Takao Tsurubuchi

Boron neutron capture therapy combined with fractionated photon irradiation for glioblastoma: A recursive partitioning analysis of BNCT patients

Eight patients to received Boron Neuron Capture Therapy (BNCT) were selected from 33 newly diagnosed glioblastoma patients (NCT(+) group). Serial 42 glioblastoma patients (NCT(-) group) were treated without BNCT. The median OS of the NCT(+) group and NCT (-) group were 24.4 months and 14.9 months. In the high risk patients (RPA class V), the median OS of the NCT(+) group tended to be better than that of NCT(-) group. 50% of BNCT patients were RPA class V.

Synthesis and evaluation of a novel liposome containing BPA-peptide conjugate for BNCT.

We aimed at securing sufficient concentrations of (10)B in boron neutron capture therapy (BNCT) by developing a new drug delivery system. We have designed and developed a novel lipid analog and succeeded in using it to develop the new boron component liposome. It consisted of three different kinds of amino acid derivatives and two fatty acids, and could react directly with the peptide synthesized first on resin by Fmoc solid-phase synthesis. In this study, lipid analog conjugated with HIV-TAT peptide (domain of human immunodeficiency virus TAT protein) and boronophenylalanine (BPA) was synthesized and successfully incorporated into liposomes.

Reversible Holocord Edema Associated with Intramedullary Spinal Abscess Secondary to an Infected Dermoid Cyst

We report a case of a holocord high-intensity lesion extending from L1 up to the medulla oblongata on T2-weighted spinal magnetic resonance imaging (MRI) associated with an intramedullary spinal abscess secondary to an infected dermoid cyst. The intraoperative findings revealed that the high-intensity lesion on the T2-weighted image was edematous tissue. The MRI change in the spinal cord gradually improved in response to the use of postoperative antibiotics. The change was considered to represent reversible inflammatory changes, as there was no neurological deficit found at the cervical level and it resolved after surgery and medical treatment. The pathomechanism is discussed herein.

The optimization of fluorescence imaging of brain tumor tissue differentiated from brain edema—-In vivo kinetic study of 5-aminolevulinic acid and talaporfin sodium

OBJECTIVE We aimed to clarify the optimal timing for the fluorescence imaging of brain tumor tissue differentiated from brain edema after the administration of photosensitizers. METHODS We have performed an in vivo study of the kinetics of 5-aminolevulinic acid (5-ALA) in comparison with talaporfin sodium using the rat brain tumor model and rat vasogenic edema model produced by cold injury. The in vivo kinetics of 5-ALA and talaporfin sodium in brain tumor model and the vasogenic edema model was determined by a fluorescence macroscope and a microplate reader. RESULTS The in vivo kinetic study of 5-ALA showed mild fluorescence intensity of protoporphyrin IX (PpIX) in brain tumor differentiated from vasogenic edema. The mean lesion-to-normal-brain ratio (L/N ratio) in the group of brain tumor model 2h after the administration of 5-ALA was 7.78+/-4.61, which was significantly higher (P<0.01) than that of the vasogenic edema 2h after the administration of 5-ALA (2.75+/-1.12). In vivo kinetic study of talaporfin sodium showed high fluorescence intensity and retention in brain tumor differentiated from vasogenic edema. The mean L/N ratio of the fluorescence intensity in the group of brain tumor model 12h after the administration of talaporfin sodium was 23.1+/-11.9, which was significantly higher (P<0.01) than that of the vasogenic edema 12h after the administration (8.93+/-8.03). CONCLUSIONS The optimization of fluorescence imaging of brain tumors differentiated from brain edema is possible in the case of 5-ALA within 6h, and also possible in the case of talaporfin sodium beyond 12h.

Amniotic fluid and serum biomarkers from women with neural tube defect–affected pregnancies: a case study for myelomeningocele and anencephaly

