Publications by authors named "Mitsutoshi Nakada"

238 Publications

[Brain Functional Networks and Awake Craniotomy for Gliomas].

No Shinkei Geka 2021 May;49(3):556-567

Department of Neurosurgery, Kanazawa University.

The sophisticated functional networks of the human brain are integral to life, controlling domains such as language understanding and production and social cognition, which are important for inter-personal communication. Glioma, a primary brain tumor, infiltrates into the brain tissue, forcing the normal brain to reorganize the neural networks(brain plasticity)to resist the invasion. Awake craniotomy for gliomas enables reliable intraoperative identification and preservation of not only the innate normal brain functional areas but also the brain functional networks that have adapted and changed in response to the tumor-invasive environment. Recent advances in neurosurgical techniques and anesthetics have enabled the performance of intraoperative mapping of various brain functions, while maintaining the patient at a high level of awake condition. Attempts have also been made to preserve not only the language functions in the left cerebral hemisphere but also the higher brain functions represented by the right frontal lobe. Herein, we introduce the neural networks of the brain that glioma surgeons need to be aware of, and further describe the indications, methods, and usefulness of awake craniotomy for preserving these networks. In addition, we will discuss topics expected to become the standard in the near future.
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http://dx.doi.org/10.11477/mf.1436204429DOI Listing
May 2021

Thyrotropin-secreting pituitary adenomas induce left atrial enlargement with subclinical atrial fibrillation: an echocardiographic study.

Pituitary 2021 May 19. Epub 2021 May 19.

Department of Neurosurgery, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Purpose: Thyrotropin-secreting pituitary adenoma (TSHoma) is rare but occasionally causes cardiovascular complications such as atrial fibrillation (AF) due to hyperthyroidism. Graves' disease (GD) is a common hyperthyroid condition often associated with subclinical AF. Some reports have shown echocardiographic changes in patients with GD. We aimed to evaluate the preoperative cardiac function in patients with TSHomas and compared the results among patients with TSHomas and GD and control subjects.

Methods: Patients with TSHomas (n = 6) and GD (n = 20) were compared with control subjects with normal cardiac function (n = 20) based on echocardiographic findings. The average age, sex, and proportions of patients with a history of diabetes mellitus and hypertension were equal in each group, and the AF prevalence was matched in patients with TSHomas and GD. The values of left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVEDs), left ventricular ejection fraction (LVEF), and left atrial diameter (LAD) were used to assess cardiac function.

Results: In echocardiography, LAD showed a significant difference between patients with TSHomas and control subjects (p = 0.026). The mean LAD values were 36.9 ± 7.1, 38.2 ± 8.9, and 28.7 ± 3.9 mm for patients with TSHomas and GD and control subjects, respectively. There were no significant differences in other echocardiographic parameters among the groups. Before treatment, serum thyroid hormone levels (free triiodothyronine and thyroxin) were not significantly different among patients with TSHomas and GD.

Conclusion: We found that patients with TSHomas or GD had enlarged LADs. This finding suggests that AF may be more hidden in patients with TSHomas than previously reported.
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http://dx.doi.org/10.1007/s11102-021-01154-3DOI Listing
May 2021

Disconnection of posterior part of the frontal aslant tract causes acute phase motor functional deficit.

Brain Cogn 2021 Jul 14;151:105752. Epub 2021 May 14.

Department of Neurosurgery, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address:

The frontal aslant tract (FAT) mainly connects the supplementary motor area (SMA) and inferior frontal gyrus. The left FAT is involved in language-related functions, while the functional role of the right FAT is not fully understood. The aim of this study was to investigate the function of the right FAT by dividing it into three segments according to the anatomical structure. A total of 34 right frontal gliomas who had undergone surgery were studied. Participants were assessed for the acute and chronic phases of several neuropsychological and motor functions. FAT was reconstructed into the anterior, middle, and posterior segments according to the cortical connections as the medial prefrontal cortex, pre-SMA, and SMA proper, respectively. The relationships between the damaged severity of each FAT segment and behavioral scores were analyzed. A significant relationship was observed only in the acute phase motor function and posterior segment of the FAT. The middle segment was involved in motor function, but it did not have a sufficient significance level compared to the posterior segment. Our study revealed that the right FAT can be divided into three segments and that its posterior segment is related to acute phase motor function.
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http://dx.doi.org/10.1016/j.bandc.2021.105752DOI Listing
July 2021

Multi-institutional survey of thymic carcinoma patients in Hokushin region.

J Cancer Res Clin Oncol 2021 May 8. Epub 2021 May 8.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Background: Thymic carcinoma is a rare neoplasm, and its prognosis is very poor. The purpose of this study was to validate the clinical and epidemiological factors, diagnosis and initial treatment of thymic carcinoma among all patients diagnosed in the registered hospital group.

Methods: We surveyed retrospective data from 152,921 cancer patients in 22 principal hospitals.

Results: A total of 88 thymic carcinoma cases were newly diagnosed. These patients were 50 men and 38 women, with a median age of 66 years old. Eight patients were discovered in cancer screening, 9 in a voluntary setting, 14 at health checkups, 25 at follow-up of other diseases, and 32 cases by introduction from another hospital. Only 14 cases had been diagnosed with localized disease, but 5 cases were accompanied by regional lymph node metastasis. Furthermore, 12 cases showed infiltration into adjacent organs, and 24 cases had distant metastasis. Eighty-three cases were diagnosed by a pathological diagnosis. A surgical approach, chemotherapy, and radiotherapy were performed for 29, 35 patients, and 31 patients, respectively, while 17 patients received best supportive care.

