Search

The challenge of vascular interventional surgery is that surgeons require to be exposed to X-ray for a long time, operating guidewires and catheters to complete the treatment. To reduce the burden of the surgeons, it is of great significance to develop a tactile sensing robot-assisted system for vascular interventional surgery. Therefore, a slave manipulator with the function of collaborative operating guidewires and catheters was developed to replace doctors to perform the surgery in the operating room. In addition, a master manipulator based on magnetorheological fluids was located on the master side, and the haptic force feedback of the system was realized by generating the tactile force acting on the doctor’s hand. To verify the proposed system, a series of experiments were carried out, the results of experiments in “Vitro” indicated that the proposed system has good performance in collaborative operating and can accurately deliver a guidewire and a catheter to the target position. The maximum tracking error of the axial motion was less than 2 mm, and the maximum tracking error of the radial motion was less than 2 degrees, which is acceptable. And under the guidance of the force feedback, the safety of the system was obviously higher than that of without force feedback, after the experiment was completed by 5 participants, the safety increased by 4.32% on average. So, we can get the results that our system is feasible and effective.

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Hypoxic stress is suspected as the pathogenesis of ALS, however, no positron emission tomography (PET...

(Purpose) Holmium laser enucleation of the prostate (HoLEP) is widely performed in recent years; however, difficulties of surgical techniques and high frequency of postoperative stress urinary incontinence (SUI) remain as significant problems. We determined the predictive factors for de novo SUI after HoLEP. (Patients and methods) A total of 303 patients with benign prostatic hyperplasia who underwent HoLEP were retrospectively evaluated between July 2013 and April 2019. Of these, 109 patients underwent MRI preoperatively. Patients who were unable to answer the questionnaire regarding their SUI because of dementia, those who presented with SUI preoperatively, and those with placed Foley catheter at the time of MRI were excluded. Hence, a total of 83 patients were eligible for the present study. We recorded the MRI findings and clinical variables, including membranous urethral length (MUL), transitional zone (TZ) volume, serum prostate-specific antigen levels, operative time, and presence or absence of SUI. The predictive factors for de novo SUI were determined using multivariable logistic regression analysis. (Results)De novo SUI occurred in 19 (22.9%) patients but disappeared in 16 (84.2%) patients at a mean duration of 14 weeks. The mean MUL was 17.2 mm. Univariate analysis showed that MRI TZ volume >40 mL, MUL ≤17 mm, operative time >100 min, and enucleation time >50 min were associated with de novo SUI. In multivariable logistic regression analysis, MUL ≤17 mm (odds ratio [OR], 23.81; 95% confidence interval [CI], 4.34-447.19; P 100 min (OR, 3.91; 95% CI, 1.20-14.01; P = 0.023) were significantly associated with de novo SUI. (Conclusions) Although de novo SUI occurred occasionally after HoLEP, most of them improved in about 3 months. The MRI measurement of MUL was shown to be a practical tool for predicting de novo SUI after HoLEP.

Bilateral rehabilitation training robotic systems have potential to promote the upper limb motor recovery of post-stroke hemiparesis patients through providing the synchronization motion between the impaired limb and contralateral limb. The active rehabilitation training based on patients’ intention can also promote the recovery effect by stimulating the activity of the ipsilateral hemisphere and contralateral hemisphere. In this paper, a novel intention-based bilateral training system using biomedical signals which represents the muscle activity information and active motion intention was proposed to promote the rehabilitation training effect. The proposed system can provide the synchronization motion to the impaired limb by the exoskeleton device according to the sEMG signals from the contralateral intact limb. A BPNN model using a novel multi-features input vector was employed for establishing the relationship between the sEMG signals and the motion intention. To verify the intention prediction performance, the comparison experiments involving both the offline phase and online phase were carried out using three different kinds of feature input vectors of sEMG. Furthermore, the real-time bilateral control experiments were conducted to verify the feasibility and effectiveness of the proposed bilateral rehabilitation system, in terms of motion synchronization tracking and the real-time characteristics.

Background Tumor hypoxia and glycolysis have been recognized as determinant factors characterizing tumor aggressiveness in malignant gliomas. To clarify in vivo hypoxia and glucose metabolism in relation to isocitrate dehydrogenase (IDH) mutation and chromosome 1p and 19q (1p/19q) codeletion status, we retrospectively analyzed hypoxia as assessed by positron emission tomography (PET) with [18F]-fluoromisonidazole (FMISO) and glucose metabolism as assessed by PET with [18F]-fluoro-2-deoxy-d-glucose (FDG) in newly diagnosed malignant gliomas. Methods In total, 87 patients with newly diagnosed supratentorial malignant (WHO grade III and IV) gliomas were enrolled in this study. They underwent PET studies with FMISO and FDG before surgery. The molecular features and histopathological diagnoses based on the 2016 WHO classification were determined using surgical specimens. Maximal tumor-to-normal ratio (TNR) was calculated for FDG PET, and maximal tumor-to-blood SUV ratio (TBR) was calculated for FMISO PET. The PET uptake values in relation to IDH mutation and 1p/19q codeletion status were statistically analyzed. Results In all tumors and malignant astrocytomas, the median FMISO TBR in IDH-wildtype tumors was significantly higher than that in IDH-mutant tumors (P P IDH-wildtype tumors tended to be higher than that in IDH-mutant tumors, but the difference was not statistically significant. In WHO grade III anaplastic astrocytomas, there were no significant differences in median FMISO TBR or FDG TNR between IDH-mutant and IDH-wildtype tumors. In IDH-mutant WHO grade III anaplastic gliomas, there were no significant differences in median FMISO TBR or FDG TNR between anaplastic astrocytomas and anaplastic oligodendrogliomas. Conclusions Tumor hypoxia as assessed by FMISO PET was informative for prediction of the IDH mutation status in newly diagnosed malignant gliomas. However, the accuracy of the discrimination was not satisfactory for clinical application. On the other hand, glucose metabolism as assessed by FDG PET could not differentiate the IDH-mutant status. Moreover, PET studies using FMISO and FDG could not predict IDH mutation and 1p/19q codeletion status in WHO grade III tumors.

