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The prevalence of chronic subdural hematoma (CSDH) associated with dural metastasis is uncertain, and appropriate treatment strategies have not been established. This study aimed to investigate the characteristics of and appropriate treatment strategies for CSDH associated with dural metastasis. We retrospectively reviewed the charts of 214 patients who underwent surgery for CSDH. The patients were divided into the dural metastasis group (DMG; n = 5, 2.3%) and no dural metastasis group (No-DMG; n = 209, 97.3%). Patient characteristics, treatment, and outcomes were compared between the two groups. Active cancer was detected in 31 out of 214 patients, 5 of whom (16.1%) had dural metastasis. In-hospital death (80.0% vs. 0%; p 0.001) and recurrence within 14 days (80.0% vs. 2.9%; p 0.001) and 60 days (80.0% vs. 13.9%; p = 0.002) were significantly prevalent in the DMG. All patients in the DMG developed subdural hematoma re-accumulation requiring emergent surgery because of brain herniation, and patients in the DMG had significantly worse recurrence-free survival (p 0.001). This relationship remained significant (p 0.001) even when the analysis was limited to the active cancer cohort (n = 31). CSDH associated with dural metastasis leads to early recurrence and death because of the difficulty in controlling subdural hematoma re-accumulation by common drainage procedures. Depending on the primary cancer status, withdrawal of active treatment and change to palliative care should be discussed after diagnosing CSDH associated with dural metastasis.

Pineal glial cysts associated with bilateral hearing impairment are very rare. Here, we present the case of a 13-year-old boy with a pineal cyst, which caused severe bilateral hearing impairment persisting from 6 years of age. When the patient was 6 years old, the bilateral hearing acuity was about 40 dB on audiometry. Upon admission to our otolaryngology department, his audiogram revealed a bilateral worsening of the hearing acuity (80 dB). Magnetic resonance imaging (MRI) revealed an abnormal pineal cyst with tectal compression from the left with hardly normal bilateral brainstem auditory evoked potentials (BAEPs). We obtained informed consent for exploratory surgery and employed the right occipital transtentorial approach for pineal cyst removal. Based on histological examination, we diagnosed a glial cyst of the pineal gland. At 12 months postoperatively, the patient's hearing improved, showing a bilateral hearing acuity of 40 dB on audiometry. Since the auditory pathway has both crossed and uncrossed fibers at the upper pons and midbrain level, compression at the lateral lemniscus or inferior colliculus level can cause bilateral hearing impairment. In the present case, there was a possible slow pineal cyst growth that eventually compressed the upper pons to the midbrain, lateral lemniscuses, or inferior colliculi from the left side, this eventually led to bilateral hearing impairment. These findings indicate that surgery can improve hearing acuity in patients with a pineal cyst associated with progressive hearing impairment.

Background Microvascular decompression (MVD) is the most effective procedure for hemifacial spasm (HFS). MVD results from nonspecialized or low-volume institutes are not always reliable. Most studies on MVD for HFS are retrospective and single centered; to the best of our knowledge, no prospective, multicenter studies exist. Objective To evaluate short- and long-term outcomes and complications in patients who underwent MVD for HFS in specialized Japanese institutions, in this multicenter, prospective, cohort study. Methods Included patients had undergone MVD for HFS in study centers between April 2012 and March 2015. Patients' postoperative grade of involuntary movements and complications were recorded postoperatively at 7 d (short-term) and at 1 (mid-term) and 3 (long-term) yr. Results A total of 486 patients (150 men, 336 women; mean age 53.9 yr with 181 patients over 60 yr) were enrolled during the study period. Neuromonitoring was used in 96.3% of the cases. The complete cure rate of symptom relief, mortality rate, and complication rate at short-term follow-up were 70.6%, 0%, and 15%, respectively. The long-term follow-up was completed by 463 patients (95.3%); the complete cure rate of symptom relief and complication rate were 87.1% and 3.0%, respectively. Conclusion Our study revealed that under expert guidance and intraoperative neuromonitoring, the long-term curative effect rate of MVD for HFS is high, while complications are uncommon and usually transient. Our results indicate that MVD is an effective and safe treatment for patients with HFS, including elderly patients.

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.

