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BACKGROUND: Ozone is one of the triggers of asthma, but its impact on the pathophysiology of asthma, such as via airway inflammation and airway hyperresponsiveness (AHR), is not fully understood. Thymic stromal lymphopoietin (TSLP) is increasingly seen as a crucial molecule associated with asthma severity, such as corticosteroid resistance. METHODS: Female BALB/c mice sensitized and challenged with house dust mite (HDM) were exposed to ozone at 2 ppm for 3 h. Airway inflammation was assessed by the presence of inflammatory cells in bronchoalveolar lavage fluid and concentrations of cytokines including TSLP in lung. Anti-TSLP antibody was administered to mice to block the signal. Survival and adhesion of bone marrow-derived eosinophils in response to granulocyte colony-stimulating factor (G-CSF) were evaluated. RESULTS: Ozone exposure increased eosinophilic airway inflammation and AHR in mice sensitized and challenged with HDM. In addition, TSLP, but not IL-33 and IL-25, was increased in lung by ozone exposure. To confirm whether TSLP signaling is associated with airway responses to ozone, an anti-TSLP antibody was administered, and it significantly attenuated eosinophilic airway inflammation, but not AHR. Interestingly, G-CSF, but not type 2 cytokines such as IL-4, IL-5, and IL-13, was regulated by TSLP signaling associated with eosinophilic airway inflammation, and G-CSF prolonged survival and activated eosinophil adhesion. CONCLUSIONS: The present data show that TSLP contributes to ozone-induced exacerbations of eosinophilic airway inflammation and provide greater understanding of ozone-induced severity mechanisms in the pathophysiology of asthma related to TSLP and G-CSF.

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Direct surgical resection remains to be the standard treatment for tuberous sclerosis complex (TSC) with subependymal giant cell astrocytoma (SEGA). Medical therapy with everolimus (mammalian target of rapamycin inhibitor or mTOR) serves as a second-line treatment for patients with SEGA who are determined to be ineligible for surgical resection. Some recent studies have reported that neoadjuvant therapy for SEGA may be a useful, novel treatment. In this study, we herein present a case of SEGA and demonstrate the efficacy of preoperative everolimus therapy. We have also examined the utility and safety of neoadjuvant therapy for SEGA and investigated four previously reported cases of preoperative administration of mTOR inhibitors. In these cases, everolimus was administered preoperatively to shrink the tumor although the duration of treatment varied. Afterward, gross total tumor removal was conducted in all the cases. No postoperative complications were reported during the follow-up period. These findings indicate that neoadjuvant therapy with an mTOR inhibitor can be a potential treatment for SEGA. The findings of this present study also suggested that a short administration period of about 2 months may be sufficient to achieve preoperative tumor reduction.

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Childhood hydrocephalus is a highly diverse disease caused by various factors, and most surgical treatments are performed during infancy. Despite the diversity of hydrocephalus pathologies, treatment options are limited. It is difficult for pediatric neurosurgeons to select and perform appropriate surgical procedures for neonates and infants. Treatment options for hydrocephalus are broadly divided into permanent and temporary. Permanent treatments include cerebrospinal fluid shunt and endoscopic third ventriculostomy; temporary treatment entails cerebrospinal fluid drainage using lumbar puncture and intermittent cerebrospinal fluid drainage with an Ommaya reservoir, ventricular drainage, and ventriculosubgaleal shunt. This article describes in detail Ommaya reservoir placement and ventricular drainage as representative procedures for temporarily treating hydrocephalus.

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BACKGROUND: Sinus pericranii is a rare cranial venous malformation resulting in a subcutaneous mass due to abnormal communication between intracranial and subperiosteal/interperiosteal veins. To date, to the best of our knowledge, there are no reports of sinus pericranii associated with syntelencephaly, a subtype of lobar holoprosencephaly. We herein report a case of sinus pericranii associated with syntelencephaly. This report can provide us better understanding of the etiology of sinus pericranii, the potential risks, and the treatment options for these patients. CASE PRESENTATION: A 2-year-4-month old female patient who received the diagnosis of syntelencephaly as a neonate presented with a subcutaneous mass in the parietal region. The mass was soft, nonpulsatile, 3 × 2 cm in size, and showed enlargement in the lying position. Color cranial Doppler ultrasound, head magnetic resonance imaging (MRI), and cerebral angiography revealed a dilated vessel passing through the parietal bone and forming a communication between the superior sagittal sinus and scalp veins. Based on these findings, sinus pericranii was diagnosed. The head MRI also showed coronal craniosynostosis, a tight posterior fossa. At age 2 years and 7 months, the patient underwent a transection of the sinus pericranii and the mass resolved without any complications or recurrences for more than 2.5 years to date. CONCLUSION: Sinus pericranii is a rare cranial and venous malformation sometimes accompanied by brain malformations or craniosynostosis that may become more apparent as the brain and skull develop. Since this condition can be complicated by intracranial hemorrhage and sinus thrombosis, early detection is necessary to determine the treatment options. Physicians should be alert to the possibility of this condition if they observe a soft cranial mass that appears to decrease in size in the sitting position and bulge in the lying position.

