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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.

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.

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 IIβ (TOP2β) as a possible regulator for neuronal differentiation in medulloblastomas and examined the pathological roles of GLI3, NM, GFAP, and TOP2β 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 TOP2β 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 TOP2β-IR was frequently observed only in NM +/GFAP− medulloblastomas. In fluorescent immunostaining, TOP2β-IR was mostly co-localized with NeuN-IR but not with GFAP-IR. In single-cell RNA sequencing, TOP2β 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.

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.

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. 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. 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. Polysomnography can be a useful indicator for cervicomedullary decompression surgery, especially in cases of seemingly asymptomatic achondroplasia with severe foramen magnum stenosis.

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.

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.

BACKGROUND We have previously investigated the expression of Gli3, a downstream target of the Sonic Hedgehog pathway, which main function is to suppress Gli1/2 in medulloblastomas. We found that Gli3 is associated with neuronal and glial differentiation in desmoplastic / nodular (D/N) type medulloblastomas (Miyahara et al., Neuropathology, 2013). In the present study, we investigated the expression of Gli3 in molecular subgroups. METHOD Thirty-one medulloblastomas treated at Niigata University between 1982 and 2013 were studied. Molecular classification into 4 subgroups (WNT-activated, SHH-activated, Group 3 and Group 4) using Nanostring and immunohistochemistry was performed. Furthermore, Gli3 and Gli1 expression in molecular subgroups was assessed using public data bases. RESULTS Nanostring was considered reliable (confidence > 0.9) in 28 cases. Four cases were classified as WNT-, 5 cases as SHH-activated, 4 cases as Group 3 and 16 cases as Group 4. Gli3 was positive in 7 out of 9 (78%) WNT-/SHH- cases, but positive in only 8 out of 19 (42.1%) non-WNT-/SHH- subgroup cases (p = 0.1145, Fisher’s exact test). R2 database analysis confirmed that Gli3 was significantly elevated in WNT- and SHH-activated medulloblastoma. Gli1 was elevated in SHH-activated cases but suppressed in WNT-activated cases. IHC analysis revealed that Gli3 was elevated inside nodules showing neuronal differentiation in D/N type medulloblastoma. Results of single cell RNA analyses were consistent with those of IHC, Nanostring and R2. CONCLUSION These results suggest that Gli3 is elevated inside the nodules of SHH-activated medulloblastoma, whereas in WNT-activated cases, Gli3 diffusely suppresses HH signaling.

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.

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.

BACKGROUND We previously reported that Gli3, which was a downstream molecule of Sonic Hedgehog signal, induced neuronal and/or glial differentiation in some types of medulloblastoma (desmoplastic/nodular medulloblastoma and medulloblastoma with extensive nodularity), and patients of medulloblastoma with neuronal differentiation showed favorable prognosis, but those with glial differentiation tended to show miserable prognosis (Miyahara H, Neuropathology, 2013). This time, we focused on Topoisomerase II β (Top2β), which was reported to induce neuronal differentiation and inhibit glial differentiation, and examined the expression of Top2β in medulloblastomas with neuronal and glial differentiations. METHODS We assessed the expression of Top2β, NeuN, and GFAP using triple fluorescent immunostaining method in medulloblastoma samples with both neuronal and glial differentiations. Furthermore, the expression of Top2β, H3K4me2, and H3K27me3 were also assessed, because Top2βwas positively or negatively regulated by H3K4me2 and H3K27me3, respectively. RESULTS Many large nuclei in the nodules, in which differentiated cells were seen, was visualized by Top2β. The Top2β signals were seen in NeuN+ cells but not GFAP+ cells. H3K4me2 signals were visualized in Top2β+ large nuclei, but H3K27me3 and NeuN+ large nuclei were distributed independently. CONCLUSIONS These results indicate that Top2β may be a molecule associated with neuronal, but not glial, differentiation of medulloblastoma cells. Drugs targeting histone modification enzymes such as EZH2 inhibitors are possible therapeutic targets as a differentiation-inducing therapy for medulloblastoma.

