Effectiveness of Keyhole Clipping of Unruptured Intracranial Aneurysms Detected by "Brain Dock" in Healthy Japanese Adults.

In Japan, brain docking has enhanced the detection of unruptured intracranial aneurysms in healthy adults. At our institution, surgical clipping is the first-line treatment for unruptured intracranial aneurysms (UIA). In this study, the differences in neurological and radiological outcomes, as well as cognitive and psychological results, between standard clipping and keyhole clipping for these aneurysms detected via brain docking were evaluated. The study included 131 aneurysms detected via "brain dock." Of these, 65 were treated with keyhole clipping surgery (keyhole clipping group), and 66 were treated with standard clipping surgery (standard clipping group). Evaluations at 3 months included the National Institutes of Health Stroke Scale, modified Rankin Scale, Mini-Mental State Examination, Hasegawa's Dementia Scale-revised, Beck Depression Inventory, Hamilton Rating Scale for Depression, and radiological abnormalities. The mean operative time and postoperative hospitalization period were significantly shorter in the keyhole clipping group than in the standard clipping group (p < 0.001). Between the groups, no significant differences in postoperative neurological complications or radiological abnormalities were found. The keyhole clipping group demonstrated slightly but significantly better Beck Depression Inventory and Hamilton Rating Scale for Depression scores than the standard clipping group (Beck Depression Inventory, p = 0.046; Hamilton Rating Scale for Depression, p < 0.01). Both the Beck Depression Inventory and Hamilton Rating Scale for Depression scores at 3 months were significantly enhanced (p < 0.001) in the keyhole clipping group. These findings propose that keyhole clipping could be considered a new therapeutic option for small UIA detected via brain docking.

Carotid Artery Stenting via Radial Access with Modified Flow Reversal Method: Case Series.

OBJECTIVE: Neuroendovascular treatment via transradial access (TRA) has gained popularity as a minimally invasive technique. However, the flow reversal (FR) system, reported useful in carotid artery stenting (CAS), cannot be applied via TRA because it requires an access route of more than 8 F. Herein, we report the utility of a modified FR system applied via TRA using a sheathless 8-F balloon guide catheter and a 2.6-F balloon catheter. METHODS: In a retrospective analysis of a single-center consecutive case series, patients with CAS and vulnerable plaques who were treated with CAS via TRA using a modified FR system from June 2022 to August 2022 were examined. High-intensity spots were assessed on postprocedural diffusion-weighted magnetic resonance images. Puncture site complications at discharge and cardiovascular events for 1 year after CAS were also evaluated. RESULTS: Ten patients were included in this study. There were no high-intensity spots on diffusion-weighted magnetic resonance images after CAS. No procedure-related complications, including radial artery occlusion or cardiovascular events, were observed. CONCLUSIONS: This study suggests that CAS with FR using our modified system is feasible via TRA and may be an effective technique with a low rate of vascular complications.

Hyperbaric hydrogen therapy improves secondary brain injury after head trauma.

Background: The pathophysiology of traumatic brain injury (TBI) is caused by the initial physical damage and by the subsequent biochemical damage (secondary brain injury). Oxidative stress is deeply involved in secondary brain injury, so molecular hydrogen therapy may be effective for TBI. Hydrogen gas shows the optimal effect at concentrations of 2% or higher, but can only be used up to 1.3% in the form of a gas cylinder mixed with oxygen gas, which may not be sufficiently effective. The partial pressure of hydrogen increases in proportion to the pressure, so hyperbaric hydrogen therapy (HBH2) is more effective than that at atmospheric pressure. Methods: A total of 120 mice were divided into three groups: TBI + non-treatment group (TBI group; n = 40), TBI + HBH2 group (n = 40), and non-TBI + non-treatment group (sham group; n = 40). The TBI and TBI + HBH2 groups were subjected to moderate cerebral contusion induced by controlled cortical impact. The TBI + HBH2 group received hyperbaric hydrogen therapy at 2 atmospheres for 90 minutes, at 30 minutes after TBI. Brain edema, neuronal cell loss in the injured hippocampus, neurological function, and cognitive function were evaluated. Results: The TBI + HBH2 group showed significantly less cerebral edema (p ≺ 0.05). Residual hippocampal neurons were significantly more numerous in the TBI + HBH2 group on day 28 (p ≺ 0.05). Neurological score and behavioral tests showed that the TBI + HBH2 group had significantly reduced hyperactivity on day 14 (p ≺ 0.01). Conclusion: Hyperbaric hydrogen therapy may be effective for posttraumatic secondary brain injury.

