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.

Right-sided Herpes Zoster Ophthalmicus Complicated by Bilateral Third, Fourth, and Sixth Cranial Nerve Palsies and Syndrome of Inappropriate Antidiuretic Hormone Secretion: A Case Report.

Cases of herpes zoster ophthalmicus (HZO) complicated by bilateral ophthalmoplegia are rare, and no cases of bilateral third, fourth, or sixth cranial nerve palsies have been reported. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a rare complication of HZO. We herein report an 80-year-old Japanese woman with right-sided HZO complicated by meningoencephalitis and discuss the pathogenesis of this condition. She developed bilateral third, fourth, and sixth cranial nerve palsies and SIADH almost simultaneously during treatment for HZO. The bilateral cranial palsy spontaneously resolved within a few months.

Streamlined workflow including nurse recognition of conjugate gaze deviation for reduced door-to-puncture time in endovascular thrombectomy: A retrospective study.

BACKGROUND: Endovascular thrombectomy is recognized as a pivotal treatment for acute ischemic stroke due to large vessel occlusion. Prolonged door-to-puncture time correlates with decreased patient independence after acute ischemic stroke. This study aimed to assess whether a streamlined workflow, including nurse recognition of conjugate gaze deviation, could reduce door-to-puncture time in endovascular thrombectomy. METHODS: This study retrospectively reviewed patients with acute ischemic stroke who underwent endovascular thrombectomy between March 2017 and March 2022 and compared a previous workflow with a streamlined workflow implemented in April 2019. In the streamlined workflow, nurses recognized conjugate gaze deviation to identify patients with large vessel occlusions and played a more active role in reducing the door-to-puncture time. We compared time metrics and outcomes, including recanalization status, parenchymal hemorrhage type 2, and favorable outcomes (modified Rankin Scale score 0-2) at three months between the previous and streamlined workflow groups. RESULTS: After the application of the streamlined workflow, the door-to-puncture time was reduced from 76 min to 68 min (p = 0.014), and the number of patients with a door-to-puncture time of less than 60 min increased (15% vs. 36%, p = 0.002). Outcomes including modified thrombolysis in cerebral infarction ≥ 2b (73% vs. 71%, p = 1.000), parenchymal hemorrhage type 2 (7% vs. 2%, p = 0.281), and favorable outcome (33% vs. 34%, p = 1.000) were comparable between the two groups. CONCLUSION: Nurse recognition of conjugate gaze deviation contributed to an 8-minute reduction in the door-to-puncture time, demonstrating the potential benefits of an organized workflow in acute ischemic stroke.

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.

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.].

Anatomical Limitation of Posterior Spinal Myelotomy for Intramedullary Hemorrhage Associated with Ependymoma or Cavernous Malformation of the High Cervical Spine.

Spinal intramedullary tumors such as ependymoma or vascular lesions such as cavernous malformation are often at risk of intramedullary hemorrhage. Surgical procedures involving the high cervical spinal cord are often challenging. This technical note included four patients who presented with acute, subacute, or gradual onset of spinal cord dysfunction associated with intramedullary hemorrhage at the C1 or C1/2 level of the high cervical spine. The mean age was 46.3 years (16-74 years). All patients underwent posterior spinal cord myelotomy of the posterior median sulcus or posterolateral sulcus. It was not to exceed the caudal opening of the fourth ventricle (foramen of Magendie) and was assumed to be as high as the caudal medulla oblongata. Total removal of the intramedullary ependymoma or cavernous malformation occurred in three of four cases, and the remaining case had subtotal removal of the ependymoma. None of the patients showed postoperative deterioration of the neurological condition. Pathological examination of all cases revealed intramedullary hemorrhage was associated with ependymoma or cavernous malformation. Posterior spinal myelotomy should be limited to the caudal opening of the fourth ventricle (foramen of Magendie), that is the caudal medulla oblongata, to avoid the significant deterioration after surgery.

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.

Bilateral Posterolateral Sulcus Approach for the Removal of Spinal Intramedullary Metastatic Adenocarcinoma: A Technical Case Report.

Spinal intramedullary metastasis is an extremely rare event that occurs in advanced cancer. The surgical indications for spinal intramedullary metastasis are highly limited because of surgical difficulty and poor prognosis. In this technical case report, we present a rare case of spinal intramedullary metastasis from the lung that recurred late after local radiation to the spinal cord. The patient progressively experienced relapsed buttock pain and developed gait and urination disorders late after treatment for lung cancer. Imaging examinations suggested the recurrence of spinal intramedullary metastasis in the conus medullaris. Systemic examinations revealed no apparent recurrence in other organs, including the primary lung lesions. Gross total resection of the tumor within the conus medullaris was safely performed using the unilateral posterolateral (PLS) approach and by addition of the contralateral PLS approach. To the best of our knowledge, this is the first case in which a spinal intramedullary metastatic tumor was successfully removed using a bilateral PLS approach.

Optic Nerve Root Enhancement in Gadolinium-Enhanced Magnetic Resonance Imaging of Rathke's Cleft Cyst.

BACKGROUND: Although most patients with Rathke's cleft cysts (RCCs) remain asymptomatic throughout their lives, visual impairment in RCCs usually indicates surgical interventions, including endoscopic drainage of the cyst. We report a case of RCC with unique findings in the optic nerve root (ONR) by magnetic resonance imaging (MRI). CASE DESCRIPTION: A 58-year-old man admitted to our hospital complained of progressive left visual impairment. Preoperative computed tomography MRI revealed a suprasellar cystic lesion that extended anteriorly, and the bilateral ONRs were lateralized with the cyst and were partially enhanced with gadolinium administration. The cyst content was drained, and the cyst wall was partially removed by endoscopic transsphenoidal surgery. Postoperatively, the patient was administered corticosteroid intravenously for 3 days, and his visual acuity improved dramatically. Postoperative MRI revealed that the volume of the cyst decreased, and the position of the bilateral ONRs normalized. Additionally, enhancement of the ONRs with gadolinium administration was not observed. Histological examination of the surgical specimen revealed a ciliated single-layer columnar epithelium with inflammatory cell infiltration. CONCLUSIONS: To our knowledge, we report the first case of a patient with RCC with ONR enhancement with gadolinium administration on MRI. This unique finding might prove that inflammation is one of the causes of visual impairment in RCC as in optic neuritis.