The observation of walking improves gait ability in chronic stroke survivors. It has also been suggested that activation of the mirror neuron system contributes to this effect. However, activation of the mirror neuron system during gait observation has not yet been assessed in sub-acute stroke patients. The objective of this study was to clarify the activation of mirror neuron system during gait observation in sub-acute stroke patients and healthy persons. In this study, we sequentially enrolled five sub-acute stroke patients who had undergone gait training and nine healthy persons. We used fMRI to detect neuronal activation during gait observation. During the observation period in the stroke group, neural activity in the left inferior parietal lobule, right and left inferior frontal gyrus was significantly higher than during the rest period. In the healthy group, neural activity in the left inferior parietal lobule, left inferior frontal gyrus, left middle frontal gyrus, left superior temporal lobule and right and left middle temporal gyrus was significantly higher than during the rest period. The results indicate that the mirror neuron system was activated during gait observation in sub-acute stroke patients who had undergone gait training and also in healthy persons. Our findings suggest that gait observation treatment may provide a promising therapeutic strategy in sub-acute stroke patients who have experienced gait training.

Glioblastoma (GBM) has high mortality rates because of extremely 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) is an emerging and promising approach combined with low-intensity ultrasonication (US) and PpIX as a sonosensitizer for cancer, whereas its efficacy is limited. Based on our previous study that down-regulation of multidrug resistant protein (MDR1) in GBM augmented 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, a MDR1 inhibitor and augmented anti-tumor effects of SDT. MDR1 down-regulation via Akt/NF-kB pathway by celecoxib was confirmed, using a NF-kB inhibitor, CAPÉ. Thus, elevation of cellar PpIX by down-regulation of MDR1 via Akt/NF-kB pathway may be crucial to potentiate the efficacy of SDT in a site-directed manner and provide a promising new therapeutic strategy for GBM.

Background Microvascular decompression (MVD) is the most effective procedure for the long-term management of trigeminal neuralgia (TGN). However, retrospective and single-center studies are inherently biased, and there are currently no prospective, multicenter studies. Objective To evaluate the short- and long-term outcomes and complications in patients with TGN who underwent MVD at specialized Japanese institutions. Methods We enrolled patients with TGN who underwent MVD between April 2012 and March 2015. We recorded their facial pain grade and complications at 7 d (short term), 1 yr (mid-term), and 3 yr (long term) postoperatively. Results There were 166 patients, comprising 60 men and 106 women (mean age 62.7 yr). Furthermore, 105 patients were aged over 60 yr. We conducted neuromonitoring in 84.3% of the cases. The complete pain relief, mortality, and complication rates at the short-term follow-up were 78.9%, 0%, and 16.3%, respectively. Overall, 155 patients (93.4%) completed the long-term follow-up, with the complete pain relief and complication rates of 80.0% and 5.2%, respectively. Conclusion In the hands of experienced neurosurgeons, MVD for TGN can achieve high long-term curative effects. In addition, complications are uncommon and usually transient. Our results indicate that MVD is an effective and safe treatment for patients with TGN, including elderly patients.

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.

BackgroundAntitumor 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.MethodsSix-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.ResultsCompared 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).ConclusionsCombination 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.

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. 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. 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. 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.

Microvascular decompression (MVD) is a widely used, safe, and effective treatment for trigeminal neuralgia (TGN). However, the extent of application of this therapeutic method and its outcomes in Japan are currently unclear. To address these questions, the authors analyzed the use of MVD for the treatment of TGN during the 33-month period from July 2010 to March 2013, using data contained in the Diagnosis Procedure Combination database. The analysis revealed that MVD was used for the treatment of TGN in 1619 cases (608 men, 1011 women), with approximately 1.66 times more women treated than men. MVD for TGN was most frequently performed in individuals 60 to 79 years of age; of particular note was the remarkable increase in the number of women in this particular category. The overall number of procedures performed per 100,000 population/year in Japan was 0.46. The number of procedures was larger in prefectures with higher populations, with a tendency toward a higher number of MVD procedures performed in the area designated West than in the East. Discharge outcomes indicated that cure and improvement were achieved in 97.6% of cases, with a mortality rate of 0.2%, and no differences in discharge outcomes between men and women. The mean length of hospital stay in patients undergoing MVD for TGN was 14.8 days. This analysis revealed discernable trends in the use of MVD for the treatment of TGN in Japan.