A teleoperated robotic catheter operating system is a solution to avoid occupational hazards caused by repeated exposure radiation of the surgeon to X-ray during the endovascular procedures. However, inadequate force feedback and collision detection while teleoperating surgical tools elevate the risk of endovascular procedures. Moreover, surgeons cannot control the force of the catheter/guidewire within a proper range, and thus the risk of blood vessel damage will increase. In this paper, a magnetorheological fluid (MR)-based robot-assisted catheter/guidewire surgery system has been developed, which uses the surgeon’s natural manipulation skills acquired through experience and uses haptic cues to generate collision detection to ensure surgical safety. We present tests for the performance evaluation regarding the teleoperation, the force measurement, and the collision detection with haptic cues. Results show that the system can track the desired position of the surgical tool and detect the relevant force event at the catheter. In addition, this method can more readily enable surgeons to distinguish whether the proximal force exceeds or meets the safety threshold of blood vessels.

Simple Summary Neurofibromatosis type 2 (NF2) is a rare genetic hereditary disease characterized by multiple central nervous system tumors, most frequently bilateral vestibular schwannomas (VSs). No chemotherapeutic agents are available for clinical use, and surgery and radiotherapy are the only therapeutic options available now. Still, neither treatment option alleviates hearing loss in patients with NF2 and VS; they may even exacerbate it. However, bevacizumab has been reported to be effective in suppressing the tumor’s growth and has shown unprecedented efficacy in improving hearing. We describe a new ongoing and novel clinical trial, BeatNF2, a randomized, double-blinded, placebo-controlled, multicenter trial to assess bevacizumab’s efficacy and safety in patients with NF2. The study’s primary endpoint is improved hearing function 24 weeks after the beginning of the treatment protocol. Abstract Neurofibromatosis type 2 (NF2) causes bilateral vestibular schwannomas (VSs), leading to deafness. VS is treated by surgery or radiation, but neither treatments prevent hearing loss. Bevacizumab was found to be effective in suppressing the tumor’s growth and may help to improve hearing. We are conducting a randomized, double-blind, multicenter clinical trial to verify the efficacy and safety of bevacizumab in NF2-related VS. The primary objective is to evaluate the efficacy of bevacizumab in improving hearing in the affected ear. One of the secondary objectives is to evaluate bevacizumab’s efficacy in rechallenge treatment in relapsed cases. Sixty patients will randomly receive either bevacizumab or a placebo and will be clinically observed for 48 weeks in the initial intervention phase. In the first half (24 weeks), they will receive either 5 mg/kg of bevacizumab or a placebo drug. In the second half, all patients will receive 5 mg/kg of bevacizumab. If hearing function deteriorated in a patient who had shown improvement during the first phase, a rechallenge dose with bevacizumab would be offered.

INTRODUCTION AND OBJECTIVE:Recent studies have suggested that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit, and its predictive ...

Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post‐Bev recurrent tumors from 9 patients were included. The expression of programmed cell death‐1 (PD‐1)/PD ligand‐1 (PD‐L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD‐L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P

Background In patients with aneurysmal subarachnoid hemorrhage (SAH), an association between hypocapnia and poor clinical outcomes has been reported. However, the optimal arterial carbon dioxide tension (PaCO2) remains unknown. The present retrospective study aimed to examine the association of abnormal PaCO2 levels with neurological outcomes and investigate the optimal target PaCO2 level in patients with SAH. Methods We retrospectively selected consecutive adult patients hospitalized in the intensive care unit (ICU) for SAH between January 2009 and April 2017. Univariate and multivariate analyses were performed to identify the independent predictors of unfavorable neurological outcomes (i.e., modified Rankin scale score of 3–6 on hospital discharge). Results Among 158 patients with SAH, 73 had unfavorable neurological outcomes. During the first 2 weeks in the ICU, the median number of PaCO2 measurements per patient was 43. The factors significantly associated with unfavorable neurological outcomes were age, Hunt and Kosnik grade, maximum lactate levels during the first 24 h, and maximum (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.03–1.21; p

