[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.

Comparison of outcomes with/without preoperative embolization for meningiomas with diluted N-butyl-2-cyanoacrylate.

BACKGROUND: Preoperative embolization for meningiomas is controversial regarding its effectiveness in reducing intraoperative blood loss and operative time. In contrast, some reports have documented improved surgical outcomes in large meningiomas. In this study, we retrospectively compared the outcomes of craniotomy for meningiomas with/without preoperative embolization with diluted N-butyl-2-cyanoacrylate (NBCA) primarily in a single institution. METHODS: Data (World Health Organization grade, Simpson grade, maximum tumor diameter, intraoperative bleeding, operative time, history of hypertension, and time from embolization to craniotomy) of patients with initial intracranial meningiomas were compared with or without preoperative embolization from January 2015 to April 2022. RESULTS: The embolization group consisted of 56 patients and the nonembolization group included 76 patients. Diluted NBCA (13% concentration for all patients) was used in 51 of 56 patients (91.1%) who underwent transarterial embolization. Permanent neurological complications occurred in 2 (3.6%) patients. Intraoperative bleeding was significantly lower in the embolization group for a maximum tumor diameter ≥40 mm (155 vs. 305 ml, respectively, p < 0.01). In the nonembolization group, for a maximum tumor diameter ≥30 mm, patients with hypertension had more intraoperative bleeding than non-hypertensive ones. CONCLUSIONS: Despite its limitations, the present results showed that, under certain conditions, preoperative embolization for intracranial meningiomas caused less intraoperative bleeding. The safety of treatment was comparable with that reported in the Japan Registry of NeuroEndovascular Therapy 3 (JR-NET3) with a complication rate of 3.7% for preoperative embolization of meningiomas, despite the treatment focused on the liquid embolization material.

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.

5-Aminolevulinic acid increases boronophenylalanine uptake into glioma stem cells and may sensitize malignant glioma to boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a high-LET particle radiotherapy clinically tested for treating malignant gliomas. Boronophenylalanine (BPA), a boron-containing phenylalanine derivative, is selectively transported into tumor cells by amino acid transporters, making it an ideal agent for BNCT. In this study, we investigated whether the amino acid 5-aminolevulinic acid (ALA) could sensitize glioma stem cells (GSCs) to BNCT by enhancing the uptake of BPA. Using human and mouse GSC lines, pre-incubation with ALA increased the intracellular accumulation of BPA dose-dependent. We also conducted in vivo experiments by intracerebrally implanting HGG13 cells in mice and administering ALA orally 24 h before BPA administration (ALA + BPA-BNCT). The ALA preloading group increased the tumor boron concentration and improved the tumor/blood boron concentration ratio, resulting in improved survival compared to the BPA-BNCT group. Furthermore, we found that the expression of amino acid transporters was upregulated following ALA treatment both in vitro and in vivo, particularly for ATB0,+. This suggests that ALA may sensitize GSCs to BNCT by upregulating the expression of amino acid transporters, thereby enhancing the uptake of BPA and improving the effectiveness of BNCT. These findings have important implications for strategies to improve the sensitivity of malignant gliomas to BPA-BNCT.

Influence of surgical position and registration methods on clinical accuracy of navigation systems in brain tumor surgery.

The aim of this study was to evaluate the influence of skin distortion due to surgical positioning on the clinical accuracy of the navigation system. The distance errors were measured in four fiducial markers (anterior, posterior, right, and left of the head) after the registration of the navigation system. The distance errors were compared between the surface-merge registration (SMR) method using preoperative imaging and the automatic intraoperative registration (AIR) method using intraoperative imaging. The comparison of the distance errors were performed in various surgical positions. The AIR method had the significant accuracy in the lateral markers than the SMR method (lateral position, 3.8 mm vs. 8.95 mm; p < 0.0001; prone position, 4.5 mm vs. 13.9 mm; p = 0.0001; 5.2 mm vs. 11.5 mm; p = 0.0070). The smallest distance errors were obtained close to the surgical field in the AIR method (3.25-3.85 mm) and in the forehead in the SMR method (3.3-8.1 mm). The AIR method was accurate and recommended for all the surgical positions if intraoperative imaging was available. The SMR method was only recommended for the supine position, because skin distortion was frequently observed in the lateral region.

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.

Vertebral artery is an anatomical landmark in the posterior unilateral resection of cervical benign nerve sheath tumors with dumbbell extension of Eden type 2 or 3.