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Sphenoid wing dysplasia (SWD) is a common orbital complication of neurofibromatosis type 1 (NF1). However, enophthalmos associated with SWD is extremely rare, and details of its natural history are unclear. We present the case of a 14-year-old boy with an early childhood diagnosis of NF1 presenting with left blepharophimosis and enophthalmos for several months. Imaging demonstrated enlargement of the left lateral SWD, progression of the posteromedial deviation of the orbital contents, and sphenoid/ethmoid sinus deformation due to left temporal lobe compression over 12 years. Two characteristic changes were revealed on imaging: enlargement of the middle cranial fossa and deformation of the sphenoid/ethmoid sinuses. The orbital contents were compressed by the intracranial pressure of the temporal lobe and were displaced posteromedially into the space created by the deformed sphenoid/ethmoid sinuses. Because orbital symptoms can gradually become apparent over years with the progression of SWD and skeletal growth, long-term follow-up of orbital symptoms is recommended in patients with NF1.

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PURPOSE: Although the endoscopic third ventriculostomy (ETV) is an effective treatment for hydrocephalus, failures do on occasion occur. In such cases, a repeat ETV or shunt insertion is usually performed. However, there is, as of yet, no clear consensus on the best measure to take in the event of a failed ETV. We herein examined the outcomes of a repeat ETV combined with choroid plexus cauterization for ETV failure. METHODS: All patients who underwent an ETV at the Department of Neurosurgery at Tokyo Metropolitan Children's Medical Center between April 2013 and March 2019 were retrospectively analyzed. RESULTS: In total, 36 patients received an ETV. Six patients experienced ETV failure; three of these underwent a repeat ETV combined with choroid plexus cauterization. Three of the six patients who experienced early ETV failure received a ventriculoperitoneal shunt. During the median follow-up period of 42 months (range: 32-73 months), all repeat ETVs were successful. CONCLUSION: A repeat ETV combined with choroid plexus cauterization can be an effective salvage therapy in the event of ETV failure.

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There are various purification methods have been developed and applied to industrial wastewater with contaminated microorganisms. We previously reported that high-voltage pulsed discharge plasma with cavitation effectively kills Escherichia coli cells. We attempted to expand the application of this disinfection method by using microorganisms such as Bacillus subtilis, Deinococcus radiodurans, and Schizosaccharomyces pombe. These microbial cells were treated with the discharge plasma, and the cell viability, DNA damage, and morphological changes were analyzed to evaluate the bactericidal effect. Interestingly, D. radiodurans, a radio-resistant bacterium showed relatively high sensitivity to the discharge plasma. On the other hand, B. subtilis and S. pombe showed the resistance, showing both sporogenesis. The amount of DNA damage in the treated cells corresponded to the cell viability, but most of the treated cells did not show any morphological changes.

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Mutations in ACTA2 gene can lead to multisystemic smooth muscle dysfunction, including cerebrovascular disease. Treatment strategies for this rare entity remain controversial, and patients are at increasing risk of neurological sequelae. We herein present the case of an 11-year-old boy previously diagnosed with an ACTA2 gene mutation who developed repetitive transient ischemic attacks and treated with bosentan, an oral endothelin receptor antagonist. Magnetic resonance imaging revealed bilateral, periventricular white matter T2 hyperintensities, and magnetic resonance angiography identified several abnormalities including fusiform dilatation in the proximal segments of internal cerebral arteries, together with followed by terminal segmental stenosis. The distal branches showed a markedly straightened course with no increase in lenticulostriate collaterals. Magnetic resonance imaging also revealed an increase in the number and size of large periventricular white matter lesions located in the left frontal lobe with the progression of ischemic symptoms. Instead of revascularization surgery, the administration of bosentan was started due to the high risk of perioperative ischemic sequelae. After bosentan initiation, the patient's repetitive episodes of cerebral ischemia ceased, and there has been no increase in the number of white matter lesions for 7 years. Bosentan might be beneficial for treating cerebral ischemia associated with ACTA2 cerebral arteriopathy by maintaining the dilatation of stenotic vessels and adequate systemic blood flow and should be considered before performing revascularization surgery.