Conclusion: The diagnosis of thymic carcinoma is still difficult, and this disease has a tragically rapid progression if when discovered during follow-up of other diseases. An innovative modality for the early detection of thymic carcinoma is needed in modern medical society.
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http://dx.doi.org/10.1007/s00432-021-03620-8DOI Listing
May 2021

Preserving Right Pre-motor and Posterior Prefrontal Cortices Contribute to Maintaining Overall Basic Emotion.

Front Hum Neurosci 2021 16;15:612890. Epub 2021 Feb 16.

Department of Neurosurgery, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.

Basic emotions such as happiness, sadness, and anger are universal, regardless of the human species, and are governed by specific brain regions. A recent report revealed that mentalizing, which is the ability to estimate other individuals' emotional states facial expressions, can be preserved with the help of awake surgery. However, it is still questionable whether we can maintain the ability to understand others' emotions by preserving the positive mapping sites of intraoperative assessment. Here, we demonstrated the cortical regions related to basic emotions awake surgery for patients with frontal glioma and investigated the usefulness of functional mapping in preserving basic emotion. Of the 56 consecutive patients with right cerebral hemispheric glioma who underwent awake surgery at our hospital, intraoperative assessment of basic emotion could be successfully performed in 22 patients with frontal glioma and were included in our study. During surgery, positive responses were found in 18 points in 12 patients (54.5%). Of these, 15 points from 11 patients were found at the cortical level, mainly the premotor and posterior part of the prefrontal cortices. Then, we focused on cortical 15 positive mappings with 40 stimulations and investigated the types of emotions that showed errors by every stimulation. There was no specific rule for the region-emotional type, which was beyond our expectations. In the postoperative acute phase, the test score of basic emotion declined in nine patients, and of these, it decreased under the cut-off value (-score ≤ -1.65) in three patients. Although the total score declined significantly just after surgery ( = 0.022), it recovered within 3 months postoperatively. Our study revealed that through direct electrical stimulation (DES), the premotor and posterior parts of the prefrontal cortices are related to various kinds of basic emotion, but not a single one. When the region with a positive mapping site is preserved during operation, basic emotion function might be maintained although it declines transiently after surgery.
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http://dx.doi.org/10.3389/fnhum.2021.612890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920969PMC
February 2021

Inflow Hemodynamics of Intracranial Aneurysms: A Comparison of Computational Fluid Dynamics and 4D Flow Magnetic Resonance Imaging.

J Stroke Cerebrovasc Dis 2021 May 1;30(5):105685. Epub 2021 Mar 1.

Department of Neurosurgery, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan. Electronic address:

Purpose: Although the inflow hemodynamics of cerebral aneurysms are key factors in their rupture and recurrence after endovascular treatments, the most available method for inflow hemodynamics evaluation remains unestablished. We compared the efficacy of inflow hemodynamics evaluation using computational fluid dynamics (CFD) analysis and that using four-dimensional (4D) flow magnetic resonance imaging (MRI).

Methods: In 23 unruptured cerebral aneurysms, the inflow hemodynamics was evaluated using both CFD and 4D flow MRI. The evaluated parameters included visually classified inflow jet patterns, the inflow rate ratio (the ratio of the inflow rate at the aneurysmal orifice to the flow rate in the proximal parent artery), and the velocity ratio (the ratio of the inflow velocity to the velocity in the proximal parent artery). The Shapiro-Wilk test was used to assess the normality of variable data, and logarithmic transformation was performed for variables with non-normal distributions. Data analysis was performed using Pearson correlation analyses and the chi-square test.

Results: There was a significant correlation between inflow jet patterns evaluated by CFD and 4D flow MRI (p = 0.008). Moreover, there was a strong correlation between the inflow rate ratios evaluated by CFD and 4D flow MRI (r = 0.801; p <0.001). Furthermore, there was a moderate correlation between the velocity ratios measured by CFD and 4D flow MRI (r = 0.559; p = 0.008).

Conclusion: Inflow hemodynamics evaluated by CFD analysis and 4D flow MRI showed good correlations in inflow jet pattern, inflow rate ratio, and velocity ratio.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105685DOI Listing
May 2021

Extracranial-intracranial high-flow bypass as a rescue therapy for incomplete cerebral aneurysm occlusion after flow diversion: A case report.

Surg Neurol Int 2021 17;12:57. Epub 2021 Feb 17.

Department of Neurosurgery, Kanazawa University, Kanazawa, Ishikawa, Japan.

Background: Excellent treatment outcomes using a pipeline embolization device (PED) have been reported. However, several limitations exist. For example, patients must receive antiplatelet therapy for at least several months, and few alternative treatments exist except for inserting additional flow diverter stents in cases where aneurysm obliteration is not obtained.

Case Description: A 67-year-old female suffered from an asymptomatic large aneurysm of the left paraclinoid internal carotid artery (ICA). She underwent endovascular coil embolization, but coil compaction was confirmed at 2-year follow-up. A PED was inserted as an additional treatment. Unfortunately, the patient was required to discontinue antiplatelet therapy to undergo orthopedic surgery for her severe osteoarthritis of the knee. However, surveillance imaging performed 2 years after insertion of the PED revealed persistent filling into the aneurysm, and we could not stop the antiplatelet therapy to proceed with orthopedic surgery. Therefore, we performed ICA trapping with extracranial-intracranial high-flow bypass to cease antiplatelet therapy promptly. Antiplatelet therapy was completed 3 months after the rescue surgery, and the patient underwent orthopedic surgery.

