associated with wafer implantation. Immunohistochemical analyses were performed using CD68, TMEM119, CD163, IBA1, BIN1, and CD31 antibodies to highlight microglia, macrophages, and tumor vascularity, and the quantitative scoring results were correlated with clinical, molecular, and surgical variables, including the effect of the ventricular opening.

Results

The carmustine wafer implanted group presented significantly less TMEM119-positive microglia within the tumor (P = 0.0002). Simple and multiple regression analyses revealed that the decrease in TMEM119-positive microglia was correlated with longer intervals between surgeries and opened ventricular systems. No correlation was observed between age, methylated O6-methylguanine DNA methyltransferase promoter expression, and the extent of surgical resection.

Conclusions

Our study findings strongly suggest that biomaterials may possess immunomodulation capacity, which is significantly impacted by the ventricular opening procedure. Furthermore, our data highlights the pathophysiological effects of the ventricular opening within the surrounding human brain, especially after the wafer implantation.

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Acknowledgements

We express our heartfelt sorrow for the passing of Ms. Yoshie Yasui. We dedicate this manuscript to her. We would like to thank Editage (www.editage.com) for reviewing the language and proofreading the manuscript carefully.

Funding

This work was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI for Early-Career Scientists, Grant Number 18K16569, a Research Grant for young medical doctors and healthcare professionals from SRL, Inc., and grants from the Ichiro Kanehara Foundation, the YOKOYAMA Foundation for Clinical Pharmacology, the Akaeda Igaku Kenkyu Foundation, the Uehara Memorial Foundation, the Japan Brain Foundation, and the Takeda Science Foundation.

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Authors and Affiliations

  1. Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan

    Ichiyo Shibahara, Hajime Handa, Madoka Inukai, Takuichiro Hide, Yoshie Yasui & Toshihiro Kumabe

  2. Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan

    Yukiko Shibahara & Madoka Inukai

  3. Department of Neurosurgery, Yamato Municipal Hospital, Yamato, Kanagawa, Japan

    Hiroyuki Hagiwara

  4. Department of General Internal Medicine, JCHO Sendai Hospital, Sendai, Miyagi, Japan

    Takashi Watanabe

  5. Division of Clinical Research, Kitasato University Hospital, Sagamihara, Kanagawa, Japan

    Yasushi Orihashi

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  1. Ichiyo Shibahara
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Contributions

Conception and study design: IS, TK. Data acquisition: IS, YS, HH, HH, MI, TH, YY. Data analysis: IS, TW, YO. Manuscript drafting: IS, YS, TK. Manuscript revising: IS, YS, TK. All authors reviewed the manuscript.

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Correspondence to Ichiyo Shibahara.

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Shibahara, I., Shibahara, Y., Hagiwara, H. et al. Ventricular opening and cerebrospinal fluid circulation accelerate the biodegradation process of carmustine wafers suggesting their immunomodulation potential in the human brain. J Neurooncol 159, 425–435 (2022). https://doi.org/10.1007/s11060-022-04078-5

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