Ulceration location is associated with clinical course in carotid stenosis.

OBJECTIVE: Plaque ulceration in carotid artery stenosis is a risk factor for cerebral ischemic events; however, the characteristics that determine plaque vulnerability are not fully understood. We thus assessed the association between plaque ulceration sites and cerebrovascular ischemic attack. METHODS: We retrospectively collected the clinical data of 72 consecutive patients diagnosed with carotid artery stenosis with plaque ulcers. After excluding patients with pseudo-occlusion, a history of previous carotid endarterectomy or carotid artery stenting before the ulcer was first discovered, follow-up data of less than 1 month, or carotid endarterectomy or carotid artery stenting performed within 1 month after the ulcer was first discovered, 60 patients were ultimately included. Patients were divided into proximal and distal groups based on the ulcer location relative to the most stenotic point. The primary endpoints were ipsilateral cerebrovascular ischemic events ("ischemic events"), such as amaurosis fugax, transient ischemic attack, or ischemic stroke due to carotid artery stenosis with plaque ulceration. The association between ulcer location and ischemic events was also assessed. RESULTS: In the patients with plaque ulcer, more patients had proximal than distal plaque ulcers (39 vs 21; P = .028). The median follow-up duration was 3.8 years (interquartile range, 1.5-6.2 years). Nineteen patients (32%) experienced ischemic event. Ischemic events occurred more frequently in the distal than in the proximal group (18% vs 59%; P = .005). Kaplan-Meier curves demonstrated a significantly shorter event-free time in the distal group (log-rank P = .021). In univariate analysis, distal ulcer location was associated with ischemic events (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.13-7.65; P = .03). Multivariate analysis using two different models also showed that distal ulcer location was independently associated with ischemic events (Model 1: OR, 3.85; 95% CI, 1.26-11.78; P = .03; Model 2: OR, 4.31; 95% CI, 1.49-12.49; P = .009). CONCLUSIONS: Patients with carotid artery stenosis and plaque ulcers located distal to the most stenotic point are more likely to experience cerebrovascular ischemic attacks. Therefore, carotid plaques with ulcers located distal to the most stenotic point may be a potential indication for surgical treatment.

A Review of Current Flow Diverters.

Flow diverter (FD) devices are new-generation stents placed in the parent artery at the aneurysmal neck to obstruct intra-aneurysmal blood flow, thus favoring intra-aneurysmal thrombosis. In Japan, about eight years have passed since health insurance approval was granted for FD devices, and FD placement to treat aneurysms has become widespread. Treatment indications have also been expanded with the introduction of novel devices. At present, three types of FD (Pipeline, FRED, and Surpass Streamline) are available in Japan. This report represents a compilation of available FD technologies and describes the current consensus on this treatment.

Pathological changes in the lenticulostriate artery indicate the mechanisms leading to intracranial hemorrhage in Moyamoya disease: a case report.

This case report details the pathological findings of a vessel wall identified as the bleeding point for intracranial hemorrhage associated with Moyamoya disease. A 29-year-old woman experienced intracranial hemorrhage unrelated to hyperperfusion following superficial temporal artery-middle cerebral artery bypass surgery. A pseudoaneurysm on the lenticulostriate artery (LSA) was identified as the causative vessel and subsequently excised. Examination of the excised pseudoaneurysm revealed a fragment of the LSA, with a disrupted internal elastic lamina and media degeneration. These pathological findings in a perforating artery, akin to the circle of Willis, provide insights into the underlying mechanisms of hemorrhage in Moyamoya disease.

Impact of tailored multimodal treatment for unruptured brain arteriovenous malformation: comparison with a randomized trial of unruptured brain arteriovenous malformations.