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A 10-year-old, male patient with a head injury caused by a fall presented with chemosis, exophthalmos, right orbital bruit, and intracranial venous reflux, based on which posttraumatic carotid cavernous fistula (CCF) was diagnosed. Coil embolization was semi-urgently performed for the dangerous venous drainage. After the treatment, right abducens nerve palsy newly appeared. To treat the neurological symptoms and preserve the parent artery, curative endovascular treatment using a pipeline embolization device (PED) with coil embolization was performed after starting dual antiplatelet therapy (DAPT). The CCF and abducens nerve palsy finally resolved, and the internal carotid artery (ICA) was remodeled. Use of the PED with adjunctive coil embolization was effective and safe in the present case of pediatric traumatic direct CCF.

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BACKGROUND: The Endoscopic Third Ventriculostomy Success Score (ETVSS) is based on the clinical features of hydrocephalus except for radiological findings. A previous study suggested that transependymal edema (TEE) as a radiological finding may be a reliable predictor of endoscopic third ventriculostomy (ETV) success in patients of all ages. We aimed to investigate whether TEE on preoperative magnetic resonance imaging can predict ETV success in pediatric patients. METHODS: Medical and radiological records of all pediatric patients with an initial ETV in our hospital between 2013 and 2019 were retrospectively reviewed. RESULTS: This study included 32 patients with hydrocephalus. The median age at surgery was 10.0 years (interquartile range: 5.6-12.9 years). There were 20 patients in the high ETVSS (90-80) group and 12 patients in the moderate ETVSS (70-50) group. The median follow-up period was 29.0 months (interquartile range: 12.9-46.2 months). The ETV success rate at the final follow-up was 81%. Preoperative brain magnetic resonance imaging revealed TEE in 20 patients and third ventricle floor ballooning in 25 patients, of whom 19 (95%) and 22 (88%), respectively, achieved successful ETV. Patients with TEE had a significantly better outcome than patients without TEE (95% vs. 58%, P = 0.018). Multivariate analysis demonstrated that the presence of TEE (odds ratio 13.6, 95% confidence interval 1.3-137.5, P = 0.027) is a significant predictor of ETV success. CONCLUSIONS: In our cohort with a high or moderate ETVSS, the ETV success rate in patients with TEE was significantly higher than in patients without TEE, suggesting that TEE may be a useful predictor of ETV success in pediatric hydrocephalus.

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Tumor-treating fields (TTFields) are alternating electric fields applied continuously to the brain by attaching two-pair arrays on the scalp. Although TTFields therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. Despite differences in the genetic etiology of the adult and pediatric forms of GBM, both have certain clinical behaviors in common, allowing us to test TTFields therapy in pediatric GBM. Recently, several, pediatric case-series using TTFields therapy have been published, and a few, prospective, pediatric studies are ongoing. Because GBMs are extremely rare in pediatric patients, where they comprise a wide variety of genetic subtypes, these pediatric studies are feasibility studies targeting various types of malignant brain tumor. Although they are important for confirming the safety and feasibility of TTFields therapy in the pediatric population, confirming its efficacy against each type of pediatric brain tumor, including the GBM, is difficult. Our clinical research team, therefore, planned an investigator-initiated clinical trial targeting pediatric supratentorial GBMs (as in adults) with the aim of expanding regulatory approval of TTFields therapy for pediatric GBM treatment based on safety and exploratory efficacy data in combination with the accumulated evidence on adult GBMs.

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ABSTRACT: Bilambdoid and sagittal synostosis (BLSS), a rare form of multisutural craniosynostosis, is sometimes known as the Mercedes-Benz syndrome due to the appearance of the fused sagittal and bilateral lambdoid sutures. Although previous studies have described some of its clinical features, the pathology of this disease is not yet fully understood. Moreover, it has been pointed out that BLSS is more common among individuals of Hispanic ethnicity, but its incidence in Asia remains unclear. In the present study, BLSS cases in Japan were analyzed to determine the characteristics of the condition in Japan. Three hospitals in Tokyo participated in the present study. Patients with BLSS who underwent cranial remodeling were included. Data on patient demographics, clinical symptoms, status of the cranial sutures, morphological subclassification, surgical procedures, developmental status, and genetic mutations were analyzed. In total, 22 patients met the enrollment criteria and were included, indicating a higher incidence of BLSS in Japan than in other nations reported in previous studies. In terms of morphological subclassification, there were 15 brachycephalic, 4 dolichocephalic, and 3 normocephalic. For the initial cranial procedure, 7 patients underwent a single-stage cranioplasty, 13 underwent a posterior distraction, and 2 underwent lateral expansion. Patients with a normocephalic cranial morphology tended to undergo surgery at an older age than patients with the other two types. Appropriate timing for surgery is important for healthy development; hence, surgeons should remember that BLSS can lead to "balanced dysmorphism" that may have led to a delay in diagnosis due to its normal-looking morphology.

