Translational research of boron neutron capture therapy for spinal cord gliomas using rat model.

Boron neutron capture therapy (BNCT) is a type of targeted particle radiation therapy with potential applications at the cellular level. Spinal cord gliomas (SCGs) present a substantial challenge owing to their poor prognosis and the lack of effective postoperative treatments. This study evaluated the efficacy of BNCT in a rat SCGs model employing the Basso, Beattie, and Bresnahan (BBB) scale to assess postoperative locomotor activity. We confirmed the presence of adequate in vitro boron concentrations in F98 rat glioma and 9L rat gliosarcoma cells exposed to boronophenylalanine (BPA) and in vivo tumor boron concentration 2.5 h after intravenous BPA administration. In vivo neutron irradiation significantly enhanced survival in the BNCT group when compared with that in the untreated group, with a minimal BBB scale reduction in all sham-operated groups. These findings highlight the potential of BNCT as a promising treatment option for SCGs.

Expression and distribution of hypoxia-inducible factor-1α and vascular endothelial growth factor in comparison between radiation necrosis and tumor tissue in metastatic brain tumor: A case report.

We report the case of a 70-year-old woman with metastatic brain tumors who underwent surgical removal of the tumor and radiation necrosis. The patient had a history of colon cancer and had undergone surgical removal of a left occipital tumor. Histopathological evaluation revealed a metastatic brain tumor. The tumor recurred six months after surgical removal, followed by whole-brain radiotherapy, and the patient underwent stereotactic radiosurgery. Six months later, the perifocal edema had increased, and the patient became symptomatic. The diagnosis was radiation necrosis and corticosteroids were initially effective. However, radiation necrosis became uncontrollable, and the patient underwent removal of necrotic tissue two years after stereotactic radiosurgery. Pathological findings predominantly showed necrotic tissue with some tumor cells. Since the vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) were expressed around the necrotic tissue, the main cause of the edema was determined as radiation necrosis. Differences in the expression levels and distribution of HIF-1α and VEGF were observed between treatment-naïve and recurrent tumor tissue and radiation necrosis. This difference suggests the possibility of different mechanisms for edema formation due to the tumor itself and radiation necrosis. Although distinguishing radiation necrosis from recurrent tumors using MRI remains challenging, the pathophysiological mechanism of perifocal edema might be crucial for differentiating radiation necrosis from recurrent tumors.

Evaluation of the Effectiveness of Boron Neutron Capture Therapy with Iodophenyl-Conjugated closo-Dodecaborate on a Rat Brain Tumor Model.

High-grade gliomas present a significant challenge in neuro-oncology because of their aggressive nature and resistance to current therapies. Boron neutron capture therapy (BNCT) is a potential treatment method; however, the boron used by the carrier compounds-such as 4-borono-L-phenylalanine (L-BPA)-have limitations. This study evaluated the use of boron-conjugated 4-iodophenylbutanamide (BC-IP), a novel boron compound in BNCT, for the treatment of glioma. Using in vitro drug exposure experiments and in vivo studies, we compared BC-IP and BPA, with a focus on boron uptake and retention characteristics. The results showed that although BC-IP had a lower boron uptake than BPA, it exhibited superior retention. Furthermore, despite lower boron accumulation in tumors, BNCT mediated by BC-IP showed significant survival improvement in glioma-bearing rats compared to controls (not treated animals and neutrons only). These results suggest that BC-IP, with its unique properties, may be an alternative boron carrier for BNCT. Further research is required to optimize this potential treatment modality, which could significantly contribute to advancing the treatment of high-grade gliomas.

Improved Boron Neutron Capture Therapy Using Integrin αvß3-Targeted Long-Retention-Type Boron Carrier in a F98 Rat Glioma Model.

