Nonconvulsive status epilepticus in patients with acute subarachnoid hemorrhage is associated with negative arterial spin labeling on peri-ictal magnetic resonance images.

Purpose: Non-convulsive status epilepticus (NCSE) is characterized by repetitive or continuous seizures without convulsions. Arterial spin labeling (ASL) is useful for assessing hyperperfusion due to neurovascular unit coupling in patients with NCSE; subarachnoid hemorrhage (SAH) impairs the neurovascular unit. We hypothesized that the sensitivity of ASL in detecting NCSE is low in patients with SAH during the acute phase. Methods: Based on ASL findings obtained within 48 h after the clinical suspicion of focal-onset NCSE, we divided 34 patients into ASL-negative (no hyperperfusion; n = 10) and ASL-positive (confirmed hyperperfusion; n = 24) groups. We further divided the two groups according to the NCSE etiology: patients who were diagnosed with NCSE within 14 days after SAH onset (acute SAH, n = 11) and patients with NCSE due to factors other acute SAH (n = 23) and compared their characteristics. Results: In 10 of the 34 patients (29.4 %) the ASL findings were normal. The rate of acute SAH was significantly higher in ASL-negative- (n = 8, 80.0 %) than ASL-positive patients (n = 3, 12.5 %). The rate of patients in aphasic status was significantly lower in ASL-negative patients (n = 1, 10 %) than in ASL-positive patients (n = 12, 50.0 %). Conclusion: Normal ASL findings alone should not be used to exclude a diagnosis of NCSE particularly in patients in the acute phase of SAH with deterioration or no improvement in consciousness.

Development of a Navigation-guided Fence-post Catheter for Brain Tumor Resection.

BACKGROUND: Navigation system devices have been developed to allow precise resection of brain tumor. The fence-post catheter techniques that use a navigation system have been used in many neurosurgery centers. However, an exclusive catheter for the fence-post catheter techniques have not been made, and substituted silicon tube of the cerebral ventricle drainage or a Nelaton catheter is widely used. OBJECTIVE: In this brief technical note, we describe a new fence-post catheter with steel tip device that was designed for more precise tissue resection and is useful in tumor resection. METHODS: The newly designed fence-post catheter helps to visually gauge the accurate depth from the tumor bottom during tumor resection. Furthermore, the catheter tip has moderate weight and is made of a non-magnetic material. RESULTS: Using our fence-post catheter, which has a metal part at the tip of the tube (length, 13 mm), operators can clearly notice that they are getting closer to base of the tumor by checking the metal part during the resection of deep tumors. CONCLUSION: Our newly developed fence-post tube enables easy confirmation of the distance to deep-tissue regions and improves the degree of safety during tumor removal. J. Med. Invest. 69 : 117-119, February, 2022.

Seizure types associated with negative arterial spin labeling and positive diffusion-weighted imaging on peri-ictal magnetic resonance imaging.

PURPOSE: Arterial spin labeling (ASL) and diffusion-weighted imaging (DWI) are useful for assessing hyperperfusion and cytotoxic edema, respectively, caused by acute seizures. This study investigated the clinical characteristics associated with normal ASL findings and DWI abnormalities in patients with acute seizures. METHODS: Overall, 41 patients with ASL and DWI images that were obtained within 48 h of focal onset seizure diagnosis, due to epilepsy or acute symptomatic seizures, were divided into groups based on initial ASL findings (ASL-negative vs. ASL-positive), and DWI abnormalities (DWI-negative vs. DWI-positive). The diagnosis was made based on seizure semiology, electroencephalography, and conventional imaging modalities. ASL and DWI abnormalities were based on visual assessment. RESULTS: Of the 41 patients, eight (19.5%) displayed normal ASL findings. The proportion of patients with focal aware seizures (FAS) was significantly higher among ASL-negative patients (62.5%) than that in ASL-positive patients (15.2%); the proportion of patients with focal impaired awareness seizures (FIAS) was significantly lower among ASL-negative patients (12.5%) than that among ASL-positive patients (57.6%). Hyperintensity findings on DWI were observed in 12 patients (29.3%, DWI-positive). The proportion of patients with FIAS was significantly higher among DWI-positive patients (75.0%) than that among DWI-negative patients (37.9%). Multivariate analysis revealed that FAS and FIAS were associated with normal ASL findings (odds ratio [OR]: 21.37, P = 0.010) and DWI abnormalities (OR = 6.11, P = 0.028). CONCLUSION: A diagnosis of seizures should not be excluded based on normal ASL findings, especially in patients with FAS. FIAS may be a risk factor for neuronal damage caused by seizure activity.

