Nonclinical pharmacodynamics of boron neutron capture therapy using direct intratumoral administration of a folate receptor targeting novel boron carrier.

Background: Boron neutron capture therapy (BNCT) is a precise particle radiation therapy known for its unique cellular targeting ability. The development of innovative boron carriers is crucial for the advancement of BNCT technologies. Our previous study demonstrated the potential of PBC-IP administered via convection-enhanced delivery (CED) in an F98 rat glioma model. This approach significantly extended rat survival in neutron irradiation experiments, with half achieving long-term survival, akin to a cure, in a rat brain tumor model. Our commitment to clinical applicability has spurred additional nonclinical pharmacodynamic research, including an investigation into the effects of cannula position and the time elapsed post-CED administration. Methods: In comprehensive in vivo experiments conducted on an F98 rat brain tumor model, we meticulously examined the boron distribution and neutron irradiation experiments at various sites and multiple time intervals following CED administration. Results: The PBC-IP showed substantial efficacy for BNCT, revealing minimal differences in tumor boron concentration between central and peripheral CED administration, although a gradual decline in intratumoral boron concentration post-administration was observed. Therapeutic efficacy remained robust, particularly when employing cannula insertion at the tumor margin, compared to central injections. Even delayed neutron irradiation showed notable effectiveness, albeit with a slightly reduced survival period. These findings underscore the robust clinical potential of CED-administered PBC-IP in the treatment of malignant gliomas, offering adaptability across an array of treatment protocols. Conclusions: This study represents a significant leap forward in the quest to enhance BNCT for the management of malignant gliomas, opening promising avenues for clinical translation.

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.

[Usefulness of Preoperative Simulation: Skull Base Approach].

Preoperative simulation images creates an accurate visualization of a surgical field. The anatomical relationship of the cranial nerves, arteries, brainstem, and related bony protrusions is important in skull base surgery. However, an operator's intention is unclear for a less experienced neurosurgeon. Three-dimensional(3D)fusion images of computed tomography and magnetic resonance imaging created using a workstation aids precise surgical planning and safety management. Since the simulation images allows to perform virtual surgery, a déjà vu effect for the surgeon can be obtained. Additionally, since 3D surgical images can be used for preoperative consideration and postoperative verification, discussion among the team members is effective from the perspective of surgical education for residents and medical students. Significance of preoperative simulation images will increase eventually.

Surgical Outcomes and Medical Costs Associated with Spinal Cord Tumors: Comparison of Extramedullary and Intramedullary Tumors.

OBJECTIVE: This study aimed to clarify the differences in the perioperative data of patients with extramedullary and intramedullary tumors and estimate the impact of surgery on medical costs. METHODS: This single-center retrospective study included consecutive patients who underwent spinal tumor resection between September 2020 and December 2022. The perioperative medical information and medical costs for individual patients were obtained from their medical records. RESULTS: Thirty-two patients with extramedullary spinal cord tumors and 18 with intramedullary spinal cord tumors were included in the study. The 2 groups had no difference in surgery-related or major systemic complications. However, the operation time and the length of hospital stay were significantly longer and activities of daily living at discharge tended to worsen in the intramedullary tumor group compared to those in the extramedullary tumor group. As a result, the discharge outcome was significantly different between the 2 groups. The total medical costs for intramedullary tumors were approximately 1.43 times higher than those for extramedullary tumors. Further, a better functional outcome at discharge can save medical costs, regardless of extramedullary or intramedullary tumors. CONCLUSIONS: Surgery for intramedullary tumors can be performed with similar perioperative risks as for extramedullary tumors. However, intramedullary tumors are associated with concerns, such as prolonged hospitalization and worsening of activities of daily living at discharge, which ultimately result in higher medical costs.

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.

Differences in mechanical thrombectomy for acute ischemic stroke on weekdays versus nights/ weekends in a Japanese primary stroke core center.