Integrin αvß3 is more highly expressed in high-grade glioma cells than in normal tissues. In this study, a novel boron-10 carrier containing maleimide-functionalized closo-dodecaborate (MID), serum albumin as a drug delivery system, and cyclic arginine-glycine-aspartate (cRGD) that can target integrin αvß3 was developed. The efficacy of boron neutron capture therapy (BNCT) targeting integrin αvß3 in glioma cells in the brain of rats using a cRGD-functionalized MID-albumin conjugate (cRGD-MID-AC) was evaluated. F98 glioma cells exposed to boronophenylalanine (BPA), cRGD-MID-AC, and cRGD + MID were used for cellular uptake and neutron-irradiation experiments. An F98 glioma-bearing rat brain tumor model was used for biodistribution and neutron-irradiation experiments after BPA or cRGD-MID-AC administration. BNCT using cRGD-MID-AC had a sufficient cell-killing effect in vitro, similar to that with BNCT using BPA. In biodistribution experiments, cRGD-MID-AC accumulated in the brain tumor, with the highest boron concentration observed 8 h after administration. Significant differences were observed between the untreated group and BNCT using cRGD-MID-AC groups in the in vivo neutron-irradiation experiments through the log-rank test. Long-term survivors were observed only in BNCT using cRGD-MID-AC groups 8 h after intravenous administration. These findings suggest that BNCT with cRGD-MID-AC is highly selective against gliomas through a mechanism that is different from that of BNCT with BPA.

Multi-Targeted Neutron Capture Therapy Combined with an 18 kDa Translocator Protein-Targeted Boron Compound Is an Effective Strategy in a Rat Brain Tumor Model.

BACKGROUND: Boron neutron capture therapy (BNCT) has been adapted to high-grade gliomas (HG); however, some gliomas are refractory to BNCT using boronophenylalanine (BPA). In this study, the feasibility of BNCT targeting the 18 kDa translocator protein (TSPO) expressed in glioblastoma and surrounding environmental cells was investigated. METHODS: Three rat glioma cell lines, an F98 rat glioma bearing brain tumor model, DPA-BSTPG which is a boron-10 compound targeting TSPO, BPA, and sodium borocaptate (BSH) were used. TSPO expression was evaluated in the F98 rat glioma model. Boron uptake was assessed in three rat glioma cell lines and in the F98 rat glioma model. In vitro and in vivo neutron irradiation experiments were performed. RESULTS: DPA-BSTPG was efficiently taken up in vitro. The brain tumor has 16-fold higher TSPO expressions than its brain tissue. The compound biological effectiveness value of DPA-BSTPG was 8.43 to F98 rat glioma cells. The boron concentration in the tumor using DPA-BSTPG convection-enhanced delivery (CED) administration was approximately twice as high as using BPA intravenous administration. BNCT using DPA-BSTPG has significant efficacy over the untreated group. BNCT using a combination of BPA and DPA-BSTPG gained significantly longer survival times than using BPA alone. CONCLUSION: DPA-BSTPG in combination with BPA may provide the multi-targeted neutron capture therapy against HG.

The Safety of Spine Surgery in the Late-Stage Elderly of 75 Years of Age or Older: A Retrospective Multicenter Study.

OBJECTIVE: The objective of this study was to verify that spine surgery for late-stage elderly (LSE) (age 65-74 years) is as safe as that for early-stage elderly (ESE) (age 65-74 years). METHODS: This retrospective multicenter study included elderly patients aged ≥65 years who underwent spine surgery between 2018 and 2021. The medical information for individual patients was obtained from medical records. Activities of daily living (ADL) were estimated using a 5-grade scale based on the Eastern Cooperative Oncology Group performance status. Good outcome was defined as ADL grade 0 or 1 at discharge; poor outcome was defined as ADL grade 2 to 4 at discharge. The postoperative complications were listed with reference to the Common Terminology Criteria for Adverse Events v5.0. RESULTS: There were 311 patients in the ESE group and 395 patients in the LSE group. Reoperation during hospitalization was significantly higher in the LSE group (4.6%) than in the ESE group (1.6%). The total number of days of hospitalization was significantly longer in the LSE group than in the ESE group. However, there was no significant difference in the postoperative complications or ADL at discharge between the 2 groups. In the statistical analysis, preoperative American Society of Anesthesiologists physical status class 3-6, underlying heart or renal disease, and cervical or thoracic spine level of surgical procedures were significantly associated with poor ADL outcomes at discharge. CONCLUSIONS: Spine surgery even for LSE can be safely done, if perioperative risk factors are appropriately managed.

Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation.