PURPOSE: The first randomized controlled study on unruptured brain arteriovenous malformations (bAVM), the ARUBA trial, demonstrate the superiority of medical management; however, it failed to completely rule out the efficacy of therapeutic interventions due to several limitations. This study aimed to examine the outcomes of multimodal interventional treatment for bAVM in terms of safety and efficacy. METHODS: We reviewed 226 consecutive patients with unruptured bAVM admitted to our institute between 2002 and 2022. Treatment methods were divided into medical management and therapeutic intervention, including microsurgery, stereotactic surgery, and endovascular intervention. First, the choice of therapeutic modalities was assessed in the pre-ARUBA (before February 2014) and post-ARUBA (after March 2014) eras. Second, the incidence of symptomatic stroke or death and functional prognosis with a modified Rankin scale (mRS) score of ≥2 at 5 years was compared between the medical management and therapeutic intervention. RESULTS: In the pre- and post-ARUBA groups, 73% and 84% of patients underwent therapeutic interventions, respectively (p = 0.053). The rate of symptomatic stroke or death was lower in patients who underwent interventional therapies than in those who underwent medical management (9.7% vs. 22%, p = 0.022); however, the opposite was observed in the ARUBA trial (31% vs. 10%). The annual incidence of stroke or death was also lower in the interventional therapy group (4.3%/y vs. 1.8%/year, hazard ratio = 0.45, 95% confidence interval: 0.18-1.08, p = 0.032). The rate of mRS score of ≥2 after a 5-year follow-up was 18% and 6% in the medical treatment and intervention groups (p = 0.14). CONCLUSIONS: The therapeutic intervention rate did not decrease, even after the publication of the ARUBA trial. The rate of stroke or death was lower in the intervention group, indicating that a tailored choice of multimodality is safe and effective for managing unruptured bAVM.

[Changes in Gamma Knife Radiosurgery(GKRS)in Patients with Metastatic Brain Tumors before and after COVID-19].

The spread of coronavirus disease 2019(COVID-19)is a concern as it may delay the detection of malignant tumors due to delayed medical checkups. We examined changes in the treatment of metastatic brain tumors before and after COVID- 19. A retrospective review of 211 patients with metastatic brain tumors who underwent initial gamma knife radiosurgery between July 2019 and December 2021 was conducted. Data collected include patient age, gender, the Karnofsky performance status(KPS), primary tumor control, number, total volume, and outcome during the COVID-19 emergency declaration period and outside of it. The patient number was 164 outside of the emergency period and 47 during the period. Symptomatic cases(KPS<90)and poor control of the primary site increased during the COVID-19 period. The treatment number and volume of brain metastasis did not change. Metastatic control after 4 months of treatment also showed no difference. The number of symptomatic patients increased during the emergency declaration period, suggesting that COVID- 19 may have reduced the rate of asymptomatic patients being seen. However, these were not enough to affect the prognosis at 4 months. Overall, the COVID-19 pandemic had a small impact on the provision of stereotactic radiotherapy for metastatic brain tumors.

Hyperperfusion Syndrome Detected by 15O-Gas Positron Emission Tomography after Clipping of a Large Unruptured Internal Carotid Artery Aneurysm: A Case Report.

Cerebral hyperperfusion syndrome (CHS) after surgical clipping for cerebral aneurysm is a rare entity. The authors present a 76-year-old woman with a large left internal carotid-posterior communicating artery aneurysm. After successful clipping with temporary occlusion of the internal carotid artery, the patient exhibited motor aphasia. 15O-gas positron emission tomography (PET) showed extreme elevation of the regional cerebral blood flow (rCBF) along with a mildly decreased regional cerebral metabolic rate for oxygen (rCMRO2) and a remarkable decrease in the oxygen extraction fraction (OEF) in the territory of the ipsilateral superior trunk of the middle cerebral artery. These data indicated local hyperperfusion. She had fully recovered from the aphasia by postoperative day (POD) 18. PET showed normalization of CBF on POD 27. To our knowledge, this is the first case report to show hyperperfusion syndrome, clearly detected by 15O-gas PET, after aneurysmal neck clipping.

Gamma Knife Surgery for Residual or Recurrent Craniopharyngioma After Surgical Resection: A Multi-institutional Retrospective Study in Japan.

Objective The optimal treatment for a craniopharyngioma has been controversial. Complete resection is ideal, but it has been difficult to obtain total resection in many cases because of intimate proximity to critical structures such as the optic pathway, hypothalamus, and pituitary gland. A growing number of studies have demonstrated the utility of radiosurgery in controlling residual or recurrent craniopharyngioma. However, most of them are small series. The aim of this multi-institutional study was to clarify the efficacy and safety of Gamma Knife (Elekta, Stockholm, Sweden) surgery for patients with a craniopharyngioma. Methods This was a multi-institutional retrospective study by 16 medical centers of the Japan Leksell Gamma Knife Society. Data on patients with craniopharyngiomas treated with Gamma Knife Surgery (GKS) between 1991 and 2013 were obtained from individual institutional review board-approved databases at each center. A total of 242 patients with craniopharyngioma were included in this study. The mean age of the patients was 41 (range, 3 to 86) years. The median follow-up time was 61.4 months (range, 3 to 180 months). The mean radiosurgery target volume was 3.1 ml (range, 0.03-22.3 ml), and the mean marginal dose was 11.4 Gy (range, 8-20.4 Gy). Results Two-hundred twenty patients were alive at the time of the last follow-up visit. The three-, five-, and 10-year overall survival rates after GKS were 95.4%, 92.5%, and 82.0%, respectively. The three-, five-, and 10-year progression-free survival rates after GKS were 73.1%, 62.2%, and 42.6% respectively. The rate of radiation-induced complications was 6.2%. Conclusion GKS is effective for controlling the tumor growth of craniopharyngiomas with an acceptable complication rate.