Dysnatremia commonly occur in the intensive care unit (ICU) management of patients with aneurysmal subarachnoid hemorrhage (SAH). However, detailed management strategies have not been provided even by current guidelines. The purposes of this study were to examine the association of abnormal serum sodium levels with unfavorable neurologic outcomes and to identify the target range of serum sodium in patients with SAH.We retrospectively reviewed all patients who were consecutively hospitalized with a confirmed diagnosis of SAH between January 2009 and December 2015. Univariate/multivariate analyses were performed to identify the independent predictors of an unfavorable neurologic outcome (modified Rankin scale of 3-6 upon hospital discharge).There were 131 patients included in this study. Unfavorable neurologic outcomes occurred in 45% of patients. On multiple regression analysis, age, Hunt and Kosnik grade, and serum sodium levels in the ICU at the maximum [odds ratio (OR), 1.18; 95% CI, 1.05-1.35; P 0.01] and minimum (OR, 0.88; 95% CI, 0.77-0.99; P = 0.048) values were significantly associated with unfavorable neurologic outcomes. The receiver operating characteristic curve analysis showed that the cut-off serum sodium levels were 145 mmol/L for maximum value and 132 mmol/L for minimum value. Patients with hyponatremia and hypernatremia during the first 2 weeks in the ICU accounted for 88.2% of patients with an unfavorable neurologic outcome; whereas, those with normal sodium levels accounted for only 15.6%.In patients with SAH, both hyponatremia and hypernatremia during ICU management were significantly associated with unfavorable neurologic outcomes.

A number of remote robotic catheter systems have been developed to protect physicians from X-ray exposure in endovascular surgery. However, the teleoperation prevents the physicians sensing the force directly which may easily result in healthy vessels injured. To realize the safe operation, a tissue protection-based VR training system has been developed in this paper to prevent collateral damage by collision. The integrated VR simulator cannot only remind the novice possible collisions by visual signs, but also cooperate with the newly designed tissue protection mechanism to remit collision trauma beforehand. Such mechanism exploits the diameter variable pulley in order to implement the safe interaction between catheter and vasculature. To testify the effectiveness of the tissue protection in training system, we invited four non-medical students to participate the successive 5 days training session. The evaluation results show that the average impingement distance (representing tissue damage) to vascular wall has been reduced to 0.6 mm, and the collision frequency is greatly decreased which implies the realization of relative safe catheterization.

OBJECTIVE Neuronavigation systems with magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging (methionine [MET], fluorothymidine [FLT], and fluoromisonidazole [FMISO]) are routinely used in glioblastoma surgery. Residual tumor identified using intraoperative MRI (IoMRI) or 5-aminolevulinic acid (5-ALA) fluorescence is removed. Neoadjuvant bevacizumab therapy is offered to patients with low Karnovsky performance status (KPS) or with tumors in eloquent regions. We evaluated the usefulness of neoadjuvant bevacizumab therapy. METHODS Twelve patients with glioblastoma with low KPS or tumors in eloquent regions on multiple PET and IoMRI evaluations were enrolled between January 2016 and April 2019. Six had received neoadjuvant bevacizumab before surgery; six had not. Postsurgical 5-ALA fluorescence (strong, vague, and none) tumor extraction rate, residual volume on MRI and PET imaging, and prognosis in the patients with and without bevacizumab were compared. RESULTS In patients with bevacizumab adjuvant therapy, the KPS scores immediately prior to surgery were 90 in 3 cases, 80 in 2, and 70 in 1. The scores in patients without bevacizumab were 50 in 2 and 40 in 4. The 5-ALA fluorescence in patients with bevacizumab was vague in one and none in five. Vague fluorescence was noted in all six patients without bevacizumab. Tumor extraction rates in patients with vs. those without bevacizumab were 97.6% vs. 91.5% by T1-Gd, 95.4% vs. 99.9% by MET, 96.2% vs. 90.2% by FLT, and 97% vs. 92% by FMISO. Corresponding residual volumes (ml) were (0.6 vs. 1.7) for T1-Gd, 1.2 vs. 2.9 for MET, 1.0 vs. 2.1 for FLT, and 0.5 vs. 1.1 for. FLT. Median progression free survival (PFS) was 10.1 vs. 4.9 months; median overall survival (OS) was 15.7 vs. 13.3 months. CONCLUSIONS Neoadjuvant bevacizumab therapy improved KPS at the time of surgery, increased extraction rate, reduced residual tumor volume, and improved PFS and OS prognosis.

Epithelioid glioblastoma is a rare subtype of glioblastoma, but the coexistence of a sarcomatous component is even rarer. An 80-year-old woman was admitted to our hospital with somnolence. Magnetic resonance imaging revealed a cystic lesion with a solid component in the left temporal-parietal lobe. Histopathological examination of the resected tumor revealed three components; namely, typical glioblastoma, sarcomatous and epithelioid components at a ratio of about 5:3:2. All components were immunohistochemically positive for vimentin and mutated BRAF (V600E) and showed focal expression of glial fibrillary acidic protein and cytokeratin AE1/AE3, but they were negative for isocitrate dehydrogenase 1. Genetic analysis revealed that both the sarcomatous and epithelioid components harbored BRAF T1799A (V600E) mutation and homozygous deletion of cyclin-dependent kinase inhibitor 2A/B. We diagnosed this tumor as epithelial glioblastoma with a sarcomatous component. Our results indicate that even when the epithelial component is not dominant, immunohistochemical and genetic investigation of BRAF mutations is useful for the diagnosis of glioblastoma subtypes. In particular, although the prognosis of epithelial glioblastoma is poor, potentially effective targeted therapies for BRAF V600E-mutated tumors are available.