Continued-Maintenance Therapy with High-dose Methotrexate Improves Overall Survival of Patients with Primary Central Nervous System Lymphoma.

BACKGROUND: PCNSL is mainly treated with HD-MTX-based chemotherapy with or without WBRT. However, As WBRT is associated with delayed neurotoxicity leading to dementia in the elderly, many institutes reported benefits of intensive chemotherapy or high-dose chemotherapy with ASCT. We investigated whether treatment with HD-MTX and rituximab, followed by continued-maintenance HD-MTX monotherapy (3.5g / m2), improves overall survival (OS). METHODS: In this retrospective, single-center trial 52 immunocompetent patients with newly diagnosed PCNSL were included. All were treated between January 2005 and December 2017. The controls were 18 patients who, between 2005 and 2011, had received 3 cycles of HD-MTX and then adjuvant treatment with WBRT. In 2011 we started HD-MTX continued-maintenance therapy to treat 34 PCNSL patients. In the induction phase, these patients received HD-MTX every 14 days until a complete response (CR) was observed. When CR was obtained, maintenance therapy with HD-MTX (3.5g / m2) was delivered every three months. RESULTS: In 3-year overall survival (OS) there was a statistically significant difference between the two groups [controls : 33.1% (95%, CI 12.4 - 55.7%) ; maintenance group : 74.9% (95%, CI 55.6 - 86.7%) (p < 0.02)]. Conclusion : The induction of HD-MTX based chemotherapy followed by continued-maintenance HD-MTX monotherapy improved OS compared with chemoradiotherapy consisting of HD-MTX followed by WBRT. J. Med. Invest. 68 : 286-291, August, 2021.

Elevated cellular PpIX potentiates sonodynamic therapy in a mouse glioma stem cell-bearing glioma model by downregulating the Akt/NF-κB/MDR1 pathway.

Glioblastoma (GBM) has high mortality rates because of extreme therapeutic resistance. During surgical resection for GBM, 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is conventionally applied to distinguish GBM. However, surgical intervention is insufficient for high invasive GBM. Sonodynamic therapy (SDT) combined with low-intensity ultrasonication (US) and PpIX, as a sonosensitizer, is an emerging and promising approach, although its efficacy is limited. Based on our previous study that down-regulation of multidrug resistant protein (MDR1) in GBM augmented the anti-tumor effects of chemotherapy, we hypothesized that elevation of cellular PpIX levels by down-regulation of MDR1 enhances anti-tumor effects by SDT. In high invasive progeny cells from mouse glioma stem cells (GSCs) and a GSC-bearing mouse glioma model, we assessed the anti-tumor effects of SDT with a COX-2 inhibitor, celecoxib. Down-regulation of MDR1 by celecoxib increased cellular PpIX levels, as well as valspodar, an MDR1 inhibitor, and augmented anti-tumor effects of SDT. MDR1 down-regulation via the Akt/NF-κB pathway by celecoxib was confirmed, using an NF-κB inhibitor, CAPÉ. Thus, elevation of cellar PpIX by down-regulation of MDR1 via the Akt/NF-κB pathway may be crucial to potentiate the efficacy of SDT in a site-directed manner and provide a promising new therapeutic strategy for GBM.

Efficacy of Intra-arterial Indocyanine Green Videoangiography in Hemangioblastoma Surgery: A Case Report.