[Analysis of Post-Recurrence Survival of Resected Lung Cancer with Brain Metastasis].

METHODS: We retrospectively evaluated the post-recurrence survival of 37 cases with brain metastases out of 439 consecutive resected cases of primary lung cancer between 2001 and 2017. FINDINGS: There was no difference in survival according to tumor size but survival was significantly shorter in patients with larger numbers of tumors. Patients initially treated with stereotactic radiosurgery(SRS)or surgical resection survived longer than those with whole-brain irradiation(WBI)(median survival: 23 months for SRS, 17 months for surgical resection, and 4 months for WBI: p<0.001 between SRS and WBI). CONCLUSIONS: As SRS is recommended for 1-4 tumors with maximum diameters ofC3 cm and surgical resection is recommended for tumors larger than 3 cm, these effective locoregional therapies should be aggressively adopted for local control of brain metastases with the aim of improved QOL and prolonged survival. Due to the deterioration of neurocognitive function, WBI should be avoided as initial treatment for brain metastases when effective locoregional therapy or systemic chemotherapy is available and reserved for leptomeningeal dissemination or miliary metastases.

Comparison of treatment results between 3- and 2-stage Gamma Knife radiosurgery for large brain metastases: a retrospective multi-institutional study.

OBJECTIVE: In order to obtain better local tumor control for large (i.e., > 3 cm in diameter or > 10 cm3 in volume) brain metastases (BMs), 3-stage and 2-stage Gamma Knife surgery (GKS) procedures, rather than a palliative dose of stereotactic radiosurgery, have been proposed. Here, authors conducted a retrospective multi-institutional study to compare treatment results between 3-stage and 2-stage GKS for large BMs. METHODS: This retrospective multi-institutional study involved 335 patients from 19 Gamma Knife facilities in Japan. Major inclusion criteria were 1) newly diagnosed BMs, 2) largest tumor volume of 10.0-33.5 cm3, 3) cumulative intracranial tumor volume ≤ 50 cm3, 4) no leptomeningeal dissemination, 5) no more than 10 tumors, and 6) Karnofsky Performance Status 70% or better. Prescription doses were restricted to between 9.0 and 11.0 Gy in 3-stage GKS and between 11.8 and 14.2 Gy in 2-stage GKS. The total treatment interval had to be within 6 weeks, with at least 12 days between procedures. There were 114 cases in the 3-stage group and 221 in the 2-stage group. Because of the disproportion in patient numbers and the pre-GKS clinical factors between these two GKS groups, a case-matched study was performed using the propensity score matching method. Ultimately, 212 patients (106 from each group) were selected for the case-matched study. Overall survival, tumor progression, neurological death, and radiation-related adverse events were analyzed. RESULTS: In the case-matched cohort, post-GKS median survival time tended to be longer in the 3-stage group (15.9 months) than in the 2-stage group (11.7 months), but the difference was not statistically significant (p = 0.65). The cumulative incidences of tumor progression (21.6% vs 16.7% at 1 year, p = 0.31), neurological death (5.1% vs 6.0% at 1 year, p = 0.58), or serious radiation-related adverse events (3.0% vs 4.0% at 1 year, p = 0.49) did not differ significantly. CONCLUSIONS: This retrospective multi-institutional study showed no differences between 3-stage and 2-stage GKS in terms of overall survival, tumor progression, neurological death, and radiation-related adverse events. Both 3-stage and 2-stage GKS performed according to the aforementioned protocols are good treatment options in selected patients with large BMs.

Neurosurgical Management and Outcomes of Cerebrovascular Disease in Pediatric Patients with Heart Disease.

