Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin.

BACKGROUND: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. METHODS: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. RESULTS: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. CONCLUSIONS: High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.

Mechanical Thrombectomy for Bihemispheric Infarction Caused by Acute Unilateral Internal Carotid Artery Occlusion in a Patient with Contralateral Chronic Carotid Occlusion: A Case Report.

Objective: We report a patient with acute bihemispheric infarction who underwent mechanical thrombectomy. Case Presentation: A 76-year-old man suddenly developed coma and quadriplegia. Brain MRI and MRA revealed acute bihemispheric infarction due to occlusions of both the internal carotid arteries (ICAs). According to the DSA findings, we considered the left ICA as chronic occlusion and the right as acute. Mechanical thrombectomy for the right ICA occlusion was performed. Total recanalization was achieved using a stent retriever 181 minutes after onset. The left hemisphere was perfused by cross circulation through the anterior communicating artery, but the symptoms did not improve. MRI the day after thrombectomy showed extensive bihemispheric infarction. Recanalization for the bilateral hemispheres was maintained, although the left ICA remained occluded. He died 2 months later due to gastrointestinal bleeding. Conclusion: Acute bihemispheric infarction due to occlusions of both ICAs is a rare entity. The symptoms are very severe and the therapeutic time window is extremely short because of absent collateral pathways. We should consider pre-existing carotid occlusive disease, determine whether the occlusions are acute or chronic, and perform prompt therapy. Further investigation is warranted to obtain a better outcome.

Low Detection Rate of H3K27M Mutations in Cerebrospinal Fluid Obtained from Lumbar Puncture in Newly Diagnosed Diffuse Midline Gliomas.

Recent studies have suggested the feasibility of detecting H3K27M mutations in the cerebrospinal fluid of diffuse midline glioma (DMG) patients. However, cerebrospinal fluid from patients in these studies were collected mainly during biopsy, ventriculo-peritoneal shunt procedures or postmortem. We assessed circulating tumor DNA (ctDNA) extracted from cerebrospinal fluid (CSF) and plasma in a series of 12 radiographically suspected and/or pathologically confirmed diffuse midline glioma patients and assessed for H3F3A K27M mutation using digital droplet PCR. In 10 patients, CSF was obtained by lumbar puncture at presentation. A definitive detection of H3F3A K27M mutation was achieved in only one case (10%); H3F3A K27M mutation was suspected in three other cases (30%). H3F3A K27M mutation was detected in two patients in CSF obtained by ventricular tap during a ventriculo-peritoneal shunt for obstructive hydrocephalus. Cases in which a definitive assessment was possible (definite H3F3A K27M or definite H3F3A wildtype) tended to be younger (median 7.5 years vs. 40.5 years; p = 0.07) and have a higher concentration of CSF protein (median 123 mg/dL vs. 27.5 mg/dL; p = 0.21) compared to nondefinite cases. Low proliferation and apoptotic rates seemed to be characteristics of DMG unfavorable for liquid biopsy. More advanced lesions with necrosis and evidence of dissemination were unlikely to be candidates for lumbar puncture due to the fear of exacerbating obstructive hydrocephalus. Methods to safely sample CSF and a more sensitive detection of ctDNA are necessary for reliable liquid biopsy of DMG at presentation.

Topoisomerase IIß immunoreactivity (IR) co-localizes with neuronal marker-IR but not glial fibrillary acidic protein-IR in GLI3-positive medulloblastomas: an immunohistochemical analysis of 124 medulloblastomas from the Japan Children's Cancer Group.