Validation of Efficacy and Safety of TachoSil ® Tissue Sealant for Vessel Transposition in Microvascular Decompression.

BACKGROUND AND OBJECTIVES: Use of TachoSil ® as the transposition material of microvascular decompression (MVD) for hemifacial spasm (HFS) and trigeminal neuralgia (TN) is easy and safe to perform, but the efficacy and safety of this technique are unknown. This study attempted to validate the efficacy and safety of TachoSil ® as a transposition material of MVD. METHODS: A retrospective study of the surgical results and complications of 63 patients (35 HFS and 28 TN) treated by the TachoSil ® technique between January 2011 and December 2021 was conducted. The efficacy of the treatment was evaluated by Kaplan-Meier survival analysis. Magnetic resonance imaging follow-up study was performed to detect any adverse events including a mass formation. RESULTS: The rate of complete disappearance of HFS was 91.4% at 1 year and estimated to be 85.7% after a 10-year follow-up. The rate of no pain without medication for TN was 85.4% at 1 year and estimated to be 69.0% after a 9-year follow-up. These surgical results are comparable with those previously reported. Flaking of TachoSil ® releasing the offending artery was only recognized in one case (1.6%). Therefore, TachoSil ® can be considered as an effective transposition material for MVD. TachoSil ® did not increase the rate of acute and subacute adverse events such as inflammation and delayed facial palsy. Magnetic resonance imaging follow-up identified no abnormalities including mass that suggested granuloma formation. CONCLUSION: The efficacy of the TachoSil ® technique for HFS and TN and the reliability of TachoSil ® as an adhesive material in MVD were verified. No adverse events associated with TachoSil ® use in MVD were found. We conclude that the TachoSil ® technique has relatively long efficacy and safety for MVD.

Cadaver investigation of the usefulness of the transstyloid diaphragm approach for high-position plaque carotid endarterectomy.

OBJECTIVES: Patients sometimes present with high cervical internal carotid artery (ICA) stenosis. This study demonstrates the usefulness of the transstyloid approach to expose the distal ICA by dissection of the styloid diaphragm covering the distal cervical ICA for carotid endarterectomy (CEA). In particular, the possible exposure length achieved by this approach was investigated using cadaveric heads. METHODS: The procedure of the transstyloid diaphragm approach was confirmed in 10 cadaveric heads (20 sides). After the carotid triangle was opened, both the posterior belly of the digastric muscle (PBDM) and the stylohyoid muscle could be divided. Then, the carotid sheath was dissected, and the glossopharyngeal nerve was identified crossing over the distal ICA. The revealed length of the ICA was measured with or without dissection of both the PBDM and the stylohyoid muscle. The specimens were dissected under the surgical microscope. RESULTS: The transstyloid diaphragm approach was achieved successfully in all specimens. The revealed lengths of the ICA with and without dissection of the styloid diaphragm were 53.7 ± 5.9 mm and 38.8 ± 2.9 mm (mean ± standard deviation), respectively. Therefore, the revealed length of the distal ICA was 14.9 ± 4.5 mm greater using the transstyloid diaphragm approach compared to the regular CEA approach. CONCLUSIONS: More of the ICA can be revealed by dissection of both the PBDM and the stylohyoid muscle. The transstyloid diaphragm approach might be helpful to reveal the distal ICA in cases of high cervical ICA stenosis.

The Short-Term Outcome of Middle Meningeal Artery Embolization for Chronic Subdural Hematoma with Mild Symptom: Case Series.