Conclusion: The authors describe a case of failure of complete obliteration after treatment using a PED, which required cessation of antiplatelet therapy to receive orthopedic surgery. Although safety and efficacy of PED treatment have been reported, we must consider the possibility of other diseases requiring discontinuation of antiplatelet therapy after PED embolization.
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http://dx.doi.org/10.25259/SNI_836_2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911044PMC
February 2021

Multi-institutional survey of cancer disparities in disabled patients in the region of northwestern Japan.

Int J Clin Oncol 2021 Jun 1;26(6):1009-1014. Epub 2021 Mar 1.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-0934, Japan.

Background: Potential disparities between cancer patients with and without disabilities remained to be validate in Japan.

Methods: We surveyed retrospective data on hospital cancer registration as well as information on disability certificates obtained through the Hokushin Ganpro database. In total, 93,545 cancer patients in 10 principal hospitals covering the region of northwestern Japan were registered with the Hokushin Ganpro database between 2010 and 2015. The database included the following data: diagnosis date, cancer type, staging, treatment, cancer detection process, and possession of a disability certificate.

Results: We found that 2983 patients, which accounted for 3.2% of the total patients, had disabilities. No significant differences in gender, age at diagnosis, cancer stage distribution, and cancer incidence rates were observed between the disabled and non-disabled patients. Even though the proportion of early-stage cancer among disabled patients differed only slightly from that in non-disabled patients, early-stage cancer was more frequently diagnosed in patients with disabilities during their regular hospital visits than in those without disabilities, who had more opportunity for early cancer detection during cancer screening. According to in-house data reflecting treatment period and process from a single hospital, all 16 disabled patients treated with chemotherapy completed the treatment until disease progression or end of predetermined cycles.

Conclusion: These results indicate that deep disparities between cancer patients with and without disabilities are not apparent and that the disabled patients in the region of northwestern Japan receive appropriate hospital follow-up.
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http://dx.doi.org/10.1007/s10147-021-01890-3DOI Listing
June 2021

A case of rapid deterioration in a subacute period after endoscopic third ventriculostomy.

Br J Neurosurg 2021 Feb 19:1-4. Epub 2021 Feb 19.

Department of Neurosurgery, Kanazawa University, Graduate School of Medical Science, Kanazawa, Japan.

Although generally a safe procedure, serious postoperative complications after endoscopic third ventriculostomy (ETV) for obstructive hydrocephaly have been rarely reported, such as delayed obstruction of the stoma at the third ventricle floor. A 20-year-old male was referred to our department because of severe headache and diplopia. A pineal tumour and obstructive hydrocephaly were detected in preoperative imaging. After tumour biopsy and ETV, the reduction of ventricle size and improvement of headaches were immediately observed. On the seventh day, however, he developed a rapidly progressing consciousness disturbance due to severe hydrocephalus leading to urgent secondary ETV. The original ventriculostomy stoma at the third ventricle floor was completely occluded by scar adhesion. The patient recovered well as previously and received additional treatment. Although very rare, occlusion of the ventriculostomy stoma can postoperatively occur in the subacute period. Patients undergoing ETV for obstructive hydrocephalus due to a pineal tumour should be carefully monitored to avoid serious consequences.
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http://dx.doi.org/10.1080/02688697.2021.1885624DOI Listing
February 2021

TERT promoter mutation confers favorable prognosis regardless of 1p/19q status in adult diffuse gliomas with IDH1/2 mutations.

Acta Neuropathol Commun 2020 11 23;8(1):201. Epub 2020 Nov 23.

Department of Neurosurgery, Dokkyo Medical University, 880, Kitakobayashi, Mibu-City, Tochigi, 321-0293, Japan.

TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n = 24) or 1p/19q codeletion (n = 6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90-100%) were associated with favorable prognosis (p < 0.05). A multivariable Cox regression model revealed that TERT promoter mutation had a significantly favorable prognostic impact (hazard ratio = 0.421, p = 0.049), while 1p/19q codeletion did not have a significant impact (hazard ratio = 0.648, p = 0.349). Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation. Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n = 17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n = 185) (5-year overall survival, 94% and 77%, respectively; p = 0.032). Our results demonstrate that TERT promoter mutation predicts favorable prognosis independent of 1p/19q codeletion in IDH-mutated gliomas. Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.
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http://dx.doi.org/10.1186/s40478-020-01078-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685625PMC
November 2020

Ependymoma with C11orf95-MAML2 fusion: presenting with granular cell and ganglion cell features.

Brain Tumor Pathol 2021 Jan 22;38(1):64-70. Epub 2020 Nov 22.