The epidemiology of patients with traumatic brain injury (TBI) has changed dramatically over recent decades as a result of rapid advances in aging societies. We assessed the influence of age on outcomes of patients with TBI and sought to identify prognostic factors for in-hospital mortality of TBI among elderly patients.Using a nationwide database, we analyzed data from 5651 patients with TBI. Univariate analysis was conducted to compare patient demographics, neurologic status on admission, radiologic findings, systemic complication rates, length of hospital stay, in-hospital mortality, and home discharge rates between elderly and nonelderly groups. Multivariable analysis was conducted to determine prognostic factors for in-hospital mortality among elderly patients.Overall in-hospital mortality was significantly higher in elderly patients (12.8% vs. 19.3%; P0.001). In-hospital mortality of elderly patients with mild TBI increased significantly at7 days after admission, whereas that of elderly patients with moderate or severe TBI was significantly higher immediately after admission. Age (odds ratio [OR], 1.62; P = 0.024), male sex (OR, 1.30; P = 0.004), Japan Coma Scale score on admission (OR, 5.95, P0.001), and incidence of acute subdural hematoma (OR, 1.89; P0.001) were associated with in-hospital mortality in elderly patients with TBI.Elderly patients with TBI showed significantly higher in-hospital mortality. Delayed increases in in-hospital mortality were observed among elderly patients with mild TBI. Level of consciousness on admission was the strongest predictor of in-hospital mortality among elderly patients.

A 72-year-old woman developed excessive somnolence as one of the symptoms of diffuse large B-cell lymphoma in the central nervous system (CNS). Although somnolence might be caused by reduced orexin secretion associated with hypothalamic lesions, neither brain MRI nor 18F-fluorodeoxyglucose positron emission tomography identified hypothalamic lesions. However, the decreased cerebrospinal fluid (CSF) orexin levels recovered to near normal values with improvement of somnolence after chemotherapy. The alteration of CSF orexin levels suggested the involvement of potential hypothalamic lesions. Therefore, measurements of CSF orexin levels may be useful for understanding the pathological background of somnolence in CNS lymphoma without hypothalamic lesions.

Background Symptomatic cyst formation after brain tumor resection is a rare complication of the early postoperative phase. We describe a complicated case of postoperative symptomatic cyst formation after gross total removal of a convexity meningioma. Case Description A 59-year-old woman presented with recent onset motor aphasia. Magnetic resonance imaging revealed a left convexity tumor. We performed gross total resection of the tumor, which was pathologically diagnosed as an atypical meningioma. Tumor resection and decompression of the normal cerebral hemisphere improved aphasia. However, 3 days after surgery, her motor aphasia worsened. Computed tomography scan confirmed that the frontal lobe was being compressed by an enlargement of the postoperative tumor cavity. Conservative therapy did not shrink the cavity, and her motor aphasia persisted. Therefore, 21 days after surgery, a drainage tube was inserted into the enlarged cavity using a neuroendoscope, which promoted shrinkage of the cavity and improved her motor aphasia. We suspected that the enlargement of the postoperative cavity was because of the presence of a valve-like structure. Conclusions Even though formation of symptomatic cystic lesions after brain tumor resection is rare, neurosurgeons should be aware of such early postoperative complications and their management strategies.

OBJECTIVE Use of the positron emission tomography (PET), such as 18F-fluorodeoxyglucose (FDG), 11C-Methionine (MET), 18F- Fluorothymidine (FLT), and 18F-Fluoromisonidazole (FMISO), is expected to lead the way for novel applications aimed at achieving efficient malignancy grading and treatment of gliomas. The aim of this study was to assess FDG, MET, FLT, and FMISO PET studies to evaluate the biological effects induced by bevacizumab (BEV) therapy in glioblastoma patients. METHODS Seventy-one patients with glioblastoma were treated biweekly with BEV from July 2013 to November 2020. FDG, MET, FLT, and FMISO PET scans were obtained at baseline and at follow-up (4 weeks after treatment onset). Measures of FDG, MET, FLT, and FMISO avidity were recorded; the measures were SUVmax, metabolic tumor volume (MTV; volume of tumor with SUV>42% of SUVmax), SUVmean (within the MTV), tumor-to-normal ratio (TNR), tumor-to blood ratio (TBR), and total lesion avidity (TLA; calculated as MTV x SUVmean). The prognostic analysis was performed in relation to the response assessment by multiple PET tracers using progression-free survival (PFS) and overall survival (OS). RESULTS Under the assessment of the Cox proportional hazard model, increased changes of FDG SUVmax, MET TLA at follow-up, FLT TLA at follow up, increased changes of FLT TLA, increased changes of FMISO TBR and FMISO MTV were significant prognostic factor of PFS. Increase changes of FDG TLA and FLT TLA and increased changes of FMISO TBR were significant prognostic factor of OS. CONCLUSION Increased changes in FLT TLA and FMISO-PET after BEV therapy may be a useful biomarker for predicting PFS and OS in glioblastoma.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. In ALS, both glucose consumption and neuronal intensity reportedly decrease in the cerebral motor cortex when measured by positron emission tomography (PET). In this study, we evaluated cervical spinal glucose metabolism, blood flow, and neuronal intensity of 10 ALS patients with upper extremity (U/E) atrophy both with 18F-2-fluoro-2-deoxy-d-glucose (18F-FDG) PET and 11C-flumazenil (11C-FMZ) PET. On the ipsilateral side of C5 and T1 levels, 18F-FDG uptake increased significantly (*p < 0.05), and was correlated with the rate of progression of the ALS FRS-R-U/E score (R = 0.645, *p = 0.041). Despite this hyperglucose metabolism, the 11C-FMZ PET study did not show a coupled increase of spinal blood flow even though neuronal intensity did not decrease. These results indicate a strong correlation between hyperglucose metabolism and ALS progression alongside the uncoupling of flow-metabolism. This mechanism, which could result in subsequent motor neuronal death, may be a potential therapeutic target for ALS.