OBJECTIVE: The term "weekend effect" refers to an increase in the mortality rate for hospitalizations occurring on weekends versus weekdays. In this study, we investigated whether such an effect exists in patients undergoing mechanical thrombectomy for acute ischemic stroke with large vessel occlusion (currently the standard treatment for this condition) at a single center in Japan. METHODS: We surveyed 151 patients who underwent mechanical thrombectomy for acute ischemic stroke with large vessel occlusion (75 and 76 patients were treated during daytime and nighttime, respectively) from January 2019 to June 2021. The items evaluated in this analysis were the rate of modified Rankin Scale ≤2 or prestroke scale, mortality, and procedural treatment time. RESULTS: The rates of modified Rankin Scale ≤2 or prestroke scale and mortality at 90 days after treatment did not differ significantly between daytime and nighttime (41.3% vs. 29.0%, p=0.11; 14.7% vs. 11.8%, p=0.61, respectively). The door-to-groin time tended to be shorter during daytime versus nighttime (57 [IQR: 42.5-70] min vs. 70 [IQR: 55-82]) min, p=0.0507). CONCLUSIONS: This study did not reveal differences in treatment outcome between daytime and nighttime in patients undergoing mechanical thrombectomy for acute ischemic stroke with large vessel occlusion. Therefore, the "weekend effect" was not observed in our institution.

Efficient neutron capture therapy of glioblastoma with pteroyl-closo-dodecaborate-conjugated 4-(p-iodophenyl)butyric acid (PBC-IP).

Boron neutron capture therapy (BNCT) has been applied for clinical trials on glioblastoma patients since 1950s, however, the low survival rate under the treatments has hampered the widespread use of BNCT. In this study, we developed a novel boron agent, PBC-IP, which consists of three functional groups: FRα-targeting, 10B resource (twelve 10B atoms in the molecule), and albumin-binding moieties. PBC-IP was selectively taken up by glioma cell lines such as C6, F98, and U87MG cells and accumulated 10- to 20-fold higher than L-4­boronophenylalanine (BPA). PBC-IP administrated intravenously to the human glioblastoma (U87MG) xenograft model showed higher boron accumulation in tumors (29.8 µg [10B]/g at 6 h) than BPA (9.6 µg [10B]/g at 3 h) at a 25 mg [10B]/kg dose, effectively suppressing tumor growth after thermal neutron irradiation. PBC-IP administrated via convection-enhanced delivery (CED) accumulated in the F98 glioma orthotopic rat model, achieving 26.5 µg [10B]/g in tumors with tumor/normal (T/N) brain and tumor/blood (T/B) boron ratios of 37.8 and 94.6, respectively, 3 h after CED. Survival at 180 days after BNCT was 50% in the PBC-IP group and 70% in the combined BPA and PBC-IP groups, with no residual brain tumors.

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.

Multimodal Management of Combined Posterior and Anterior Surgical Approach and Postoperative Pharmacological Therapy for Giant Cell Tumor of the Cervical Spine Encasing the Vertebral Artery: A Technical Case Report.

Giant cell tumor (GCT) of bone is essentially benign but locally aggressive, and the rate of local recurrence is high when the resection is not enough. En bloc resection is recommended as an ideal solution for GCT to decrease the risk of local recurrence, but it remains challenging for cervical GCT. In this technical case report, we present a case of extensively infiltrating GCT of the cervical spine completely encasing the vertebral artery (VA) on one side. The tumor was distributed to layers A-D, sectors 3-8 based on the Weinstein-Boriani-Biagini staging. Combined posterior and anterior surgical approach for the cervical spine was successfully performed and followed by postoperative adjuvant pharmacological therapy. This kind of multimodal management may be one of the solutions for advanced cervical GCT.

Corrigendum: Evaluation of the Effectiveness of the Tap Test by Combining the Use of Functional Gait Assessment and Global Rating of Change.

[This corrects the article DOI: 10.3389/fneur.2022.846429.].

Evaluation of the Effectiveness of the Tap Test by Combining the Use of Functional Gait Assessment and Global Rating of Change.