Department of Neurosurgery, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

C11orf95-RELA fusion or, less frequently, YAP1 fusion is recurrently detected in most cases of supratentorial ependymoma. Other fusions have rarely been reported in some cases of supratentorial ependymoma, and little is known about their pathological or clinical features. Here, we present a case of supratentorial ependymoma with unusual pathological findings and C11orf95-MAML2 fusion. A 23-year-old man was admitted to our hospital because of headache and vomiting. Magnetic resonance imaging revealed a cystic lesion in the right frontal lobe, and gross total resection of the tumor was performed. Pathologically, the tumor was mainly composed of typical ependymal lesions with perivascular pseudorosettes and contained some atypical lesions, with granular and ganglion cell features. The tumor was diagnosed as anaplastic ependymoma, which was classified as grade III on the World Health Organization scale, and found to be RELA fusion-positive in the DNA methylation analysis. However, the tumor was negative for C11orf95-RELA fusion, and RNA sequencing detected C11orf95-MAML2 fusion. The patient has not received adjuvant therapy and has remained alive without any evidence of disease for 30 months, suggesting that the prognosis might be better than that of typical C11orf95-RELA fusion-positive ependymoma.
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http://dx.doi.org/10.1007/s10014-020-00388-6DOI Listing
January 2021

Awake surgery for right frontal lobe glioma can preserve visuospatial cognition and spatial working memory.

J Neurooncol 2021 Jan 2;151(2):221-230. Epub 2020 Nov 2.

Department of Neurosurgery, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Purpose: Awake surgery is the standard treatment to preserve motor and language functions. This longitudinal study aimed to evaluate the resection rate and preservation of neurocognitive functions in patients with right frontal lobe glioma who underwent awake surgery.

Methods: Thirty-three patients (mean age, 48.0 years) with right frontal lobe glioma who underwent awake surgery at our hospital between 2013 and 2019 were included. Fourteen, thirteen, and six cases had WHO classification grades of II, III, and IV, respectively. We evaluated visuospatial cognition (VSC) and spatial working memory (SWM) before and three months after surgery. Relevant brain areas for VSC and SWM were intraoperatively mapped, whenever the task was successfully accomplished. Therefore, patients were divided into an intraoperative evaluation group and a non-evaluation group for each function, and the resection rate and functional outcomes were compared.

Results: The removal rate in the evaluation group for VSC and SWM were similar to that in the non-evaluation group. Chronic impairment rate of VSC was significantly lower in the evaluation than in the non-evaluation group (5.6% vs. 33.3%, p = 0.034). No patient showed postoperative SWM impairment in the evaluation group as opposed to the non-evaluation group (16.7%, p = 0.049). The probability of resection of the deeper posterior part of the middle frontal gyrus, the relevant area of VSC, was higher in the non-evaluation group than in the evaluation group.

Conclusions: We statistically verified that awake surgery for right frontal lobe glioma results in successful preservation of VSC and SWM with satisfying resection rates.
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http://dx.doi.org/10.1007/s11060-020-03656-9DOI Listing
January 2021

Oculomotor nerve palsy in pituitary apoplexy associated with pituitary adenoma: a radiological analysis with fast imaging employing with steady-state acquisition.

Acta Neurochir (Wien) 2021 02 31;163(2):383-389. Epub 2020 Oct 31.

Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Purpose: Oculomotor nerve palsy (ONP) occasionally occurs in cases of pituitary apoplexy (PA) associated with pituitary adenoma, but its mechanism remains unclear. Intracranial nerves are clearly visualized by fast-imaging employing with steady-state acquisition (FIESTA). Here, we assessed the oculomotor nerve compression in patients with PA associated with pituitary adenoma using FIESTA.

Methods: Twenty-eight cases of PA, with or without ONP, were retrospectively reviewed. All patients had undergone preoperative FIESTA. Two neuroradiologists, unaware of the patient's clinical symptoms, evaluated the presence and location of oculomotor nerve compression due to the tumor.

Results: Thirteen of the twenty-eight PA cases were associated with ONP. Tumor size and degree of cavernous sinus invasion were not significantly different between the ONP and non-ONP groups. Even in the ONP group, 8/13 (62%) tumors did not show cavernous sinus invasion. Via FIESTA, the presence of oculomotor nerve compression was confirmed in 11/13 (85%) and 5/15 (33%) cases in the ONP and non-ONP groups, respectively (p = 0.008). The radiologists' diagnoses of laterality of nerve compression (right or left) were consistent with the patient's affected eye. In the ONP group, the location of the nerve compression was located at the entry point to the cavernous sinus, the so-called oculomotor triangle, in 9/11 (82%) cases and intra cavernous sinus in 2/11 (18%) cases.

Conclusion: Compression at the oculomotor triangle is considered the main cause of ONP with PA in pituitary adenomas.
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http://dx.doi.org/10.1007/s00701-020-04632-yDOI Listing
February 2021

Glioma Stem-Like Cells Can Be Targeted in Boron Neutron Capture Therapy with Boronophenylalanine.

Cancers (Basel) 2020 Oct 19;12(10). Epub 2020 Oct 19.

Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka 590-0494, Japan.

As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. B(n,α)Li capture reaction produces alpha particles whose short paths (5-9 µm) lead to selective killing of tumor cells. P-boronophenylalanine (BPA) is a chemical compound used in clinical trials for BNCT. Here, we used mass cytometry (Cytof) to investigate whether glioma stem-like cells (GSLCs) take up BPA or not. We used GSLCs, and cells differentiated from GSLCs (DCs) by fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA or CD98 cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2-4 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2 or Nestin GSLCs were BPA, whereas only 36.9% of glial fibrillary acidic protein (GFAP) DCs were BPA. Therefore, GSLCs may take up BPA and could be targeted by BNCT.
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http://dx.doi.org/10.3390/cancers12103040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603373PMC
October 2020

Prediction of internal carotid artery aneurysm recurrence by pressure difference at the coil mass surface.

Neuroradiology 2021 Apr 14;63(4):593-602. Epub 2020 Sep 14.

Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Purpose: A previous study on computational fluid dynamics reported that a high pressure difference (PD) at the surface of a coil mass is a strong predictor of aneurysm recurrence after coil embolization. PD was calculated using a virtual post-coiling model (VM), created by manually cutting the aneurysm by the flat plane from an anatomic model created with pre-coil embolization data; however, its credibility has not been fully evaluated. This study aims to clarify whether PD values calculated using the post-coiling model, which reflects the actual coil plane, are a strong predictor of aneurysm recurrence.

Methods: Fifty internal carotid artery aneurysms treated with endovascular coil embolization were analyzed (7 recanalized, 43 stable). We created and subjected two post-coiling models, namely, VM and the real post-coiling model (RM), constructed from the post-coil embolization data. The relationship between PD and aneurysm recurrence was examined using these models. PD and its constituent three parameters were compared between VM and RM.

Results: PD values calculated using RM showed significantly higher aneurysm recurrence in recurrence group than stable group (p < 0.001), and multivariate analysis showed that PD in RM (p = 0.02; odds ratio, 36.24) was significantly associated with aneurysm recurrence. The receiver operating characteristic analysis revealed that PD values accurately predicted aneurysm recurrence (area under the curve, 0.977; cutoff value, 3.08; sensitivity, 100%; specificity, 97.7%). All four parameters showed a significant correlation with VM and RM (p < 0.001).

Conclusion: Use of PD to predict recurrence after coil embolization can be clinically relevant.
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http://dx.doi.org/10.1007/s00234-020-02553-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966142PMC
April 2021

Motor Functional Reorganization Is Triggered by Tumor Infiltration Into the Primary Motor Area and Repeated Surgery.

Front Hum Neurosci 2020 14;14:327. Epub 2020 Aug 14.

Department of Neurosurgery, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.

In patients with gliomas, motor deficits are not always observed, even though tumor cells infiltrate into the motor area. Currently, it is recognized that this phenomenon can occur through the neuroplasticity potential. The aim of this study is to investigate the characteristics of motor functional reorganization in gliomas. Out of 100 consecutive patients who underwent awake surgery, 29 patients were assessed as regards their motor function and were retrospectively explored to determine whether positive motor responses were elicited. A total of 73 positive mapping sites from 27 cases were identified, and their spatial anatomical locations and activated region by functional MRI were analyzed. Additionally, the factors promoting neuroplasticity were analyzed through multiple logistic regression analysis. As a result, a total of 60 points (21 cases) were found in place, while 13 points (17.8%) were found to be shifted from anatomical localization. Reorganizations were classified into three categories: Type 1 (move to ipsilateral different gyrus) was detected at nine points (four cases), and they moved into the postcentral gyrus. Type 2 (move within the ipsilateral precentral gyrus) was detected at four points (two cases). Unknown type (two cases) was categorized as those whose motor functional cortex was moved to other regions, although we could not find the compensated motor area. Two factors for the onset of reorganization were identified: tumor cells infiltrate into the primary motor area and repeated surgery ( < 0.0001 and = 0.0070, respectively). Our study demonstrated that compensation can occur mainly in two ways, and it promoted repeated surgery and infiltration of tumor into the primary motor area.
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http://dx.doi.org/10.3389/fnhum.2020.00327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457049PMC
August 2020

Effect of Neck Size on the Inflow Magnitude Evaluated on 4D Flow MRI in Unruptured Internal Carotid Artery Aneurysms.

J Stroke Cerebrovasc Dis 2020 Oct 11;29(10):105116. Epub 2020 Jul 11.

Department of Neurosurgery, Graduate School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Ishikawa, Japan.

Background: A neck size >4.0 mm is a risk factor for recanalization after coil embolization. The high inflow magnitude of pretreatment wide-neck aneurysms may be correlated to recanalization. We aimed to elucidate the effect of the neck size on the inflow magnitude evaluated on four-dimensional (4D) flow magnetic resonance imaging (MRI) in pretreatment unruptured internal carotid artery (ICA) aneurysms.

Methods: Thirty-three untreated ICA aneurysms were subjected to 4D flow MRI to evaluate the inflow magnitude parameters including the maximum spatially-averaged inflow velocity (MSAIV), maximum inflow velocity, maximum inflow rate (MIR), and their ratios to each corresponding flow parameter in the parent artery.

Results: The neck size was linearly correlated to all inflow parameters investigated in this study. A strong correlation was observed between the neck size and the following: MSAIV (r = .755, p < .0001), MIR (r = .715, p < .0001), MSAIV ratio (r = .724, p < .0001), and MIR ratio (r = .741, p < .0001). The predicted value of MIR ratio of an aneurysm with the neck size of 4.0 mm was 23.0% and 20.6%, based on the linear regression equation of all aneurysms and on that of aneurysms with the neck size >4.0 mm, respectively.

Conclusions: The neck size was linearly correlated with the inflow magnitude of unruptured ICA aneurysms. Inflow magnitude evaluation using 4D flow MRI may help to hemodynamically identify aneurysms with a high risk of recanalization after endovascular coil embolization.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105116DOI Listing
October 2020

RBPJ contributes to the malignancy of glioblastoma and induction of proneural-mesenchymal transition via IL-6-STAT3 pathway.

Cancer Sci 2020 Nov 22;111(11):4166-4176. Epub 2020 Sep 22.

Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.