Background: In the cervical nerve sheath tumor (NST) surgery with dumbbell extension of Eden type 2 or 3, selection of anterior, posterior, or combined approach remains controversial. Objectives: This technical note aimed to propose possible advantages of the posterior unilateral approach (PUA). Methods: Six patients who underwent the surgical treatment of cervical NSTs with dumbbell extension of Eden type 2 or 3 were included. The critical surgical steps included (1) complete separation of extradural and intradural procedures, (2) careful peeling of the neural membranes (epineurium and perineurium) from the tumor surface in the extradural procedure, (3) complete removal of the extradural tumor within the neural membranes, (4) intradural disconnection of tumor origin, and (5) intentional tumor removal up to the vertebral artery (VA), i.e., the VA line. Results: The tumor location of dumbbell extension was Eden types 2 and 3 in two and four patients. Gross total resection was achieved in two patients and intentional posterior removal of the tumor to the VA line was achieved in the remaining four patients. No vascular or neural injuries associated with surgical procedures occurred. Postoperative neurological assessment revealed no symptomatic aggravation in all patients. No secondary surgery was performed during the study period. Conclusion: PUA was safe and less invasive for functional recovery and tumor resection, if the anatomical relationship between the tumor and VA is clearly understood. The VA line is an important anatomical landmark to limit the extent of tumor resection.

Pituitary stone resulting in visual dysfunction and spontaneous rhinorrhea in nonfunctioning pituitary adenoma: illustrative case.

BACKGROUND: Calcifications in pituitary adenomas are rare, being found in only 5.4%-25% of reported cases. These are divided into eggshell-like calcifications around the tumor and nodular calcifications at the center of the tumor, the latter of which are called "pituitary stones" (PSs). OBSERVATIONS: The authors report the case of a 60-year-old male with a nonfunctional pituitary adenoma with PSs and asymptomatic ventricular dilatation who presented with spontaneous cerebrospinal fluid (CSF) rhinorrhea and rapid visual aggravation without an increase in tumor size over the course of 4 years. After endoscopic transnasal surgery, his visual acuity immediately improved temporarily. It was believed that the increased intracranial pressure due to secondary hydrocephalus resulted in visual aggravation; thus, a ventriculoperitoneal (VP) shunt was created. After creation of the VP shunt, the patient's visual acuity improved gradually and completely. Histological findings showed that adenoma cells were observed among the lamellar bone trabeculae. To the best of the authors knowledge, this is the first report of osteoid metaplasia-type PSs in nonfunctioning pituitary adenoma. LESSONS: PSs formed near the sellar floor and caused spontaneous CSF rhinorrhea due to direct mechanical stress on the dura mater and optic nerves, which may have caused meningitis and secondary hydrocephalus that resulted in visual impairment independent of tumor size.

Secondary parkinsonism caused by chronic subdural hematomas owing to compressed cortex and a disturbed cortico-basal ganglia-thalamocortical circuit: illustrative case.

BACKGROUND: Chronic subdural hematoma (CSDH) is a commonly encountered condition in neurological and neurosurgical practice, but the presence of concomitant parkinsonism is extremely rare. Basal ganglia disturbance is a well-known underlying mechanism; however, few cases present with cerebral cortex compression as the cause of symptoms. OBSERVATIONS: A 52-year-old man was referred to the authors' hospital with a 5-week history of gait disturbance and suspected Parkinson's disease. Neurological examination revealed a mask-like face, stooped posture, left-predominant rigidity, and postural instability. The authors initiated dopamine agonist administration, and brain magnetic resonance imaging (MRI) was scheduled. One week later, MRI showed bilateral CSDHs. The hematomas markedly compressed the bilateral cerebral cortex, whereas the midbrain and basal ganglia structures were intact. The patient underwent burr hole drainage and was discharged after 9 days without sequelae. LESSONS: CSDH can cause parkinsonism by compressing the cerebral cortex, which is a part of the cortico-basal ganglia-thalamocortical circuit. Surgery leads to positive outcomes, as illustrated by this case, in which cerebral cortex compression caused parkinsonism.

Determining the endocrine disruption potential of industrial chemicals using an integrative approach: Public databases, in vitro exposure, and modeling receptor interactions.