Brain radiation necrosis (RN) or neurocognitive disorder is a severe adverse effect that may occur after radiation therapy for malignant brain tumors or head and neck cancers. RN accompanies inflammation which causes edema or micro-bleeding, and no fundamental treatment has been developed. In inflammation, lysophospholipids (LPLs) are produced by phospholipase A2 and function as bioactive lipids involved in sterile inflammation in atherosclerosis or brain disorders. To elucidate its underlying mechanisms, we investigated the possible associations between lysophospholipids (LPLs) and RN development in terms of microglial activation with the purinergic receptor P2X purinoceptor 4 (P2RX4). We previously developed a mouse model of RN and in this study, measured phospholipids and LPLs in the brains of RN model by liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses. We immune-stained microglia and the P2RX4 in the brains of RN model with time-course. We treated RN model mice with ivermectin, an allosteric modulator of P2RX4 and investigate the effect on microglial activation with P2RX4 and LPLs' production, and resulting effects on overall survival and working memory. We revealed that LPLs (lysophosphatidylcholine (LPC), lysophosphatidyl acid, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylinositol, and lysophosphatidylglycerol) remained at high levels during the progression of RN with microglial accumulation, though phospholipids elevations were limited. Both microglial accumulation and activation of the P2RX4 were attenuated by ivermectin. Moreover, the elevation of all LPLs except LPC was also attenuated by ivermectin. However, there was limited prolongation of survival time and improvement of working memory disorders. Our findings suggest that uncontrollable increased LPC, even with ivermectin treatment, promoted the development of RN and working memory disorders. Therefore, LPC suppression will be essential for controlling RN and neurocognitive disorder after radiation therapy.

Boron neutron capture therapy for urological cancers.

Boron neutron capture therapy is based on a nuclear reaction between the nonradioactive isotope boron-10 and either low-energy thermal neutrons or high-energy epithermal neutrons, which generate high linear energy transfer α particles and a recoiled lithium nucleus (7 Li) that selectively destroys the DNA helix in tumor cells. Boron neutron capture therapy is an emerging procedure aimed at improving the therapeutic ratio for the traditional treatment of various malignancies, which has been studied clinically in a variety of diseases, including glioblastoma, head and neck cancer, cutaneous melanoma, hepatocellular carcinoma, lung cancer, and extramammary Paget's disease. However, boron neutron capture therapy has not been clinically performed for urological cancers, excluding genital extramammary Paget's disease that appeared at the scrotum to penis area. In this review, we aimed to provide an updated summary of the current clinical literature of patients treated with boron neutron capture therapy and to focus on the future prospects of boron neutron capture therapy for urological cancers.

Boron neutron capture therapy and add-on bevacizumab in patients with recurrent malignant glioma.

BACKGROUND: Although boron neutron capture therapy has shown excellent survival data, previous studies have shown an increase in radiation necrosis against recurrent malignant glioma. Herein, we proposed that bevacizumab may reduce radiation injury from boron neutron capture therapy by re-irradiation. We evaluated the efficacy and safety of a boron neutron capture therapy and add-on bevacizumab combination therapy in patients with recurrent malignant glioma. METHODS: Patients with recurrent malignant glioma were treated with reactor-based boron neutron capture therapy. Treatment with bevacizumab (10 mg/kg) was initiated 1-4 weeks after boron neutron capture therapy and was administered every 2-3 weeks until disease progression. Initially diagnosed glioblastomas were categorized as primary glioblastoma, whereas other forms of malignant glioma were categorized as non-primary glioblastoma. RESULTS: Twenty-five patients (14 with primary glioblastoma and 11 with non-primary glioblastoma) were treated with boron neutron capture therapy and add-on bevacizumab. The 1-year survival rate for primary glioblastoma and non-primary glioblastoma was 63.5% (95% confidence interval: 33.1-83.0) and 81.8% (95% confidence interval: 44.7-95.1), respectively. The median overall survival was 21.4 months (95% confidence interval: 7.0-36.7) and 73.6 months (95% confidence interval: 11.4-77.2) for primary glioblastoma and non-primary glioblastoma, respectively. The median progression-free survival was 8.3 months (95% confidence interval: 4.2-12.1) and 15.6 months (95% confidence interval: 3.1-29.8) for primary glioblastoma and non-primary glioblastoma, respectively. Neither pseudoprogression nor radiation necrosis were identified during bevacizumab treatment. Alopecia occurred in all patients. Six patients experienced adverse events ≥grade 3. CONCLUSIONS: Boron neutron capture therapy and add-on bevacizumab provided a long overall survival and a long progression-free survival in recurrent malignant glioma compared with previous studies on boron neutron capture therapy alone. The add-on bevacizumab may reduce the detrimental effects of boron neutron capture therapy, including pseudoprogression and radiation necrosis. Further studies of the combination therapy with a larger sample size and a randomized controlled design are warranted.