OBJECT The authors sought to identify novel biomarkers for early detection of neural tube defects (NTDs) in human fetuses. METHODS Amniotic fluid and serum were drawn from women in the second trimester of pregnancy. The study group included 2 women pregnant with normal fetuses and 4 with fetuses displaying myelomeningocele (n = 1), anencephaly (n = 1), holoprosencephaly (n = 1), or encephalocele (n = 1). Amniotic fluid stem cells (AFSCs) were isolated and cultured. The cells were immunostained for the stem cell markers Oct4, CD133, and Sox2; the epigenetic biomarkers H3K4me2, H3K4me3, H3K27me2, H3K27me3, H3K9Ac, and H3K18Ac; and the histone modifiers KDM6B (a histone H3K27 demethylase) and Gcn5 (a histone acetyltransferase). The levels of 2 markers for neural tube development, bone morphogenetic protein-4 (BMP4) and sonic hedgehog (Shh), were measured in amniotic fluid and serum using an enzyme-linked immunosorbent assay. RESULTS The AFSCs from the woman pregnant with a fetus affected by myelomeningocele had higher levels of H3K4me2, H3K4me3, H3K27me2, and H3K27me3 and lower levels of KDM6B than the AFSCs from the women with healthy fetuses. The levels of H3K9ac, H3K18ac, and Gcn5 were also decreased in the woman with the fetus exhibiting myelomeningocele. In AFSCs from the woman carrying an anencephalic fetus, levels of H3K27me3, along with those of H3K9Ac, H3K18ac, and Gcn5, were increased, while that of KDM6B was decreased. Compared with the normal controls, the levels of BMP4 in amniotic fluid and serum from the woman with a fetus with myelomeningocele were increased, whereas levels of Shh were increased in the woman pregnant with a fetus displaying anencephaly. CONCLUSIONS The levels of epigenetic marks, such as H3K4me, H3K27me3, H3K9Ac, and H3K18A, in cultured AFSCs in combination with levels of key developmental proteins, such as BMP4 and Shh, are potential biomarkers for early detection and identification of NTDs in amniotic fluid and maternal serum.

Dose distribution and clinical response of glioblastoma treated with boron neutron capture therapy

The dose distribution and failure pattern after treatment with the external beam boron neutron capture therapy (BNCT) protocol were retrospectively analyzed. BSH (5 g/body) and BPA (250 mg/kg) based BNCT was performed in eight patients with newly diagnosed glioblastoma. The gross tumor volume (GTV) and clinical target volume (CTV)-1 were defined as the residual gadolinium-enhancing volume. CTV-2 and CTV-3 were defined as GTV plus a margin of 2 and 3 cm, respectively. As additional photon irradiation, a total X-ray dose of 30 Gy was given to the T2 high intensity area on MRI. Five of the eight patients were alive at analysis for a mean follow-up time of 20.3 months. The post-operative median survival time of the eight patients was 27.9 months (95% CI=21.0-34.8). The minimum tumor dose of GTV, CTV-2, and CTV-3 averaged 29.8+/-9.9, 15.1+/-5.4, and 12.4+/-2.9 Gy, respectively. The minimum tumor non-boron dose of GTV, CTV-2, and CTV-3 averaged 2.0+/-0.5, 1.3+/-0.3, and 1.1+/-0.2 Gy, respectively. The maximum normal brain dose, skin dose, and average brain dose were 11.4+/-1.5, 9.6+/-1.4, and 3.1+/-0.4 Gy, respectively. The mean minimum dose at the failure site in cases of in-field recurrence (IR) and out-field recurrence (OR) was 26.3+/-16.7 and 14.9 GyEq, respectively. The calculated doses at the failure site were at least equal to the tumor control doses which were previously reported. We speculate that the failure pattern was related to an inadequate distribution of boron-10. Further improvement of the microdistribution of boron compounds is expected, and may improve the tumor control by BNCT.

Combined use of sodium borocaptate and buthionine sulfoximine in boron neutron capture therapy enhanced tissue boron uptake and delayed tumor growth in a rat subcutaneous tumor model

We have previously reported that buthionine sulfoximine (BSO) enhances sodium borocaptate (BSH) uptake by down regulating glutathione (GSH) synthesis in cultured cells. This study investigated the influence of BSO on tissue BSH uptake in vivo and the efficacy of BSH-BSO-mediated boron neutron capture therapy (BNCT) on tumor growth using a Fisher-344 rat subcutaneous tumor model. With BSO supplementation, boron uptake in subcutaneous tumor, blood, skin, muscle, liver, and kidney was significantly enhanced and maintained for 12h. Tumor growth was significantly delayed by using BSO. With further improvement in experimental conditions, radiation exposure time, together with radiation damage to normal tissues, could be reduced.