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PURPOSE: The occipital bone is located on the boundary between the membranous and cartilage bones and contains a wide variety of accessory sutures. In this study, we describe the age distribution of pediatric patients who are less than 2 years of age with occipital cranial sutures using a three-dimensional computed tomography (3D-CT). METHODS: A total of 167 consecutive patients who are less than 2 years of age and underwent computed tomography for head trauma were included in this study. RESULTS: Based on the results of this study, various types of sutures were observed among the pediatric participants. In particular, superior median fissures, mendosal sutures, other interparietal segment's accessory sutures, and interparietal sutures were noted in 21%, 35%, 9%, and 6% of the participants, respectively. Additionally, Wormian bones within the lambdoid suture were noted in 32% of the patients. The median age of children with superior median fissure and mendosal suture was 0 month. Meanwhile, superior median fissure was not observed among children older than 5 months of age. In this population, 13 patients (8%) were found to have skull fracture. CONCLUSIONS: Knowledge of the normal cranial anatomy and developmental patterns of cranial sutures is crucial in the evaluation of questionable fractures in the occipital region. A combination of 3D-CT and axial bone window imaging is useful in differentiating normal structures from pathological changes in the cranium.

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INTRODUCTIONS: A specific mutation in the ACTA2 gene is known to cause multisystemic smooth muscle dysfunction syndrome, which is associated with cerebrovascular diseases and various organ disorders. Cerebral infarctions resulting from severe vasculopathy can be refractory; however, there are no previous reports describing the detailed clinical course of recurrent cerebral infarctions due to an ACTA2 mutation. Herein, we report a patient with an ACTA2 mutation who experienced multiple refractory cerebral infarctions in early childhood. PATIENT DESCRIPTION: The patient was aged 1 year and 5 months at her first episode of cerebral infarction. Arteriopathy due to an ACTA2 mutation was diagnosed based on the characteristic cerebrovascular findings and abnormal physical findings, such as bilateral dilated pupils. Bilateral encephaloduroarteriosynangiosis and encephalogaleosynangiosis were performed after the first episode. Because the cerebral infarctions recurred postoperatively, administration of cilostazol followed by bosentan was started. However, despite these treatments she experienced seven cerebral infarctions by age 2 years and 6 months. INTERPRETATION: Cerebral infarctions in patients with a specific ACTA2 mutation can occur even in early childhood, recur frequently, and cause severe motor and cognitive impairment. Physicians should be highly aware of this disease and be ready to provide the medical and surgical interventions necessary to minimize the disabling sequelae.

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OBJECTIVE: The present report aimed to document the clinical features of a case of Marshall-Smith syndrome (MSS), an extremely rare embryonic developmental disorder with associated craniosynostosis. PATIENT AND METHOD: We presented herein a case of a 2-year-old female patient with MSS who underwent fronto-orbital advancement for multisuture craniosynostosis. RESULTS: The patient's proptosis improved after surgery, and no further surgical intervention was required for corneal exposure. A second FOA followed by revision tarsorrhaphy further improved eye closure. CONCLUSION: Surgical procedures to correct dysplastic features and limit neurological impairment are a worthwhile supportive treatment for improving the quality of life and general condition of patients with MSS.