Acromegaly is caused by excessive growth hormone secretion, usually from pituitary adenomas. Somoatostatin analogues are widely used as primary or adjunctive therapy in the management of acromegaly. In this report, we present a case with remarkable shrinkage of a tumor after relatively short-term octreotide long-acting release (LAR) administration. During the 30-month follow-up after starting octreotide LAR, there was no recurrence of acromegaly with remarkable shrinkage of the tumor on pituitary magnetic resonance imaging. A literature review of the predictors for tumor shrinkage after the administration of somatostatin analogues in patients with acromegaly is also discussed in relation to this case.

To accurately and rapidly screen for higher brain dysfunction, we developed a screening test named the "higher brain dysfunction screening test" (HIBRID-ST). Previous studies have reported a decrease in higher brain function with age. However, whether HIBRID-ST can detect a decrease in higher brain function in healthy persons remains unclear. We aimed to assess the usefulness of HIBRID-ST for evaluating higher brain function in healthy persons. We recruited 60 persons without physiological abnormalities and divided them into six equal groups based on their age (20s-70s). HIBRID-ST addresses orientation, short-term memory, word recall, situational awareness, visual short-term memory, and graphic replication and includes the Trail Making and Kana-hiroi tests. There was a significant negative correlation between the participants' age and their total HIBRID-ST score (ρ = -0.68, p < 0.01). The total HIBRID-ST score of participants in their 70s was significantly lower than that of participants in their 20s-60s; the total HIBRID-ST score of participants in their 60s was significantly lower than that of participants in their 20s-50s. Our findings show that HIBRID-ST accurately detects an age-related decline in higher brain function. Further studies are needed to examine the usefulness of HIBRID-ST in patients with higher brain dysfunction. J. Med. Invest. 64: 280-285, August, 2017.

Arterial spin labeling (ASL) involves perfusion imaging using the inverted magnetization of arterial water. If the arterial arrival times are longer than the post-labeling delay, labeled spins are visible on ASL images as bright, high intra-arterial signals (IASs); such signals were found within occluded vessels of patients with acute ischemic stroke. The identification of the occluded segment in the internal carotid artery (ICA) is crucial for endovascular treatment. We tested our hypothesis that high IASs on ASL images can predict the occluded segment.Our study included 13 patients with acute ICA occlusion who had undergone angiographic and ASL studies within 48 h of onset. We retrospectively identified the high IAS on ASL images and angiograms and recorded the occluded segment and the number of high IAS-positive slices on ASL images. The ICA segments were classified as cervical (C1), petrous (C2), cavernous (C3), and supraclinoid (C4).Of seven patients with intracranial ICA occlusion, five demonstrated high IASs at C1-C2, suggesting that high IASs could identify stagnant flow proximal to the occluded segment. Among six patients with extracranial ICA occlusion, five presented with high IASs at C3-C4, suggesting that signals could identify the collateral flow via the ophthalmic artery. None had high IASs at C1-C2. The mean number of high IAS-positive slices was significantly higher in patients with intra- than extracranial ICA occlusion.High IASs on ASL images can identify slow stagnant and collateral flow through the ophthalmic artery in patients with acute ICA occlusion and help to predict the occlusion site.

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. Electronic supplementary material The online version of this article (doi:10.1007/s11060-017-2380-5) contains supplementary material, which is available to authorized users.

Background The reported 30-day mortality rate after brain tumor surgery is 2.2% to 2.9%, with a postoperative hematoma (POH) as the most frequent cause of death. Objective To investigate the risk factors for a POH requiring a recraniotomy after brain tumor surgery in a large, contemporary, single-institution consecutive series. Methods We included 1149 patients who underwent surgery for intracranial tumors at the Tokushima University Hospital from 1997 to 2014. The patient charts were retrospectively studied from our prospectively collected database. We analyzed the risk factors, type of hemorrhage, time to reoperation, and outcomes. Results The incidence of a POH requiring a recraniotomy was 2.09%. Among the patients with a POH requiring a recraniotomy, 12.5% died within 30 days of the first surgery. The incidence of a POH requiring a recraniotomy significantly correlated with the incidence of a hemangioblastoma, infratentorial tumors, and a prolonged operative time (>10 h), but not with the patient age or sex, surgical procedure (biopsy or craniotomy), surgical type (primary or secondary), bleeding volume, or intraoperative blood transfusion requirement. A recraniotomy for a POH was performed in 54% of the patients just after the first operation, and within 24 h for 79% of the patients. The clinical status at the time of discharge deteriorated in 52% of the patients. Conclusion Hemangioblastomas, infratentorial tumors, and an operative time exceeding 10 h were significantly correlated with an increased risk of a POH; these factors were responsible for 12.5% of the 30-day surgical mortality rate.