This data article contains supporting information regarding the research article entitled “Traumatic brain injury accelerates amyloid-β deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer׳s disease” (H. Shishido, Y. Kishimoto, N. Kawai, Y. Toyota, M. Ueno, T. Kubota, Y. Kirino, T. Tamiya, 2016) [1]. Triple-transgenic (3×Tg)-Alzheimer׳s disease (AD) model mice exhibited significantly poorer spatial learning than sham-treated 3×Tg-AD mice 28 days after traumatic brain injury (TBI). Correspondingly, amyloid-β (Aβ) deposition within the hippocampus was significantly greater in 3×Tg-AD mice 28 days after TBI. However, data regarding the short-term and long-term influences of TBI on amyloid precursor protein (APP) accumulation in AD model mice remain limited. Furthermore, there is little data showing whether physical activity and motor learning are affected by TBI in AD model mice. Here, we provide immunocytochemistry data confirming that TBI induces significant increases in APP accumulation in 3×Tg-AD mice at both 7 days and 28 days after TBI. Furthermore, 3×Tg-AD model mice exhibit a reduced ability to acquire conditioned responses (CRs) during delay eyeblink conditioning compared to sham-treated 3×Tg-AD model mice 28 days after TBI. However, physical activity and motor performance are not significantly changed in TBI-treated 3×Tg-AD model mice.

// Ryota Tamura 1 , Toshihide Tanaka 2 , Keisuke Miyake 3 , Yusuke Tabei 4 , Kentaro Ohara 5 , Oltea Sampetrean 6 , Maya Kono 1 , Katsuhiro Mizutani 1 , Yohei Yamamoto 2 , Yuichi Murayama 7 , Takashi Tamiya 3 , Kazunari Yoshida 1 and Hikaru Sasaki 1 1 Department of Neurosurgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan 2 Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwashita, Kashiwa-shi, Chiba, Japan 3 Department of Neurosurgery, Kagawa University Hospital, Ikedo, Mituki-cho, Kita-gun, Kagawa, Japan 4 Department of Neurosurgery, Japan Red Cross Medical Center, Hiroo, Shibuya-ku, Tokyo, Japan 5 Division of Diagnostic Pathology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan 6 Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan 7 Department of Neurosurgery, Jikei University Hospital, Nishishinbashi, Minato-ku, Tokyo, Japan Correspondence to: Hikaru Sasaki, email: // Keywords : bevacizumab; neoadjuvant; vascular normalization; hypoxia; glioma stem cell Received : February 08, 2016 Accepted : May 09, 2016 Published : May 17, 2016 Abstract To date, no clinical observations have been reported for histopathological changes in human gliomas under antiangiogenic treatment. We collected six glioblastomas resected under bevacizumab treatment. Histopathological investigation was performed by hematoxilyn-eosin staining and immunohistochemistry for CD34, VEGF, VEGFR1/2, HIF-1α, CA9, and nestin as compared to eleven control glioblastomas to assess the differences in histological features, microvessel density, expression of VEGF and its receptors, tumor oxygenation, and status of glioma stem-like cells. In the six tumors resected under bevacizumab, microvascular proliferation was absent, and microvessel density had significantly decreased compared with that of the controls. The expressions of VEGF and its receptors were downregulated in two cases of partial response. HIF-1α or CA9 expression was decreased in five of the six tumors, whereas the decreased expression of these markers was noted in only one of the 11 control glioblastomas. The expression of nestin significantly decreased in the six tumors compared with that of the controls, with the remaining nestin-positive cells being relatively concentrated around vessels. We provide the first clinicopathological evidence that antiangiogenic therapy induces the apparent normalization of vascular structure, decrease of microvessel density, and improvement of tumor oxygenation in glioblastomas. These in situ observations will help to optimize therapy.