We previously reported observing GLI3 in medulloblastomas expressing neuronal markers (NM) and/or glial fibrillary acidic protein (GFAP). Furthermore, patients with medulloblastomas expressing NM or GFAP tended to show favorable or poor prognosis, respectively. In the present study, we focused on the role of topoisomerase IIß (TOP2ß) as a possible regulator for neuronal differentiation in medulloblastomas and examined the pathological roles of GLI3, NM, GFAP, and TOP2ß expressions in a larger population. We divided 124 medulloblastomas into three groups (NM-/GFAP-, NM +/GFAP-, and GFAP +) based on their immunoreactivity (IR) against NM and GFAP. The relationship among GLI3, NM, GFAP, and TOP2ß was evaluated using fluorescent immunostaining and a publicly available single-cell RNA sequencing dataset. In total, 87, 30, and 7 medulloblastomas were classified as NM-/GFAP-, NM + /GFAP-, and GFAP +, and showed intermediate, good, and poor prognoses, respectively. GLI3-IR was frequently observed in NM +/GFAP- and GFAP + , and TOP2ß-IR was frequently observed only in NM +/GFAP- medulloblastomas. In fluorescent immunostaining, TOP2ß-IR was mostly co-localized with NeuN-IR but not with GFAP-IR. In single-cell RNA sequencing, TOP2ß expression was elevated in CMAS/DCX-positive, but not in GFAP-positive, cells. NM-IR and GFAP-IR are important for estimating the prognosis of patients with medulloblastoma; hence they should be assessed in clinical practice.

Application of 7 tesla magnetic resonance imaging for pediatric neurological disorders: Early clinical experience.

Ultra-high field magnetic resonance imaging (MRI) has been introduced for use in pediatric developmental neurology. While higher magnetic fields have certain advantages, optimized techniques with specific considerations are required to ensure rational and safe use in children and those with pediatric neurological disorders (PNDs). Here, we summarize our initial experience with clinical translational studies that utilized 7 tesla (T)-MRI in the fields of developmental neurology. T2-reversed images and three-dimensional anisotropy contrast imaging enabled the depiction of targeted pathological brain structures with better spatial resolution. Diffusion imaging and susceptibility-weighted imaging enabled visualization of intracortical, subcortical, and intratumoral microstructures in vivo within highly limited scan times appropriate for patients with PNDs. 7T-MRI appears to have significant potential to enhance the depiction of the structural and functional properties of the brain, particularly those associated with atypical brain development.

GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma.

Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.

[Surgical Case of Accidental Infantile Acute Subdural Hematoma Caused by Household Minor Head Trauma:Hyperperfusion during Postoperative Hemispheric Hypodensity, Namely "Big Black Brain"].

We experienced a case of an accidental infantile acute subdural hematoma caused by household minor head trauma(Nakamura type I intracranial hemorrhage)with postoperative hemispheric hypodensity lesion(Big Black Brain)whose pathophysiology was analyzed using perfusion MRI. A ten-month-old boy was admitted to our hospital in a comatose state. His mother revealed that the boy suffered a fall from a sofa bed. A CT scan indicated massive acute subdural hematoma in the left cerebral hemisphere. Emergency craniotomy and hematoma evacuation were performed. On postoperative day 3, CT revealed hemispheric hypodensity, and the boy suffered from status epilepticus. MRI on the following day showed widespread white matter hyperintensity in diffusion-weighted images, and MRA demonstrated dilation of the middle cerebral artery. Perfusion MRI using the dynamic susceptibility contrast method revealed a marked increase in cerebral blood flow in the left hemisphere. These abnormal MRI and MRA findings disappeared on postoperative day 13. Status epilepticus also improved upon administration of multi-antiepileptic drugs. Fundoscopy findings on postoperative day 3 showed small bilateral petechial or brush retinal hemorrhages. However, whole-body examination did not show any problems, and was consistent with the mother's account. Thus, we judged non-abusive head trauma. Although follow-up MRI showed diffuse atrophy of the left cerebral hemisphere, the boy aged well without obvious paresis or verbal developmental delay as judged by a follow-up more than a year later. Based on these results, we speculated that hyperperfusion caused by dilation of the cerebral artery was related to the postoperative hemispheric hypodensity, namely "Big Black Brain".

A Case of Curative Onyx Embolization for Tentorial dAVF via Low-flow Feeders with Temporary Balloon Occlusion of High-flow Feeders.

Objective: For curative Onyx embolization of dural arteriovenous fistulas (dAVF) with multiple feeders, it is essential to select the optimal target artery as well as to control the blood flow at the fistula point. We report a case of tentorial dAVF (TdAVF) treated by Onyx embolization under flow control using balloon catheters. Case Presentation: A 66-year-old male was admitted to our hospital for treatment of TdAVF detected incidentally by MRI, which revealed a dilated and tortuous vein around the cerebellum. Cerebral angiography demonstrated a TdAVF, fed mainly by bilateral middle meningeal arteries (MMA) and bilateral occipital arteries (OA), with the fistula point at the torcular and venous drainage to the two superior vermian veins (SVVs). Onyx 18 was injected from the low-flow feeder of the MMA under flow control by occluding the high-flow feeder of the OA using balloon catheters, obliterating the arteriovenous shunt. Conclusion: In treatment of TdAVF involving low- and high-flow feeders, Onyx embolization via the low-flow feeder with temporary balloon occlusion of other high-flow feeders is a useful method. This technique makes it easier for Onyx to penetrate the fistula point.

