Cerebrospinal fluid dissemination of high-grade gliomas following boron neutron capture therapy occurs more frequently in the small cell subtype of IDH1R132H mutation-negative glioblastoma

Abstract

We have used boron neutron capture therapy (BNCT) to treat patients in Japan with newly diagnosed or recurrent high-grade gliomas and have observed a significant increase in median survival time following BNCT. Although cerebrospinal fluid dissemination (CSFD) is not usually seen with the current standard therapy of patients with glioblastoma (GBM), here we report that subarachnoid or intraventricular CSFD was the most frequent cause of death for a cohort of our patients with high-grade gliomas who had been treated with BNCT. The study population consisted of 87 patients with supratentorial high-grade gliomas; 41 had newly diagnosed tumors and 46 had recurrent tumors. Thirty of 87 patients who were treated between January 2002 and July 2013 developed CSFD. Tumor histology before BNCT and immunohistochemical staining for two molecular markers, Ki-67 and IDH1R132H, were evaluated for 20 of the 30 patients for whom pathology slides were available. Fluorescence in situ hybridization (FISH) was performed on 3 IDH1R132H-positive and 1 control IDH1R132H-negative tumors in order to determine chromosome 1p and 19q status. Histopathologic evaluation revealed that 10 of the 20 patients’ tumors were IDH1R132H-negative small cell GBMs. The remaining patients had tumors consisting of other IDH1R132H-negative GBM variants, an IDH1R132H-positive GBM and two anaplastic oligodendrogliomas. Ki-67 immunopositivity ranged from 2 to 75%. In summary, IDH1R132H-negative GBMs, especially small cell GBMs, accounted for a disproportionately large number of patients who had CSF dissemination. This suggests that these tumor types had an increased propensity to disseminate via the CSF following BNCT and that these patients are at high risk for this clinically serious event.

A realistic appraisal of boron neutron capture therapy as a cancer treatment modality

“…In a cohort of 22 patients with recurrent gliomas there was a significant prolongation in mean survival time of 9.1 months following BNCT versus 4.4 months for those that had received other types of salvage therapy following their recurrence. However, 30 of the 87 patients who were treated between January 2002 and July 2013 subsequently developed cerebrospinal fluid (CSF) dissemination of their tumors, and a disproportionate number of these had small cell glioblastomas (GBM) [ 25 ]. Beginning in 2012 a Phase II clinical trial was initiated using a cyclotron-based accelerator neutron source manufactured by Sumitomo Heavy Industries, however, the results of this trial have yet to be reported.…”

Importance of radiobiological studies for the advancement of boron neutron capture therapy (BNCT)

“…demonstrated that ascorbic acid scavenged long-lived radicals and apparently protect against mutagenicity of BNCT in CHO-K1 cells. Another study showed that BNCT could increase the metastatic capability of high-grade gliomas because of bystander effects in adjacent cells, and that the nuclear factor kappa B (NFκB) could be implicated in this bystander response (Ref 147…”

Symptoms, Diagnosis and Treatment of Hemangioblastoma Dissemination

“…There was no identification of lymphovascular or necrosis invasion. One of the research conducted by Kondo et al, evaluated cerebrospinal fluid dissemination through the therapy of boron neutron capture method (BNCT) [16]. The study conducted in Japan diagnosed high graded gliomas.…”