Objective: Magnetic resonance imaging alone is not sufficient for the diagnosis and therapy outcomes in brain tumors. We herein examined the utility of positron emission tomography (PET) studies for diagnosis in brain tumors. Methods: Between April 2009 and June 2020, 320 patients with central nervous diseases, including 140, 65, 52, 52, and 11 patients with glioma, metastatic brain tumor, malignant lymphoma, meningioma, and demyelinating disease, respectively, underwent PET studies (FDG, MET, FLT, and FMISO) in our department. Lesion/normal (L/N) ratios for FDG, MET, and FLT and lesion/blood ratio (L/B ratio) for FMISO were compared. The glioma subtypes were compared based on the 2016 World Health Organization classification (IDH-mut, Codel, IDH-wt, GBM), and metastatic brain tumors, malignant lymphomas, meningiomas, and demyelinating diseases were compared with GBM. Results: In glioma, the cutoff MET L/N ratios to distinguish between IDH-mut and Codel, IDH-mut and GBM, Codel and GBM, and IDH-wt and GBM were 3.61, 4.42, 4.92, and 4.33, respectively, and the cutoff FLT L/N ratios to distinguish between IDH-mut and IDH-wt, IDH-mut and GBM, Codel and GBM, and IDH-wt and GBM were 3.43, 6.46, 3.39, and 7.56, respectively. The cutoff FDG and MET L/N ratios between metastatic brain tumors and GBM were 2.27 and 4.89; the cutoff FDG L/N and FMISO L/B ratios between malignant lymphoma and GBM were 4.68 and 2.13; and the cutoff FDG and MET L/N ratios between meningioma and GBM were 1.58 and 4.36. Demyelinating disease and GBM were distinguishable by FDG, MET, and FLT L/N ratios of 2.29, 3.32, and 5.85, and FMISO L/B ratio of 1.68. Conclusion: Four PET tracers were required to differentiate glioma subtypes. FDG and MET are useful for distinguishing GBM from metastatic brain tumor, malignant lymphoma, and meningioma, whereas accumulation was lower for all four PET tracers in demyelinating diseases than in GBM.

There has been growing awareness of the correlation between an episode of traumatic brain injury (TBI) and the development of Alzheimer’s disease (AD) later in life. It has been reported that TBI accelerated amyloid-β (Aβ) pathology and cognitive decline in the several lines of AD model mice. However, the short-term and long-term effects of TBI by the weight-drop method on amyloid-β pathology and cognitive performance are unclear in wild-type (WT) mice. Hence, we examined AD-related histopathological changes and cognitive impairment after TBI in wild-type C57BL6J mice. Five- to seven-month-old WT mice were subjected to either TBI by the weight-drop method or a sham treatment. Seven days after TBI, the WT mice exhibited significantly lower spatial learning than the sham-treated WT mice. However, 28 days after TBI, the cognitive impairment in the TBI-treated WT mice recovered. Correspondingly, while significant amyloid-β (Aβ) plaques and amyloid precursor protein (APP) accumulation were observed in the TBI-treated mouse hippocampus 7 days after TBI, the Aβ deposition was no longer apparent 28 days after TBI. Thus, TBI induced transient amyloid-β deposition and acute cognitive impairments in the WT mice. The present study suggests that the TBI could be a risk factor for acute cognitive impairment even when genetic and hereditary predispositions are not involved. The system might be useful for evaluating and developing a pharmacological treatment for the acute cognitive deficits.

BACKGROUND: We conducted a phase III trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)-A24+ recurrent glioblastoma to develop a new treatment modality. METHODS: We randomly assigned 88 recurrent glioblastoma patients to receive PPV (n = 58) or the placebo (n = 30) at a 2-to-1 ratio. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebos were injected 1×/week for 12 weeks. RESULTS: Our trial met neither the primary (overall survival [OS]) nor secondary endpoints. Unfavorable factors for OS of 58 PPV patients compared with 30 placebo patients were SART2-93 peptide selection (n = 13 vs 8, hazard ratio [HR]: 15.9), ≥70 years old (4 vs 4, 7.87), >70 kg body weight (10 vs 7, 4.11), and performance status (PS)3 (8 vs 2, 2.82), respectively. Consequently, the median OS for PPV patients without SART2-93 selection plus one of these 3 favorable factors (

OBJECTIVE: Image-guided surgery, such as neuronavigation systems with magnetic resonance imaging (MRI) have become standard techniques for glioma surgeries. However, MRI is limited by correct metabolism of glioma cells. Positron-emission tomography (PET) uses radiotracers to achieve metabolic and molecular imaging, but can only be evaluated preoperatively. We compared the utility of intraoperative real-time MRI (IoMRI) and multiple PET studies (methionine [MET], fluorothymidine [FLT], and fluoromisonidazole [FMISO]) for malignant glioma surgery. METHODS: Between January 2016 and May 2018, 39 patients with gliomas underwent IoMRI, whereas 19 (excluding biopsy cases) underwent multiple PET studies for tumor removal. Of these 19 patients, 12 had recurrence and 7 did not. Excision rate and residual region by IoMRI and PET studies were compared. RESULTS: The respective excision rates in the recurrent and nonrecurrent groups were 91.9% (80.499) and 97.7% (92.7100) with IoMRI, 92.3% (79.297.1) and 99.4% (98.3100) with MET, 94.5% (84.597.5) and 99.2% (97.5100) with FLT, and 95.9% (90.298.3) and 98.7% (93.5100) with FMISO. In the recurrent group, the residual volume of each PET tracer was significantly larger than that of IoMRI. All recurrences wherein accumulation areas of each PET tracer remained in the IoMRI excision areas were detected. Recurrence was observed from these sites, particularly the residual region overlapping residual accumulations of MET and FLT. CONCLUSIONS: Fusion of IoMRI images with preoperative multiple PET images during navigation remains challenging. When accumulation areas of more than two PET tracers, particularly MET and FLT, overlap with the residual IoMRI region, considering tumor removal becomes important.