Reactor-based boron neutron capture therapy for 44 cases of recurrent and refractory high-grade meningiomas with long-term follow-up.

BACKGROUND: High-grade meningioma (HGM) is difficult to treat, and recurrent HGM after radiotherapy has an especially poor prognosis. We retrospectively analyzed the cases of 44 consecutive patients with recurrent and refractory HGM who were treated by reactor-based boron neutron capture therapy (BNCT). METHODS: In 2005-2019, we treated 44 recurrent and refractory HGMs by reactor-based BNCT. We analyzed the patients' tumor shrinkage, overall survival (OS) after initial diagnosis, OS after BNCT, progression-free survival (PFS) post-BNCT, and treatment failure patterns. RESULTS: The median OS (mOS) after BNCT and mOS after initial diagnosis were 29.6 (95% CI: 16.1-40.4) and 98.4 (95% CI: 68.7-169.4) months, respectively. The median follow-up after BNCT was 26 (6.4-103) months. The grade 2 (20 cases) and 3 (24 cases) post-BNCT mOS values were 44.4 (95% CI: 27.4-not determined) and 21.55 (10.6-30.6) months, respectively (P = .0009). Follow-up images were obtained from 36 cases at >3 months post-BNCT; 35 showed tumor shrinkage during the observation period. The post-BNCT median PFS (mPFS) of 36 cases was 13.7 (95% CI: 8.3-28.6) months. The post-BNCT mPFS values in patients with grade 2 and 3 disease were 24.3 (95% CI: 9.8-not determined) and 9.4 (6.3-14.4) months, respectively (P = .0024). Local recurrence was observed in only 22.2% of cases. These results showed good local tumor control and prolonged survival for recurrent HGM cases. CONCLUSIONS: Most of these cases had relatively large tumor volumes. The proportion of grade 3 patients was extremely high. Our patients thus seemed to have poor prognoses. Nevertheless, reactor-based BNCT exerted relatively good local control and favorable survival for recurrent and refractory HGMs.

Boron neutron capture therapy using dodecaborated albumin conjugates with maleimide is effective in a rat glioma model.

Introduction Boron neutron capture therapy (BNCT) is a biologically targeted, cell-selective particle irradiation therapy that utilizes the nuclear capture reaction of boron and neutron. Recently, accelerator neutron generators have been used in clinical settings, and expectations for developing new boron compounds are growing. Methods and Results In this study, we focused on serum albumin, a well-known drug delivery system, and developed maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) as a boron carrying system for BNCT. Our biodistribution experiment involved F98 glioma-bearing rat brain tumor models systemically administered with MID-AC and demonstrated accumulation and long retention of boron. Our BNCT study with MID-AC observed statistically significant prolongation of the survival rate compared to the control groups, with results comparable to BNCT study with boronophenylalanine (BPA) which is the standard use of in clinical settings. Each median survival time was as follows: untreated control group; 24.5 days, neutron-irradiated control group; 24.5 days, neutron irradiation following 2.5 h after termination of intravenous administration (i.v.) of BPA; 31.5 days, and neutron irradiation following 2.5 or 24 h after termination of i.v. of MID-AC; 33.5 or 33.0 days, respectively. The biological effectiveness factor of MID-AC for F98 rat glioma was estimated based on these survival times and found to be higher to 12. This tendency was confirmed in BNCT 24 h after MID-AC administration. Conclusion MID-AC induces an efficient boron neutron capture reaction because the albumin contained in MID-AC is retained in the tumor and has a considerable potential to become an effective delivery system for BNCT in treating high-grade gliomas.

Efficacy of Boron Neutron Capture Therapy in Primary Central Nervous System Lymphoma: In Vitro and In Vivo Evaluation.