Intravenous indocyanine green (ICG) videoangiography is reportedly useful for vascular neurosurgery, and for treating hemangioblastoma due to its high vascularity. Videoangiography obtained after intra-arterial ICG injection has emerged as a more useful option than that after intravenous injection. This report offers the first description of a case of hemangioblastoma successfully treated using intra-arterial ICG videoangiography, and describes the efficacy of this technique. A 20-year-old man presented with progressive cerebellar ataxia and dysphagia. Magnetic resonance imaging (MRI) revealed an enhanced solid tumor in the medulla oblongata. Digital subtraction angiography (DSA) showed a highly vascularized tumor. Surgery was performed to remove the tumor in a hybrid operating room. A catheter was introduced into the vertebral artery (VA) for intra-arterial ICG videoangiography. Superficial feeders and drainers were identified and flow dynamic changes in the tumor were assessed by intra-arterial ICG videoangiography. The tumor was removed after confirming lack of flow in the drainer. Intra-arterial ICG videoangiography was more useful than intravenous ICG videoangiography in hemangioblastoma surgery for identifying feeders and drainers and assessing flow dynamics in the tumor. Use of Flow 800 made these findings simpler and easier to evaluate.

Basic research and surgical techniques for brain arteriovenous malformations.

Arteriovenous malformations (AVMs) are hemorrhagic vascular diseases in which arteries and veins are directly connected with no capillary bed between the two. We herein introduce the results of basic research of this disease and surgical techniques based on our data and experiences. The results obtained from our research show that cell death- and inflammation-related molecules changed or became activated compared with control specimens. These findings indicate that chronic inflammation occurs in and around the nidus of AVMs. Various molecules are involved in the mechanisms of cell death and angiogenesis during this process. Confirmation of blood flow in the nidus is very important to avoid hemorrhagic complications during surgical removal of the nidus. The risk of hemorrhage increases when the blood flow in the nidus is not reduced. We reported the advantages of serial indocyanine green videoangiography, which is used to assess the blood flow during AVM nidus removal. Since publication of the ARUBA trial and Scottish Audit, treatments with high morbidity have not been allowed. It is especially important for neurosurgeons to treat low Spetzler-Martin grade AVMs with low morbidity. J. Med. Invest. 67 : 222-228, August, 2020.

Downregulation of the CCL2/CCR2 and CXCL10/CXCR3 axes contributes to antitumor effects in a mouse model of malignant glioma.

Glioblastoma multiforme involves glioma stem cells (GSCs) that are resistant to various therapeutic approaches. Here, we studied the importance of paracrine signaling in the glioma microenvironment by focusing on the celecoxib-mediated role of chemokines C-C motif ligand 2 (CCL2), C-X-C ligand 10 (CXCL10), and their receptors, CCR2 and CXCR3, in GSCs and a GSC-bearing malignant glioma model. C57BL/6 mice were injected with orthotopic GSCs intracranially and divided into groups administered either 10 or 30 mg/kg celecoxib, or saline to examine the antitumor effects associated with chemokine expression. In GSCs, we analyzed cell viability and expression of chemokines and their receptors in the presence/absence of celecoxib. In the malignant glioma model, celecoxib exhibited antitumor effects in a dose dependent manner and decreased protein and mRNA levels of Ccl2 and CxcL10 and Cxcr3 but not of Ccr2. CCL2 and CXCL10 co-localized with Nestin+ stem cells, CD16+ or CD163+ macrophages and Iba-1+ microglia. In GSCs, celecoxib inhibited Ccl2 and Cxcr3 expression in a nuclear factor-kappa B-dependent manner but not Ccr2 and CxcL10. Moreover, Ccl2 silencing resulted in decreased GSC viability. These results suggest that celecoxib-mediated regulation of the CCL2/CCR2 and CXCL10/ CXCR3 axes may partially contribute to glioma-specific antitumor effects.

Downregulation of PD-L1 via FKBP5 by celecoxib augments antitumor effects of PD-1 blockade in a malignant glioma model.