Introduction Although oxygen administration is fundamental in the management of aneurysmal subarachnoid hemorrhage (SAH) patients in the acute stage, hyperoxia has harmful effects. The effects of hyperoxia on neurological outcomes in SAH patients are unclear. We aimed to examine the association of hyperoxia during the first 24 h in the intensive care unit (ICU) with unfavorable neurological outcomes in SAH patients. Methods We retrospectively selected consecutive adult patients admitted to ICU for SAH between January 2009 and April 2018. We defined normoxia during the first 24 h in ICU as PaO2 of 60 mm Hg to 120 mm Hg, mild hyperoxia as PaO2 of 121 mm Hg to 200 mm Hg, moderate hyperoxia as PaO2 of 201 mm Hg to 300 mm Hg, and severe hyperoxia as PaO2 of >300 mm Hg. Univariate and multivariate analyses were performed to examine the association between hyperoxia during the first 24 h in ICU and unfavorable neurological outcomes (i.e., modified Rankin scale score of 3-6 at hospital discharge). Results Among 196 SAH patients, 90 had unfavorable neurological outcomes. Hyperoxia was observed in 93.4% of patients. No significant association was observed between unfavorable neurological outcomes and hyperoxia in overall patients. However, we found that early hyperoxia in ICU was significantly associated with unfavorable neurological outcomes in SAH patients with Hunt and Kosnik (HK 95% confidence interval, 1.10-2.94; P = 0.02). Conclusions Early hyperoxia was not associated with unfavorable neurological outcomes in overall SAH patients, but it was associated with unfavorable neurological outcomes in those with H&K grades I to III.

Non-invasive positron emission tomography (PET) enables the measurement of metabolic and molecular processes with high sensitivity. PET plays a significant role in the diagnosis, prognosis, and treatment of brain tumors and predominantly detects brain tumors by detecting their metabolic alterations, including energy metabolism, amino acids, nucleic acids, and hypoxia. Glucose metabolic tracers are related to tumor cell energy and exhibit good sensitivity but poor specificity for malignant tumors. Amino acid metabolic tracers provide a better delineation of tumors and cellular proliferation. Nucleic acid metabolic tracers have a high sensitivity for malignant tumors and cellular proliferation. Hypoxic metabolism tracers are useful for detecting resistance to radiotherapy and chemotherapy. Therefore, PET imaging techniques are useful for detecting biopsy-targeting points, deciding on tumor resection, radiotherapy planning, monitoring therapy, and distinguishing brain tumor recurrence or progression from post-radiotherapy effects. However, it is not possible to use only one PET tracer to make all clinical decisions because each tracer has both advantages and disadvantages. This study focuses on the different kinds of PET tracers and summarizes their recent applications in patients with gliomas. Combinational uses of PET tracers are expected to contribute to differential diagnosis, prognosis, treatment targeting, and monitoring therapy.

Although current treatment advances prolong patient survival, treatment for glioblastoma (GBM) in the elderly has become an emerging issue. The definition of "elderly" differs across articles; GBM predominantly occurs at an age ≥65 years, and the prognosis worsens with increasing age. Regarding molecular markers, isocitrate dehydrogenase (IDH) mutations are less common in the elderly with GBM. Meanwhile, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation has been identified in approximately half of patients with GBM. Surgery should be considered as the first-line treatment even for elderly patients, and maximum safe resection is recommended if feasible. Concurrently, radiotherapy is the standard adjuvant therapy. Hypofractionated radiotherapy (e.g., 40 Gy/15 Fr) is suitable for elderly patients. Studies also supported the concurrent use of temozolomide (TMZ) with radiotherapy. In cases wherein elderly patients cannot tolerate chemoradiation, TMZ monotherapy is an effective option when MGMT promoter methylation is verified. Conversely, tumors with MGMT unmethylated promoter may be treated with radiotherapy alone to reduce the possible toxicity of TMZ. Meanwhile, the efficacy of bevacizumab (BEV) in elderly patients remains unclear. Similarly, further studies on the efficacy of carmustine wafers are needed. Based on current knowledge, we propose a treatment diagram for GBM in the elderly.

Introduction In case of cavernous sinus dural arteriovenous fistula (CSDAVF), transvenous embolization (TVE) of the cavernous sinus (CS) via the inferior petrosal sinus (IPS) is generally performed. However, various approach routes have been reported when the accessibility of the IPS is challenging. We herein report a case of CSDAVF treated by TVE with direct puncture of the facial vein. Case report A 70-year-old woman who suffered from tinnitus, chemosis, diplopia and bruit was referred to our hospital. Digital subtraction angiography (DSA) demonstrated CSDAVF. We initially attempted to perform TVE via the IPS route; however, we could not guide a catheter to the CS because of an anatomical difficulty. Then, we performed percutaneous direct puncture of the dilated facial vein, and successfully treated the patient. Conclusion When navigating microcatheter to the CS is difficult because of an anatomical difficulty of the IPS, direct puncture of the facial vein is a feasible route.