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. 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. 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. MRVn visualizes the anterior portion of ChPl3V with significant sensitivity and the posterior portion with lower one.

Neuroendoscopy has become common in the field of pediatric neurosurgery. As an alternative procedure to cerebrospinal fluid shunt, endoscopic third ventriculostomy has been the routine surgical treatment for obstructive hydrocephalus. However, the indication is still debatable in infantile periods. The predictors of late failure and how to manage are still unknown. Recently, the remarkable results of endoscopic choroid plexus coagulation in combination with third ventriculostomy, reported from experiences in Africa, present puzzling complexity. The current data on the role of neuroendoscopic surgery for pediatric hydrocephalus is reported with discussion of its limitations and future perspectives, in this review.

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.

Object Sacrococcygeal dimples in the gluteal fold, also known as coccygeal pits, are observed in 2%–4% of newborns. Sacrococcygeal dimples are not generally considered to be associated with a significant risk of intraspinal anomalies and therefore are not thought to require further radiographic evaluation. Accordingly, the precise incidence and nature of intraspinal lesions that may be associated with sacrococcygeal dimples is unclear. This study was conducted to determine the incidence of intraspinal lesions in patients with intergluteal dimples. Methods In this study, the authors used MRI to evaluate 103 children who were seen at the Niigata University Medical and Dental Hospital between 2006 and 2011 because of skin abnormalities in the lumbosacral region. Of these children, 14 were excluded as having a subcutaneous fatty mass, and 5 were excluded because the dimples were above the gluteal fold or did not end at the coccyx. The remaining 84 patients were classified according to whether the bottom of the dimple was visible (shallow) or not (deep). The authors also retrospectively examined other skin abnormalities and coexisting anomalies. Results The mean age at the time of MRI evaluation was 11.7 months. Magnetic resonance imaging led to the identification of fibrolipoma of the terminal filum (FTF) in 14 cases (16.7%); 6 of these patients also had a low conus. Classified by depth, there were 58 cases with shallow and 26 with deep dimples. Fibrolipoma of the terminal filum was found in significantly more patients with deep dimples (9 [34.6%]) than in those with shallow dimples (5 [8.6%]). The frequency of other congenital anomalies was significantly higher in patients with FTF-associated dimples (6 [42.9%] of 14) than in those with dimples that were not associated with FTF (9 [12.9%] of 70). Conclusions Fibrolipoma of the terminal filum was identified by MRI in 16.7% of patients with sacrococcygeal dimples. The risk of FTF increased when the dimples were deeply excavated or were accompanied by congenital anomalies. Magnetic resonance imaging should be performed to identify intraspinal lesions when there are high risk factors for intraspinal abnormalities, or when an ultrasound screening suggests intraspinal abnormalities.

BACKGROUND: We have previously investigated the expression of Gli3, a downstream target of the Sonic Hedgehog pathway, which main function is to suppress Gli1/2 in medulloblastomas. We found that Gli3 is associated with neuronal and glial differentiation in desmoplastic / nodular (D/N) type medulloblastomas (Miyahara et al., Neuropathology, 2013). In the present study, we investigated the expression of Gli3 in the molecular subgroups. METHOD: Thirty-one medulloblastomas treated at Department of Neurosurgery, Niigata University between 1982 and 2013 were retrospectively studied. Molecular classification into 4 subgroups (WNT-activated, SHH-activated, Group 3 and Group 4) was performed using Nanostring. HE and NeuN, GFAP, beta-catenin, GAB-1, and YAP-1 immunohistochemistry was performed. Furthermore, Gli3 and Gli1 expression in each molecular subgroup was assessed in the public data base R2. RESULTS: Nanostring was considered reliable (confidence > 0.9) in 28 cases. Four cases were classified as WNT- activated, 5 cases as SHH-activated, 4 cases as Group 3 and 16 cases as Group 4. Gli3 was positive in 7 out of 9 (78%) WNT-/SHH- cases, whereas Gli3 was positive in only 8 out of 19 (42.1%) non-WNT-/SHH- subgroup (p = 0.1145, Fishers exact test). R2 database analysis confirmed that Gli3 was significantly elevated in WNT- and SHH-activated medulloblastoma. Gli1 was elevated in SHH-activated cases but suppressed in WNT-activated cases. IHC analysis revealed that Gli3 was elevated inside the nodules of D/N type medulloblastoma. Neuronal differentiation was seen in these nodules. CONCLUSION: These results suggest that Gli3 is elevated inside the nodules of SHH-activated medulloblastoma, whereas in WNT-activated cases, Gli3 suppresses HH signaling in the entire tumor.