Microvascular decompression (MVD) is widely used as a safe and effective treatment for hemifacial spasm (HFS). However, the extent of application of this therapeutic method and its outcomes in Japan are currently unclear. To address these questions, we analyzed the utilization of MVD for the treatment of HFS during the 33- month period from July 2010 to March 2013. We conducted an analysis on data contained in the Diagnosis Procedure Combination database in Japan. This analysis showed that MVD was used for the treatment of HFS in 2907 cases (men, 916; women, 1991) with 2.2 times more women treated than men. MVD for HFS was most frequently performed in women aged 50 to 69 years; however, most men were aged between 40 and 59 years at the time of the procedure. The numbers of procedures performed per 100,000 population/year were 0.83 overall in Japan, with the numbers larger in prefectures with larger populations. Regarding discharge outcomes, the mortality rate was 0.1%. The mean length of hospital stay in patients undergoing MVD for HFS was 14.7 days. This analysis provides preliminary information regarding the trends in the performance of MVD for the treatment of HFS in Japan. Further studies on other registries that contain data obtained by standardized assessment methods and that include long-term outcomes and postoperative complications are required.

Purpose : To compare data on brain tumors derived from intravoxel incoherent motion (IVIM) and arterial spin labeling (ASL) imaging with multiple parameters obtained on dynamic susceptibility contrast (DSC) perfusion MRI and to clarify the characteristics of IVIM and ASL perfusion data from the viewpoint of cerebral blood flow (CBF) analysis. Methods : ASL-CBF and IVIM techniques as well as DSC examination were performed in 24 patients with brain tumors. The IVIM data were analyzed with the two models. The relative blood flow (rBF), relative blood volume (rBV) corrected relative blood volume (crBV), mean transit time (MTT), and leakage coefficient (K2) were obtained from the DSC MRI data. Results : The ASL-CBF had the same tendency as the perfusion parameters derived from the DSC data, but the permeability from the vessels had less of an effect on the ASL-CBF. The diffusion coefficient of the fast component on IVIM contained more information on permeability than the f value. Conclusion : ASL-CBF is more suitable for the evaluation of perfusion in brain tumors than IVIM parameters. ASL-CBF and IVIM techniques should be carefully selected and the biological significance of each parameter should be understood for the correct comprehension of the pathological status of brain tumors. J. Med. Invest. 66 : 308-313, August, 2019.

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 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.

We review current topics in sport-related head injuries including acute subdural hematoma (ASDH), traumatic cerebrovascular disease, cerebral concussion, and chronic traumatic encephalopathy (CTE). Sports-related ASDH is a leading cause of death and severe morbidity in popular contact sports like American football and Japanese judo. Rotational acceleration can cause either cerebral concussion or ASDH due to rupture of a parasagittal bridging vein. Although rare, approximately 80% of patients with cerebral infarction due to sport participation are diagnosed with ischemia or infarction due to arterial dissection. Computed tomography angiography, magnetic resonance angiography, and ultrasound are useful for diagnosing arterial dissection; ultrasound is particularly useful for detecting dissection of the common and internal carotid arteries. Repeated sports head injuries increase the risks of future concussion, cerebral swelling, ASDH, and CTE. To avoid fatal consequences of CTE, it is essential to understand the criteria for safe post-concussion sports participation. Once diagnosed with a concussion, an athlete should not be allowed to return to play on the same day and should not resume sports before the concussion symptoms have completely resolved. Information about the risks and management of head injuries in different sports should be widely disseminated in educational institutions and by sport organization public relations campaigns.

