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Metastatic spinal tumors are increasingly prevalent due to advancements in cancer treatment, leading to prolonged survival rates. This rising prevalence highlights the need for developing more effective therapeutic approaches to address this malignancy. Boron neutron capture therapy (BNCT) offers a promising solution by delivering targeted doses to tumors while minimizing damage to normal tissue. In this study, we evaluated the efficacy and safety of BNCT as a potential therapeutic option for spine metastases in mouse models induced by A549 human lung adenocarcinoma cells. The animal models were randomly allocated into three groups: untreated (n = 10), neutron irradiation only (n = 9), and BNCT (n = 10). Each mouse was administered 4-borono-L-phenylalanine (250 mg/kg) intravenously, followed by measurement of boron concentrations 2.5 h later. Overall survival, neurological function of the hindlimb, and any adverse events were assessed post irradiation. The tumor-to-normal spinal cord and blood boron concentration ratios were 3.6 and 2.9, respectively, with no significant difference observed between the normal and compressed spinal cord tissues. The BNCT group exhibited significantly prolonged survival rates compared with the other groups (vs. untreated, p = 0.0015; vs. neutron-only, p = 0.0104, log-rank test). Furthermore, the BNCT group demonstrated preserved neurological function relative to the other groups (vs. untreated, p = 0.0004; vs. neutron-only, p = 0.0051, multivariate analysis of variance). No adverse events were observed post irradiation. These findings indicate that BNCT holds promise as a novel treatment modality for metastatic spinal tumors.
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Terapia por Captura de Neutrón de Boro , Modelos Animales de Enfermedad , Neoplasias de la Columna Vertebral , Terapia por Captura de Neutrón de Boro/métodos , Animales , Ratones , Humanos , Neoplasias de la Columna Vertebral/radioterapia , Neoplasias de la Columna Vertebral/secundario , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/patología , Fenilalanina/análogos & derivados , Fenilalanina/uso terapéutico , Células A549 , Médula Espinal/efectos de la radiación , Médula Espinal/patología , Línea Celular Tumoral , Boro/uso terapéutico , FemeninoRESUMEN
The debate regarding the role and clinical impact of radiotherapy for meningiomas remains underdeveloped due to insufficient evidence. However, following recent revisions in the WHO classification and the integration of molecular diagnostics, there has been a substantial shift in the stratification of recurrence risks. Nevertheless, the specific circumstances under which radiotherapy proves crucial remain unclear. As risk stratification becomes more refined, the effectiveness of radiotherapy in treating high-risk meningiomas continues to be a contentious issue. Concurrently, there is vigorous discussion regarding the management of 'brain invasion in otherwise benign'(BIOB)meningiomas. The incorporation of PET imaging alongside MRI for defining radiation targets is increasingly acknowledged as advantageous. Boron neutron capture therapy(BNCT), which specifically targets the biological characteristics of tumor cells in invasive regions, is also gaining significant traction as a promising therapeutic approach for meningiomas with infiltrative components.
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Neoplasias Meníngeas , Meningioma , Meningioma/radioterapia , Meningioma/diagnóstico por imagen , Humanos , Neoplasias Meníngeas/radioterapia , Neoplasias Meníngeas/diagnóstico por imagenRESUMEN
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.
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Terapia por Captura de Neutrón de Boro , Neoplasias Encefálicas , Glioma , Albúminas , Animales , Boro/uso terapéutico , Compuestos de Boro/uso terapéutico , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/patología , Humanos , Maleimidas , Ratas , Distribución TisularRESUMEN
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.
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Hemorragia de los Ganglios Basales , Malformaciones Vasculares del Sistema Nervioso Central , Embolización Terapéutica , Senos Transversos , Anciano , Angiografía Cerebral , Duramadre , Humanos , MasculinoRESUMEN
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.
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Terapia por Captura de Neutrón de Boro , Neoplasias Encefálicas , Glioma , Neoplasias de la Médula Espinal , Ratas , Animales , Neoplasias Encefálicas/patología , Ratas Endogámicas F344 , Boro , Investigación Biomédica Traslacional , Compuestos de Boro/farmacología , Glioma/patologíaRESUMEN
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.
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There are few studies about boron neutron capture therapy (BNCT) for cervical cancer. The present study evaluated the biodistribution of boronophenylalanine (BPA) and the effect of BNCT on cervical cancer cell lines. BPA exposure and neutron irradiation of cervical cancer cell lines resulted in decreased survival fraction compared to irradiation only. In vivo cervical cancer tumor boron concentration was highest at 2.5 h after BPA intraperitoneal administration, and higher than in the other organs. BNCT may be effective against cervical carcinoma.
