Tomoru Miwa

Nationwide investigation of the current status of therapeutic neuroendoscopy for ventricular and paraventricular tumors in Japan: Clinical article

OBJECT The authors report their investigation on the current status of neuroendoscopic biopsy for ventricular and paraventricular tumors as well as treatment for associated hydrocephalus in Japan. METHODS Patients who had undergone therapeutic neuroendoscopy between 2005 and 2009 were included in this study. The main items examined were age; sex; localization of tumor; pathological diagnosis using biopsy; the presence, treatment, and efficacy of treatment of associated hydrocephalus; perioperative complications; activities of daily living (ADL) before and after therapeutic neuroendoscopy; and the presence of dissemination during the postoperative course. RESULTS Seven hundred fourteen patients from 123 sites (462 male and 252 female patients, mean age 33.3 years) were enrolled. Localization of the tumor was mainly classified into the lateral ventricle in 91 patients, the third ventricle in 339, the fourth ventricle in 18, the suprasellar region in 75, and other paraventricular areas in 191 patients. The most commonly observed tumors were germ cell tumors in the third ventricle (177 cases [39%]), cystic lesions in the suprasellar region (56 cases [75%]), and astrocytic tumors in the thalamus-basal ganglia (71 cases [38%]). Although 641 (92.8%) of 691 patients could receive neuroendoscopic diagnosis using biopsy, the diagnosis obtained with endoscopic biopsy differed from the final diagnosis based on subsequent craniotomy in 18 patients and clinical course in 3 patients. Of these 21 patients, 7 had astrocytic tumors, 4 had pineal tumors, 6 had germ cell tumors, and 4 had other tumors. The final diagnostic accuracy rate was 89.7%. Associated hydrocephalus was observed in 517 patients (72.4%), of whom 316 and 39 underwent third ventriculostomy and fenestration of the septum, respectively. The response rates were 96.2% and 89.7%, respectively. Third ventriculostomy was required for recurrence of hydrocephalus in 41 patients (13.0%), and the long-term response rate was therefore 83.2% (263 of 316 patients). Perioperative complications other than fever, such as new onset of or progressive hydrocephalus, infection due to CSF leakage, and bleeding in the ventricle or tumor, were found in 81 patients (11.3%). The median Karnofsky Performance Scale score before endoscopic surgery was 80, but it increased to 90 after surgery. The score was thus significantly increased after surgery (p < 0.0001, Mann-Whitney U-test). Activities of daily living after surgery decreased due to perioperative complications in 15 patients (2.1%). The incidence of new dissemination after endoscopic biopsy was 6.8% and not high compared with routine surgical treatment. CONCLUSIONS The authors concluded that neuroendoscopic diagnosis using biopsy for ventricular and paraventricular tumors is adequately accurate and safe. It was demonstrated that endoscopic procedures play important roles not only in the treatment of hydrocephalus associated with intra- and paraventricular tumors but also in significantly improving ADL. Furthermore, the long-term outcome of endoscopic third ventriculostomy was clearly favorable.

Trochlear nerve schwannoma with intratumoral hemorrhage : Case report

OBJECTIVE AND IMPORTANCE:Schwannomas originating from the trochlear nerve without neurofibromatosis are extremely rare. Thirty-four cases have previously been reported in the literature, and only 25 cases were pathologically diagnosed. In addition, intratumoral hemorrhage in intracranial schwannomas is also rare. Approximately 30 cases of intracranial schwannomas with intratumoral hemorrhage have been reported. CLINICAL PRESENTATION:A 42-year-old man presented with left hemiparesis and right trochlear nerve palsy. Magnetic resonance imaging revealed an abnormal cystic lesion beside the brainstem. His symptoms rapidly worsened after enlargement of the mass because of intratumoral hemorrhage. INTERVENTION:Gross total removal of the tumor was performed via the anterior transpetrosal approach. The tip of the trochlear nerve was fanned out and unified with the tumor. The tumor was diagnosed as a schwannoma. CONCLUSION:The patients hemiparesis improved postoperatively, and he was discharged 1 week after the operation. Magnetic resonance imaging performed 4 months later revealed no regrowth of the tumor. Only right trochlear nerve palsy has persisted. This report is the second case of intratumoral hemorrhage from a trochlear nerve schwannoma.