Highlights • This report describes a patient with VHL syndrome and uncontrolled hypertension due to pheochromocytoma who developed obstructive hydrocephalus and underwent craniotomy for the excision of a cerebellar hemangioblastoma combined with a laparoscopic adrenalectomy. • A rare case of cerebellar hemangioblastoma excision in a patient with von Hippel–Lindau disease complicated by uncontrolled hypertension due to pheochromocytoma. • There is hardly any literature on emergency craniotomy in a patient with von Hippel–Lindau disease. • There are no clear treatment guidelines for the emergency excision of cerebellar hemangioblastomas in patients with intracranial hypertension complicated by abnormal hypertension due to pheochromocytoma whose blood pressure is not sufficiently controlled before surgery., Introduction This report describes a patient with Von Hippel–Lindau (VHL) syndrome and uncontrolled hypertension due to pheochromocytoma who underwent craniotomy for the excision of a cerebellar hemangioblastoma combined with a laparoscopic adrenalectomy. Case report A 31-year-old man presented with severe headache. MRI showed areas of abnormal enhancement in the left cerebellum that were determined to be hemangioblastoma with mass effect and obstructive hydrocephalus. His blood pressure rose abruptly and could not be controlled. CT of the abdomen revealed bilateral suprarenal tumors, and the patient was diagnosed as having VHL syndrome.On the third day, he presented with increasing headache, a decreased level of consciousness, and hemiparesis. We were not able to perform an craniotomy because abdominal compression in the prone or sitting position resulted in severe hypertension. We performed ventricular drainage to control his ICP. On the fifth day, we first performed a bilateral laparoscopic adrenalectomy to control ICP and then moved the patient to the prone position before performing a craniotomy to remove the left cerebellar hemangioblastoma. Discu ssion & conclusion In patients with pheochromocytoma, the effects of catecholamine oversecretion can cause significant perioperative morbidity and mortality, but these can be prevented by appropriate preoperative medical management. When carrying out an excision of cerebellar hemangioblastomas in patients with intracranial hypertension complicated by abnormal hypertension due to pheochromocytoma whose blood pressure is not sufficiently controlled, tumor resection of the pheochromocytoma prior to cerebellar hemangioblastoma excision in the same surgery may prevent increased ICP and reduce perioperative risk.

Biological characteristics of glioblastoma multiforme (GBM), such as resistance to chemo- and radiotherapy and their infiltrative and proliferative nature, suggest that these tumors contain cancer stem cells. However, there are few reports of drug treatments for gliomas that specifically target stem cells. Cyclooxygenase (COX)-2 overexpression is associated with increased angiogenesis, tumor invasion, and the development of tumor cell resistance to apoptosis. Celecoxib is a selective COX-2 inhibitor that has shown anti-neoplastic activity in several malignancies, but this has not been investigated in glioma stem cells (GSCs). We addressed this in the present study by examining the effect of celecoxib on GSCs derived from neural stem cells. Celecoxib induced apoptosis and inhibited proliferation in GSCs. In an orthotopic animal model of GBM, celecoxib suppressed tumor growth, prolonged survival, and reduced the expression levels of C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 10, which are associated with monocyte infiltration and cell proliferation, respectively. These results provide evidence for the anti-neoplastic activity of celecoxib in GSCs and suggest that it can be effective for the treatment of GBM.

The purpose of this study was to evaluate the clinical outcome of boron neutron capture therapy (BNCT) and conventional treatment in patients with newly diagnosed glioblastoma. Since 1998 we treated 23 newly-diagosed GBM patients with BNCT without any additional chemotherapy. Their median survival time was 19.5 months ; the 2-, 3-, and 5-year survival rates were 31.8%, 22.7%, and 9.1%, respectively. The clinical results of BNCT in patients with GBM are similar to those of recent conventional treatments based on radiotherapy with concomitant and adjuvant temozolomide.

We review the current topic in sports-related head injuries including acute subdural hematoma (ASDH), concussion, and chronic traumatic encephalopathy (CTE). Sports-related ASDH is a leading cause of death and severe morbidity in popular contact sports like American football in the USA and judo in Japan. It is thought that rotational acceleration is most likely to produce not only cerebral concussion but also ASDH due to the rupture of a parasagittal bridging vein, depending on the severity of the rotational acceleration injury. Repeated sports head injuries increase the risk for future concussion, cerebral swelling, ASDH or CTE. To avoid fatal consequences or CTE resulting from repeated concussions, an understanding of the criteria for a safe post-concussion return to play (RTP) is essential. Once diagnosed with a concussion, the athlete must not be allowed to RTP the same day and should not resume play before the concussion symptoms have completely resolved. If brain damage has been confirmed or a subdural hematoma is present, the athlete should not be allowed to participate in any contact sports. As much remains unknown regarding the pathogenesis and pathophysiology of sports-related concussion, ASDH, and CTE, basic and clinical studies are necessary to elucidate the crucial issues in sports-related head injuries.