Notch signaling plays a pivotal role in many cancers, including glioblastoma (GBM). Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) is a key transcription factor of the Notch signaling pathway. Here, we interrogated the function of RBPJ in GBM. Firstly, RBPJ expression of GBM samples was examined. Then, we knocked down RBPJ expression in 2 GBM cell lines (U251 and T98) and 4 glioblastoma (GBM) stem-like cell lines derived from surgical samples of GBM (KGS01, KGS07, KGS10 and KGS15) to investigate the effect on cell proliferation, invasion, stemness, and tumor formation ability. Expression of possible downstream targets of RBPJ was also assessed. RBPJ was overexpressed in the GBM samples, downregulation of RBPJ reduced cell proliferation and the invasion ability of U251 and T98 cells and cell proliferation ability and stemness of glioblastoma stem-like cells (GSC) lines. These were accompanied by reduced IL-6 expression, reduced activation of STAT3, and inhibited proneural-mesenchymal transition (PMT). Tumor formation and PMT were also impaired by RBPJ knockdown in vivo. In conclusion, RBPJ promotes cell proliferation, invasion, stemness, and tumor initiation ability in GBM cells through enhanced activation of IL-6-STAT3 pathway and PMT, inhibition of RBPJ may constitute a prospective treatment for GBM.
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http://dx.doi.org/10.1111/cas.14642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648018PMC
November 2020

So-called bifocal tumors with diabetes insipidus and negative tumor markers: are they all germinoma?

Neuro Oncol 2021 02;23(2):295-303

Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.

Background: The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed.

Methods: A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan.

Results: Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them.

Conclusion: All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.
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http://dx.doi.org/10.1093/neuonc/noaa199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906060PMC
February 2021

Leukemia-Associated Rho Guanine Nucleotide Exchange Factor and Ras Homolog Family Member C Play a Role in Glioblastoma Cell Invasion and Resistance.

Am J Pathol 2020 10 18;190(10):2165-2176. Epub 2020 Jul 18.

Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona. Electronic address:

Glioblastoma (GBM) is the most common primary malignant brain cancer in adults. A hallmark of GBM is aggressive invasion of tumor cells into the surrounding normal brain. Both the current standard of care and targeted therapies have largely failed to specifically address this issue. Therefore, identifying key regulators of GBM cell migration and invasion is important. The leukemia-associated Rho guanine nucleotide exchange factor (LARG) has previously been implicated in cell invasion in other tumor types; however, its role in GBM pathobiology remains undefined. Herein, we report that the expression levels of LARG and ras homolog family members C (RhoC), and A (RhoA) increase with glial tumor grade and are highest in GBM. LARG and RhoC protein expression is more prominent in invading cells, whereas RhoA expression is largely restricted to cells in the tumor core. Knockdown of LARG by siRNA inhibits GBM cell migration in vitro and invasion ex vivo in organotypic brain slices. Moreover, siRNA-mediated silencing of RhoC suppresses GBM cell migration in vitro and invasion ex vivo, whereas depletion of RhoA enhances GBM cell migration and invasion, supporting a role for LARG and RhoC in GBM cell migration and invasion. Depletion of LARG increases the sensitivity of GBM cells to temozolomide treatment. Collectively, these results suggest that LARG and RhoC may represent unappreciated targets to inhibit glioma invasion.
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http://dx.doi.org/10.1016/j.ajpath.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527857PMC
October 2020

Potential therapeutic effect of targeting glycogen synthase kinase 3β in esophageal squamous cell carcinoma.

Sci Rep 2020 07 16;10(1):11807. Epub 2020 Jul 16.

Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-0934, Japan.

Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal cancer and is often refractory to current therapies. Development of efficient therapeutic strategies against ESCC presents a major challenge. Glycogen synthase kinase (GSK)3β has emerged as a multipotent therapeutic target in various diseases including cancer. Here we investigated the biology and pathological role of GSK3β in ESCC and explored the therapeutic effects of its inhibition. The expression of GSK3β and tyrosine (Y)216 phosphorylation-dependent activity was higher in human ESCC cell lines and primary tumors than untransformed esophageal squamous TYNEK-3 cells from an ESCC patient and tumor-adjacent normal esophageal mucosa. GSK3β-specific inhibitors and small interfering (si)RNA-mediated knockdown of GSK3β attenuated tumor cell survival and proliferation, while inducing apoptosis in ESCC cells and their xenograft tumors in mice. GSK3β inhibition spared TYNEK-3 cells and the vital organs of mice. The therapeutic effect of GSK3β inhibition in tumor cells was associated with G0/G1- and G2/M-phase cell cycle arrest, decreased expression of cyclin D1 and cyclin-dependent kinase (CDK)4 and increased expression of cyclin B1. These results suggest the tumor-promoting role of GSK3β is via cyclin D1/CDK4-mediated cell cycle progression. Consequently, our study provides a biological rationale for GSK3β as a potential therapeutic target in ESCC.
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http://dx.doi.org/10.1038/s41598-020-68713-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367341PMC
July 2020

The Multipotential of Leucine-Rich α-2 Glycoprotein 1 as a Clinicopathological Biomarker of Glioblastoma.

J Neuropathol Exp Neurol 2020 08;79(8):873-879

From the Department of Pathology; Department of Neuropathology, St. Mary's Hospita, Kurume, Japan.

