Intraoperative Photodynamic Diagnosis Using Talaporfin Sodium Simultaneously Applied for Photodynamic Therapy against Malignant Glioma: A Prospective Clinical Study.

Kazuhide Shimizu,Takashi Maruyama,Takayuki Yasuda,Taketoshi Maehara,Takashi Komori,Takakazu Kawamata,Yu Fujii,Masayuki Nitta,Yoshihiro Muragaki,Ken Masamune

doi:10.3389/fneur.2018.00024

Abstract

The goal of this study was to demonstrate the feasibility of intraoperative photodynamic diagnosis (PDD) of malignant glioma using the fluorescence from talaporfin sodium (TS), which is used simultaneously for photodynamic therapy (PDT). Patients with suspected primary malignant glioma who were eligible for surgical removal of the tumor and PDT with TS were enrolled in this prospective study. Tissue samples were obtained from the contrast-enhanced (CE) region and from the surrounding non-contrast-enhanced (NCE) marginal tissue at the boundary between the tumor and normal tissue. The excised samples were set into a fluorescence measurement system, which consisted of a semiconductor laser with a 400-nm wavelength for excitation, and a compact spectrometer for detection, which were applied and received through a custom-made probe consisting of coaxial optical fibers. The fluorescence spectrum was obtained, and peak intensity was calculated. Tumor cellularity was histopathologically analyzed and semi-quantitatively classified into four (0-3) categories. 86 samples from 17 surgical cases were available for fluorescence measurement and analysis. The fluorescence from TS had a single peak at 664 nm that was easily distinguished from the 400-nm excitation light. Samples from the CE regions showed higher fluorescence intensity than those from the NCE regions (P < 0.001). DAPI staining and fluorescence microscopy confirmed that cells in the CE regions showed red fluorescence in their cytoplasm. The fluorescence was notably strong along vascular endothelium. CE samples from newly diagnosed versus recurrent cases showed no difference in fluorescence intensity (P = 0.26). Among all samples (CE and NCE combined), the fluorescence intensity was very high in those of histopathological class 3, and a trend of increased fluorescence according to histopathological class (P < 0.001) was shown. Differences between class 0 and 3 (P < 0.001), class 1 and 3 (P < 0.001), and class 2 and 3 (P = 0.018) were significant. Intraoperative simultaneous PDD and PDT with TS can be performed for patients with malignant glioma. The blue excitation light that is used for 5-aminolevulinic acid PDD can be used for our technique (TS-PDD). The strong fluorescence from pathologically malignant tissues may be due at least in part to the involvement of microvascular structures.

Highlights

Malignant glioma is a brain tumor characterized by its infiltrative nature
In photodynamic therapy (PDT) for brain tumors, a tumor-selective photosensitizer is administered before surgery, and an excitation light of the appropriate power and wavelength is applied to the tumor or its removal cavity
PDT with Talaporfin sodium (TS) was shown to have good clinical safety and efficacy and excellent outcomes, which led to its regulatory approval in Japan [13,14,15]; notably, this method has recently been described as a promising tool for the treatment of malignant brain tumors [11]

Summary

Introduction

The most common type of malignant glioma is glioblastoma multiforme (GBM), which has a grim prognosis even after intensive surgical treatment and adjuvant radiation and chemotherapies. In PDT for brain tumors, a tumor-selective photosensitizer is administered before surgery, and an excitation light of the appropriate power and wavelength is applied to the tumor or its removal cavity. When illuminated with such light, the photosensitizer is activated and exhibits a tumoricidal effect by producing singlet oxygen with oxidation properties only in the tumor cells, which suppresses the growth of residual infiltrative tumor cells [11, 12]. PDD with TS (TS-PDD) could be highly beneficial for achieving maximal tumor resection by detecting residual tumor, followed by applying PDT with TS, given that 5-ALA and TS are not used in combination due to the potential for exacerbated side effects (hyper-photosensitivity)

Methods

Results

Discussion

Conclusion