OBJECTIVE: A few reports have demonstrated the efficacy of middle meningeal artery embolization (MMAE) alone for mildly symptomatic chronic subdural hematoma (CSDH); however, the clinical course in the early posttreatment period remains unclear. The purpose of this study was to analyze the short-term outcomes of this technique at our center. METHODS: This study was based on a retrospective analysis of a single-center consecutive case series. Patients with mildly symptomatic CSDH treated with MMAE alone between July 2020 and June 2022 were examined. Neurological examinations and head computed tomography scans were performed before treatment and 1, 7, 14, and 28 days after treatment. The clinical course of the patients was analyzed. In particular, symptom improvement within 1 week from treatment or rescue evacuation and the factors associated were evaluated. RESULTS: Fifteen patients were included in this study. No procedure-related complications occurred. Partial or complete recovery within the first week from treatment was observed in 10 cases (66.7%), and the symptoms resolved completely in a median of 26 (6.5-33.5) days. Rescue evacuation was needed in 3 cases (20.0%). The hematoma volume and midline shift gradually decreased from baseline, with a significant improvement within the first week (P = 0.030 and 0.0032, respectively). CONCLUSIONS: MMAE alone provides relatively early improvement in cases of mildly symptomatic CSDH and may be a potential alternative to surgical evacuation or medical therapy.

A case of meningioma originating from the lateral wall of the cavernous sinus.

Meningioma originating from the lateral wall of the cavernous sinus is rare with only two reported cases. A 67-year-old man presented with recent memory disturbance and partial seizure. Magnetic resonance imaging revealed a well-demarcated and homogeneously enhanced mass lesion originating from the lateral wall of the left cavernous sinus. Total tumor removal was performed through a combined epi- and intradural approach. Histological diagnosis was transitional meningioma. Postoperative course was uneventful. This combined approach was helpful for cranial nerve preservation, total tumor removal, and bleeding control from the feeder of the tumor.

Mixed pial and dural arteriovenous fistula after craniotomy: case report and literature review.

Dural arteriovenous fistula (AVF) is known to occur after craniotomy, but mixed pial and dural AVF after craniotomy has not been reported. A 45-year-old man who had undergone surgical clipping of an unruptured aneurysm 2 years previously presented with small subcortical hemorrhage from mixed pial and dural AVF. Surgical disconnection could not be cured completely due to the granulomatous tissue around the aneurysm, and the presence of an undetected shunt. Postoperative digital subtraction angiography showed a new pial AVF supplied by the middle cerebral artery pial branches. Many branches were associated with the remnant aneurysm and pial AVF, so we did not try to embolize the fistula. Gamma knife surgery was performed as adjuvant radiotherapy, which achieved angiographically complete occlusion of the shunt points. Multimodal approaches including surgery, endovascular intervention, and radiotherapy are needed for radiological and clinical cure of mixed pial and dural AVF. Long-term follow up is essential.

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

Here, we investigated the detailed molecular oncogenic mechanisms of a novel receptor tyrosine kinase (RTK) fusion, KLC1-ROS1, with an adapter molecule, KLC1, and an RTK, ROS1, discovered in pediatric glioma, and we explored a novel therapeutic target for glioma that possesses oncogenic RTK fusion. When wild-type ROS1 and KLC1-ROS1 fusions were stably expressed in the human glioma cell lines A172 and U343MG, immunoblotting revealed that KLC1-ROS1 fusion specifically activated the JAK2-STAT3 pathway, a major RTK downstream signaling pathway, when compared with wild-type ROS1. Immunoprecipitation of the fractionated cell lysates revealed a more abundant association of the KLC1-ROS1 fusion with JAK2 than that observed for wild-type ROS1 in the cytosolic fraction. A mutagenesis study of the KLC1-ROS1 fusion protein demonstrated the fundamental roles of both the KLC1 and ROS1 domains in the constitutive activation of KLC1-ROS1 fusion. Additionally, in vitro assays demonstrated that KLC1-ROS1 fusion upregulated cell proliferation, invasion, and chemoresistance when compared to wild-type ROS1. Combination treatment with the chemotherapeutic agent temozolomide and an inhibitor of ROS1, JAK2, or a downstream target of STAT3, demonstrated antitumor effects against KLC1-ROS1 fusion-expressing glioma cells. Our results demonstrate that KLC1-ROS1 fusion exerts oncogenic activity through serum-independent constitutive activation, resulting in specific activation of the JAK-STAT pathway. Our data suggested that molecules other than RTKs may serve as novel therapeutic targets for RTK fusion in gliomas.