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Terapia por Captura de Neutrón de Boro , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/radioterapia , Boro/uso terapéutico , Terapia por Captura de Neutrón de Boro/métodos , Distribución Tisular , Compuestos de Boro/uso terapéuticoRESUMEN
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.
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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.
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Malignant glioma is a highly invasive tumor, and elucidating the glioma invasion mechanism is essential for developing novel therapies. We aimed to highlight actin alpha 2, smooth muscle (ACTA2) as potential biomarkers of brain invasion and distant recurrence in malignant gliomas. Using the human malignant glioma cell line, U251MG, we generated ACTA2 knockdown (KD) cells treated with small interfering RNA, and the cell motility and proliferation of the ACTA2 KD group were analyzed. Furthermore, tumor samples from 12 glioma patients who underwent reoperation at the time of tumor recurrence were utilized to measure ACTA2 expression in the tumors before and after recurrence. Thereafter, we examined how ACTA2 expression correlates with the time to tumor recurrence and the mode of recurrence. The results showed that the ACTA2 KD group demonstrated a decline in the mean motion distance and proliferative capacity compared to the control group. In the clinical glioma samples, ACTA2 expression was remarkably increased in recurrent samples compared to the primary samples from the same patients, and the higher the change in ACTCA2 expression from the start to relapse, the shorter the progression-free survival. In conclusion, ACTA2 may be involved in distant recurrence in clinical gliomas.
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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.
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Terapia por Captura de Neutrón de Boro , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Ratas , Animales , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Ácido Butírico/uso terapéutico , Ratas Endogámicas F344 , Boro/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/radioterapia , Glioma/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Compuestos de Boro/químicaRESUMEN
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.
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BACKGROUND: Acryloyl chloride is a highly toxic volatile liquid that can cause pulmonary edema. However, no sufficient treatment reports have been published to date. Here, we report a case of acute respiratory distress syndrome (ARDS) caused by acryloyl chloride inhalation. CASE PRESENTATION: The patient was a 36-year-old man with accidental exposure to acryloyl chloride. The patient had dyspnea and wet cough, with approximately 88% percutaneous oxygen saturation at room air. He was diagnosed with ARDS and admitted to the intensive care unit. Initially, he was treated with a high-flow nasal cannula and sivelestat sodium. However, due to the possibility of delayed exacerbation, the patient was switched to methylprednisolone. Oxygenation gradually improved, and the patient was discharged on the day 8 of hospitalization. CONCLUSION: We report the case of a patient who developed ARDS with delayed exacerbation after the inhalation of acryloyl chloride, which was treated without endotracheal intubation.
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Local recurrence of colorectal cancer (CRC) can occur in patients after curative resection, and additional surgical resection may therefore be required; however, this is a significant burden for patients, because additional surgical resection may necessitate the resection of other organs such as the bladder, prostate, uterus, or sacral bone. Therefore, there is a need for alternative therapeutic strategies. We focused on boron neutron capture therapy (BNCT) as a treatment modality that can selectively target tumor cells without excessive damage to normal tissues. The usefulness of BNCT to pelvic CRC remains unknown. This study investigated the anti-cancer effect of boronophenylalanine (BPA)-mediated BNCT in a previously established mouse model of pelvic recurrence of CRC. Uptake of BPA in CRC was observed both in vitro and in vivo, and the concentrations were sufficient for BNCT. Our results are the first to show that BPA-mediated BNCT prolonged the survival of experimental mice with pelvic tumors; moreover, it did not cause any obvious severe side effects in the treated animals. In conclusion, BPA-mediated BNCT could contribute to treating local recurrence of pelvic CRC.
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Terapia por Captura de Neutrón de Boro , Neoplasias Colorrectales , Neoplasias de la Boca , Neoplasias Pélvicas , Animales , Compuestos de Boro/uso terapéutico , Terapia por Captura de Neutrón de Boro/efectos adversos , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Colorrectales/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Neoplasias de la Boca/patología , Neoplasias Pélvicas/tratamiento farmacológico , Neoplasias Pélvicas/etiologíaRESUMEN
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.
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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.
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Terapia por Captura de Neutrón de Boro , Encéfalo/efectos de la radiación , Neoplasias del Sistema Nervioso Central/radioterapia , Linfoma/radioterapia , Animales , Apoptosis/efectos de la radiación , Boro/química , Boro/aislamiento & purificación , Boro/farmacología , Encéfalo/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/patología , Irradiación Craneana , Modelos Animales de Enfermedad , Humanos , Linfoma/tratamiento farmacológico , Linfoma/patología , Metotrexato/farmacología , Ratones , Fenilalanina/química , Fenilalanina/aislamiento & purificación , Fenilalanina/farmacología , Distribución Tisular/efectos de los fármacosRESUMEN
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.