Leucine-rich α-2 glycoprotein 1 (LRG1) is a diagnostic marker candidate for glioblastoma. Although LRG1 has been associated with angiogenesis, it has been suggested that its biomarker role differs depending on the type of tumor. In this study, a clinicopathological examination of LRG1's role as a biomarker for glioblastoma was performed. We used tumor tissues of 155 cases with diffuse gliomas (27 astrocytomas, 14 oligodendrogliomas, 114 glioblastomas). The immunohistochemical LRG1 intensity scoring was classified into 2 groups: low expression and high expression. Mutations of IDH1, IDH2, and TERT promoter were analyzed through the Sanger method. We examined the relationship between LRG1 expression level in glioblastoma and clinical parameters, such as age, preoperative Karnofsky performance status, tumor location, extent of resection, O6-methylguanine DNA methyltransferase promoter, and prognosis. LRG1 high expression rate was 41.2% in glioblastoma, 3.7% in astrocytoma, and 21.4% in oligodendroglioma. Glioblastoma showed a significantly higher LRG1 expression than lower-grade glioma (p = 0.0003). High expression of LRG1 was an independent favorable prognostic factor (p = 0.019) in IDH-wildtype glioblastoma and correlated with gross total resection (p = 0.002) and the tumor location on nonsubventricular zone (p = 0.00007). LRG1 demonstrated multiple potential as a diagnostic, prognostic, and regional biomarker for glioblastoma.
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http://dx.doi.org/10.1093/jnen/nlaa058DOI Listing
August 2020

Laminin Subunit Alpha-4 and Osteopontin Are Glioblastoma-Selective Secreted Proteins That Are Increased in the Cerebrospinal Fluid of Glioblastoma Patients.

J Proteome Res 2020 08 16;19(8):3542-3553. Epub 2020 Jul 16.

Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. The purpose of the present study was to identify GBM cell-selective secreted proteins by analyzing conditioned media (CM) from GBM, breast, and colon cancer cell lines using sequential window acquisition of all theoretical spectra-mass spectrometry (SWATH-MS) and targeted proteomics. We identified 2371 proteins in the CM from GBM and the other cancer cell lines. Among the proteins identified, 15 showed significantly higher expression in the CM from GBM cell lines than in those from other cancer cell lines. These GBM-selective secreted proteins were further quantified in the cerebrospinal fluid (CSF) from patients with GBM. Laminin subunit alpha-4 (LAMA4) and osteopontin (OPN) had increased expression levels in the CSF from GBM patients compared to those from non-brain tumor patients. In addition, the areas under the curves in a receiver operating characteristic analysis of LAMA4 and OPN were greater than 0.9, allowing for discrimination of GBM patients from non-brain tumor patients. The CSF levels of LAMA4 and OPN were also significantly correlated with the GBM tumor volume. These results suggest that LAMA4 and OPN are secreted from GBM cells into the CSF and appear to be candidates as diagnostic markers and therapeutic targets for GBM.
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http://dx.doi.org/10.1021/acs.jproteome.0c00415DOI Listing
August 2020

[Ⅰ. Consideration of Cognitive Functions in the Surgical Treatment for Brain Tumors].

Gan To Kagaku Ryoho 2020 Jun;47(6):893-898

Dept. of Neurosurgery, Kanazawa University.

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June 2020

Neuroprotective Effects of Endogenous Secretory Receptor for Advanced Glycation End-products in Brain Ischemia.

Aging Dis 2020 May 9;11(3):547-558. Epub 2020 May 9.

2Department of Neurosurgery and.

The receptor for advanced glycation end-products (RAGE) is expressed on human brain endothelial cells (HBEC) and is implicated in neuronal cell death after ischemia. We report that endogenous secretory RAGE (esRAGE) is a splicing variant form of RAGE that functions as a decoy against ischemia-induced neuronal cell damage. This study demonstrated that esRAGE was associated with heparan sulphate proteoglycans on HBEC. The parabiotic experiments between human esRAGE overexpressing transgenic (Tg), RAGE knockout (KO), and wild-type (WT) mice revealed a significant neuronal cell damage in the CA1 region of the WT side of parabiotic WT→WT mice, but not of Tg→WT mice, 7 days after bilateral common carotid artery occlusion. Human esRAGE was detected around the CA1 neurons in the WT side of the parabiotic Tg→WT pair, but not in the KO side of the Tg→KO pair. To elucidate the dynamic transfer of esRAGE into the brain, we used the blood-brain barrier (BBB) system (PharmaCo-Cell) with or without RAGE knockdown in endothelial cells. A RAGE-dependent transfer of esRAGE was demonstrated from the vascular to the brain side. These findings suggested that esRAGE is associated with heparan sulphate proteoglycans and is transferred into the brain via BBB to exert its neuroprotective effects in ischemia.
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http://dx.doi.org/10.14336/AD.2019.0715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220285PMC
May 2020

Glioma-derived extracellular vesicles promote tumor progression by conveying WT1.

Carcinogenesis 2020 09;41(9):1238-1245

Department of Immunology, Kanazawa University Graduate School of Medical Sciences, Takara, Kanazawa, Ishikawa, Japan.