Feasibility and Challenges of Transradial Approach in Neuroendovascular Therapy: A Retrospective Observational Study.

Objective: Transradial approach (TRA) is increasingly used as a viable alternative to the traditional transfemoral approach (TFA) in neuroendovascular therapy (NET) owing to its potential anatomical benefits and lower puncture-site complication rates. However, the real-world challenges of implementing TRA-NET have not been thoroughly studied, particularly those related to guide catheter (GC) placement. In this study, we aimed to explore the feasibility and challenges of TRA-NET, with a specific focus on GC placement. Methods: This retrospective observational study included patients who underwent NET at our institution between December 2019 and May 2022. Procedural success was defined as the successful placement of a GC in the target vessel. Cases in which a Simmons-shaped GC was used or the approach was changed to TFA were classified as difficult. Safety was assessed based on the rate of severe puncture-site complications requiring either blood transfusion or surgical intervention. Results: Among the 310 patients who underwent NET during the study period, 222 (71.6%) with a median age of 74 years were selected for TRA-NET. The target vessel was in the left anterior circulation (LtAC) in 101 (45.5%) patients, and 8-F GCs were the most frequently used (40.1%). TRA-NET achieved a 95.0% success rate, with a switch to TFA required in 5.0% of the cases. Procedural challenges occurred in 42 (18.9%) patients, primarily in those with LtAC lesions. Specifically, a type III aortic arch (p <0.0001) and age ≥80 years (p = 0.01) were significantly associated with procedural difficulties. Radial artery evaluation was confirmed in 66 cases (29.7%), revealing one instance (1.5%) of radial artery occlusion. No severe puncture-site complications were observed. Conclusion: TRA-NET may provide substantial therapeutic benefits without significant limitations in device use. However, it may be challenging, particularly in older patients and those with a type III aortic arch with LtAC lesions. Consequently, careful selection of the approach route is imperative.

Prophylactic Intraventricular Piping Method Prevents Entrapped Temporal Horn After Removal of Ventricle Trigone Meningioma: Technical Note.

BACKGROUND: An entrapped temporal horn (ETH) is one of the critical complications after tumor removal in the lateral ventricle trigone that sometimes becomes life threatening. OBJECTIVE: We sought to develop a novel intraoperative method of prophylactic intraventricular piping (PIP) just after tumor removal to prevent ETH. METHODS: Three patients with meningiomas in the lateral ventricle trigone were treated by a novel intraoperative method of PIP just after tumor removal to prevent ETH. Silicone catheters normally used as ventricular drainage catheters were cut to 5- to 6-cm length and inserted into the tumor cavity to ensure communication between the temporal horn and the atrium or the body of the lateral ventricle through the piping straddling the trigone. RESULTS: None of our patients developed ETH during the follow-up period without complications caused by the tube placement. CONCLUSIONS: PIP might be beneficial to prevent ETH because constant osmotic pressure and constant cerebrospinal fluid pulse wave transmission are maintained between each compartment of the lateral ventricle.

Superior Effectiveness of a Newly Developed Nonadherent Polyurethane-Coated Surgical Patty for Hemostasis.