Overlapping Stents and Coil Embolization of Ruptured Anterior Cerebral Artery Dissecting Aneurysms in the Acute Phase.

Objective: To report a case of ruptured anterior cerebral artery dissection treated with stent-assisted coil embolization with overlapping stents. Case Presentation: A 51-year-old woman developed subarachnoid hemorrhage the day after transient left hemiparesis. Angiography revealed a ruptured anterior cerebral artery dissecting aneurysm. We conducted stent-assisted coil embolization with the overlapping stent technique on the day after the hemorrhage. She recovered steadily without rebleeding. Six months after embolization, no recurrence was found on angiography. Conclusion: Although an acceptable result was achieved in this case, the safety and efficacy of this procedure are unconfirmed. A larger number of cases should be accumulated.

De Novo Pineal Region Germinoma in the Seventh Decade of Life: A Case Report.

Germ cell tumors typically occur in children and adolescents. We here report a rare case of de novo pineal region germinoma in the seventh decade of life. A 62-year-old man presented with double vision. Computerized tomography and magnetic resonance imaging (MRI) identified a heterogeneously enhanced tumor with calcification in the pineal region with ventricular dilatation due to aqueduct stenosis. The tumor had not been observed at all on MRI obtained 2 years previously. The patient underwent endoscopic biopsy and third ventriculostomy for the obstructive hydrocephalus. The tumor was histopathologically diagnosed as a pure germinoma. The patient underwent radiomonotherapy, resulting in his complete remission, which was confirmed by a series of follow-up MRI studies and hematological examinations. Intracranial germinoma should be considered in the differential diagnosis of pineal region tumors regardless of age, even though the tumor was undetectable on the previous neuroimaging.

Detectability of the choroid plexus of the third ventricle with magnetic resonance ventriculography.

PURPOSE: To clarify the detectability of the choroid plexus of the third ventricle (ChPl3V) with magnetic resonance ventriculography (MRVn) employing a steady-state free precession (SSFP) sequence in comparison to surgical endoscopic movies as a golden standard, as we encountered some clinical cases of total agenesis of corpus callosum (ACC) where we could not recognize the choroid plexus of the third ventricle and found no previous article addressing this problem. MATERIALS AND METHODS: This retrospective study included consecutive patients from 2010 to 2016 for whom endoscopic evaluation of the third ventricle was conducted. The anterior portion of the right and left streaks of ChPl3V was evaluated in 8 patients on 16 sites, while the posterior portion of both streaks of ChPl3V was evaluated in 13 patients on 26 sites. Sensitivity of MRVn to visualize ChPl3V with endoscopic movies as the golden standard was calculated. RESULTS: Sensitivity of MRVn in visualizing the anterior portion of ChPl3V was 0.813, and that for the posterior portion 0.692. The anterior portion of ChPl3V was visualized in all cases where no tumor contacted the foramen of Monro. CONCLUSION: MRVn visualizes the anterior portion of ChPl3V with significant sensitivity and the posterior portion with lower one.

MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas.

Diffuse midline gliomas (DMGs) show resistance to many chemotherapeutic agents including temozolomide (TMZ). Histone gene mutations in DMGs trigger epigenetic changes including DNA hypomethylation, one of which is a frequent lack of O6-methyl-guanine-DNA methyltransferase (MGMT) promoter methylation, resulting in increased MGMT expression. We established the NGT16 cell line with HIST1H3B K27M and ACVR1 G328E gene mutations from a DMG patient and used this cell line and other DMG cell lines with H3F3A gene mutation (SF7761, SF8628, JHH-DIPG1) to analyze MGMT promoter methylation, MGMT protein expression, and response to TMZ. Three out of 4 DMG cell lines (NGT16, SF8628, and JHH-DIPG1) had unmethylated MGMT promoter, increased MGMT expression, and showed resistance to TMZ treatment. SF7761 cells with H3F3A gene mutation showed MGMT promoter methylation, lacked MGMT expression, and sensitivity to TMZ treatment. NGT16 line showed response to ALK2 inhibitor K02288 treatment in vitro. We confirmed in vitro that MGMT expression contributes to TMZ resistance in DMG cell lines. There is an urgent need to develop new strategies to treat TMZ-resistant DMGs.