Single-Copy Gain of Chromosome 1q Is a Negative Prognostic Marker in Pediatric Nonependymal, Nonpilocytic Gliomas

BACKGROUND:Reports of genetic analyses on pediatric gliomas are few, and those tumors have been far less characterized than adult gliomas. OBJECTIVE:To characterize the genetic and biological features of pediatric gliomas. METHODS:We investigated 23 pediatric nonependymal, nonpilocytic gliomas for chromosomal copy number aberrations (CNAs) by comparative genomic hybridization (CGH), mutations of isocitrate dehydrogenase (IDH) genes by direct sequencing, and proliferative activity and expression of O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry. RESULTS:The most frequent CNA was single-copy gain of chromosome 1q, with 10 of 20 successfully investigated tumors showing the abnormality (50%). Other CNAs detected by CGH included gain on 7q (+7q) in 6, +9q in 5, +17q in 5, and + 7p in 4 cases. Gain of entire chromosome 7 was rare (2 cases), and codeletion of 1p and 19q was not detected. Gain of 1q was significantly predictive for shorter progression-free survival (PFS) and overall survival (OS), and even more closely associated with poor clinical outcome than histological grade (P = .0009 for PFS, P = .003 for OS by 1q status; P = .004 for PFS, P = .035 for OS by high-grade vs low-grade). Gain of 1q was also significantly correlated with proliferative activity (P = .0002), and tumors with 1q gain showed a trend toward higher MGMT expression (P = .27). Mutation of IDH1 gene was detected in only 2 of 17 tumors successfully analyzed. CONCLUSION:Single copy gain of 1q is associated with biological features of pediatric gliomas, and is a negative prognostic marker in patients with those tumors.

Molecular characteristics of pediatric non-ependymal, non‑pilocytic gliomas associated with resistance to temozolomide

Temozolomide constitutes current standard of care for adult patients with high-grade gliomas. However, results for pediatric gliomas are rather disappointing. In order to investigate the molecular differences between pediatric and adult gliomas that could affect sensitivity to temozolomide, we studied 23 pediatric non-ependymal, non-pilocytic gliomas in comparison to 59 consecutive adult gliomas for the expression of O6-methylguanine methyltransferase (MGMT) and the DNA mismatch repair protein, mutS homolog 6 (MSH6) by immunohistochemistry, as well as for the presence or absence of promoter methylation of the MGMT gene by methylation-specific PCR. The expression of MGMT in pediatric gliomas was significantly higher than in adult gliomas, as shown by immunohistochemistry (p=0.00004). This association was conserved if statistical analysis was carried out only in astrocytic tumors (diffuse astrocytoma, anaplastic astrocytoma and glioblastoma, p=0.00007), or in oligodendroglial tumors (oligodendroglioma and anaplastic oligodendroglioma, p=0.020). Although methylation-specific PCR was successfully performed only in 15 pediatric gliomas, it also showed a trend toward less frequent methylation in pediatric as opposed to adult gliomas (p=0.242). MSH6 was almost equally expressed in pediatric and adult gliomas. Pediatric gliomas appear to have a distinct molecular profile associated with resistance to temozolomide. Higher expression of MGMT and a trend toward less frequent methylation of the promoter region of MGMT gene may partly account for relative resistance to temozolomide in pediatric gliomas as compared to adult gliomas.

Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: Clinical evidence of crosslink between FGFR and RAS signaling pathways

Dysregulation in the RAS signaling cascade results in a family of malformation syndromes called RASopathies. Meanwhile, alterations in FGFR signaling cascade are responsible for various syndromic forms of craniosynostosis. In general, the phenotypic spectra of RASopathies and craniosynostosis syndromes do not overlap. Recently, however, mutations in ERF, a downstream molecule of the RAS signaling cascade, have been identified as a cause of complex craniosynostosis, suggesting that the RAS and FGFR signaling pathways can interact in the pathogenesis of malformation syndromes. Here, we document a boy with short stature, developmental delay, and severe craniosynostosis involving right coronal, bilateral lambdoid, and sagittal sutures with a de novo mutation in exon1 of SHOC2 (c.4A > G p.Ser2Gly). This observation further supports the existence of a crosslink between the RAS signaling cascade and craniosynostosis. In retrospect, the propositus had physical features suggestive of a dysregulated RAS signaling cascade, such as fetal pleural effusion, fetal hydrops, and atrial tachycardia. In addition to an abnormal cranial shape, which has been reported for this specific mutation, craniosynostosis might be a novel associated phenotype. In conclusion, the phenotypic combination of severe craniosynostosis and RASopathy features observed in the propositus suggests an interaction between the RAS and FGFR signaling cascades. Patients with craniosynostosis in combination with any RASopathy feature may require mutation screening for molecules in the FGFR‐RAS signaling cascade.