Antithrombotic treatment has substantial risks, even in pediatric patients. We retrospectively evaluated the management and outcomes of consecutive pediatric patients who underwent neurosurgical treatment for cerebrovascular disease with cardiovascular disease between 1998 and 2017. Patients were divided into patients with comorbid cardiovascular disease (group I); and patients with cardiovascular disease as a primary disease of intracranial complication, without (group IIa) or with (group IIb) extracorporeal circulations. Postoperative resumption of antithrombotic agents was generally initiated within 48 h. Our study included 26 patients; five were categorized as group I, 15 as group IIa, and six as group IIb. All intracranial diseases in groups IIa and IIb were exclusively hemorrhagic. Preoperative anticoagulation therapy was used in one patient (20%) in group I, 13 patients (86.7%) in group IIa, and six patients (100%) in group IIb. Postoperative intracranial hemorrhagic events were observed in one patient (20%) in group I, three patients (20%) in group IIa, and four patients (66.7%) in group IIb. Re-operations were conducted in two (13.3%) and three patients (50%) in groups IIa and IIb, respectively. Death occurred in five (33.3%) and four patients (66.7%) in groups IIa and IIb, respectively. The remaining two patients in group IIb returned to candidate status for implantation. Emergent surgery for patients with intracranial hemorrhage associated with cardiovascular disease has a high risk of postoperative hemorrhagic events and high rate of re-operations with poor vital outcomes, especially in patients with extracorporeal circulations. We should consider maximum neurosurgical treatment achievable with optimal management of antithrombotic treatment.

Treatment Results of Gamma Knife Radiosurgery for Central Neurocytoma: Report of a Japanese Multi-Institutional Cooperative Study.

OBJECTIVE: Central neurocytoma (CN) is a rare benign neuronal tumor, and a limited number of reports have described the usefulness of radiosurgery for a relatively large group of patients. We evaluated the effectiveness and outcomes of Gamma Knife radiosurgery (GKS) for CN in a Japanese multi-institutional study. METHODS: We performed retrospective analysis of 36 patients with CN who were treated with GKS in 12 institutes in Japan. All patients underwent surgery before GKS. The median tumor volume at GKS was 4.9 mL (range, 0.07-23.4 mL), and the median radiation dose prescribed to the tumor margin was 15 Gy (range, 10-20 Gy). The median follow-up period was 54.5 months (range, 3-180 months). RESULTS: The local tumor progression-free survival rates at 5 and 10 years were 94% and 86%, respectively. Three patients developed distant dissemination 16-90 months later. Overall progression-free survival was unrelated to the prescribed dose (<15 Gy vs. ≥15 Gy, P = 0.62), tumor size (<6 mL vs. ≥6 mL, P = 0.46), gender (P = 0.36), age (<30 vs. ≥30 years, P = 0.37), target of GKS (residual vs. recurrence, P = 0.90), and type of enhancement (homogeneous vs. inhomogeneous, P = 0.19). Two permanent complications occurred with 1 intratumoral hemorrhage and 1 radiation injury. CONCLUSIONS: GKS is effective for CN because of its high rate of long-term local tumor control. GKS may have a potential role as a primary treatment for asymptomatic, relatively small tumors in the absence of hydrocephalus without surgical resection.

Estrogen in the medial preoptic nucleus of the hypothalamus modulates cold responses in female rats.

The present study examined the effect of the central administration of estrogen on responses to the cold. Estrogen or cholesterol was applied locally to the medial preoptic nucleus (MPO) or dorsomedial hypothalamic nucleus (DMH) of the hypothalamus in free-moving ovariectomized rats. Forty-eight hours after the application, rats had 2-h exposure at 10 or 25 degrees C. Body temperature (T(b)) and the tail surface temperature (T(tail)) were continuously measured by telemetry and thermography, respectively. The change of T(b) at 10 degrees C from the 25 degrees C baseline was higher in the estrogen application in the MPO than that in the cholesterol application; however, such difference was not observed in the DMH application. The uncoupling 1 protein mRNA level in the interscapular brown adipose tissue involved in non-shivering thermogenesis was not different between the estrogen and cholesterol applications in the MPO and DMH. T(tail) decreased in the cold, which was greater after the estrogen application in the MPO than after the cholesterol application. These results show that estrogen affects the MPO in female rats, changing T(b) in the cold. Moreover, suppression of heat loss from the tail may be involved in the mechanism.

[Two cases of lung cancer patients with postoperative brain metastases obtaining long-term survival after gamma knife radiosurgery].