BACKGROUND Antitumor therapies targeting programmed cell death-1 (PD-1)/its ligand-1 (PD-L1) are influential at present stage. However, in glioblastoma (GBM), the expression of PD-L1 is variable and the role of anti-PD-1 antibody therapy is still unclear. The high expression of PD-L1 affects cell proliferation and invasion in GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested our hypothesis that a COX-2 inhibitor, celecoxib may play a role on anti-PD-1 antibody treatment via down-regulation of PD-L1. METHODS Six weeks old male C57BL/6 mice subjected to intracranial injection of mice glioma stem cells (GSCs) were randomly divided into four treatment groups; vehicle control (VC), celecoxib, anti PD-1 antibody or the combination of celecoxib and anti-PD-1 antibody groups and examined antitumor effects. To verify the mechanisms underlying antitumor effects, mice GSCs and human GBM cells were used. RESULTS Compared to each single treatment in the glioma model, the combination therapy of anti PD-1 antibody and celecoxib significantly decreased the tumor volume and improved the survival period. Importantly, the high expression of PD-L1 in the glioma model, mice GSCs and human GBM cells was decreased by celecoxib. Interestingly, the reduction of PD-L1 was associated with post-transcriptional regulation of co-chaperone FK506-binding protein 5 (FKBP5) by celecoxib. The combination therapy of anti PD-1 antibody with celecoxib could be a promising therapeutic strategy targeting PD-L1 in GSCs and GBM. CONCLUSIONS Down-regulation of PD-L1 via FKBP5 by celecoxib may play a role on the antitumor effects under the overwhelmed expression of PD-L1.

Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase, is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma and their functional roles in malignant glioma are not well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas, glioblastomas, and non-neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knock-down and the over-expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas.

Craniopharyngiomas are 5–10 % of all pediatric tumors, but are seldomly encountered in the perinatal period. Only seven instances of a truly antenatal diagnosis of a congenital craniopharyngioma that subsequently underwent radical surgery have been reported. We present the case of a patient who received the diagnosis of a suprasellar tumor during the prenatal period and received radical surgery. We report a case of a neonatal craniopharyngioma treated surgically. The pregnancy progressed uneventfully until a routine ultrasound at 37 weeks of gestation showed a 15 × 15 mm high echoic mass in the center of the fetal head. Neonatal Gd-enhanced T1-weighted MRI at 5 days of life showed a homogenously enhanced mass (16×22×15 mm) in the sellar and suprasellar lesion. As the tumor showed rapid growth at the 3rd month of life, the patient underwent a surgical treatment and the mass was totally removed. Three years later, the physical and mental development of the patient was normal, and Gd-MRI studies showed no tumor recurrence. The present case is the eighth case of a truly antenatal diagnosis of a craniopharyngioma that underwent successful radical surgery. Craniopharyngioma is a benign tumor and thought to be a slow growing tumor in childhood. The results of radical surgery were very poor, and the mortality and morbidity rates were high in the previous reports due to the huge size of tumor at operation. The present case demonstrated the rapid growth in short interval of Gd-MRI. This is the first report of tumor kinetics of congenital craniopharyngioma with previous reports. The calculated tumor doubling time in our case was 37 days.

Purpose In the imaging of intra-axial brain tumors, we sometimes found areas of high signal intensity around the enhanced tumor lesions on arterial spin labeling (ASL) magnetic resonance (MR) imaging. We undertook this study to investigate the relationship between high signal intensity on ASL imaging outside the area of contrast enhancement (CE) and histological diagnosis of intra-axial brain tumors. Methods We examined images from 28 consecutive patients with intra-axial brain tumors who underwent ASL and CE MR imaging-three with low grade glioma (LGG), 13 with high grade glioma (HGG), six with metastasis, and six with primary central nervous system lymphoma (PCNSL)-and divided imaging findings into an "ASL dominant" group when hyperintensity on ASL was found outside the CE area and a "CE dominant" group when hyperintensity on ASL was not found outside the area of enhancement. We then analyzed the relationship between imaging findings and the histological diagnosis of the tumors. Results Four cases were excluded because of poor quality of ASL images, 7 cases were classified as ASL dominant, and 17 cases were classified as CE dominant. The histological diagnoses of ASL dominant cases were LGG in 3 cases, HGG in 3 cases, and PCNSL in one case. Those of CE dominant cases were HGG in 10 cases, metastasis in 5 cases, and PCNSL in 2 cases. All cases with brain metastasis were classified as CE dominant. Conclusion The high signal intensity outside the area of contrast enhancement is probably caused by increased perfusion or vascular proliferation, which indicates the presence of glioma or PCNSL and not metastasis. This finding indicates a new utility for ASL images in the diagnosis of brain tumors as a supplement to the conventional measurement of perfusion obtained from ASL images.

This study sought to determine the diagnostic utility of perfusion parameters derived from dynamic contrast-enhanced (DCE) perfusion MRI with a short acquisition time (approximately 3.5 min) in patients with glioma, brain metastasis, and primary CNS lymphoma (PCNSL). Twenty-six patients with 29 lesions (4 low-grade glioma, 13 high-grade glioma, 7 metastasis, and 5 PCNSL) underwent DCE-MRI in a 3 T scanner. A ROI was placed on the hotspot of each tumor in maps for volume transfer contrast K trans , extravascular extracellular volume V e , and fractional plasma volume V p . We analyzed differences in parameters between tumors using the Mann–Whitney U test. We calculated sensitivity and specificity using receiver operating characteristics analysis. Mean K trans values of LGG, HGG, metastasis and PCNSL were 0.034, 0.31, 0.38, 0.44, respectively. Mean Ve values of each tumors was 0.036, 0.57, 0.47, 0.96, and mean Vp value of each tumors was 0.070, 0.086, 0.26, 0.17, respectively. Compared with other tumor types, low-grade glioma showed lower K trans (P

Approximately half of the patients with low-grade glioma (LGG) treated surgically suffer recurrence or metastasis. Malignant transformation sometimes occurs after several years and no effective drug treatment has been established yet. Though the selective COX-2 inhibitor celecoxib showed anti-tumor effects against several malignant tumors, its effects against LGG remain to be established. To test our hypothesis that the celecoxib has an anti-tumor effect in LGG, we used human glioma and GBM cell lines (1321N1, SW1088, U87MG, U251MG, and NHA). First, we confirmed the high expression of COX-2 in 12 tissue samples from glioma patients: astrocytoma (glioma grade II, n=2), anaplastic astrocytoma (glioma grade III, n=5), and glioblastoma (glioma grade IV, n=5). We also found that the COX2 expression in LGG cell lines was higher than that in the non-neoplastic region and in normal brain cells. We demonstrated that celecoxib suppressed LGG cell proliferation in a dose-dependent manner. Next, we investigated the mechanisms underlying the anti-tumor effects and found that celecoxib inhibited the generation of prostaglandin E2 and induced apoptosis and cell-cycle arrest. Finally we manifested that celecoxib inhibits the activation of the AKT/survivin and AKT/ID3 pathways in LGG. These findings suggest that celecoxib may have promising therapeutic potential and that early celecoxib treatment to patients with LGG may be beneficial.

Objective To determine the features of catastrophic judo head injuries and the effects of prevention activities. Study Design Retrospective descriptive epidemiological study Methods We reviewed catastrophic head injuries in 44 judo players reported in the System for Compensation of Loss or Damage in the All Japan Judo Federation from 2003 to 2015. Prevention activities such as safety manual creation and enlightenment courses for judo instructors, including understanding of the consensus statement on concussion, were introduced in 2011. The incidences of death and poor outcomes before (Group A) and after (Group B) these prevention activities were compared. Results The majority of catastrophic head injuries were acute subdural hematoma. The average patient age was 16.5 years. Most of the injured patients were novices without fully developed physical stamina and skills. Furthermore, Ukemi, a protection technique applied while being thrown, had not been fully mastered. Among 36 Group A players, 8 (23%) had a prior history of judo-related head injury with posttraumatic headache. In 4 of these 8 patients, CT and/or MRI detected a thin subdural hematoma during evaluation for persistent headache. Annual rates of catastrophic head injury were 4.0 in Group A for 9 years and 2.0 in Group B for 4 years, and the annual respective mortality rates were 2.0 and 0.25. Both rates were reduced after the prevention action introduced in 2011, although the decreases were not statistically significant. Conclusions Continuous prevention activities can reduce catastrophic judo head injuries. Competing interests Authors have no conflicts of interest regarding this study.

The purpose of this study was to evaluate the clinical outcome of BSH-based intra-operative BNCT (IO-BNCT) and BSH and BPA-based non-operative BNCT (NO-BNCT). We have treated 23 glioblastoma patients with BNCT without any additional chemotherapy since 1998. The median survival time (MST) of BNCT was 19.5 months, and 2-year, 3-year and 5-year survival rates were 26.1%, 17.4% and 5.8%, respectively. This clinical result of BNCT in patients with GBM is superior to that of single treatment of conventional radiotherapy compared with historical data of conventional treatment.

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.

Astroblastomas are rare glial tumors. We report a case of 33-year-old woman with high-grade astroblastoma with hypervascularity. She had a one-month history of right visual disturbance and papillar edema. MRI revealed a lobulated mass with cysts and flow voids in the right superficial frontal lobe, a phenomenon described as "bubbly appearance". Right carotid angiography demonstrated marked tumor stain and early venous filling. MR spectroscopy showed an increase in myoinositol and the choline/creatine ratio, and decreased N-acetyl aspartate. The lipid and lactate level was not increased. The well-circumscribed tumor was totally resected. Histological examination showed perivascular pseudorosettes and hyalinization of blood vessels with high cellularity, anaplastic nuclear features, focal necrosis, mitosis, and endothelial proliferation. Immunohistochemically, glial fibrillary acidic protein and S-100 protein were intensely positive and the MIB-1 labeling index was high(20%)in the tumor cells. Based on these findings, a diagnosis of high-grade astroblastoma was made. The patient received postoperative radiotherapy and chemotherapy with temozolomide and suffered no relapse in the course of 3 years after surgery. Characteristically, astroblastomas manifest a "bubbly appearance" and a lobulated mass on MRI scans. As these tumors tend to be hypervascular, angiograms are useful for designing the operative strategy. However, their low-or high grade is difficult to ascertain preoperatively based on MRI-, MRS-, and DSA findings. The standard therapy for high-grade astroblastoma is total resection and postoperative radiation therapy. As the incidence of tumor recurrence is high, we recommend additional chemotherapy with TMZ.

Boron neutron capture therapy (BNCT) has been reported to be effective in the patients with glioblastoma multiforme (GBM). Median survival time (MST) of GBM patients treated with BNCT is approximately two years. GBM patients surviving 2 or 3 years are considered long-term survivors. In general, most recurrences are local and dissemination is rare. We report an unusual patient with three recurrences; the first and the second recurrences were local, and the third recurrence was dissemination nine years after BNCT.

The purpose of this study was to clarify the correlation between the radiation dose and histopathological findings in patients with glioblastoma multiforme (GBM) treated with boron neutron capture therapy (BNCT). Histopathological studies were performed on specimens from 8 patients, 3 had undergone salvage surgery and 5 were autopsied. For histopathological cure of GBM at the primary site, the optimal minimal dose to the gross tumor volume (GTV) and the clinical target volume (CTV) were 68Gy(w) and 44Gy(w), respectively.

Interferon-beta (IFN-β) is reported to augment anti-tumor effects by temozolomide in glioblastoma via down-regulation of MGMT. Promyelocytic leukemia (PML), a gene induced by IFN-β, is a tumor suppressor. Here, we report for the first time that in combination therapy, an IFN-β-induced increase in endogenous PML contributes to anti-tumor effects in p53 wild- and mutant glioma cells in a xenograft mice model. The increased PML promoted the accumulation of p73, a structural and functional homolog of p53, to fuse the coactivator Yes-associated-protein in the PML nuclear bodies. The adjuvant therapy targeted at PML may be a promising therapeutic strategy for glioblastoma.