Background: Although the tap test for patients with suspected idiopathic normal pressure hydrocephalus (iNPH) is still often performed as part of the preoperative evaluation, it is true that some studies have reported the limitations of the tap test, claiming that it does not provide the additional information for appropriate patient selection for surgery. We aimed to determine whether a better method of pre- and post-tap test assessment could lead to appropriate patient selection for shunting. Methods: We performed the tap test as part of the preoperative evaluation in all 40 patients who underwent lumboperitoneal shunt surgery for iNPH from April 2021 to September 2021. We retrospectively analyzed the patient data. We examined whether a comprehensive evaluation of the effect of the tap test using the Functional Gait Assessment (FGA) and Global Rating of Change (GRC) scales would identify a wider range of patients who would benefit from shunt surgery than the 3-m Timed Up and Go test (TUG) alone. Results: Assuming a prevalence of 1% for iNPH, the TUG had a sensitivity of 0.23, specificity of 0.71, positive likelihood ratio of 0.79, and negative likelihood ratio of 1.09. When improvement in either the FGA or the GRC was used as a criterion for the validity of the tap test, the sensitivity was 0.88, specificity was 0.17, positive likelihood ratio was 1.06, and negative likelihood ratio was 0.71. Conclusion: Improvement in either the FGA or the GRC is a more sensitive criterion for the effectiveness of the tap test for the gait aspect than the TUG. Since the negative likelihood ratio is lower than that for the TUG alone, it is more appropriate to exclude patients with neither FGA nor GRC improvement from surgical indications than to exclude surgical indications based on a negative TUG.

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.

A Case of Puncture-Site Giant Pseudoaneurysm Following Recanalization Therapy for Acute Ischemic Stroke: Marked Growth and Rupture of a Femoral Artery Pseudoaneurysm.

Objective: We report a case of the marked growth and rupture of a giant femoral artery pseudoaneurysm at the puncture site that developed after recanalization therapy for acute basilar artery occlusion. Case Presentation: A 79-year-old woman developed acute ischemic stroke due to atherosclerotic basilar artery occlusion. Endovascular intervention was performed and recanalization of the affected vessel was achieved. However, she developed brainstem infarction and consciousness disturbance persisted. The femoral access site was treated using a vascular closure device at the end of the procedure. A right femoral artery pseudoaneurysm of approximately 5 cm in size was found 2 weeks after onset during the examination for deep venous thrombosis with right lower extremity edema. Manual compression did not achieve thrombotic occlusion of the aneurysm due to obesity and leg edema. Considering the severe neurological status of the patient, the pseudoaneurysm was followed up without surgical treatment. Dual antiplatelet therapy and direct oral anticoagulant agents were administered. Four weeks after onset, the pseudoaneurysm presented rapid growth, and on the 35th day after onset, it exceeded 15 cm in size and ruptured, causing hemorrhagic shock with massive femoral hematoma. Pseudoaneurysm resection and hematoma removal were performed surgically, and the patient recovered. However, improvement of neurological manifestations was poor and the modified Rankin Scale at 90 days after onset was 5. Conclusion: A case of giant femoral artery pseudoaneurysm following recanalization therapy for acute ischemic stroke was reported. Pseudoaneurysms at the puncture site can rupture after significant growth. Curative treatment is required without delay.

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.

[Tentorial Dural Arteriovenous Fistula with Bithalamic Lesions and Bilateral Basal Ganglia Hemorrhage:A Case Report].

OBJECTIVE: We report an unusual case of tentorial dural arteriovenous fistula(DAVF)with bithalamic lesions and bilateral intracranial hemorrhage. CASE PRESENTATION: A 73-year-old man presented with lethargy and progressive cognitive decline. Imaging demonstrated bithalamic edematous lesions and bilateral basal ganglia hemorrhage in the right putamen and left internal capsule. Angiography revealed tentorial DAVF fed by both the internal and external carotid arteries. A shunted pouch was present in the superior petrosal sinus, and retrograde reflux drainage was see in the deep venous system, including the basal vein, vein of Galen, and internal cerebral veins with congestion. Initially, transarterial embolization was palliatively performed, and subsequently, a microsurgery achieved obliteration of the tentorial DAVF. Postoperatively, the bilateral thalamic changes disappeared, although sequela of the intracranial hemorrhage persisted. CONCLUSION: Deep venous congestion due to tentorial DAVF induced unusual bithalamic lesions and bilateral basal ganglia hemorrhage. Tentorial DAVF was treated with combined endovascular and surgical operations. Tentorial AVF is an aggressive vascular disease, and prompt diagnosis and treatment are necessary.