We report two cases of lung cancer patients with postoperative solitary brain metastases obtaining long-term survival after gamma knife stereotactic radiosurgery. Both were seventies men and had good performance status without active extracranial disease. In one case, an asymptomatic metastatic brain tumor 1.8 cm in maximum diameter appeared one year and two months after the operation and was irradiated with gamma knife resulting in complete local control for seven years. He is alive with solitary lung metastasis in good performance status. In the other case, gamma knife was employed for a metastatic brain tumor 2.7 cm in maximum diameter that appeared nine months after the operation accompanying incomplete left hemiplegia. Six months later, the tumor was enlarged and gamma knife was repeated, but the tumor growth could not be suppressed. Following deterioration of hemiplegia and appearance of convulsion, he died of neurological disorder three years and two months after the onset of brain metastasis. Gamma knife stereotactic radiosurgery for metastatic brain tumors is less invasive and a repeatable technique, and is expected to provide a good local control and a survival benefit for appropriately selected patients.

[Therapeutic strategy for isolated dissecting aneurysms of the posterior inferior cerebellar artery: report of three cases and review of literature].

Dissecting aneurysm of the posterior inferior cerebellar artery (PICA) is a relatively rare disease and its treatment has not been well established. The authors analyzed the clinical and anatomical features of 38 reported lesions and three of our cases to clarify the "best therapeutic modality". The average age was 45.0 years old and 27 patients were male. Left-sided predominance (26 cases) was noted. As to the mode of onset, 23 cases were subarachnoid hemorrhage, 16 were ischemia, and 6 were Wallenberg's syndrome. Anatomically, the sites of dissection were located in the proximal segment of PICA in 31 lesions (75.6%). Review of the cases show that 30 (75%) patients underwent surgical therapy, and 7 (17.5%) patients underwent endovascular treatment. Twenty six patients who took surgical therapy and 5 patients who took endovascular treatment had excellent or good outcome. The critical point in therapeutic procedure is the preservation of perforating branches arising from PICA, therefore surgical trapping with the revascularization of PICA (usually extracranial-PICA anastomosis), in which these tiny branches are secured under microscopic manipulation, has the advantage in principle.

A dyad symmetry element in the fibroblast growth factor-2 gene promoter with different levels of activity in astrocytoma and hepatocelluar carcinoma cell lines.

Fibroblast growth factor-2 (FGF-2) gene expression is reported to be spatially and temporally regulated in the process of development, normal growth, and wound healing. We postulated that its constitutive expression in human malignant astrocytoma cells is due to loss of function of the regulatory mechanism of FGF-2 gene expression. Here, we report the characterization of a unique element in the FGF-2 gene promoter. We investigated the transcriptional regulation of the FGF-2 gene in a human malignant astrocytoma (U87MG) and a human hepatocellular carcinoma (HepG2) cell line. We found that a dyad symmetry element (DSE) in the FGF-2 gene promoter exhibited different promoter activities; in HepG2 cells it did, while in U87MG cells it did not, exhibit repressive activity. Examination of the relative promoter activities of the DSE in a thymidine kinase promoter revealed it exerted different activities, just as it did in the 2 cell lines studied. Gel shift assay demonstrated that 2 proteins bound to the DSE in nuclear extracts from HepG2 cells and that one protein was missing in nuclear extracts from U87MG cells. These results suggest that the DSE has a crucial role as a transcriptional regulatory element of FGF-2 gene expression.

Effects of combination chemotherapy with biscoclaurine-derived alkaloid (Cepharanthine) and nimustine hydrochloride on malignant glioma cell lines.

In the treatment of malignant glioma, chemotherapy plays a critical role as do surgical resection and irradiation. Cepharanthine (CEP), a biscoclaurine-derived alkaloid, reportedly potentiates the effects of antitumor agents and induces apoptosis in some cancer cells. Here, we examined the effects of CEP, alone and in combination with nimustine hydrochloride (ACNU), on the in vitro proliferation of malignant glioma cells. The cell lines used were U87MG, U251MG, and T98G. At concentrations from 1 to 10 microg/ml, CEP-promoted cell proliferation somewhat; growth inhibition was noted at concentrations of 15 microg/ml and higher. Phase-contrast microscopy showed that cells tended to detach from the culture dishes and that cell density became sparse at the higher concentrations. DAPI fluorescence nuclear staining revealed condensation and fragmentation of nuclei, indicating the induction of apoptosis. To examine the cascade of apoptosis, the caspase inhibitors YVAD and DEVD were added. They inhibited CEP-induced apoptosis in U251MG cells (a p53-mutant cell line), but not in U87MG cells (a p53 wild-type cell line), suggesting that in CEP-induced apoptosis two possible cascades are in play. In combination with ACNU, the effects of the higher concentrations of CEP were enhanced.