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OBJECTIVE: The basal encephalocele (BEC) is the rarest form of encephalocele, with an incidence of about 1/35,000 live births. The incidence of its subtype, sphenoidal BEC, is even lower at about 1/700,000 live births. The aim of this study was to propose the optimal surgical approach to repairing BEC, with special attention to the reconstruction of the skull base bone defect. METHODS: Fourteen consecutive pediatric patients with BEC who underwent surgical repair between March 2004 and March 2020 (10 boys and 4 girls, age 25 days to 7 years, median age 4 months) were enrolled. The follow-up period of the surviving patients ranged from 53 to192 months (mean 119.8 months). The patient demographics, BEC subtypes, preoperative clinical condition, radiographic findings, surgical procedures, and postoperative course were retrospectively analyzed. RESULTS: There were 4, 8, and 2 cases of sphenoidal BEC, sphenoethmoidal BEC, and ethmoidal BEC, respectively. The size of the bone defect was small in 3 patients, medium in 7, and large in 4 patients. All the patients with sphenoethmoidal and ethmoidal BEC showed associated congenital anomalies other than cleft palate. In total, 25 operations were performed. Two patients underwent multiple operations, whereas the remaining 9 patients received only 1 operation. The transoral transpalatal approach was the initial procedure used in all 14 patients. The transfrontobasal approach was applied as an additional procedure in 2 patients and as part of a 1-stage combined operation in 2 patients. Autograft bone alone was used for skull base reconstruction in 17 early operations. A titanium mesh/plate was used in the remaining 8 operations without any perioperative complications. All BECs were successfully repaired. Three patients died during the clinical course due to causes unrelated to their surgery. All but one of the surviving patients started growth hormone replacement therapy before school age. CONCLUSIONS: Based on the authors' limited experience, the key to successful BEC repair involves circumferential dissection of the BEC and a firm reconstruction of the skull base bone defect with a titanium plate/mesh. The transoral transpalatal approach is a promising, reliable procedure that may be used in the initial operation. When a cleft palate is absent, transnasal endoscopic repair is recommended. The transfrontobasal approach should be reserved for cases with a huge BEC and other anomalies. Long-term prognosis is apparently favorable in survivors.

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INTRODUCTION: Jacobsen syndrome (JS) is caused by a deletion at the terminus of the long arm of chromosome 11. There are few reports of JS associated with cerebral white matter abnormalities (WMA), and the etiology, pathophysiology, and time-dependent changes in WMA with JS still remain unclear. CASE REPORT: The patient was a 2-month-old female with several morphological anomalies, including trigonocephaly, ectropion, flat nasal bridge, low-set ears, and sparse eyebrows. Chromosome analysis (G-banding karyotyping) of 46,XX,del(11)(q23.3) led to the diagnosis of JS. Head MRI performed at age 9 months indicated diffuse WMA with hyperintense signals on T2-weighted imaging. MRI at age 2.5 years demonstrated a decrease in the WMA and progressive myelination. DISCUSSION: These findings suggested that the WMA in the present patient were due to chronic white matter edema associated with a deletion in the 11q terminal region of HEPACAM/GlialCAM, a causative gene for megalencephalic leukoencephalopathy with subcortical cysts type 2B (MLC2B). As with some of MLC2B patients, the WMA in the present patient improved over time. The present report is the first to document dramatic changes in WMA in JS visualized by serial MRI examinations from the neonatal period through early childhood. CONCLUSION: The findings of the present study suggested that WMA in JS are due to chronic white matter edema associated with HEPACAM/GlialCAM deletion and show gradual improvement over time, as seen in some MLC2B patients.

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INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a type of brain malignancy with a very poor prognosis. Although various radiation and chemotherapy protocols have been attempted, only conventional radiotherapy has yielded improvements in survival. In this study, we aimed to compare proton therapy versus conventional photon radiotherapy in terms of the outcomes of pediatric patients with DIPG. METHODS: This retrospective review included 12 pediatric patients with newly diagnosed DIPG who received a total proton therapy dose of 54 Gy (relative biological effectiveness) in 30 fractions at the University of Tsukuba Hospital between 2011 and 2017 (proton group). We additionally reviewed the medical records of 10 patients with DIPG who previously underwent conventional photon radiotherapy at our institute (historical cohort). RESULTS: The median progression-free survival (PFS) duration was 5 months (range 1-11 months), and the 6-, 12-, and 18-month PFS rates were 50%, 33%, and 25%, respectively. The median overall survival (OS) duration was 9 months (range 4-48 months), and the 6-, 12-, 18-, and 24-month OS rates were 66.8%, 50%, 41%, and 20%, respectively. There were no significant differences in survival between the proton and historical groups (PFS, p = 0.169 and OS, p = 0.16). CONCLUSIONS: Proton therapy was well tolerated by the majority of patients. No severe adverse events, including radiation necrosis, were recorded. Proton therapy did not yield superior survival outcomes vs. conventional photon radiotherapy in patients with DIPG at our institution. Further research is needed to identify the factors associated with better survival in this population.

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Activation of the RAS pathway through either the activation of genes that accelerate the pathway or the suppression of genes that inhibit the pathway leads to a group of disorders collectively referred to as RASopathies. The key molecules of the RAS pathway are KRAS, HRAS, and NRAS. Mutations in these three RAS homolog genes have been shown to be associated with RASopathies. Recently, two patients with a Noonan syndrome phenotype were shown to carry mutations in the yet another RASopathy gene, MRAS (muscle RAS oncogene homolog). Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers. The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy. We confirmed that the MRAS gene represents a causative gene for RASopathy.

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