Environmental and occupational exposure to industrial chemicals has been linked to toxic and carcinogenic effects in animal models and human studies. However, current toxicology testing does not thoroughly explore the endocrine disrupting effects of industrial chemicals, which may have low dose effects not predicted when determining the limit of toxicity. The objective of this study was to evaluate the endocrine disrupting potential of a broad range of chemicals used in the petrochemical sector. Therefore, 139 chemicals were classified for reproductive toxicity based on the United Nations Globally Harmonized System for hazard classification. These chemicals were evaluated in PubMed for reported endocrine disrupting activity, and their endocrine disrupting potential was estimated by identifying chemicals with active nuclear receptor endpoints publicly available databases. Evaluation of ToxCast data suggested that these chemicals preferentially alter the activity of the estrogen receptor (ER). Four chemicals were prioritized for in vitro testing using the ER-positive, immortalized human uterine Ishikawa cell line and a range of concentrations below the reported limit of toxicity in humans. We found that 2,6-di-tert-butyl-p-cresol (BHT) and diethanolamine (DEA) repressed the basal expression of estrogen-responsive genes PGR, NPPC, and GREB1 in Ishikawa cells, while tetrachloroethylene (PCE) and 2,2'-methyliminodiethanol (MDEA) induced the expression of these genes. Furthermore, low-dose combinations of PCE and MDEA produced additive effects. All four chemicals interfered with estradiol-mediated induction of PGR, NPPC, and GREB1. Molecular docking demonstrated that these chemicals could bind to the ligand binding site of ERα, suggesting the potential for direct stimulatory or inhibitory effects. We found that these chemicals altered rates of proliferation and regulated the expression of cell proliferation associated genes. These findings demonstrate previously unappreciated endocrine disrupting effects and underscore the importance of testing the endocrine disrupting potential of chemicals in the future to better understand their potential to impact public health.

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.

Prioritization of reproductive toxicants in unconventional oil and gas operations using a multi-country regulatory data-driven hazard assessment.

BACKGROUND: Recent trends have witnessed the global growth of unconventional oil and gas (UOG) production. Epidemiologic studies have suggested associations between proximity to UOG operations with increased adverse birth outcomes and cancer, though specific potential etiologic agents have not yet been identified. To perform effective risk assessment of chemicals used in UOG production, the first step of hazard identification followed by prioritization specifically for reproductive toxicity, carcinogenicity and mutagenicity is crucial in an evidence-based risk assessment approach. To date, there is no single hazard classification list based on the United Nations Globally Harmonized System (GHS), with countries applying the GHS standards to generate their own chemical hazard classification lists. A current challenge for chemical prioritization, particularly for a multi-national industry, is inconsistent hazard classification which may result in misjudgment of the potential public health risks. We present a novel approach for hazard identification followed by prioritization of reproductive toxicants found in UOG operations using publicly available regulatory databases. METHODS: GHS classification for reproductive toxicity of 157 UOG-related chemicals identified as potential reproductive or developmental toxicants in a previous publication was assessed using eleven governmental regulatory agency databases. If there was discordance in classifications across agencies, the most stringent classification was assigned. Chemicals in the category of known or presumed human reproductive toxicants were further evaluated for carcinogenicity and germ cell mutagenicity based on government classifications. A scoring system was utilized to assign numerical values for reproductive health, cancer and germ cell mutation hazard endpoints. Using a Cytoscape analysis, both qualitative and quantitative results were presented visually to readily identify high priority UOG chemicals with evidence of multiple adverse effects. RESULTS: We observed substantial inconsistencies in classification among the 11 databases. By adopting the most stringent classification within and across countries, 43 chemicals were classified as known or presumed human reproductive toxicants (GHS Category 1), while 31 chemicals were classified as suspected human reproductive toxicants (GHS Category 2). The 43 reproductive toxicants were further subjected to analysis for carcinogenic and mutagenic properties. Calculated hazard scores and Cytoscape visualization yielded several high priority chemicals including potassium dichromate, cadmium, benzene and ethylene oxide. CONCLUSIONS: Our findings reveal diverging GHS classification outcomes for UOG chemicals across regulatory agencies. Adoption of the most stringent classification with application of hazard scores provides a useful approach to prioritize reproductive toxicants in UOG and other industries for exposure assessments and selection of safer alternatives.

Neurosurgical microscopic solid laser-based light inhibits photobleaching during fluorescence-guided brain tumor removal with 5-aminolevulinic acid.

BACKGROUND: Fluorescence image guided surgery (FIGS) with 5-aminolevulinic acid for malignant gliomas improves surgical outcome. One of the problems during FIGS is photobleaching under surgical microscopic white light. A solid laser-based white light source for neurosurgery that we developed does not include light with a wavelength of around 405nm, which is strongly absorbed by protoporphyrin IX. In the present study, we examined the efficacy of this light source to prevent the photobleaching of protoporphyrin IX-induced fluorescence. METHODS: Filter papers transfused with protoporphyrin IX solution and a coronally sectioned F98 glioma rat model pretreated with 50mg/kg 5-aminolevulinic acid were continuously exposed to white light. One group was exposed to conventional xenon-based white light and another group was exposed to laser-based white light. Fluorescence at a wavelength of 635nm was measured with a radiospectrometer (in vitro study) and the relative fluorescence brightness was also measured in digital images (in vivo study) under excitation from violet blue light emitted from diodes every 5min. RESULTS AND CONCLUSION: Estimated time for 50% photobleaching was prolonged about two times in the laser-based white light exposure group compared with that in the xenon-based white light exposure group (9.1/18.7min). In the brain tumor rat model, it was also prolonged about 2.7 times (15.1/40.7min). A laser-based white light source may inhibit photobleaching during FIGS for malignant gliomas. This light source for neurosurgical microscopy has the potential to prolong the prognosis of malignant glioma patients.