BACKGROUND: Cotton patty is usually used to aspirate blood and cerebrospinal fluid to maintain a dry field. However, the cotton patty easily adheres to the vessels by capillary action, especially in combination with hemostat. Therefore, re-bleeding may be induced by removal of the cotton patty stuck to the vessel despite initial control of the bleeding. METHODS: We have developed a new cotton patty (Non-Stina X®, Hakujuji, Co., Ltd., Tokyo, Japan) which does not adhere to the vessels. The newly developed cotton patty is made of 100% cotton, with only the contact surface coated with polyurethane film which prevents capillary action. The coated side includes many holes to allow aspiration from both sides. RESULTS: The characteristics of four different surgical patties including our new patty which are available for surgical use in Japan were investigated. Transverse sections of four different surgical patties were investigated by light microscopy (magnification ×150). Our new cotton patty did not show any fluffing on the polyurethane-coated surface. However, other surgical patties showed some fluffing on their surfaces. The friction coefficients of four different surgical patties were investigated. Our new cotton patty had the lowest of the four neurosurgical patties. We confirmed the nonadherent characteristic using with hemostats of gelatinous sponge or fibrin glue-soaked oxidized cellulose cotton during hemostasis in neurosurgical procedures. The polyurethane-coated cotton patty could be removed easily from the hemostats without re-bleeding. CONCLUSIONS: The newly developed polyurethane-coated cotton patty is more effective for bleeding control from vessels with several types of hemostat due to the nonadherent characteristics.

Local Application of Magnesium Sulfate Solution Suppressed Cortical Spreading Ischemia and Reduced Brain Damage in a Rat Subarachnoid Hemorrhage-Mimicking Model.

OBJECTIVE: Cortical spreading depolarization (CSD), cortical spreading ischemia (CSI), and early brain injury are involved in the occurrence of delayed brain ischemia after subarachnoid hemorrhage (SAH). We tested whether local application of magnesium (Mg) sulfate solution suppressed CSD and CSI, and decreased brain damage in a rat SAH-mimicking model. METHODS: Nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) and high concentration potassium solution were topically applied to simulate the environment after SAH. We irrigated the parietal cortex with artificial cerebrospinal fluid (ACSF), containing L-NAME (1 mM), K+ (35 mM), and Mg2+ (5 mM). Forty-five rats were divided into 3 groups: sham surgery (sham group), L-NAME + [K+]ACSF (control group), and L-NAME + [K+]ACSF + [Mg2+] (Mg group). CSD was induced by topical application with 1 M KCl solution in 3 groups. The effects of Mg administration on CSD and cerebral blood flow were evaluated. Histological brain tissue damage, body weight, and neurological score were assessed at 2 days after insult. RESULTS: Mg solution significantly shortened the total depolarization time, and reduced CSI, histological brain damage, and brain edema compared with those of the control group (P < 0.05). Body weight loss was significantly suppressed in the Mg group (P < 0.05), but neurological score did not improve. CONCLUSIONS: Local application of Mg suppressed CSI and reduced brain damage in a rat SAH-mimicking model. Mg irrigation therapy may be beneficial to suppress brain damage due to CSI after SAH.

Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance.

Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ-R-GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBM. As a model of TMZ-R-GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ-R-cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ-R-cells after the administration of each drug, the antitumor effects of TMZ against TMZ-R-cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ-R-cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ-R-GBM.

Usefulness and feasibility of repeated tail artery cannulations in the rat.

Rat ventral caudal artery (VCA, tail artery) cannulation for blood pressure monitoring and blood sampling is essential for maintaining consistent procedures in rat models. Double or triple insults are sometimes necessary, but repeated VCA cannulations have not been compared with repeated femoral artery cannulations. In addition, the collateral system for resistance to ischemia in the rat tail is unclear. Our present study revealed that repeated VCA cannulations on different days was a better technique than repeated femoral artery cannulations in terms of surgical time, postsurgical weight loss and ischemic complications. Furthermore, the lateral caudal arteries and the segmental anastomosing vessels were important for resistance to ischemic complications after VCA occlusion.

Ruptured Dissecting Aneurysm of the Carotid Artery 12 Years after Gamma Knife Therapy for Pituitary Adenoma.