BACKGROUND: Antitumor therapies targeting programmed cell death-1 (PD-1) or its ligand-1 (PD-L1) are used in various cancers. However, in glioblastoma (GBM), the expression of PD-L1 varies between patients, and the relationship between this variation and the efficacy of anti-PD-1 antibody therapy remains unclear. High expression levels of PD-L1 affect the proliferation and invasiveness of GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested the hypothesis that the COX-2 inhibitor celecoxib potentiates anti-PD-1 antibody treatment via the downregulation of PD-L1. METHODS: Six-week-old male C57BL/6 mice injected with murine glioma stem cells (GSCs) were randomly divided into four groups treated with vehicle, celecoxib, anti-PD-1 antibody, or celecoxib plus anti-PD-1 antibody and the antitumor effects of these treatments were assessed. To verify the mechanisms underlying these effects, murine GSCs and human GBM cells were studied in vitro. RESULTS: Compared with that with each single treatment, the combination of celecoxib and anti-PD-1 antibody treatment significantly decreased tumor volume and prolonged survival. The high expression of PD-L1 was decreased by celecoxib in the glioma model injected with murine GSCs, cultured murine GSCs, and cultured human GBM cells. This reduction was associated with post-transcriptional regulation of the co-chaperone FK506-binding protein 5 (FKBP5). CONCLUSIONS: Combination therapy with anti-PD-1 antibody plus celecoxib might be a promising therapeutic strategy to target PD-L1 in glioblastoma. The downregulation of highly-expressed PD-L1 via FKBP5, induced by celecoxib, could play a role in its antitumor effects.

The risk of hemorrhage in stereotactic biopsy for brain tumors.

Objective : One major complication associated with STB is intratumoral hematoma, which is also the most common cause of morbidity related to permanent paralysis and mortality in STB. The risk of perioperative hemorrhage is generally between 1% and 10%, but this could be an underestimation since it is not common for many neurosurgeons to perform CT scans after uncomplicated STBs. In this study, we describe the incidence of cerebral hemorrhage, including asymptomatic cerebral hemorrhage. Methods : We recently reviewed data on the diagnosis rate and occurrence of complications, including symptomatic and asymptomatic cerebral hemorrhage, in 80 patients who underwent STB at our facility between 2005 and 2014. Results : Histological diagnosis was established for 75 cases (93.8%), glioma was the most frequently encountered tumor. Symptomatic hemorrhage was observed in two cases (2.6%), with the symptoms subsiding within two days. The morbidity and mortality rate was 0%. However, asymptomatic hemorrhages were observed in 23 cases (28.8%). Conclusion : Stereotactic biopsy is a less invasive procedure for obtaining samples of brain tumors for diagnosis. The bleeding of the tissue-resection cavity that includes asymptomatic hemorrhage occurs at a constant rate. It is important to reduce the symptomatic bleeding associated with stereotactic biopsy. J. Med. Invest. 66 : 314-318, August, 2019.

Metastatic tumor to the orbital cavity from a primary carcinoma of the uterine cervix†:†a case report.

Metastatic tumors to the orbit of the eye, especially from primary carcinomas of the uterine cervix are very rare. A 64-year-old woman with a history of carcinoma of the uterine cervix presented with right eye pain and blepharoptosis for 2 weeks. Magnetic resonance imaging revealed a mass at the right orbital apex. Surgical extirpation was performed due to severe pain. Postoperative pathology demonstrated a poorly differentiated squamous cell carcinoma. The origin was ultimately considered to be the carcinoma of the uterine cervix. In conclusion, this report describes a rare case of a metastatic tumor at the orbital apex derived from the cervix of the uterus. J. Med. Invest. 66 : 355-357, August, 2019.

Down-regulation of MDR1 by Ad-DKK3 via Akt/NFκB pathways augments the anti-tumor effect of temozolomide in glioblastoma cells and a murine xenograft model.

BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant of brain tumors. Acquired drug resistance is a major obstacle for successful treatment. Earlier studies reported that expression of the multiple drug resistance gene (MDR1) is regulated by YB-1 or NFκB via the JNK/c-Jun or Akt pathway. Over-expression of the Dickkopf (DKK) family member DKK3 by an adenovirus vector carrying DKK3 (Ad-DKK3) exerted anti-tumor effects and led to the activation of the JNK/c-Jun pathway. We investigated whether Ad-DKK3 augments the anti-tumor effect of temozolomide (TMZ) via the regulation of MDR1. METHODS: GBM cells (U87MG and U251MG), primary TGB105 cells, and mice xenografted with U87MG cells were treated with Ad-DKK3 or TMZ alone or in combination. RESULTS: Ad-DKK3 augmentation of the anti-tumor effects of TMZ was associated with reduced MDR1 expression in both in vivo and in vitro studies. The survival of Ad-DKK3-treated U87MG cells was inhibited and the expression of MDR1 was reduced. This was associated with the inhibition of Akt/NFκB but not of YB-1 via the JNK/c-Jun- or Akt pathway. CONCLUSIONS: Our results suggest that Ad-DKK3 regulates the expression of MDR1 via Akt/NFκB pathways and that it augments the anti-tumor effects of TMZ in GBM cells.

Blocking COX-2 induces apoptosis and inhibits cell proliferation via the Akt/survivin- and Akt/ID3 pathway in low-grade-glioma.

Approximately half of surgically-treated patients with low-grade-glioma (LGG) suffer recurrence or metastasis. Currently there is no effective drug treatment. While the selective COX-2 inhibitor celecoxib showed anti-neoplastic activity against several malignant tumors, its effects against LGG remain to be elucidated. Ours is the first report that the expression level of COX-2 in brain tissue samples from patients with LGG and in LGG cell lines is higher than in the non-neoplastic region and in normal brain cells. We found that celecoxib attenuated LGG cell proliferation in a dose-dependent manner. It inhibited the generation of prostaglandin E2 and induced apoptosis and cell-cycle arrest. We also show that celecoxib hampered the activation of the Akt/survivin- and the Akt/ID3 pathway in LGGs. These findings suggest that celecoxib may have a promising therapeutic potential and that the early treatment of LGG patients with the drug may be beneficial.

Blocking of the interaction between Wnt proteins and their co-receptors contributes to the anti-tumor effects of adenovirus-mediated DKK3 in glioblastoma.

The effect of the third member of the Dickkopf family (DKK3) in the Wnt pathway in glioblastoma remains unclear. We first demonstrated the non-specific interaction of Wnt3a and Wnt5a with the receptors LRP6 and ROR2 and the up-regulation of the Wnt pathway in glioblastoma cells. We used an adenovirus vector and found that an increase in DKK3 protein attenuated the expression of Wnt3a, Wnt5a and LRP6, but not of ROR2, and their interaction, thereby affecting both canonical- and non-canonical Wnt downstream cascades. This produced anti-tumor effects in GBM xenograft models. The suppression of Wnt pathways upstream by DKK3 may have promise for the treatment of glioblastoma.

Ruptured distal accessory anterior cerebral artery aneurysm--case report.

A 48-year-old man presented with an extremely rare aneurysm arising from an accessory anterior cerebral artery (ACA) manifesting as sudden onset of headache lasting for 5 days. Neurological examination on admission revealed no abnormalities. Computed tomography showed subarachnoid hemorrhage of the interhemispheric fissure and intraparenchymal hematoma of the left cingulate gyrus. Magnetic resonance and cerebral angiography revealed a saccular aneurysm of the distal portion of the accessory ACA classified as the bihemispheric type. Neck clipping of the aneurysm was performed via an interhemispheric approach 17 days after symptom onset. The patient made a good postoperative recovery without neurological deficit. Distal accessory ACA aneurysms tend to arise from the first bifurcation and supply parietal branches. The aneurysms tend to occur on the bihemispheric type of distal accessory ACA. Hemodynamic stress may contribute to formation or development of these aneurysms.