INTRODUCTION Bevacizumab (BEV) therapy has been used for pediatric high grade glioma,however the evidence and effectiveness are not understood yet. METHODS We report 7 cases (age 2 to 10 years old) of pediatric high grade glioma treated with BEV. One case is thalamic diffuse midline glioma H3K27 mutant (DMGH3K27M),one case is brain stem DMGH3K27M,one case is cerebellar high grade glioma,and 4 cases are diffuse intrinsic pontine glioma (DIPG) diagnosed clinically without biopsy. 5 cases were treated with BEV when diagnosed as recurrence after chemo-radiotherapy. One case was treated for rapid tumor progression during radiotherapy. One case was started on BEV therapy with radiation and concomitant temozolomide therapy. RESULT The number of times of BEV was 2 to 13 times (median 7 times). The period of BEV was 1 to 9 months (median 4 months). One case which was treated with BEV at rapid progression during radiation showed good response on imaging and improvement of symptoms. 4 of 5 cases who were treated at recurrence clinically showed mild symptomatic improvement. One case treated with BEV and radiotherapy initially was not evaluated. The adverse effects of BEV included wound complication of tracheostomy and rash. CONCLUSION BEV showed good response for rapid progression during radiotherapy,and mild response for recurrence cases. BEV is thought to be an effective therapeutic agent for pediatric HGG at recurrence and rapid tumor progression during radiotherapy.

Medulloblastoma (MB) is a malignant cerebellar tumor arising in children,and its ontogenesis is regulated by Sonic Hedgehog (Shh) signaling. No data are available regarding the correlation between expression of Gli3, a protein lying downstream of Shh, and neuronal differentiation of MB cells, or the prognostic significance of these features. We re-evaluated the histopathological features of surgical specimens of MB taken from 32 patients, and defined 15 of them as MB with neuronal differentiation (ND), three as MB with both glial and neuronal differentiation (GD), and 14 as differentiation-free (DF) MB.Gli3-immunoreactivity (IR) was evident as a clear circular stain outlining the nuclei of the tumor cells.The difference in the frequency of IR between the ND+GD (94.4%) and DF (0%) groups was significant (P < 0.001). The tumor cells with ND showed IR for both Gli3 and neuronal nuclei. Ultrastructurally, Gli3-IR was observed at the nuclear membrane. The overall survival and event-free survival rates of the patients in the ND group were significantly higher than those in the other groups. The expression profile of Gli3 is of considerable significance, and the association of ND with this feature may be prognostically favorable in patients with MB.