Periadolescent rats (P41-50) exhibit increased susceptibility to D-methamphetamine-induced long-term spatial and sequential learning deficits compared to juvenile (P21-30 or P31-40) or adult rats (P51-60).

We have previously shown that P11-20 treatment with d-methamphetamine (MA) induces impaired spatial navigation in the Morris water maze (MWM), whereas P1-10 treatment does not. Little is known about the long-term behavioral consequences of MA during juvenile, adolescent, and early adult brain development. In dose-response experiments, we tested successive 10-day intervals of exposure to MA in rats (P21-30, P31-40, P41-50, and P51-60; four doses per day). MA dosing prior to P21 produces little or no toxicity; however, we observed an increased toxicity with advancing age. Across-age comparisons revealed no MWM acquisition or Cincinnati water maze (CWM) effects after MA treatment on P21-30 (2.5-10 mg/kg/dose), P31-40 (1.25-7.5 mg/kg/dose), or P51-60 (1.25-5.0 mg/kg/dose); however, significantly impaired MWM acquisition was observed after P41-50 MA treatment at the highest dose (6.25 mg/kg/dose). Learning in the CWM was also impaired in this group. No effects were seen at 1.25, 2.5, or 5 mg/kg/dose following P41-50 MA treatment. MWM reversal learning trials after P41-50 treatment showed a trend towards longer latency in all MA dose groups, but no effect on double-reversal trials. Reversal and double-reversal also showed no effects at the other exposure ages. No differences in straight channel swimming or cued learning in the MWM were seen after MA treatment at any exposure age. P41-50 is the periadolescent stage of brain development in rodents. The effects observed at this age may suggest a previously unrecognized period of susceptibility for MA-induced cognitive deficits.

Developmental D-methamphetamine treatment selectively induces spatial navigation impairments in reference memory in the Morris water maze while sparing working memory.

In previous studies, we have shown that P11-20 treatment with D-methamphetamine (MA) (10 mg/kg x 4/day at 2-h intervals) induces impairments in spatial learning and memory in the Morris water maze after the offspring reach adulthood. Using a split-litter, multiple dose, design (0, 5, 10, and 15 mg/kg MA administered s.c. 4/day at 2-h intervals), the spatial learning effect was further explored with a multiple shifted platform (reversal), reference memory-based procedure and a working memory procedure. Prior to spatial learning, animals were first tested for swimming ability (in a straight swimming channel), sequential learning (in the Cincinnati multiple-T water maze), and proximal cue learning (in the Morris water maze). Rats were then assessed in the hidden platform, reference memory-based spatial version of the Morris maze for acquisition and on five subsequent phases in which the platform was moved to new locations. After the reference memory-based, fixed platform position learning phases, animals were tested in the trial-dependent, matching-to-sample, working memory version of the Morris maze. No group differences were found in straight channel, sequential maze, or cued Morris maze performance. By contrast, all MA groups were impaired in spatial learning during acquisition, multiple shift, and shifted with a reduced platform phases of reference memory-based learning. In addition, MA animals were impaired on memory (probe) trials during the acquisition and shifted with a reduced platform phases of learning. No effects on trial-dependent, matching-to-sample, working memory were found. The findings demonstrate that neonatal treatment with MA induces a selective impairment of reference memory-based spatial learning while sparing sequential, cued, and working memory-based learning.

Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth, litter effects or injection stress.

Previously, we have shown that rats administered MDMA from postnatal (P) days 11-20 had reductions in body weight during the period of treatment and as adults they had deficits in sequential and spatial learning and memory. In the present study, to control for weight reductions, we used litters with double the number of offspring to induce growth restriction comparable to that of standard size litters treated with MDMA. Litters were treated twice daily from P11 to 20 with vehicle or MDMA (20 mg/kg) or only weighed. Males, but not females, exposed to MDMA had longer latencies and more errors in the Cincinnati water maze compared to males of the other treatments. In the Morris water maze (210 cm pool, 10x10 cm platform), the MDMA animals were impaired relative to all other treatments during acquisition. Only the MDMA females showed deficits when the platform was shifted to a new location, however, both MDMA males and females were impaired when the location of the platform was again shifted and a reduced platform (5x5 cm) used. No differences were observed in the ability to swim a straight channel, locate a platform with a cue, or the endocrine response to forced swim among the treatment groups. No differences were seen between animals injected with saline and those only weighed. The data suggest that factors, such as growth retardation, multiple injections, or the composition of the litter, do not affect the development of learning and memory impairments resulting from P11 to 20 MDMA exposure. The large litter approach offers a novel method to control for undernutrition during the preweaning period in rodents.