Objective: We report a rare case of carotid artery dissection leading to fatal epistaxis 12 years after Gamma knife surgery. Case Presentation: A 65-year-old woman underwent Gamma knife surgery for remnant pituitary adenoma adjacent to the left cavernous sinus after transsphenoidal tumor removal. After 12 years, she developed repetitive critical hematemesis subsequent to cardiopulmonary arrest, and a dissecting aneurysm of the cavernous segment of the left internal carotid artery (ICA) was identified by cerebral angiography after resuscitation and massive blood transfusion. Effective hemostasis was confirmed by endovascular embolization to occlude the affected carotid artery. She was transferred to a rehabilitation facility 1 month after onset. Conclusion: The etiology of this pathology may have been a collapsed vasa vasorum or fibrosis of adventitia on the carotid wall adjacent to the irradiated site. We need to suspect this rare but serious pathology in patients with histories of irradiation of the cavernous region who develop massive hematemesis of unknown origin.

Intravenous Hydrogen Therapy With Intracisternal Magnesium Sulfate Infusion in Severe Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Poor-grade subarachnoid hemorrhage still has a poor prognosis. This randomized controlled clinical trial evaluated intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy in patients with poor-grade subarachnoid hemorrhage. METHODS: Thirty-seven patients with poor-grade subarachnoid hemorrhage were randomized to Mg+H2, Mg, and control groups. Mg and Mg+H2 groups received intracisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days. Mg+H2 group also received intravenous hydrogen-rich solution infusion for 14 days. Primary outcome measures were occurrence of delayed cerebral ischemia and cerebral vasospasm. Secondary outcome measures were modified Rankin Scale and Karnofsky performance status at 3 and 12 months, Barthel index at 12 months, and serum and cerebrospinal fluid malondialdehyde and neuron-specific enolase. RESULTS: Serum neuron-specific enolase levels were significantly lower in the Mg+H2 group from days 3 to 14 than in the control group. Cerebrospinal fluid neuron-specific enolase levels were also significantly lower in the Mg+H2 group from days 3 to 7 than in the control group. Incidences of cerebral vasospasm and delayed cerebral ischemia were significantly higher in the control group than in other groups. Modified Rankin Scale and Karnofsky performance status did not significantly differ between the three groups at 3 months. Modified Rankin Scale scores 0 to 2 were more common in the Mg and Mg+H2 groups at 1 year. Barthel index was higher in the Mg+H2 group than in the control group. CONCLUSIONS: Intracisternal magnesium sulfate infusion started immediately after surgery reduces the incidence of cerebral vasospasm and delayed cerebral ischemia and improves clinical outcomes without complications in patients with poor-grade subarachnoid hemorrhage. Intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy decreases serum malondialdehyde and neuron-specific enolase and improves Barthel index, indicating hydrogen has additional effects. Registration: URL: https://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000014696.

Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation.

To manage refractory and invasive glioblastomas (GBM)s, photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT) was recently approved in clinical practice. However, the molecular machineries regulating resistance against NPe6-PDT in GBMs and mechanisms underlying the changes in GBM phenotypes following NPe6-PDT remain unknown. Herein, we established an in vitro NPe6-mediated PDT model using human GBM cell lines. NPe6-PDT induced GBM cell death in a NPe6 dose-dependent manner. However, this NPe6-PDT-induced GBM cell death was not completely blocked by the pan-caspase inhibitor, suggesting NPe6-PDT induces both caspase-dependent and -independent cell death. Moreover, treatment with poly (ADP-ribose) polymerase inhibitor blocked NPe6-PDT-triggered caspase-independent GBM cell death. Next, it was also revealed resistance to re-NPe6-PDT of GBM cells and GBM stem cells survived following NPe6-PDT (NPe6-PDT-R cells), as well as migration and invasion of NPe6-PDT-R cells were enhanced. Immunoblotting of NPe6-PDT-R cells to assess the behavior of the proteins that are known to be stress-induced revealed that only ERK1/2 activation exhibited the same trend as migration. Importantly, treatment with the MEK1/2 inhibitor trametinib reversed resistance against re-NPe6-PDT and suppressed the enhanced migration and invasion of NPe6-PDT-R cells. Overall, enhanced ERK1/2 activation is suggested as a key regulator of elevated malignant phenotypes of GBM cells surviving NPe6-PDT and is therefore considered as a potential therapeutic target against GBM.