BACKGROUND: Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation method. High-dose methotrexate and whole-brain radiation therapy (WBRT) are the recommended treatments for primary central nervous system lymphoma (PCNSL). This tumor responds well to initial treatment but relapses even after successful treatment, and the prognosis is poor as there is no safe and effective treatment for relapse. In this study, we aimed to conduct basic research to explore the possibility of using BNCT as a treatment for PCNSL. METHODS: The boron concentration in human lymphoma cells was measured. Subsequently, neutron irradiation experiments on lymphoma cells were conducted. A mouse central nervous system (CNS) lymphoma model was created to evaluate the biodistribution of boron after the administration of borono-phenylalanine as a capture agent. In the neutron irradiation study of a mouse PCNSL model, the therapeutic effect of BNCT on PCNSL was evaluated in terms of survival. RESULTS: The boron uptake capability of human lymphoma cells was sufficiently high both in vitro and in vivo. In the neutron irradiation study, the BNCT group showed a higher cell killing effect and prolonged survival compared with the control group. CONCLUSIONS: A new therapeutic approach for PCNSL is urgently required, and BNCT may be a promising treatment for PCNSL. The results of this study, including those of neutron irradiation, suggest success in the conduct of future clinical trials to explore the possibility of BNCT as a new treatment option for PCNSL.

Chronic pathophysiological changes in the normal brain parenchyma caused by radiotherapy accelerate glioma progression.

Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-ß1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. The current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.

Accelerator-based BNCT for patients with recurrent glioblastoma: a multicenter phase II study.

BACKGROUND: Boron neutron capture therapy (BNCT) utilizes tumor-selective particle radiation. This study aimed to assess the safety and efficacy of accelerator-based BNCT (AB-BNCT) using a cyclotron-based neutron generator (BNCT 30) and 10B-boronophenylalanine (SPM-011) in patients with recurrent malignant glioma (MG) (primarily glioblastoma [GB]). METHODS: This multi-institutional, open-label, phase II clinical trial involved 27 recurrent MG cases, including 24 GB cases, who were enrolled from February 2016 to June 2018. The study was conducted using the abovementioned AB-BNCT system, with 500 mg/kg SPM-011 (study code: JG002). The patients were bevacizumab-naïve and had recurrent MG after standard treatment. The primary endpoint was the 1-year survival rate, and the secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results were compared to those of a previous Japanese domestic bevacizumab trial for recurrent GB (JO22506). RESULTS: The 1-year survival rate and median OS of the recurrent GB cases in this trial were 79.2% (95% CI: 57.0-90.8) and 18.9 months (95% CI: 12.9-not estimable), respectively, whereas those of JO22506 were 34.5% (90% CI: 20.0-49.0) and 10.5 months (95% CI: 8.2-12.4), respectively. The median PFS was 0.9 months (95% CI: 0.8-1.0) by the RANO criteria. The most prominent adverse event was brain edema. Twenty-one of 27 cases were treated with bevacizumab following progressive disease. CONCLUSIONS: AB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG. AB-BNCT may increase the risk of brain edema due to re-irradiation for recurrent MG; however, this appears to be controlled well with bevacizumab.

The Therapeutic Effects of Dodecaborate Containing Boronophenylalanine for Boron Neutron Capture Therapy in a Rat Brain Tumor Model.

BACKGROUND: The development of effective boron compounds is a major area of research in the study of boron neutron capture therapy (BNCT). We created a novel boron compound, boronophenylalanine-amide alkyl dodecaborate (BADB), for application in BNCT and focused on elucidating how it affected a rat brain tumor model. METHODS: The boron concentration of F98 rat glioma cells following exposure to boronophenylalanine (BPA) (which is currently being utilized clinically) and BADB was evaluated, and the biodistributions in F98 glioma-bearing rats were assessed. In neutron irradiation studies, the in vitro cytotoxicity of each boron compound and the in vivo corresponding therapeutic effect were evaluated in terms of survival time. RESULTS: The survival fractions of the groups irradiated with BPA and BADB were not significantly different. BADB administered for 6 h after the termination of convection-enhanced delivery ensured the highest boron concentration in the tumor (45.8 µg B/g). The median survival time in the BADB in combination with BPA group showed a more significant prolongation of survival than that of the BPA group. CONCLUSION: BADB is a novel boron compound for BNCT that triggers a prolonged survival effect in patients receiving BNCT.