Object Radiation monotherapy—prophylactic craniospinal or whole-brain irradiation paired with a radiation boost to the primary tumor—is the standard treatment for intracranial germinomas at the authors' institution. The authors assessed long-term outcomes of patients with germinoma who underwent therapy and identified factors affecting them. Methods The authors retrospectively analyzed data obtained in 46 patients (35 males and 11 females, age 5–43 years at diagnosis) who had been treated for intracranial germinomas between 1990 and 2009 at the authors' institution. Thirty patients had germinomas in localized regions and 16 in multiple regions. Thirty-eight patients (83%) underwent radiotherapy alone (craniospinal irradiation in 32 and whole-brain irradiation in 6). Seven patients underwent radiochemotherapy and 1 underwent chemotherapy alone. The mean radiation doses for the whole brain, spine, and primary tumor site were 26.9, 26.6, and 49.8 Gy, respectively. The median follow-up period was 125 months. Results The 10-year overall and recurrence-free survival rates were 93.3% and 89.3%, respectively. None of the 38 patients who received radiation monotherapy developed a recurrent lesion, whereas 1 of 7 who underwent radiochemotherapy and the 1 patient who underwent chemotherapy had a recurrent lesion. Of the entire population, 26 patients required hormone replacement therapy, 2 had short stature, and 1 developed a radiation-induced meningioma. Seventeen of the 25 childhood- or adolescent-onset patients were 19 years or older at the latest follow-up visit, 15 of whom graduated from senior high school, and only 2 of whom graduated from college. Of 34 patients who were 19 years or older at the latest visit, 4 were students, 18 worked independently, 4 worked in sheltered workplaces, and 8 were unemployed. Of the 34 patients, 4 got married after the initial treatment, 3 of whom had children. There were 8 patients (17%) with low postoperative Karnofsky Performance Scale (KPS) scores that were significantly associated with impaired neurocognitive functions, severe surgical complications, and neurological impairments. In 10 of the 46 patients, KPS scores at the latest visit were lower than their postoperative KPS scores. These decreases in KPS scores were significantly correlated with a delayed decline in neurocognitive functions in childhood-onset patients and a postoperative impairment of neurocognitive functions in patients with adolescent- or adult-onset germinoma. Conclusions No tumor recurrence occurred in germinoma patients treated with the authors' radiation monotherapy, which appears to be effective enough to cure the tumor. Brain damage caused by tumors themselves and surgical complications were found to adversely affect functional outcomes in patients regardless of their age. Although radiotherapy rarely caused late adverse effects in patients with adolescent- or adult-onset, in some childhood-onset lesions, the radiation seems to carry the risk of neurocognitive dysfunctions, which are attributable to late adverse effects. Accordingly, treatments for germinoma patients should be selected according to a patient's age and the extent of the tumor and with particular care to avoid surgical complications.

The authors report a rare case involving the occurrence of metachronous pure germinomas long after treatment of a mixed germ cell tumor (GCT) categorized as having a poor prognosis. A neurohypophysial germinoma occurred 4 years and 6 months after the initial treatment of a mixed pineal GCT containing a yolk sac tumor and a germinoma. Furthermore, intramedullary germinomas occurred 21 years after the initial treatment of the mixed GCT and 15 years after the second treatment of the neurohypophysial germinoma. The neurohypophysial germinoma was not confirmed histopathologically, but the intramedullary germinoma was histopathologically diagnosed as a pure germinoma. Serum α-fetoprotein levels at the second neurohypophysial and third intramedullary occurrences of the germinomas were less than 10 ng/ml. Therefore, no yolk sac components seemed to be contained in the tumors. The second neurohypophysial and third intramedullary germinomas might be recurrences of the germinoma component of the pineal mixed GCT, which consisted of a yolk sac tumor and a germinoma. However, it seems very unlikely that only the germinoma, categorized in the good prognosis group, would be the only one to recur. Hence, it seems plausible that both the second and the third occurrences of pure germinoma were de novo metachronous GCTs arising after the pineal mixed GCT was cured. The authors' case indicates the possibility of multicentric GCTs in the CNS.

Objective To analyze the effect of intrathecal (IT) chemotherapy for disseminated medulloblastoma. Materials and methods Twenty-one patients received IT chemotherapy using the chemotherapeutic agents of methotrexate (MTX) and nitrosoureas (ACNU, MCNU) including nine patients for residual leptomeningeal lesions after initial surgery and radiation, and 12 for a recurrence with leptomeningeal dissemination. Of these 21 patients, 12 received a lumbar and/or ventricular bolus injection of the chemotherapeutic agents, one received the ventriculolumbar perfusion of the agents, and eight received both the perfusion and bolus injection. The doses ranged from 6– 7 mg/m 2 of ACNU for perfusion and 3–3.5 mg/m 2 of ACNU, MCNU, or MTX for the bolus injection, and the cycles were administered from 3 to 12 times for perfusion and from 5 to 54 times for the bolus injection. The effects of chemotherapy were assessed by both radiological and cytological examinations, and the clinical symptoms were also assessed. Radiological and/or cytological responses were observed in 10 of 21 patients (47.6%), including seven cases demonstrating a complete remission. The 5year overall survival rate and 5-year survival rate after dissemination were 61.5 and 46.4%, respectively. Five patients who received a lumbar bolus injection of nitrosoureas experienced paraplegia and double incontinence. One patient who received a ventricular injection of nitrosoureas experienced truncal ataxia. Conclusion IT chemotherapy was found to be effective in some cases with refractory disseminated medulloblastoma and it seems to be an appropriate treatment choice for leptomeningeal recurrence. However, the frequent bolus injections of nitrosoureas should be avoided to prevent the side effects.