Glioma persists as one of the most aggressive primary tumors of the central nervous system. Glioma cells are known to communicate with tumor-associated macrophages/microglia via various cytokines to establish the tumor microenvironment. However, how extracellular vesicles (EVs), emerging regulators of cell-cell communication networks, function in this process is still elusive. We report here that glioma-derived EVs promote tumor progression by affecting microglial gene expression in an intracranial implantation glioma model mouse. The gene expression of thrombospondin-1 (Thbs1), a negative regulator of angiogenesis, was commonly downregulated in microglia after the addition of EVs isolated from different glioma cell lines, which endogenously expressed Wilms tumor-1 (WT1). Conversely, WT1-deficiency in the glioma-derived EVs significantly attenuated the Thbs1 downregulation and suppressed the tumor progression. WT1 was highly expressed in EVs obtained from the cerebrospinal fluid of human patients with malignant glioma. Our findings establish a novel model of tumor progression via EV-mediated WT1-Thbs1 intercellular regulatory pathway, which may be a future diagnostic or therapeutic target.
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http://dx.doi.org/10.1093/carcin/bgaa052DOI Listing
September 2020

Direct evidence of the relationship between brain metastatic adenocarcinoma and white matter fibers: A fiber dissection and diffusion tensor imaging tractography study.

J Clin Neurosci 2020 Jul 11;77:55-61. Epub 2020 May 11.

Department of Neurosurgery, Kanazawa University, Kanazawa, Ishikawa, Japan.

It is commonly known that brain metastases usually have clear boundaries in magnetic resonance imaging. However, little is known regarding the trajectory of white matter fibers around the tumors, especially using the fiber dissection technique. Here, we focused on the anatomical interaction between white matter fibers and the tumor, using the fiber dissection in a postmortem brain with metastatic tumor and compared the findings with those of diffusion tensor imaging (DTI) tractography. One postmortem human brain hemisphere with metastatic adenocarcinoma in the Broca's area was dissected using fiber dissection following the Klingler's method. In order to compare the in vitro and in vivo results, additional brains from 15 patients with metastatic adenocarcinomas, the volumes of which were comparable to that of the adenocarcinoma in the brain used for fiber dissection, were analyzed using DTI tractographic reconstruction. Morphological findings of white matter bundles running around the tumor were compared between the two techniques. In the fiber dissection technique, the superior longitudinal fascicle, arcuate fascicle, and frontal aslant tract could be dissected, and the white matter bundles were curved and retracted to avoid the tumor. In all the cases analyzed, white matter fibers or streamlines surrounding the tumor avoided the lesion. Using the fiber dissection technique, this is the first direct evidence to elucidate the anatomy of white matter fibers affected by a metastatic brain. This suggests that brain metastatic adenocarcinoma is an intra-axial neoplasm with extra-axial white matter structures.
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http://dx.doi.org/10.1016/j.jocn.2020.05.043DOI Listing
July 2020

Cavernous Sinus Dural Arteriovenous Fistula with an Enhanced Lesion in the Brainstem Mimicking a Malignant Tumor.

World Neurosurg 2020 08 11;140:13-17. Epub 2020 May 11.

Division of Neuroscience, Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Japan.

Background: Cavernous sinus (CS) dural arteriovenous fistula (dAVF) with an enhanced lesion in the brainstem is rare, and an enhanced lesion in the brainstem might be indicative of irreversibility.

Case Description: A 77-year-old woman presented with double vision and ataxia. Magnetic resonance imaging showed a unilateral enhancement lesion in the pons, so a malignant brain tumor was suspected. A cerebral angiogram revealed CS-dAVF with retrograde leptomeningeal venous drainage (RLVD) to the brainstem. Transvenous embolization with selective coil embolization of RLVD was performed, and the symptoms and imaging improved dramatically.

Conclusions: DAVFs with RLVD should be mentioned as a differential diagnosis of enhanced lesions in the brainstem. Transvenous embolization with selective coil embolization of RLVD was effective for the treatment of CS-dAVF, and a unilateral enhanced brainstem lesion may be reversible.
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http://dx.doi.org/10.1016/j.wneu.2020.04.165DOI Listing
August 2020

Intra-aneurysmal embolization of cellulose porous beads to regenerate vessel wall: an experimental study.

Neuroradiology 2020 Sep 1;62(9):1169-1175. Epub 2020 May 1.

Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Purpose: Although the treatment of intracranial cerebral aneurysms with detachable coils is now widely accepted, the problem of coil compaction and recanalization remains unsolved. If the vessel wall can be regenerated at the neck orifice of an aneurysm, thereby reducing the blood flow into the aneurysm, the recurrence rate of the aneurysm would decrease. Accordingly, we aimed to insert cellulose porous beads (CPBs) into rat models of external carotid artery (ECA) aneurysm and study their efficacy in promoting vessel wall regeneration.

Methods: Using a rat aneurysm model, we examined the tissue response to CPBs that were inserted into the ligated ECA sac of rats. The sacs were removed on days 14, 42, 84, and 180 after insertion and subjected to conventional and immunohistochemical examination. We evaluated the tissue response in the ECA sacs and observed the vessel wall regeneration progress.

Results: At the neck orifice of the aneurysm in which the CPB was inserted, a layer of regenerating α-smooth muscle actin-positive spindle cells was observed on day 14. The regenerative cell layer gradually thickened until day 42 and, thereafter, the thickness remained unchanged until day 180. A monolayer of factor VIII-positive cells also appeared at the neck orifice on day 14 and covered the entire orifice until day 180. The CPBs were stably localized in the sac without degradation or signs of inflammation.

Conclusion: CPBs may be promising as embolic materials that can induce stable vessel wall regeneration at the neck orifice of an aneurysm without surrounding inflammatory reactions.
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http://dx.doi.org/10.1007/s00234-020-02440-wDOI Listing
September 2020