Boron neutron capture therapy for malignant brain tumors.

BACKGROUND: Boron neutron capture therapy (BNCT) is tumor-selective particle radiation therapy that depends on the nuclear capture and fission reactions. These reactions occur when a non-radioactive boron isotope (10B) is irradiated with low-energy thermal neutrons to yield high linear energy transfer α-particles and lithium-7 nuclei within a limited path length, i.e., an almost one-cell diameter. The 10B-containing cells can then be selectively destroyed by these potent particles. BNCT has been applied in the field of malignant brain tumors for newly diagnosed and recurrent malignant gliomas (chiefly glioblastomas). CLINICAL RESULTS: These clinical applications of BNCT have been performed with reactor-based neutron sources over the past decades. We also applied reactor-based BNCT for 58 newly diagnosed glioblastomas and 68 recurrent malignant gliomas including 52 glioblastomas. In this review article, we summarize the clinical results from the literature concerning BNCT for these high-grade gliomas (including our research). We also applied reactor-based BNCT for 46 cases of recurrent and refractory high-grade meningiomas, and some of the results will be presented herein. FUTURE PROSPECTS: In Japan, neutron sources have been shifted from reactors to accelerators. Phase 1 and 2 clinical trials have been performed for recurrent malignant gliomas using accelerator-based neutron sources, and now fortunately, a cyclotron-based neutron generator has been approved as a medical device by Japanese regulatory authority, as the world's first accelerator-based BNCT system for medical use. We also discuss the future prospects of accelerator-based BNCT in hospitals as therapy for malignant brain tumors.

Synthesis and Evaluation of Dodecaboranethiol Containing Kojic Acid (KA-BSH) as a Novel Agent for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a form of tumor-cell selective particle irradiation using low-energy neutron irradiation of boron-10 (10B) to produce high-linear energy transfer (LET) alpha particles and recoiling 7Li nuclei (10B [n, alpha] 7Li) in tumor cells. Therefore, it is important to achieve the selective delivery of large amounts of 10B to tumor cells, with only small amounts of 10B to normal tissues. To develop practical materials utilizing 10B carriers, we designed and synthesized novel dodecaboranethiol (BSH)-containing kojic acid (KA-BSH). In the present study, we evaluated the effects of this novel 10B carrier on cytotoxicity, 10B concentrations in F98 rat glioma cells, and micro-distribution of KA-BSH in vitro. Furthermore, biodistribution studies were performed in a rat brain tumor model. The tumor boron concentrations showed the highest concentrations at 1 h after the termination of administration. Based on these results, neutron irradiation was evaluated at the Kyoto University Research Reactor Institute (KURRI) with KA-BSH. Median survival times (MSTs) of untreated and irradiated control rats were 29.5 and 30.5 days, respectively, while animals that received KA-BSH, followed by neutron irradiation, had an MST of 36.0 days (p = 0.0027, 0.0053). Based on these findings, further studies are warranted in using KA-BSH as a new B compound for malignant glioma.

PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma.

BACKGROUND: The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. METHODS: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. RESULTS: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95% CI: 0-94.6) than intratumoral macrophages (27.5%; 95% CI: 0-81.1, p = 0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p = 0.0429), with very low coefficient correlation (ρ = 0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p = 0.0008; better MSKCC score, p = 0.0103; peritumoral macrophages: low proportion of LDH elevation, p = 0.0064) and longer OS (for intratumoral macrophages: high PD-L1 = 60 months, 95% CI = 30-132.6; low PD-L1 = 24 months, 95% CI = 11-48; p = 0.032; for peritumoral macrophages: high PD-L1 = 60 months, 95% CI = 30.7-NR; low PD-L1 = 14 months, 95% CI = 3-26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR = 0.30, 95% CI = 0.12-0.77, p = 0.0129). CONCLUSIONS: Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.

Radiological diagnosis of brain radiation necrosis after cranial irradiation for brain tumor: a systematic review.

INTRODUCTION: This systematic review aims to elucidate the diagnostic accuracy of radiological examinations to distinguish between brain radiation necrosis (BRN) and tumor progression (TP). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats.

Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl-closo-dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)-a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 ± 29.6 µg B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21-24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26-36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25-37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28-40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects.