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Recently, the survival of the high-risk population of preterm infants has steadily improved, and the severity of prematurity is a growing threat of gestational-age-related fatal conditions. Posthemorrhagic hydrocephalus (PHH) is the most common but serious neurological complication in premature infants, which can have life-threatening consequences during the acute phase in the neonatal period and life-long psychomotor and cognitive sequelae in their later life. Although neonatologists, pediatric neurologists, and pediatric neurosurgeons have investigated a diversified strategy for several decades, a consensus on the best management of PHH in premature infants still must be reached. Several approaches have tried to reduce the incidence of intraventricular hemorrhage (IVH) and mitigate the effect of IVH-related hydrocephalus. This paper reviews and discusses the clinical feature of PHH in premature infants, general/nonsurgical management of prematurity for IVH prevention, and posthemorrhagic management, and how and when to intervene.

Data on the outcomes of CyberKnife-based hypofractionated stereotactic radiosurgery (hSRS) for intracranial and extracranial nonvestibular schwannomas (nVSs) are not sufficient.Patients who underwent hSRS for nVSs between 2010 and 2019 were retrospectively reviewed.A total of 39 patients with 39 nVSs were identified. The mean age was 53 (±18) years, and 20 patients (51%) were women. Twenty-five patients (64%) had previous surgeries. Seventeen patients (44%) had nVSs extending outside the cranium. The mean prescribed dose covering 95% of the planning target volume was 22 Gy (±3.7 Gy), the mean fractionation was 4 (±2), and the mean target volume was 13 cmWe summarized the treatment outcomes of hSRS for nVSs. Although all patients achieved radiological tumor control, the risk of either transient or permanent ARE was high. Therefore, it is necessary to monitor patients for clinical deterioration due to AREs.

Objective To assess long-term outcomes of hypofractionated stereotactic radiotherapy (hSRT) for head and neck paragangliomas (HNPGs). Methods Patients who underwent hSRT with CyberKnife for HNPGs from 2010 to 2019 were retrospectively reviewed. Results A total of 34 HNPGs in 29 patients were identified. Mean patient age was 50 ± 16 years, and 15 patients (52%) were female. Fifteen patients (55%) had undergone previous procedures. Four cases (14%) were functional in hormone production. According to the Fisch classification, 1 (3%) case was B, 12 (42%) cases were C, 14 (48%) cases were D, and 2 (7%) cases were unclassified. 1 The median prescribed dose covering 95% of the planning target volume was 2500 cGy (interquartile range 2100–2600 cGy), and the median target volume was 10 cm3 (interquartile range 6.0–18.3 cm3). The local control rate was 97%. The median progression-free survival was 66 months (interquartile range 28–95 months), and 96% of patients were free of tumor progression at 8 years. During follow-up, 1 case (3%) resulted in permanent facial nerve palsy (House-Brackmann grade II), and another case (3%) resulted in asymptomatic cerebellar radiation necrosis. Univariate and multivariate analysis showed that no previous surgical history (odds ratio 8.58, 95% confidence interval 1.2–59.7, P = 0.03) was a positive predictor of symptomatic improvement. Conclusions hSRT for HNPGs was an effective treatment with minimal side effects over the long term and may have a role as first-line therapy, especially for symptomatic nonfunctional HNPGs, for better symptom control.

Although the use of newly developed procedures such as endoscopic third ventriculostomy or coagulation of the choroid plexus has gradually expanded, ventriculoperitoneal(VP)shunts are still not obsolete. They are the most commonly performed surgery for treating pediatric hydrocephalus. Young neurosurgeons may frequently encounter this CSF diversion procedure in clinical practice. However, the VP shunt remains a failure-prone procedure, as exemplified by obstruction, infection, mechanical shunt failure, over drainage, and distal catheter site-specific failures. Therefore, surgery requires exquisite techniques, especially in the pediatric population, to meet the needs of the child's growth. This article sheds light on the refined methodology for pediatric VP shunting with meticulous details of the surgical technique. Neurosurgeons must always remember that appropriate ICP control has a major impact on patient development and that a stably functioning VP shunt can deliver the full potential of children with hydrocephalus.

This is the first report of a carotid aneurysm that developed from a cavernous carotid artery contiguous with a prolactinoma during medical treatment of the prolactinoma, which gradually grew larger while the tumor regressed. A 78-year-old woman presented with headache and neurological symptoms indicating the involvement of cranial nerves in the cavernous sinus. Gadolinium-enhanced T1-weighted magnetic resonance imaging on admission revealed an abnormal right cavernous sinus, with an approximately 17 mm mass extending into the right cavernous portion of the internal carotid artery, and was contiguous with the intracavernous carotid artery. She was diagnosed with pituitary apoplexy due to a prolactinoma and started cabergoline treatment. After medical treatment, a carotid aneurysm emerged. The aneurysm continued to grow and reached a maximum diameter of 10.4 mm at 81 months after the initiation of treatment. The patient underwent endovascular coil embolization, following which the aneurysm regressed. Association between a prolactinoma and the development of a contiguous aneurysm remains undetermined. However, this is an odd phenomenon, and to the best of our knowledge, this is the first reported case of the development of an aneurysm that was associated with a pituitary tumor.

When trigeminal neuralgia recurs after microvascular decompression surgery, re-operation may be indicated if trigeminal nerve compression remains. However, surgery for recurrent trigeminal neuralgia is more difficult because of adhesions between the prosthesis, such as the Teflon sling, and the surrounding structures, including the blood vessels, in addition to common post-open surgery adhesions.A case of a patient with recurrent trigeminal neuralgia is presented.Preoperative evaluation of the compression of the trigeminal nerve is important. The pre-existing prosthesis does not necessarily need to be removed entirely.

Few reports exist demonstrating the effects of stereotactic radiotherapy (SRT) on the central skull base meningiomas (CSMs). A retrospective analysis of 113 patients was performed. The median age was 62 (IQR 50–72) years old, and 78 patients (69%) were female. Upfront SRT was performed in 41 (36%), where 17 (15%) patients were asymptomatic. The other SRT was for postoperative adjuvant therapy in 32 (28%), and for the recurrent or relapsed tumors in 40 (35%) patients. Previous operation was done in 74 patients (66%). Among the available pathology in 46 patients, 37 (80%) were WHO grade I, 8 (17%) were grade II, and 1 (2%) was grade III. The median prescribed dose covered 95% of the planning target volume was 25 (IQR 21–25) Gy, and the median target volume was 9.5 (IQR 3.9–16.9) cm3. The median progression-free survival (PFS) was 48 (IQR 23–73) months and 84% and 78% were free of tumor progression at 5 and 10 years respectively. The median follow-up was 49 (IQR 28–83) months. PFS was better in grade I than grade II (p = 0.02). No other baseline factors including the history of previous operation were associated with PD or PFS. Adverse events of radiation therapy were radiation-induced optic neuropathy (0.9%), and cerebral edema (4.4%). Asymptomatic cavernous carotid stenosis was found in three (2.7%), five (4.4%) underwent ventriculoperitoneal shunt placement for normal pressure hydrocephalus, and five (4.4%) died. SRT is useful for the management of CSMs with a low rate of adverse events.

Patients with distant metastases of borderline phyllodes tumors (PT) are rare, and their prognosis is very poor. Here, we report the case of a 59-year-old Japanese woman with metastatic brain, lung, stomach, and colon lesions originating from a borderline PT in her left breast. After surgical treatment of the left frontal lobe tumor and the right upper lung tumor, and first-line chemotherapy with doxorubicin monotherapy, magnetic resonance imaging (MRI) revealed new metastatic lesions in the left cerebrum and bilateral frontal lobe. A next-generation sequencing clinical assay revealed that her tumor had platelet-derived growth factor receptor beta (PDGFRB) point mutation (p.N666K). On the basis of genetic analysis, a multitargeted tyrosine kinase inhibitor, pazopanib, was administered as the second-line chemotherapy. Most of her metastatic lesions, including brain metastases, showed a deep shrinkage, which persisted for 12 months. This is the first report that PDGFRB, which is a druggable pathogenic alteration, exists in PT. Genotype-matched therapy can be effectively used to treat rare malignant tumors.

Background The long-term outcomes of CyberKnife-based hypofractionated stereotactic radiotherapy (SRT) for intra/ extracranial non-vestibular schwannomas (nVS) need to be accumulated. Method Patients who received SRT by CyberKnife for nVS from 2010 to 2019 were retrospectively reviewed. Results A total of 45 patients with nVS were identified. The mean age was 53 (± 18) years old, and 23 patients (51%) were female. Twenty-nine patients (64%) had previous procedures. As for the tumor extension, 22 (49%) nVS were classified as primary intracranial, five (11%) were classified as intra/ extracranial (dumbbell shape), and 18 (40%) were classified as primary extracranial. The median prescribed dose, covering 95% of the planning target volume, was 21 (IQR 21 – 25) Gy, and the median target volume was 7 (IQR 3.6-13.1) cm3. The local control rate of nVS for patients without neurofibromatosis type 2 (NF2) was 100%. Old age (OR 0.92, p-value 0.03) and previous surgery (OR 0.02, p-value 0.02) were significant risk factors for no symptomatic improvement. The progression-free survival was 74 (±33) months clinically and 69 (IQR 36 – 94) months radiologically. During follow-up, two cases (4%) with NF2 resulted in treatment failure, 13 cases (41%) resulted in transient tumor expansion (TTE), 10 (22%) suffered from transient adverse radiation effect (ARE), and two (4%) resulted in permanent ARE. Conclusions Hypofractionated SRT for head, neck, and spine nVS was an effective treatment regardless of tumor extension relative to the cranium. Although the risk of permanent ARE was low, some patients experienced transient clinical worsening due to TTE.

Sinking skin flap syndrome (SSFS), also known as syndrome of the trephined, is one of the complications of decompressive craniectomy. The definitive treatment for the condition is cranioplasty, but there are cases where that is not an option. We report a seventy-seven-year-old male patient with disturbance of consciousness after removal of infected bone flap and debridement. The skin showed marked depression and SSFS was diagnosed. The scalp had contracted due to infection and debridement so as to need skin grafting. Cranioplasty with a full-size bone flap was not an option. Reconstruction of the temporal line with autologous rib graft was performed. The patient became alert after the operation.

Background: Cerebellar hemorrhage is rare in children, and its cause is usually vascular disorders such as arteriovenous malformations or hematological disorders. Case Description: A previously healthy 10-year-old girl presented with a loss of consciousness following sudden headache and vomiting. A non-contrast brain computed tomography (CT) scan revealed a massive cerebellar hemorrhage with obstructive hydrocephalus; however, subsequent CT angiography (CTA) showed no vascular abnormalities. An emergency craniotomy was performed to evacuate the hematoma, and histological analysis of the specimen obtained from the tissue surrounding the hematoma revealed a pilocytic astrocytoma (PA). Six months after the ictus, her recovery was scored at 2 on the modified Rankin Scale. Conclusion: PA can be a cause of critical cerebellar hemorrhage. In this case of life-threatening massive hematoma, CTA was useful to exclude a major vascular pathology and to save time.

BACKGROUND Endoscopic surgery is widely used for intraventricular and skull base tumor resections; however, its utility is not limited to deep parts of the brain. METHOD A 73-year-old female presented with left-side hemiparesis and seizures due to a relapsed atypical meningioma of convexity. The tumor was located just under a synthetic bone substitute and was covered by a delicate myocutaneous free flap, preventing the usual skin incision route to approach the lesion. RESULT The tumor was successfully removed using an endoscope without damaging the flap. CONCLUSION With the aid of an endoscope, a superficial meningioma could be removed with the affected dura through a small craniotomy.

In a previous study, we showed that folate receptor‐α (FRα) translocates to the nucleus where it acts as a transcription factor and upregulates Hes1, Oct4, Sox2, and Klf4 genes responsible for pluripotency. Here, we show that acetylation and phosphorylation of FRα favor its nuclear translocation in the presence of folate and can cause a phenotypic switch from differentiated glial cells to dedifferentiated cells. shRNA‐FRα mediated knockdown of FRα was used to confirm the role of FRα in dedifferentiation. Ocimum sanctum hydrophilic fraction‐1 treatment not only blocks the folate mediated dedifferentiation of glial cells but also promotes redifferentiation of dedifferentiated glial cells, possibly by reducing the nuclear translocation of ~38 kDa FRα and subsequent interaction with chromatin assembly factor‐1. stem cells 2019;37:1441–1454, Possible mechanisms by which Ocimum sanctum hydrophilic fraction‐1 prevents the formation of folate receptor‐α complex are: (a) the caffeoylquinic acid component of O. sanctum hydrophilic fraction‐1 presumably decreases acetylation of folate receptor‐α by decreasing the acetyl transferase or increasing the deacetylases activity, and subsequent nuclear translocation, and (b) since nuclear folate receptor‐α binds to chromatin assembly factor‐1 in folate‐induced dedifferentiated cells and not in differentiated glial cells, the reduction of folate receptor‐α in the nucleus by O. sanctum hydrophilic fraction‐1 may reactivate chromatin assembly factor‐1 and favor differentiation.

Few reports exist demonstrating the effects of CyberKnife radiotherapy (CKRT) on the central skull base meningiomas (CSMs). Retrospective analysis of 113 patients were performed. The median age was 62 (IQR 50 – 72) years old, and 78 patients (69%) were female. Upfront CKRT was performed in 41 (36%), where 17 (15%) patients were asymptomatic. The other CKRT was for postoperative adjuvant therapy in 32 (28%), and for the recurrent or relapsed tumors in 40 (35%) patients. Previous operation was done in 74 patients (66%). Among the available pathology in 46 patients, 37 (80%) were WHO grade I, 8 (17%) were grade II, and 1 (2%) were grade III. The median prescribed dose covered 95% of the planning target volume was 2500 (IQR 2100 – 2500) cGy and the median target volume was 9.5 (IQR 3.9 – 16.9) cm3. The median PFS was 48 (IQR 23 – 73) months and 84% and 78% were free of tumor progression at five, and 10 years respectively. The median follow-up was 49 (IQR 28 – 83) months. PFS was better in grade I than grade II (p = 0.02). No other baseline factors including the history of previous operation was associated with PD or PFS. Adverse events of radiation therapy were radiation- induced optic neuropathy (0.9%), and cerebral edema (4.4%). Asymptomatic cavernous carotid stenosis was found in three (2.7%), five (4.4%) underwent ventriculoperitoneal shunt placement for normal pressure hydrocephalus, and five (4.4%) died. CKRT is useful for the management of CSMs with low rate of adverse events.

IntroductionTo analyze the long-term follow-up data of CyberKnife treatment (CKT) for head and neck paragangliomas (HNPGs). MethodsPatients who received CKT to HNPGs from 2010 to 2019 were retrospectively reviewed. ResultsA total of 34 HNPGs from 29 patients were identified. The mean age was 50 (± 16) years old, and 15 patients (52%) were female. Previous operation was done in 15 patients (55%). Four cases (14%) were functional in hormone production. According to Fisch classification, one case (3%) was B, 12 (42%) were C, 14 (48%) were D, and two cases (7%) were out of classification. The median prescribed dose covered 95% of the planning target volume was 2500 (IQR 2100 – 2600) cGy and the median target volume was 10 (IQR 5.8 – 21.3) cm3. The local control rate was 97%. The median progression-free survival was 66 (IQR 27.5 – 95.0) months and 93.8%, and 91.7% were free of tumor progression at five, and seven years respectively. During the follow-up, one case (3%) resulted in permanent facial nerve palsy (CTCAE 1, House-Brackmann grade II), and another case (3%) resulted in asymptomatic cerebellar radiation necrosis. Univariate and multivariate analysis showed no previous surgical history (OR 10.3, 95% CI 1.5 – 69.3, p = 0.02) was a positive predictor of symptom improvement. We devised a treatment flow-chart based on our finding. ConclusionsCKT for HNPGs was an effective treatment with little side effect over the long term and should be considered the first-line therapy for symptomatic nonfunctional HNPGs for better symptom control.

Background: A dissection beginning from a point distal to the endpoint of the carotid endarterectomy (CEA) is called distal carotid artery dissection (CAD), which is known as one of the significant surgical complications of CEA. Case Description: We present a case of distal CAD as a perioperative complication after CEA using indwelling shunt. We estimated this pathophysiology to be caused by the mechanical conflict of the inflated balloon with the elongated styloid process. Conclusion: Since a distal CAD can cause severe, irreversible neurological deficits, preoperative assessment of the styloid process should be routinely performed in CEA.

Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have been associated with steroid-responsive cortical encephalitis and comorbid generalized epilepsy. A 44-year-old woman developed repeated epilepsia partialis continua (EPC) without generalized seizures and was anti-MOG antibody-positive. Radiological abnormalities were detected in the bilateral medial frontoparietal cortices, but there were no cerebrospinal fluid abnormalities. She achieved remission with anti-epileptic drugs alone. However, encephalitis recurred four months later when pleocytosis appeared, and steroid therapy was effective. Altogether, EPC without typical cerebrospinal fluid features can be an early sign of anti-MOG antibody-positive encephalitis. Thus, patients with EPC of unknown etiology need to be screened for anti-MOG antibodies.

Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive tumors of the central nervous system that predominantly affect infants. Although adult AT/RT are rare, accumulated cases have revealed adult-specific AT/RT in the sellar region. Twelve previously reported cases of sellar AT/RT exclusively occurred in adult females, suggesting biological differences from conventional infant AT/RT. We herein investigated a series of 6 sellar AT/RT for histopathologic features, the molecular status of the INI1/SMARCB1 gene, and clinical courses. All 6 cases were adult females, ranging in age from 21 to 69 years old. Tumors were histologically characterized by a hemangiopericytoma-like stag-horn vasculature within a dense, diffuse proliferation of jumbled cells and a small number of scattered rhabdoid cells. This vascular pattern is not a common finding in AT/RT and appears to be a characteristic histology of sellar AT/RT. Biallelic alterations in the INI1 gene were identified by fluorescence in situ hybridization, direct sequencing, and multiple ligation-dependent probe amplification analyses in 4 of the 5 cases analyzed. Three of the 4 cases harbored 2 different mutations, presumably on different alleles (compound heterozygous mutations), and 1 case of which had a splice-site mutation. Combined with previous findings, the prevalence of compound heterozygous mutations and splice-site mutations was significantly higher in sellar AT/RT than in pediatric AT/RT. Sellar AT/RT represent a clinicopathologically and possibly genetically distinct variant of AT/RT showing a characteristic demography, different patterns of INI1 alterations, and a histology featured by a unique vasculature.

Spontaneous recanalization of an atherosclerotic internal carotid artery (ICA) occlusion has been previously reported as a rare phenomenon, but spontaneous re-occlusion shortly after recanalization under antiplatelet therapy has not been documented yet. A 63-year-old man presented with impaired consciousness and left-sided hemiparesis. Magnetic resonance imaging showed new infarction in the right middle cerebral artery territory because of right cervical internal carotid artery occlusion, which became spontaneously patent on computed tomography angiography on the sixth day of admission. So carotid endarterectomy was planned. However, the ICA was recurrently occluded on the preoperative magnetic resonance angiogram three weeks later on admission, which condition was also confirmed during the subsequent surgery. In patients with severe ICA stenosis, patency may dynamically change even under antiplatelet therapy.

Superficial temporal artery (STA)-middle cerebral artery (MCA) bypass, and STA-anterior cerebral artery (ACA) bypass, are options for direct revascularisation of anterior circulation. However, some patients don't have a suitable STA to use as a donor, so an alternative procedure must be performed. A 59-year-old, right-handed man presented with dysphasia and right-sided hemiparesis due to a transient ischaemic attack. Imaging studies revealed severe stenosis of the left internal carotid artery bifurcation. Iodoamphetamine single photon emission computed tomography demonstrated reduced cerebrovascular reserve capacity in the left hemisphere. The patient was started on antiplatelet therapy, but the ischaemic attacks persisted after one month. Thus, revascularisation of the ACA and MCA territories was considered. Digital subtraction angiography revealed prominence in the left occipital artery (OA) and posterior auricular artery (PAA), while the left STA was hypoplastic, terminating at the squamous suture level. Therefore, anastomoses were performed between both the OA and ACA and the PAA and MCA. Revascularisation was successful, and the ischaemic attacks disappeared. OA-ACA bypass, together with PAA-MCA bypass, may be effective for wide cerebral revascularisation when the STA is not available.

The vital role of folic acid is to reduce the risk of having a neonate afflicted with neural tube defects. The prevalence of neural tube defects (myelomeningocele and anencephaly) has been reported in an incomplete form over the last 40 years in Japan. We aimed to evaluate the total number of neural tube defects including those delivered or terminated, to clarify the proportion of those terminated, and to internationally compare their prevalence. Through information on >311 000 deliveries obtained from 262 hospitals/clinics for 2 years of 2014 and 2015, we identified that the rate of total neural tube defects (termination of pregnancy, live births and stillbirths) was 8.29 per 10 000 deliveries for the year 2014 and was 8.72 for 2015, which were 1.5 and 1.6 times higher than the respective values (live births and stillbirths) reported. It is also observed that the ratio of the total number of myelomeningocele (termination of pregnancy, live births, and stillbirths) to that of anencephaly was approximately 1:1.2, that a half of pregnancies afflicted with neural tube defects were terminated, and that the proportion of termination of pregnancy due to myelomeningocele and due to anencephaly was 20% and 80%, respectively. Internationally, the real prevalence of neural tube defects in Japan was comparatively high, ranking fifth among the seven developed countries. In conclusion, the real prevalence of total neural tube defects was approximately 1.5 times higher than that currently reported by the Japan Association of Obstetricians and Gynecologists.

INTRODUCTION In recent years, hypofractionated radiotherapy (HRT) 40Gy in 15 fractions with concomitant temozolomide(TMZ) has come to be used as standard treatment for elderly glioblastoma. However, the treatment duration of 3–4 weeks for radiation is not enough short, and there is also a problem of radiation sickness. We performed hypofractionated stereotactic radiotherapy with CyberKnife (CK) for less than 2weeks. We retrospectively analyzed eight newly diagnosed elderly patients with glioblastoma treated by CK. METHODS Surgical cavity, contrast enhanced lesion, FLAIR high signal intensity area were set as gross tumor volume (GTV). To planned target volume (PTV) as GTV + 2 mm, Marginal dose (D95) 35 Gy in 5 fractions (Fr) was prescribed. The dose prescription and number of fractions were adjusted taking into consideration dose distribution, dose-limiting for important organs such as optic chiasm and brainstem. RESULTS The eight patients consisted of 3 men and 5 women. The median age was 78 (range 68–84) years old. All patients were pathologically diagnosed as glioblastoma. Two of 8 cases had undergone gross total removal of contrast area. Median postoperative KPS was 70 (40–80). Thirty three (28–33.5) Gy was administered in 5 (3–10) Fr to PTV 117 (44–243) ml. TMZ was used in 7 patients. Bevacizumab (BEV) was used together from 4 weeks after surgery in 5 patients. Progression-free survival was 6.5 (2.9–10.6) months and overall survival was 17.5 (7.1–28.5) months. 7 patients had experienced controllable hypertension with antihypertensive agents, Two patients had suffered from deep vein thrombosis, and anticoagulation therapy was used. One patient had nausea and malaise due to TMZ and had continue BEV alone. Asymptomatic cerebral infarction in the radiation field was observed in a patient. CONCLUSION CK treated in less than half duration of conventional HRT is expected as less invasive treatment.

BACKGROUND The prognosis for patients with recurrent glioblastoma after Bevacizumab (Bev) treatment is extremely poor. No effective treatment has been established. PURPOSE We retrospectively investigated the efficacy and safety of hypofractionated stereotactic radiotherapy with Cyberknife (CK-HSRT) for recurrent glioblastoma after Bev treatment in our institution. METHODS GTV (Gross tumor volume) was set in the FLAIR abnormal high signal area that resulted in the contrast lesion and invasive recurrence, and PTV (Planning target volume) = GTV + 2 mm. As aimed CK dose,30 Gray(Gy) in 5 fraction was performed on PTV. Bev(10mg/kg biweekly) was continued after CK. The case background, treatment effect, survival and adverse events were investigated for 21 cases from January 2013 to the end of May 2018. RESULTS The median age was 69 (range;31–85) years, and The D95% marginal dose was 27.5 (23–35) Gy in 5 (3–8) divisions. Median PTV was 112 (2–305) ml. The median time to progression after CK was 3.9 months, and the median overall survival after CK was 10.9 months. Early treatment-related adverse events included hair loss in the irradiated area, seizures, headache, nausea and vomiting. As late treatment-related adverse events, symptomatic cerebral radiation necrosis was not observed, but 2 cases of symptomatic cerebral infarction and a case of cerebral hemorrhage were observed. All cases were treated conservatively. CONCLUSION CK-HSRT may be well tolerated and effective as a salvage treatment for the patients with recurrent glioblastoma after Bev.

Neurofibromatosis type 1 (NF1) is common, occurring in 1/3000 live births, and results in skin pigmentation and the growth of tumors along nerves in the skin, brain, and other parts of the body. Loss of polycomb repressive complex 2 (PRC2) has been implicated in the tumorigenesis of Schwann cells (SCs) in malignant peripheral nerve sheath tumors (MPNSTs). In the absence of PRC2, the H3K27me repressive marks are absent and thus the SCs can re-enter the cell cycle and form tumors. In the absence of PRC2, nucleosome remodeling deacetylase (NuRD) chromatin silencing complex, by itself cannot takes over its function. To compensate for the loss of PRC2 complex, there must be a decrease in activating histone marks, H3K27Ac and H3K4me3, by a reciprocal increase in HDAC2 expression and the decrease in H3K4 methylation. Using a systems biology approach as a part of the combination therapy, we have identified a novel naturally occurring multi-target cocktail in the methanolic extracts from the hydrophilic fraction of Ocimum Sanctum leaves (OSHP-1) as potential treatment option for MPNSTs. Here we show that OSHP-1 (i) increased the expression of HDAC2 (a component of NuRD), and decreased the expression of lysine acetyl transferase 7 (KAT7); (ii) altered FRα signaling and disrupted the DNA replication complex comprising of FRα-NuRD-PCNA-CAF-1; (iii) reversed the expression of certain actively transcribed genes PAX2, FOXN4, IGF2 and TLX1 in NF1-MPNST cells; (iv) increased the expression of a Schwann cell differentiation marker NCAM-140 KD. Thus, NuRD and KAT7 in NF1-MPNST can be potential therapeutic targets.

Chemotherapy is an adjuvant treatment for glioblastomas, however, chemotherapy remains palliative because of the development of multidrug resistance (MDR). Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in recurrent glioblastomas. CD133 positive (CD133+) glioma cancer stem-like cells (GCSCs) markedly promote drug resistance and exhibit increased DNA damage repair capability; thus they have a key role in determining tumor chemosensitivity. Although CD133, DNA-dependent protein kinase (DNA-PK), and MDR1 are elevated in CD133+ GCSCs, the relationship among these molecules has not been elucidated. In this study, MDR glioblastoma cell lines were created in response to prolonged doxorubicin chemotherapy. CD133, DNA-PK and MDR1 were markedly elevated in these cells. CD133 and DNA-PK may increase MDR1 via the phosphatidylinositol-3-kinase (PI3K)-Akt signal pathway. PI3K downstream targets Akt and nuclear factor (NF)-κB, which interacts with the MDR1 promoter, were also elevated in these cells. Downregulation of CD133 and DNA-PK by small interfering RNA, or inhibition of PI3K or Akt, decreased Akt, NF-κB and MDR1 expression. The results indicate that CD133 and DNA-PK regulate MDR1 through the PI3K- or Akt-NF-κB signal pathway. Consequently, a novel chemotherapeutic regimen targeting CD133 and DNA-PK in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for individuals who present with glioblastoma.

Object The authors sought to identify novel biomarkers for early detection of neural tube defects (NTDs) in human fetuses. Methods Amniotic fluid and serum were drawn from women in the second trimester of pregnancy. The study group included 2 women pregnant with normal fetuses and 4 with fetuses displaying myelomeningocele (n = 1), anencephaly (n = 1), holoprosencephaly (n = 1), or encephalocele (n = 1). Amniotic fluid stem cells (AFSCs) were isolated and cultured. The cells were immunostained for the stem cell markers Oct4, CD133, and Sox2; the epigenetic biomarkers H3K4me2, H3K4me3, H3K27me2, H3K27me3, H3K9Ac, and H3K18Ac; and the histone modifiers KDM6B (a histone H3K27 demethylase) and Gcn5 (a histone acetyltransferase). The levels of 2 markers for neural tube development, bone morphogenetic protein–4 (BMP4) and sonic hedgehog (Shh), were measured in amniotic fluid and serum using an enzyme-linked immunosorbent assay. Results The AFSCs from the woman pregnant with a fetus affected by myelomeningocele had higher levels of H3K4me2, H3K4me3, H3K27me2, and H3K27me3 and lower levels of KDM6B than the AFSCs from the women with healthy fetuses. The levels of H3K9ac, H3K18ac, and Gcn5 were also decreased in the woman with the fetus exhibiting myelomeningocele. In AFSCs from the woman carrying an anencephalic fetus, levels of H3K27me3, along with those of H3K9Ac, H3K18ac, and Gcn5, were increased, while that of KDM6B was decreased. Compared with the normal controls, the levels of BMP4 in amniotic fluid and serum from the woman with a fetus with myelomeningocele were increased, whereas levels of Shh were increased in the woman pregnant with a fetus displaying anencephaly. Conclusions The levels of epigenetic marks, such as H3K4me, H3K27me3, H3K9Ac, and H3K18A, in cultured AFSCs in combination with levels of key developmental proteins, such as BMP4 and Shh, are potential biomarkers for early detection and identification of NTDs in amniotic fluid and maternal serum.

Background Although brain arteriovenous malformations (AVM) usually remain asymptomatic during pregnancy, they can cause intracranial hemorrhage and lead to serious neurological deficits. Nowadays, it is accepted that treatment of a ruptured brain AVM during pregnancy should be based on neurologic, not obstetric, indications. Recently, endovascular treatment has been recognized as a treatment option associated in pregnant patients with brain AVMs. Case presentation A 34-year-old woman presented at 25 weeks of gestation with a history of severe headache followed by severe consciousness disturbance. Brain CT showed a subcortical hematoma in the right occipital lobe along with bilateral intraventricular hematomas. A cerebral angiogram was performed to confirm the diagnosis, which revealed right occipital AVM. At 27 weeks of gestation, endovascular embolization of the AVM was attempted under general anesthesia. The feeding artery and the nidus were simultaneously obliterated by injection of 50 % n-butyl-cyanoacrylate. As a result, the blood flow into the nidus was drastically decreased and the risk of re-bleeding was substantially reduced. At 38 weeks of gestation, elective cesarean section was performed to deliver the baby under combined spinal-epidural anesthesia (CSEA). An infant weighing 3665 g was delivered, with Apgar scores of 8 and 9 at 1 and 5 min, respectively. Postoperative analgesia was provided by a continuous infusion of ropivacaine via the epidural catheter. The infant was confirmed as not having any congenital anomalies. On POD 5, both of the patient and the infant were discharged home without any medical problems. The mother has shown no evidence of re-bleeding from the intracranial lesion since, and the infant is thriving well. Conclusions Endovascular treatment in pregnant women is associated with various unique concerns. However, it can be carried out safely and effectively and is useful not only for saving the mother’s life but also for allowing the pregnancy to continue to term.

Although maternal intake of folic acid (FA) prevents neural tube defects in 70% of the population, the exact mechanism of prevention has not been elucidated. We hypothesized that FA affects neural stem cell (NSC) proliferation and differentiation. This hypothesis was examined in a folate-responsive spina bifida mouse model, Splotch (Sp(-/-)), which has a homozygous loss-of-function mutation in the Pax3 gene. Neurospheres were generated with NSCs from the lower lumbar neural tube of E10.5 wild-type (WT) and Sp(-/-) embryos, in the presence and absence of FA. In the absence of FA, the number of neurospheres generated from Sp(-/-) embryos compared with WT was minimal (P0.05). Addition of FA to Sp(-/-) cultures increased the expression of a Pax3 downstream target, fgfr4, and rescued NSC proliferative potential, as demonstrated by a significant increase in neurosphere formation (P0.01). To ascertain if FA affected cell differentiation, FA-stimulated Sp(-/-) neurospheres were allowed to differentiate in the continued presence or absence of FA. Neurospheres from both conditions expressed multi-potent stem cell characteristics and the same differentiation potential as WT. Further, multiple neurospheres from both WT and FA-stimulated Sp(-/-) cell cultures formed extensive synaptic connections. On the whole, FA-mediated rescue of neural tube defects in Sp(-/-) embryos promotes NSC proliferation at an early embryonic stage. FA-stimulated Sp(-/-) neurospheres differentiate and form synaptic connections, comparable to WT.

Prenatal folic acid (FA) supplementation prevents neural tube defects. Folate receptor alpha (FRα) is critical for embryonic development, including neural crest (NC) development. Previously we showed that FRα translocates to the nucleus in response to FA, where it acts as a transcription factor. In this study, we examined if FA through interaction with FRα regulates stem cell characteristics of cranial neural crest cells (CNCCs)-critical for normal development. We hypothesized that FRα upregulates coding genes and simultaneously downregulates non-coding miRNA which targets coding genes in CNCCs. Quantitative RT-PCR and chromatin immunoprecipitation showed that FRα upregulates Oct4, Sox2, and Klf4 by binding to their cis-regulator elements-5′ enhancer/promoters defined by H3K27Ac and p300 occupancy. FA via FRα downregulates miRNAs, miR-138 and miR-let-7, which target Oct4 and Trim71 (an Oct4 downstream effector), respectively. Co-immunoprecipitation data suggests that FRα interacts with the Drosha-DGCR8 complex to affect pre-miRNA processing. Transfecting anti-miR-138 or anti-miR-let-7 into non-proliferating neural crest cells (NCCs) derived from Splotch (Sp−/−), restored their proliferation potential. In summary, these results suggest a novel pleiotropic role of FRα: (a) direct activation of Oct4, Sox2, and Klf4 genes; and (b) repression of biogenesis of miRNAs that target these genes or their effector molecules.

The epigenetic mechanism of folic acid (FA) action on dorsal root ganglion (DRG) cell proliferation and sensory neuron differentiation is not well understood. In this study, the ND7 cell line, derived from DRG cells, was used to elucidate this mechanism. In ND7 cells differentiated with dbcAMP and NGF, Hes1 and Pax3 levels decreased, whereas Neurog2 levels showed a modest increase. Chromatin immunoprecipitation (ChIP) assays examining epigenetic marks at the Hes1 promoter showed that FA favored increased H3K9 and H3K19 acetylation and decreased H3K27 methylation. Hence, FA plays a positive role in cell proliferation. In differentiated ND7 cells, H3K27 methylation decreased, whereas H3K9 and H3K18 acetylation increased at the Neurog2 promoter. FA did not favor this phenotypic outcome. Additionally, in differentiated ND7 Neurog2 associated with the NeuroD1 promoter, FA decreased this association. The results suggest that the switch from proliferation to sensory neuron differentiation in DRG cells is regulated by alterations in epigenetic marks, H3K9/18 acetylation and H3K27 methylation, at Hes1 and Neurog2 promoters, as well as by Neurog2 association with NeuroD1 promoter. FA although positive for proliferation, does not appear to play a role in differentiation.

The mechanism(s) behind folate rescue of neural tube closure are not well understood. In this study we show that maternal intake of folate prior to conception reverses the proliferation potential of neural crest stem cells in homozygous Splotch embryos (Sp(-/-)) via epigenetic mechanisms. It is also shown that the pattern of differentiation seen in these cells is similar to wild-type (WT). Cells from open caudal neural tubes of Sp(-/-) embryos exhibit increased H3K27 methylation and decreased expression of KDM6B possibly due to up-regulation of KDM6B targeting micro-RNAs such as miR-138, miR-148a, miR-185, and miR-339-5p. In our model, folate reversed these epigenetic marks in folate-rescued Sp(-/-) embryos. Using tissue from caudal neural tubes of murine embryos we also examined H3K27me2 and KDM6B association with Hes1 and Neurog2 promoters at embryonic day E10.5, the proliferative stage, and E12.5, when neural differentiation begins. In Sp(-/-) embryos compared with WT, levels of H3K27me2 associated with the Hes1 promoter were increased at E10.5, and levels associated with the Neurog2 promoter were increased at E12.5. KDM6B association with Hes1 and Neurog2 promoters was inversely related to H3K27me2 levels. These epigenetic changes were reversed in folate-rescued Sp(-/-) embryos. Thus, one of the mechanisms by which folate may rescue the Sp(-/-) phenotype is by increasing the expression of KDM6B, which in turn decreases H3K27 methylation marks on Hes1 and Neurog2 promoters thereby affecting gene transcription.

Neurofibromatosis type 1 (NF1) is common, occurring in 1 in 3000 live births, and results in skin pigmentation and the growth of tumors along nerves in the skin, brain, and other parts of the body. It arises from a mutated and non-functional tumor suppressor gene NF1. Tumors of the peripheral nerves, called neurofibromas and of the main eye nerve, called optic glioma, are debilitating and deadly. Epigenetic mechanisms have been shown to play an important role in the progression of neurofibromas to malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs with polycomb repressive complex 2 (PRC2) loss showed complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3). We hypothesized that owing to the loss of this repressive complex PRC2, there is an overexpression of genes related to tumorigenesis in MPNSTs because of reciprocal gain of the activation marks such as trimethylation at lysine 4 of histone H3 (H3K4me3) and acetylation of lysine 27 of histone H3 (H3K27Ac) at their promoters. Using RT-PCR, we observed an increase in the expression of candidate oncogenes genes PAX2, FOXN4, IGF2 and TLX1 in NF1 associated MPNST cell line ST88-14 versus the normal Schwann cells and normal human fibroblasts. Western blots using purified histones revealed that there was an increase in the expression of H3K4me3, H3K9me2, H3K18Ac and H3K27Ac. Recently, aqueous extracts of Ocimum Sanctum has been used as investigational cancer preventive drug. We wanted to know the effects of extracts of O. Sanctum on MPNST cell line ST88-14. Treatment of ST88-14 cells with the hydrophilic fraction of methanolic extract of Ocimum Sanctum (OSHP-1) not only showed a dose dependent decrease in the above histone marks but also showed an increase in the expression of N-CAM 140KD, characteristic of mature Schwann cells, in addition to a significant decline in proliferation. Further evaluation of the nuclear extracts showed that OSHP-1 treatment increased the expression of HDAC2, a component of NuRD complex and decreased that of lysine acetyl transferase 7 (KAT7) in a dose dependent manner suggesting that both HDAC2 and KAT7 may be responsible for the decrease in the acetylation of H3K27Ac and therefore reversal of the tumorigenic MPNSTs to a differentiated Schwann cell phenotype. Chromatin immunoprecipitation (ChIP) data revealed H3K27Ac occupancy on candidate genes (PAX2, FOXN4, IGF2 and TLX1) promoters was reduced by OSHP-1 treatment. In conclusion, OSHP-1 reprograms the epigenome and may be an effective treatment option for NF1 associated MPNSTs. Citation Format: Chandra S. Mayanil, Mariam M. Khan, Vineet Mohanty, Raj Kumar, Guifa Xi, Shunsuke Ichi, Bal Ram Singh, Barbara Mania-Farnell, Tadanori Tomita. Reprogramming the epigenome as an effective treatment option for neurofibromatosis1 associated malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2084.

Pax3 regulates neural crest cell migration and is critical during neural crest development. TGFbs modify neural crest cell migration and differentiation. TGFbeta2 nullizygous embryos (TGFbeta2(-/-)Pax3(+/+)) display open neural tube and bifid spine, whereas in wild type embryos, the neural tube is closed. In previous work, we have demonstrated that Pax3 regulates TGFbeta2 by directly binding to cis-regulatory elements on its promoter. In this study, we found that the TGFbeta2 nullizygous phenotype can be reversed to the wild type phenotype by down-regulating one allele of Pax3, as in TGFbeta2(-/-)Pax3(+/-) embryos obtained through breeding TGFb2(+/-)Pax3(+/-) mice. The data in this paper suggest that Pax3 and TGFbeta2 interact in a coordinated gene regulatory network, linked by common downstream effector genes, to bring about this phenotypic reversal. Downstream effectors may include Hes1, Ngn2 and Sox9, as well as other genes involved in neuronal differentiation.

Pax3 is expressed early during embryonic development in spatially restricted domains including limb muscle, neural crest, and neural tube. Pax3 functions at the nodal point in melanocyte stem cell differentiation, cardiogenesis and neurogenesis. Additionally Pax3 has been implicated in migration and differentiation of precursor cell populations. Currently there are questions about how Pax3 regulates these diverse functions. In this study we found that in the absence of functional Pax3, as in Splotch embryos, the neural crest cells undergo premature neurogenesis, as evidenced by increased Brn3a positive staining in neural tube explants, in comparison with wild-type. Premature neurogenesis in the absence of functional Pax3 may be due to a change in the regulation of basic helix–loop–helix transcription factors implicated in proliferation and differentiation. Using promoter-luciferase activity measurements in transient co-transfection experiments and electro-mobility shift assays, we show that Pax3 regulates Hairy and enhancer of split homolog-1 (Hes1) and Neurogenin2 (Ngn2) by directly binding to their promoters. Chromatin immunoprecipitation assays confirmed that Pax3 bound to cis-regulatory elements within Hes1 and Ngn2 promoters. These observations suggest that Pax3 regulates Hes1 and Ngn2 and imply that it may couple migration with neural stem cell maintenance and neurogenesis.

The neural crest (NC) is a population of cells between the dorsal ectoderm and the neural tube in vertebrate embryos. Regulatory mechanisms ranging from epigenetics to microRNAs (miRNAs) to post-translational protein modifications, work coordinately to fine-tune NC activity. miRNAs affect genes transcriptionally by directly interacting with either their 3′UTR or their 5′UTR. Affected genes include those of chromatin-modifying enzymes such as EZH2 and KDM6B. A lack of optimal levels of chromatin-modifying enzymes may in turn affect miRNA biogenesis as well as the transcriptional regulation of other genes. Overall, noncoding RNA genes and protein-coding genes interact in a network that, when connected to chromatin regulation, affects the expression of both noncoding and coding genes in neural crest development. This chapter highlights that role.

The present report describes the case of a 57-year-old male patient with spinal dural arteriovenous fistula (AVF). During the diagnostic examination, intravenous steroid therapy was implemented. The next day, the patient's symptoms were mildly improved and magnetic resonance imaging showed that the spinal cord swelling was markedly reduced. After the angiographic diagnosis of spinal dural AVF fed from the radicular artery originating from the sixth intercostal artery, the shunts were surgically interrupted by cutting the drainage vein. Clinical deterioration after steroid therapy was reported in several previous papers on this disorder. Based on the present case, however, we propose the possibility that intravenous steroid therapy is a viable option for presurgical management.

Maternal folate intake has reduced the incidence of human neural tube defects by 60-70 %. However, 30-40 % of cases remain nonresponsive to folate intake. The main purpose of this study was to understand the molecular mechanism of folate nonresponsiveness in a mouse model of neural tube defect.We used a folate-nonresponsive Fkbp8 knockout mouse model to elucidate the molecular mechanism(s) of folate nonresponsiveness. Neurospheres were grown from neural stem cells isolated from the lumbar neural tube of E9.5 Fkbp8 (-/-) and wild-type embryos. Immunostaining was used to determine the protein levels of oligodendrocyte transcription factor 2 (Olig2), Nkx6.1, class III beta-tubulin (TuJ1), O4, glial fibrillary acidic protein (GFAP), histone H3 Lys27 trimethylation (H3K27me3), ubiquitously transcribed tetratricopeptide repeat (UTX), and Msx2, and quantitative real-time (RT)-PCR was used to determine the message levels of Olig2, Nkx6.1, Msx2, and noggin in neural stem cells differentiated in the presence and absence of folic acid.Fkbp8 (-/-)-derived neural stem cells showed (i) increased noggin expression; (ii) decreased Msx2 expression; (iii) premature differentiation--neurogenesis, oligodendrogenesis (Olig2 expression), and gliogenesis (GFAP expression); and (iv) increased UTX expression and decreased H3K27me3 polycomb modification. Exogenous folic acid did not reverse these markers.Folate nonresponsiveness could be attributed in part to increased noggin expression in Fkbp8 (-/-) embryos, resulting in decreased Msx2 expression. Folate treatment further increases Olig2 and noggin expression, thereby exacerbating ventralization.