Two embryonal CNS tumors, atypical teratoid/rabdoid tumor (AT/RT) and primitive neuroectodermal tumor (PNET), may be confused with each other and misdiagnosed. Here we report an infant with a congenital supratentorial tumor, which was detected by fetal MRI at 37 weeks gestation. On routine histological examination, the tumor was composed mainly of small undifferentiated cells, among which many rhabdoid cells and occasional sickle-shaped embracing cells were observed. No mesenchymal or epithelial areas were evident. Our impression was that the tumor was an atypical example of AT/RT. Immunohistochemically, almost all the tumor cells were strongly positive for vimentin. However, epithelial membrane antigen was notably negative, and most of the tumor cell nuclei were clearly positive for INI1. In addition, many tumor cells were positive for neurofilament protein. There were also occasional small areas containing many tumor cells positive for glial fibrillary acidic protein. Finally, a diagnosis of PNET, with a rhabdoid phenotype and expression of neuronal and glial markers, was made. In the present case, application of INI1 immunostaining was very helpful for distinguishing PNET from AT/RT.

For pineal nongerminomatous malignant germ cell tumors (NGMGCTs), we mainly performed radical tumor resection during initial treatment combined with adjuvant therapy. We retrospectively analyzed 17 patients treated for pineal NGMGCTs between 1986 and 2007 at the University of Niigata. Twelve patients underwent total or subtotal resection of their tumor via the occipital transtentorial approach. Five patients underwent partial resection, and four of them later underwent total resection by salvage surgery. After surgery, eight patients were treated with combined radiochemotherapy including whole-brain irradiation, two received radiation monotherapy, one had chemotherapy with local irradiation, and six were treated with chemotherapy alone. The median follow-up period for surviving patients was 179 months. The 10-year overall survival and progression-free survival rates for the radiochemotherapy group were both 75.0 % (two patients had a recurrence and died); the rates for other adjuvant therapies were 77.8 % (two died) and 22.2 % (seven had a recurrence), respectively. Radiochemotherapy was significantly associated with an increased rate of progression-free survival compared with the other adjuvant therapies (p = 0.0396). For pineal NGMGCTs, initial treatment strategies including gross total resection of the tumor before or after whole-brain irradiation and chemotherapy provided good therapeutic outcomes. Obtaining complete remission of the primary tumor, irrespective of the timing of surgical resection (i.e., before or after adjuvant therapies), or complete response by neoadjuvant radiochemotherapy during an initial treatment appears to be essential for improving therapeutic outcomes of intracranial NGMGCTs.