Purpose This study assesses the behavior of serial blood lactate measurements during intensive care unit (ICU) stay to identify prognostic factors of unfavorable neurological outcomes (UO) in patients with aneurysmal subarachnoid hemorrhage (SAH). Methods We retrospectively reviewed all patients who were consecutively hospitalized with SAH between 2009 and 2016. Arterial blood lactate levels were routinely obtained on admission and every 6 h in the ICU. Univariate/multivariate analyses were performed to identify independent predictors of UO (modified Rankin scale of 3–6 upon hospital discharge). Results There were 145 patients with 46% of UO. Initially, increased lactate levels reached maximum levels during the first 24 h and then decreased to within the normal range. Then, the levels slightly increased again to within the normal range for the next 24 h, especially in UO. On multiple regression analysis, lactate levels measured at 24 h, and 48 h after admission were strong predictors of UO. Lactate level measured at 48 h after admission demonstrated the greatest accuracy and the highest specificity (area under the curve, 0.716; sensitivity, 40%; specificity, 92.1%). Conclusions The lactate level at 48 h after admission was the most accurate predictor of UO with a high specificity in SAH patients.

The metabolic function of the liver changes sequentially during early life in mammals to adapt to the marked changes in nutritional environment. Accordingly, hepatic fatty acid β-oxidation is activated after birth to produce energy from breast milk lipids. However, how it is induced during the neonatal period is poorly understood. Here we show DNA demethylation and increased mRNA expression of the fatty acid β-oxidation genes in the postnatal mouse liver. The DNA demethylation does not occur in the fetal mouse liver under the physiologic condition, suggesting that it is specific to the neonatal period. Analysis of mice deficient in the nuclear receptor peroxisome proliferator–activated receptor α (PPARα) and maternal administration of a PPARα ligand during the gestation and lactation periods reveal that the DNA demethylation is PPARα dependent. We also find that DNA methylation of the fatty acid β-oxidation genes are reduced in the adult human liver relative to the fetal liver. This study represents the first demonstration that the ligand-activated PPARα-dependent DNA demethylation regulates the hepatic fatty acid β-oxidation genes during the neonatal period, thereby highlighting the role of a lipid-sensing nuclear receptor in the gene- and life-stage–specific DNA demethylation of a particular metabolic pathway.

The present study investigates the neuroprotective effects of d-allose, a rare sugar, against ischemia/reperfusion injury in a gerbil model. Transient forebrain ischemia was induced by occlusion of the bilateral common carotid arteries for 5 min. D-Allose was intravenously injected before and after ischemia (200 mg/kg). Extracellular glutamate and lactate release from the gerbil brain, and PO₂ profiles were monitored during ischemia and reperfusion. We also examined neuronal death and oxidative damage in the hippocampus one week after ischemia reperfusion, and investigated functional outcome. D-Allose administration suppressed glutamate and lactate release compared to vehicle controls. Brain damage, 8-OHdG levels (a marker of oxidative stress) and locomotor activities were significantly decreased by D-allose treatment. The present results suggest that d-allose reduces delayed neuronal death and behavioral deficits after transient ischemia by changing cerebral metabolism and inhibiting oxidative stress.

Background: Pain is regarded as one of the most common nonmotor symptoms in Parkinson's disease (PD). In particular, musculoskeletal pain has been reported as the most common type of PD-associated pain. Crowned dens syndrome (CDS), related to microcrystalline deposition in the periodontoid process, is the main cause of acute or chronic cervical pain. Case Presentation: This report describes the case of an 87-year-old woman who had severe bradykinesia, muscle rigidity, gait disturbance and neck pain. Laboratory examination revealed marked elevations of white blood cells (10,100/µl) and C-reactive protein (CRP; 8.63 mg/dl). She was primarily diagnosed with severe and untreated PD, corresponding to Hoehn and Yahr scale score IV, with musculoskeletal pain and urinary tract infection. The patient was treated with antiparkinsonism drugs, antibiotic agents and nonsteroidal anti-inflammatory drugs, but they had only limited effects. Cervical plain computed tomography (CT) scanning detected remarkable crown-like calcification surrounding the odontoid process. Based on CT findings, the patient was diagnosed as having CDS with PD, and was immediately treated with corticosteroid. The severe neck rigidity with pain and the serum CRP level (0.83 mg/dl) of the patient were drastically improved within a week by the additional corticosteroid therapy. Conclusion: Severe neck rigidity and bradykinesia in this patient might have strengthened the chondrocalcinosis around the odontoid process. Cervical plain CT scan is necessary and useful for the definitive diagnosis of CDS. CDS should be considered as a differential diagnosis of a possible etiology for musculoskeletal pain related to rigidity and bradykinesia in PD.

Purpose Hypoxia and its consequences at the molecular level promote tumour progression and affect patient prognosis. One of the main early cellular events evoked by hypoxia is induction of hypoxia-inducible factor 1 (HIF-1) and subsequent upregulation of vascular endothelial growth factor (VEGF). In this study we sought to determine whether hypoxia detected by 18F-fluoromisonidazole (FMISO) PET accurately reflects the expression of HIF-1α and VEGF in the tumour and can be used as a biomarker of antiangiogenic treatment and as a prognostic factor in newly diagnosed and recurrent malignant gliomas.