This systematic review aims to elucidate the diagnostic accuracy of radiological examinations to distinguish between brain radiation necrosis (BRN) and tumor progression (TP). We divided diagnostic approaches into two categories as follows—conventional radiological imaging [computed tomography (CT) and magnetic resonance imaging (MRI): review question (RQ) 1] and nuclear medicine studies [single photon emission CT (SPECT) and positron emission tomography (PET): RQ2]—and queried. Our librarians conducted a comprehensive systematic search on PubMed, the Cochrane Library, and the Japan Medical Abstracts Society up to March 2015. We estimated summary statistics using the bivariate random effects model and performed subanalysis by dividing into tumor types—gliomas and metastatic brain tumors. Of 188 and 239 records extracted from the database, we included 20 and 26 studies in the analysis for RQ1 and RQ2, respectively. In RQ1, we used gadolinium (Gd)-enhanced MRI, diffusion-weighted image, MR spectroscopy, and perfusion CT/MRI to diagnose BRN in RQ1. In RQ2, 201Tl-, 99mTc-MIBI-, and 99mTc-GHA-SPECT, and 18F-FDG-, 11C-MET-, 18F-FET-, and 18F-BPA-PET were used. In meta-analysis, Gd-enhanced MRI exhibited the lowest sensitivity [63%; 95% confidence interval (CI): 28–89%] and diagnostic odds ratio (DOR), and combined multiple imaging studies displayed the highest sensitivity (96%; 95% CI: 83–99%) and DOR among all imaging studies. In subanalysis for gliomas, Gd-enhanced MRI and 18F-FDG-PET revealed low DOR. Conversely, we observed no difference in DOR among radiological imaging in metastatic brain tumors. However, diagnostic parameters and study subjects often differed among the same imaging studies. All studies enrolled a small number of patients, and only 10 were prospective studies without randomization. Differentiating BRN from TP using Gd-enhanced MRI and 18F-FDG-PET is challenging for patients with glioma. Conversely, BRN could be diagnosed by any radiological imaging in metastatic brain tumors. This review suggests that combined multiparametric imaging, including lesional metabolism and blood flow, could enhance diagnostic accuracy, compared with a single imaging study. Nevertheless, a substantial risk of bias and indirectness of reviewed studies hindered drawing firm conclusion about the best imaging technique for diagnosing BRN.

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is a promising real-time navigation method in the surgical resection of malignant gliomas. In order to determine whether this method is applicable to metastatic brain tumors, we evaluated the usefulness of intraoperative fluorescence patterns and histopathological features in patients with metastatic brain tumors. We retrospectively reviewed the cases of 16 patients with metastatic brain tumors who underwent intraoperative 5-ALA fluorescence-guided resection. Patients were given 20 mg/kg of 5-ALA orally 2 h prior to the surgery. High-powered excitation illumination and a low-pass filter (420, 450, or 500 nm) were used to visualize the fluorescence of protoporphyrin IX (PpIX), the 5-ALA metabolite. We evaluated the relationships between the fluorescence and histopathological findings in both tumoral and peritumoral brain tissue. Tumoral PpIX fluorescence was seen in only 5 patients (31%); in the remaining 11 patients (69%), there was no fluorescence in the tumor bulk itself. In 14 patients (86%), vague fluorescence was seen in peritumoral brain tissue, at a thickness of 2–6 mm. The histopathological examination found cancer cell invasion of adjacent brain tissue in 75% of patients (12/16), at a mean ± SD depth of 1.4 ± 1.0 mm (range 0.2–3.4 mm) from the microscopic border of the tumor. There was a moderate correlation between vague fluorescence in adjacent brain tissue and the depth of cancer cell invasion (P = 0.004). Peritumoral fluorescence may be a good intraoperative indicator of tumor extent, preceding more complete microscopic gross total resection. Institutional Review Board of Osaka Medical College No. 42, registered February 17, 1998, and No. 300, registered April 1, 2008. They were retrospectively registered.

Photodynamic therapy (PDT), which involves light excitation of photosensitizers (PSs) to induce tissue destruction, has attracted attention as a potential alternative treatment for malignant brain tumors because of high tumor-to-normal (TN) tissue contrast, low photon energy, and minimal invasion.^1,2 The treatment effectiveness of PDT has been demonstrated with Photofrin³, talaporfin sodium,^4,5 and 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX).^6,7 ALA-induced PpIX is expected to have few side effects. Compared with other PSs, it has a higher TN uptake ratio^6,8 and faster discharge from the body within 48 h.⁹ In addition, for deeply seated brain tumors, interstitial photodynamic therapy (iPDT) with ALA,^10,11 which involves insertion of cylindrical light diffusers into tissues to efficiently direct photons to target regions, has been more effective in clinical studies compared with existing standard treatments.^12,13 Several clinical studies have demonstrated that iPDT outcomes depend on the light dose, which is determined by the irradiation conditions, such as the number of inserted cylindrical light diffusers, their positions, the light fluence rate, and the irradiation time.¹³ The relationships between treatment outcomes and treatment conditions should be analyzed for safe and effective use of ALA iPDT. Although further clinical studies might be able to provide these data, the collection of malignant brain tumor cases is difficult because these cancers are rare. In addition, many technical difficulties remain to be overcome in directly measuring the interaction of PSs and light in vivo.¹⁴

Objective: This study is intended to objectively clarify the relationship between the fluorescence intensity emitted by protoporphyrin IX (PpIX), which is a metabolite of 5-aminolevulinic acid (ALA), and histological findings during glioblastoma surgery. Background: ALA is widely used for the intraoperative detection of tumors. There are several reports about the fluorescence of PpIX and the histological findings of tumors, but judgments about the fluorescence intensity depend largely on the subjective sense of each surgeon. Methods: We quantified the PpIX fluorescence intensity emitted from tissue specimens using a spectroradiometer and evaluated the relationship between a spectral radiance of 635 nm and the histopathological features of surgical specimens of glioblastoma. Surgical samples from glioblastoma patients consist of a strongly fluorescent area (SFA) or vaguely fluorescent area (VFA). Hematoxylin and eosin staining, immunohistochemical Ki-67, and CD31 staining were performed to evaluate the cell density, MIB-1 index, and vascularity, respectively. The fluorescence intensities of each sample were compared with each histopathological parameter. Results: Cell density, MIB-1 index, and total vascular area were significantly correlated with PpIX fluorescence radiance. 87.5% of SFA were judged to be tumor bulk consisting mostly of tumor cells and 12.5% peritumoral invaded brain. In the VFA, 100% of specimens were judged to be peritumoral invaded brain. Conclusions: ALA-induced PpIX fluorescence has quantitatively correlated well with histopathological malignant features both in SFA and VFA. These findings suggest that not only SFA but also VFA should be removed to the highest extent that does not cause neurological symptoms.