Diffuse type brainstem glioma is one of the most malignant types of brain tumors and the prognosis is extremely poor. The proliferative potential of these tumors is presumed to be very high, but there is little information about the cell kinetics of brainstem glioma because surgical resection is rarely performed. The histological grade, tumor spread, growth potential, and prognosis were evaluated in 40 autopsy cases of diffuse type brainstem glioma. To quantify the growth potentials of individual tumors, the proliferating cell indices of Ki-67 (MIB-1) and proliferating cell nuclear antigen (PCNA) monoclonal antibodies were measured. Mean MIB-1 and PCNA proliferating cell indices were 20.4% (24 cases) and 37.0% (28 cases), respectively, in 34 glioblastomas. The median survival time was 40 weeks in 22 treated patients. The mean PCNA proliferating cell index was 10.8% in four of five anaplastic astrocytomas and the median survival time in four treated patients was 91 weeks. The MIB-1 and PCNA proliferating cell indices of one astrocytoma were 2.9% and 20.3%, respectively, and the survival time was 56 weeks. The overall median survival time was 32 weeks. There was a significant difference in PCNA proliferating cell indices between glioblastomas and anaplastic astrocytomas (p < 0.05) and there was a significant difference in survival time between glioblastomas (40 weeks) and anaplastic astrocytomas plus astrocytoma (74 weeks) among the treated patients (p < 0.05). Supratentorial extension was more frequent in glioblastomas than in anaplastic astrocytomas (p < 0.05). Our results suggest that the majority of diffuse type brainstem gliomas are glioblastoma and the proliferative potential is probably as high as that of adult supratentorial glioblastoma. Supratentorial extension and dissemination are relatively frequent in the advanced stage. Anaplastic astrocytoma or astrocytoma is rarer and less infiltrative and proliferative, and carries a slightly better prognosis than glioblastoma.

The authors report a rare case of a huge hypervascular tentorial cavernous angioma treated with preoperative endovascular embolization, followed by successful gross-total removal. A 15-year-old girl presented with scintillation, diplopia, and papilledema. Computed tomography and MRI studies revealed a huge irregularly shaped tumor located in the right occipital and suboccipital regions. The tumor, which had both intra- and extradural components, showed marked enhancement and invasion of the overlying occipital bone. Angiography revealed marked tumor stain, with blood supply mainly from a large branch of the left posterior meningeal artery. Therefore, this lesion was diagnosed as a tentorium-based extraaxial tumor. For differential diagnosis, meningioma, hemangiopericytoma, and malignant skull tumor were considered. Tumor feeders were endovascularly embolized with particles of polyvinyl alcohol. On the following day, the tumor was safely gross totally removed with minimum blood loss. Histopathological examination confirmed the diagnosis of cavernous angioma. To date, there have been no reports of tentorium-based cavernous angiomas endovascularly embolized preoperatively. A tentorial cavernous angioma is most likely to show massive intraoperative bleeding. Therefore, preoperative embolization appears to be quite useful for safe maximum resection. Hence, the authors assert that the differential diagnosis of tentorium-based tumors should include tentorial cavernous angioma, for which preoperative endovascular embolization should be considered.

Background. Modern magnetic resonance imaging (MRI) diagnosis of Tolosa-Hunt syndrome rests upon demonstration of cavernous sinus abnormalities. We present a case of Tolosa-Hunt syndrome who has no abnormal mass lesion in the cavernous sinuses on MRI but with a diagnostic lesion on magnetic resonance angiography (MRA). Clinical Presentation. A 48-year-old woman developed acute periorbital pain and abducens palsy of the right side at the first episode, and subacute peri-orbital pain and rapidly deteriorating visual acuity on the left side at the second episode with a four months interval. MRI showed no soft-tissue abnormality in the cavernous sinuses. Findings. MRA demonstrated a narrowing of the right cavernous carotid artery at the first episode, and narrowings of the left clinoid carotid and ophthalmic arteries at the second episode. Based on these findings, the patient underwent urgent steroid therapy and the symptoms resolved dramatically in each episode. Follow-up MRA confirmed resolution of arterial narrowings. Interpretation. MRA may help prompt the noninvasive diagnosis in certain cases of Tolosa-Hunt syndrome with little inflammatory reaction in the cavernous sinus but with predominant intra- and juxta-cavernous periarteritis.