Current practices and future directions of therapeutic strategy in glioblastoma: Survival benefit and indication of BNCT

Since 1998, we are performing clinical studies on treatment of GBM using conventional fractionated photon radiation therapy (CRT), proton beam therapy (PBT) or boron neutron capture therapy (BNCT). We investigated whether these radiation modalities improves the survival of patients with GBM. Sixty-eight cases of newly diagnosed GBM have been treated in our institution. After surgery, radiation therapy was performed using CRT with a dose of 60.0-61.2 Gy (n=36), hyperfractionated PBT concomitant with fractionated photon irradiation with a total dose of 96.6 Gy (n=17), or a single fraction of BNCT (n=15). In PBT, the surrounding volume of 2 cm from main tumor mass and the volume of perifocal edema were irradiated at dose of 75.6 and 60 Gy, respectively. The median OS time of the case series of BNCT for GBM has been reported as 13-20.7 M. In this study, the median OS and median time to MR change (TTM) for all patients were 25.7 and 11.9 M, respectively. The 1- and 2-year survival rates were 85.7% and 45.5%, respectively. On the other hand, in the patients who underwent CRT and ACNU-based chemotherapy, OS and 2-year survival rate were 14.2M and 17.9%, respectively. In the patients who underwent high-dose PBT, OS and 2-year survival rate were 21.3M and 38.5%, respectively. The present small case series of selected patients showed survival benefit after BNCT. The comparison using previously reported prognostic factor-based classifications suggest that outcome of BNCT in terms of survival appeared to have non-inferiority compared to the standard therapy. With respect to the case series as a high-dose radiation trial, the outcome (OS: 9.5-25 M) of previously reported may still be comparable to that of BNCT. Randomized trials of comparably selected patients are required to demonstrate conclusively that prolonged survival is a result of this tumor-selective radiotherapy.

Feasibility of boron neutron capture therapy for malignant spinal tumors.

Treatment of malignant spinal cord tumors is currently ineffective. The characteristics of the spine are its seriality, small volume, and vulnerability: severe QOL impairment can be brought about by small neuronal damage. The present study aimed to investigate the feasibility of BNCT as a tumor-selective charged particle therapy for spinal cord tumors from the viewpoint of protecting the normal spine. A previous report suggested the tolerance dose of the spinal cord was 13.8 Gy-Eq for radiation myelopathy; a dose as high as 11 Gy-Eq demonstrated no spinal cord damage in an experimental animal model. We calculated the tumor dose and the normal spinal cord dose on a virtual model of a spinal cord tumor patient with a JAEA computational dosimetry system (JCDS) treatment planning system. The present study made use of boronophenylalanine (BPA). In these calculations, conditions were set as follows: tumor/normal (T/N) ratio of 3.5, blood boron concentration of 12 ppm, tumor boron concentration of 42 ppm, and relative biological effectiveness (RBE) values for tumor and normal spinal cord of 3.8 and 1.35, respectively. We examined how to optimize neutron irradiation by changing the beam direction and number. In our theoretical example, simple opposed two-field irradiation achieved 28.0 Gy-Eq as a minimum tumor dose and 7.3 Gy-Eq as a maximum normal spinal dose. The BNCT for the spinal cord tumor was therefore feasible when a sufficient T/N ratio could be achieved. The use of F-BPA PET imaging for spinal tumor patients is supported by this study.

Boron neutron capture therapy for newly diagnosed glioblastoma: A pilot study in Tsukuba

Neutron capture therapy (NCT) theoretically allows an unique tumor-cell-selective high-LET particle radiotherapy. The survival benefits and safety of NCT were evaluated in 15 patients with newly diagnosed glioblastoma multiforme (GBM). Seven patients received intra-operative (IO-) NCT and eight patients received external beam (EB-) NCT. Sulfhydryl borane (BSH, 5 g/body) was administered intravenously 12 h before neutron irradiation. Additionally, p-dihydroxyboryl-phenylalanine (BPA, 250 mg/kg) was given 1 h before irradiation to the eight patients who underwent EB-NCT. EB-NCT was combined with fractionated photon irradiation. Five of 15 patients were alive at analysis for a mean follow-up time of 20.3 M. In 11 of 15 patients followed up for more than 1-year, eight (72.7%) maintained their Karnofsky performance status (KPS; 90 in 6 and 100 in 2). The median overall survival (OS) and time to magnetic resonance (MR) change (TTM) for all patients were 25.7 and 11.9 M, respectively. There was no difference in TTM between the IO-NCT (12.0 M) and EB-NCT (11.9 M) groups. The 1- and 2-year survival rates were 85.7% and 45.5%, respectively. This NCT pilot study in 15 patients with newly diagnosed GBM showed survival benefits, suggesting that the neutron capture reaction may function sufficiently to control tumors locally, and that further optimized studies in large series of patients are warranted.