Polysomnography as an indicator for cervicomedullary decompression to treat foramen magnum stenosis in achondroplasia.

OBJECTIVE: Management of cervicomedullary compression due to foramen magnum stenosis in achondroplasia remains controversial, especially for patients with no symptoms or mild symptoms. We examined the effectiveness of polysomnography (PSG) as an indicator for cervicomedullary decompression treatment. METHODS: We retrospectively reviewed nine achondroplasia cases (mean age 1 year and 9 months) treated from 2008 to 2015. All patients were examined by PSG, magnetic resonance imaging (MRI), and otolaryngeal fibroscopy. We analyzed demographic data, clinical presentation, degree and type of respiratory impairment, severity of foramen magnum stenosis and concomitant cervicomedullary compression, treatment (conservative or surgical), and clinical outcome. RESULTS: Eight of nine patients presented with no severe symptoms in the daytime. However, MRI revealed four severe, four moderate, and one mild case of cervicomedullary compression, and PSG demonstrated severe sleep apnea in four cases and moderate sleep apnea in five cases. All sleep apnea cases were obstructive or obstructive-dominant. Fibroscopy revealed no upper airway stenosis in six cases and mild stenosis in three cases. Four patients who had severe sleep-related respiratory disturbance on PSG and severe or moderate cervicomedullary compression were treated by cervicomedullary decompression. Three of these patients demonstrated improved sleep respiration soon after surgery, while one required temporary tracheostomy due to bilateral vocal cord paralysis caused by compression during intratracheal intubation. CONCLUSION: Polysomnography can be a useful indicator for cervicomedullary decompression surgery, especially in cases of seemingly asymptomatic achondroplasia with severe foramen magnum stenosis.

MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas and MGMT Silencing to Temozolomide Sensitivity in IDH-Mutant Gliomas.

Histone H3 mutations are frequently found in diffuse midline gliomas (DMGs), which include diffuse intrinsic pontine gliomas and thalamic gliomas. These tumors have dismal prognoses. Recent evidence suggests that one reason for the poor prognoses is that O6-methylguanine-DNA methyltransferase (MGMT) promoter frequently lacks methylation in DMGs. This review compares the epigenetic changes brought about by histone mutations to those by isocitrate dehydrogenase-mutant gliomas, which frequently have methylated MGMT promoters and are known to be sensitive to temozolomide.

Adult Chiari Type 1 Malformation with Holocord Syringomyelia Associated with Sagittal Synostosis.

Craniosynostosis associated with Chiari malformation (CM) is usually found in infants with an underdeveloped posterior fossa. We here present a case of adult craniosynostosis, CM, and symptomatic syringomyelia caused by the protrusion of the posterior rim of the foramen magnum without a tight posterior fossa. A 22-year-old woman with an abnormal head shape and forearm hypesthesia was given a diagnosis of sagittal suture synostosis with CM and syringomyelia caused by foramen magnum stenosis. She underwent foramen magnum decompression with a C1 laminectomy without cranial vault expansion or duraplasty. Her symptoms and radiographical findings improved after surgery. In cases of non-operative craniosynostosis with CM, clinicians should be alert to late-onset syringomyelia and choose surgical strategies according to the pathophysiology.

[Bilateral Internal Carotid Artery Dissection Caused by Elongated Styloid Processes:A Case Report].