We established two glioma cell lines from two surgical specimens obtained at different times from the same patient. One (No. 9R), which was derived from the recurrent tumor (glioblastoma, grade IV), proliferated more rapidly in vitro than the other (No. 9) from the primary tumor (slightly anaplastic astrocytoma, grade II–III). No. 9R showed heterotransplantability in nude mice, whereas No. 9 did not. These findings indicate that No. 9R has a more aggressive or malignant nature than No. 9. Both cell lines showed homozygous deletion of the representative tumor suppressor p16 and p15 genes, but no p53 gene alteration. However, examination of the overall mRNA expression profile using a commercially available cDNA-spotted membrane revealed much higher expression levels of several mRNAs, at least, in No. 9R than in No. 9, although the relationship between these mRNAs and the growth potentials remained unknown. These two cell lines, derived from the same individual, with different proliferating potentials may be useful for studies on the molecular bases of glioma malignancy and progression.

To determine whether various clinical factors are related to long-term outcomes of patients with sporadic cerebellar hemangioblastomas.Subjects included 36 patients (19 men and 17 women) who underwent resection of sporadic hemangioblastoma in the cerebellum. Age at surgery ranged from 17-79 years (mean, 49.7 years). The tumor size, which was defined as the largest diameter of the lesion including the extratumoral cyst, ranged from 10-67 mm (mean, 36.4 mm). Obstructive hydrocephalus secondary to mass effect on the fourth ventricle was present in 21 (58.3%) patients preoperatively.Total tumor removal was achieved in 31 of 36 patients (86%). In 4 (11%) patients with solid tumors, postoperative hematoma occurred in the removal cavity, and hematoma removal was required immediately after surgery. We followed 30 patients for12 months after the initial surgery (mean, 72.9 months; range, 12-274 months). Recurrence of hemangioblastoma developed in 4 of 30 patients (13%) at 6 months, 17 months, 6 years, and 22 years after surgery. At the final follow-up examination, 9 (30%) of 30 patients showed some residual neurologic symptoms (poor group), whereas the remaining 21 patients showed no deficits (good group). Using univariate analysis, both age at surgery and tumor characteristics (cystic or solid) were significantly related to long-term patient outcomes (P0.05). However, in a multiple logistic regression analysis, only tumor characteristics were correlated with outcomes (P = 0.017). At the final follow-up examination, patients with solid tumors more frequently showed poor outcomes than patients with cystic tumors.The solid configuration observed on preoperative images of sporadic cerebellar hemangioblastomas is one of the most important clinical factors related to both immediate and long-term outcomes after surgery.

Lesions associated with a thickened pituitary stalk (TPS lesions) revealed by magnetic resonance imaging have a diverse pathology. Accordingly, for clinical decision-making, it is necessary to make a diagnosis based on histopathological examination of the TPS lesions. The objectives of this study were to review endoscopic biopsies of TPS lesions and to assess the surgical strategy for treating these lesions. Eleven patients (four males and seven females) aged from 6 to 75 years underwent endoscopic biopsy of a TPS lesion between 2006 and 2011 at University of Niigata. The relationships of the extent of lesions with surgical approaches were retrospectively examined. Among the 11 patients, a biopsy was performed via an endoscopic transsphenoidal approach for five with intrasellar lesions; via an endoscopic extended transsphenoidal approach for two with localized TPS lesions; and via an endoscopic intraventricular approach for four with the lesion protruding from the infundibulum. Histopathological examinations of all the lesions confirmed diagnoses of germinoma in four patients, hypophysitis in three, Langerhans cell histiocytosis in two, craniopharyngioma in one, and cancer metastasis in one. None of the 11 patients had further deterioration of pituitary function postoperatively. Endoscopic biopsy of TPS lesions is a less invasive alternative to open biopsy requiring transcranial surgery. The endoscopic transsphenoidal approach is most suitable for biopsies of TPS lesions associated with intrasellar lesions. Otherwise, the endoscopic intraventricular approach seems reasonable for intraventricular lesions protruding from the infundibulum, and the endoscopic extended transsphenoidal approach appears appropriate for localized TPS lesions.