We report a case of bilateral internal carotid artery(ICA)dissection associated with bilateral elongated styloid processes(ESPs). A 46-year-old man presented with transient aphasia and left visual disturbance at a business meeting. He complained of a foreign body sensation in his throat during swallowing for two years. Magnetic resonance imaging(MRI)demonstrated fresh small infarcts in the left corona radiata. Magnetic resonance angiography(MRA)revealed string signs bilaterally in the cervical ICAs. The patient was diagnosed with bilateral idiopathic ICA dissection and was treated with ozagrel and clopidogrel. Three-dimensional computed tomographic angiogram(3DCTA)indicated bilateral ESPs and bilateral ICA stenosis. 3DCTA with the patient's head tilting and neck extension revealed that each ICA was compressed by the ipsilateral ESP. A follow-up MRA showed complete normalization of bilateral ICAs after neck rest and anti-platelet therapy, following which, clopidogrel was stopped. The patient wore a soft cervical collar until the operation, to avoid contact between the ESPs and ICAs due to changes in head position. Bilateral ESP resection was performed to prevent recurrence of cerebral ischemic events caused by ICA dissection. The patient was discharged one week after the surgery without any neurological deficit. There was no recurrence of symptoms during the next eight months after the operation.

Third Ventricle Germ Cell Tumor Originating from the Infundibulum with Rapidly Expansive Enlargement.

We present a pediatric case of a rapidly expanding third ventricle germ cell tumor (GCT). A 14-year-old boy suffered from gradual-onset central diabetes insipidus (DI) and received desmopressin treatment. Magnetic resonance imaging (MRI) showed nonspecific findings of the pituitary-hypothalamic axis. Nine months after the initial DI diagnosis, he developed progressively worsening headache. MRI demonstrated a third ventricle tumor causing noncommunicating hydrocephalus, although an MRI 16 weeks before admission did not show the lesion. We performed gross total resection (GTR) of the tumor in 2 stages: a translamina terminalis approach and an extended transsphenoidal approach. The lesion was histologically diagnosed as immature teratoma with some germinoma. His noncommunicating hydrocephalus resolved after surgery. Through postoperative radiochemotherapy (whole ventricle: 23.4 Gy/13 fractions, tumor bed: 27.0 Gy/15 fractions, and 3 courses of carboplatin-etoposide), he has was in complete remission at the 3-year follow-up and has continued his high school program. This case suggests the following: (1) a mixed GCT originating from the neurohypophysis/infundibulum can show rapidly expansive growth in a child with central DI; (2) GTR and adjuvant radiochemotherapy can result in a good therapeutic outcome in rapidly expanding GCT; and (3) the extended transsphenoidal approach is a complementary approach to transcranial resection of anterior third ventricle GCTs.

Perifocal Inflammatory Reaction with Volume Fluctuation Caused by Diagnostic Radiation-Induced Regression in Germinoma Makes Histological Diagnosis Difficult despite Its Disappearance following Treatment: A Significant Pitfall and Countermeasures to It.

We present a pediatric case of neurohypophyseal germinoma with a perifocal inflammatory reaction (PIR) with volume fluctuation caused by diagnostic radiation-induced regression (DRIR). On-target biopsy failed to confirm the histology because PIR hardly contained any germinoma cells. DRIR-related fluctuation of the tumor volume disguised germinoma as inflammation. We analyzed the cerebrospinal fluid (CSF) and detected a high level of placental alkaline phosphatase (PLAP), which demonstrated the neurohypophyseal lesion to be germinoma and brought the patient from successful radiochemotherapy up to complete remission. PIR adjacent to the germinoma (PIRAG) disappeared completely following radiochemotherapy, although it contained almost no germinoma cells. Examination of the CSF-PLAP level can complement the diagnosis of germinoma and will decrease the risk of misdiagnosis. Neurosurgeons should keep in mind PIRAG, DRIR, and the diagnostic value of CSF-PLAP when germinoma is suspected.

Mobile spinal enterogenous cyst resulting in intermittent paraplegia in a child: case report.

The authors report the case of a mobile spinal enterogenous cyst in a 2-year-old boy, who was admitted to the hospital several times for intermittent paraplegia. Magnetic resonance imaging and CT revealed an isolated cyst in the lumbar spinal canal. The symptoms were caused by transient myelopathy of the conus medullaris and radiculopathy of the cauda equina due to the changing size and location of the cyst. The cyst was surgically extirpated, after which the symptoms resolved. The histopathological diagnosis was enterogenous cyst. The clinical history of intraspinal enterogenous cyst is usually progressive. Mobility and changes in size are rare pathophysiological findings. The authors speculate that the cyst wall did not adhere to the surrounding structures and had ruptured and quickly reformed. Enterogenous cyst should be considered in the differential diagnosis of spinal intradural cysts in children with radiculomyelopathy.