Diffuse intrinsic brainstem gliomas are considered to be inoperable. We report our initial experience of temozolomide (TMZ) administration into brainstem by intracerebral (i.c.) microinfusion using a rat brainstem glioblastoma allograft model.Forty-eight Fischer 344 female rats were used. In a feasibility study, various doses of i.c.-TMZ (1-10 mg) were administered into the brainstem using AlzetTM pumps in order to evaluate survival rates and neurotoxicity. For tumor implantation, rats received an injection of 10(5) 9 L gliosarcoma cells. For local therapy, 5 days after inoculation, a total amount of 1 mg of TMZ or saline was administered into the brainstem at 1 μl/h over 7 days (n = 8/group). For systemic therapy, rats were treated with an orally administered maximum daily dose of 50 mg/kg TMZ for 5 consecutive days. Survival time and neurological deficit were recorded as outcome parameters.In the neurotoxicity study, low dose TMZ (1 mg) was feasible to be administered into brainstem over 7 days without neurological deficit. Using high dose TMZ (5-10 mg), marked neurotoxic effect was observed. In the brainstem tumor study, survival was significantly prolonged in low dose i.c.-TMZ group compared to control rats (median survival 23.5 versus 29.5 days; p0.01). Systemic therapy with maximal oral-TMZ dose resulted in longer survival time compared to low dose i.c.-TMZ group (median survival 33.5 versus 29.5 days; p0.01).i.c.-TMZ is feasible and effective against rat brainstem glioblastoma allograft. However, we could not show superior potential of i.c.-TMZ compared to oral-TMZ administration. Modification of TMZ infusion with systemic therapy warrants future investigations.

We herein report a rare case of cerebellopontine angle (CPA) medulloblastoma originating in the brainstem that demonstrated a very unusual clinical presentation and radiological appearances. A 25-year-old female was admitted to our hospital with a right hearing disturbance and a right facial palsy. A small non-enhanced lesion having minimal mass effect in the right CPA was identified by using a 1.5-tesla-MR system, whose size remained almost unchanged a year. The 3-tesla MR images revealed that the precise region was in the right side of the tegmentum of the lower pons to the inferior cerebellar peduncle and the flocculus. MR spectroscopic images using a 3-tesla system revealed a high ratio of choline-to-N-acetylaspartate in the region of interest in comparison to the contra-lateral side. Craniotomy and biopsy were performed. The histopathological diagnosis was medulloblastoma. The patient received craniospinal irradiation and chemotherapy, and achieved complete remission by the time of the follow-up MR images. She is now doing well with a full recovery of the right facial palsy. MR spectroscopic imaging is considered to be quite useful for the management of this rare type of brainstem tumor.

✓ Nontumoral bilateral occlusion of the Monro foramina is a rare clinical condition. Treatment includes shunt placement, endoscopic procedures, or both. The authors describe the case of a 22-year-old woman who had previously undergone placement of a ventriculoperitoneal shunt via a right frontal approach for management of triventricular dilation due to aqueductal stenosis. Six years postoperatively she presented with right-sided slit-ventricle syndrome and stenosis of the right Monro foramen, which was treated with an endoscopic third ventriculostomy and fenestration of the septum pellucidum. Two years later she presented with bilateral lateral ventricular dilation. Inspection of the right lateral ventricle with a fiberscope revealed occlusion of the septum pellucidum fenestration; on observation, the right Monro foramen was covered by thick, tough granulation tissue and the left was occluded by thin membranous tissue. Repeated fenestration of the septum pellucidum and left Monro foraminoplasty were therefore performed by perforating this thin tissue. A stent was then introduced into the third ventricle via the right lateral ventricle, the fenestration in the septum pellucidum, and the left Monro foramen. The authors note that fiberscopes are in general more maneuverable than rigid endoscopes and conclude that they are particularly useful for the treatment of this type of hydrocephalus.

A case of safely treated parasellar cyst by endoscopic fenestration of the third ventricular floor from outside of the ventricle to establish communications between the cyst and the ventricle is reported. During the endoscopic procedures, the anterior commissure and the foramina of Monro could be clearly observed using this approach. In treating parasellar cysts with thick walls, endoscopic fenestration of the third ventricular floor in the reverse direction, i.e., from inside of the cyst, should be considered.