A glioblastoma arising from the attached region where a meningioma had been totally removed

The co‐occurrence of different histological tumors in the nervous system is rare and is mainly associated with phakomatoses or radiation exposure. A 72‐year‐old man underwent surgery for a frontal convexity meningioma. Four years after the surgery, a new lesion was detected in the attached region where the meningioma had been removed. The second tumor exhibited a high degree of cellularity, atypical mitosis, pseudo‐palisading and microvascular proliferation, and was immunohistologically positive for GFAP and was diagnosed as a glioblastoma. Wild‐type isocitrate dehydrogenase 1 was found in the second specimen. A genetic analysis using comparative genomic hybridization showed a DNA copy number loss on 1p35, 9pter‐21, 10, 11q23, 13q, 14q, 20q, 22q and a gain on 7 in the second specimen. Although the mechanism responsible for the consecutive occurrence of meningioma and glioblastoma has not been elucidated, five hypotheses are feasible: (i) the lesions occurred incidentally; (ii) a low‐grade astrocytoma present at the time of the first operation transformed into a high‐grade glioma during the next 4 years; (iii) radiation received during the endovascular treatment induced glioblastoma; (iv) a brain scar created at the time of the first operation for meningioma led to the occurrence of a glioblastoma; and (v) the previous meningioma affected the surrounding glial cells, causing neoplastic transformation.

Genetic characterization of adult infratentorial gliomas

Adult infratentorial gliomas are rare and have not been well studied. We therefore conducted genetic analysis of those tumors to see if there was any characteristic that could be relevant in clinical management and understanding of tumorigenesis. Nineteen adult infratentorial gliomas were analyzed for chromosomal aberration by comparative genomic hybridization, and for expression of p53 and epidermal growth factor receptor (EGFR) by immunohistochemistry. The most frequent chromosomal aberration was the gain of 7p, and five of the seven cerebellar or fourth ventricle malignant gliomas had that aberration. However, the gain of 7q, the characteristic abnormality of supratentorial astrocytomas commonly associated with the gaining of 7p, was observed only in 1 of 11 adult infratentorial astrocytic tumors. Combined losses of 1p and 19q, the genetic hallmark of oligodendroglioma, were not observed. Results of immunohistochemistry of p53 and EGFR were comparable to those reported in supratentorial gliomas. Our findings might suggest the presence of distinct tumorigenic pathway in adult infratentorial gliomas.

Guideline for management and treatment of fetal and congenital hydrocephalus: Center Of Excellence—Fetal and Congenital Hydrocephalus Top 10 Japan Guideline 2011

IntroductionHydrocephalus does not indicate a single clinical entity, but includes a variety of clinicopathological conditions caused by excessive cerebrospinal fluid (CSF) based on the disturbed circulation. Recent progress in prenatal neuroimagings such as MRI and ultrasound echoencephalography on fetus enables to understand clinicopathological conditions of CSF circulation disorder in conjunction with morphological changes in the central nervous system properly. It has been revealed that the CSF dynamics develop in the theory of evolution from the immature brain, as in the animals with the minor CSF pathway predominance, towards matured adult human brain together with the completion of the major CSF pathway: the “Evolution Theory in CSF Dynamics”. Now, we can analyze CSF circulation dynamically and also analyze the flow velocity and direction of CSF movement.Center of Excellence—Fetal Hydrocephalus Top 10 JapanAlong with this technical improvement, the standards of clinicopathological evaluation of hydrocephalus as well as the classification and concept of hydrocephalus shall undergo a major upgrade. Based on such remarkable improvement in the recent practical diagnostic evaluation of fetal hydrocephalus, it is now required to update the guideline for management and treatment of fetal and congenital hydrocephalus, and a nationwide study group; Center of Excellence—Fetal Hydrocephalus Top 10 Japan, was organized in 2008 in Japan. The retrospective analysis of 333 cases of congenital hydrocephalus indicated a fact that 43% of these cases were diagnosed prenatally, and the majority of cases were treated in these top 10 institutes in Japan. Now, congenital hydrocephalus diagnosed immediately after birth is regarded as to be based on embryonic stage; brain disorder in patients with congenital hydrocephalus should be considered in conjunction with neuronal mature process of embryonic stage. The fact is supported by the current trends in hydrocephalus research represented by “Perspective Classification of Congenital Hydrocephalus” and “Multi-categorical Hydrocephalus Classification”. The ultimate goal of hydrocephalus treatment remains achieving arrested hydrocephalus by shunt surgeries. In the future, to achieve arrested hydrocephalus, minimum quantity of CSF to be drained should be elucidated. Consideration for accurate operative indication of ETV along with new neuroendoscopic device development and analysis of CSF circulation is expected in the future. The data in this prospective multicenter analysis in this guideline are credited in Oxford Evidence level 2b (Grade II).

Rapid spontaneous regression of multicentric infantile myofibromatosis in the posterior fossa and lumbar vertebra

Infantile myofibromatosis is the most common fibrous tumor of infancy and early childhood. It typically occurs in skin, subcutaneous tissue, muscle, bone, and/or viscera. In patients without visceral involvement, the prognosis is excellent, generally with spontaneous regression of the tumor nodules in 1 to 2 years [1]. However, they show unfavorable prognosis within the first few months of life if there is visceral involvement [1]. Intracranial involvement is rare, and to our knowledge, only 17 such cases have been reported [1–15]. Although lesions usually arise from the dura [16] and grow in one direction, either epidural or subdural, in our case, there was equal growth epidurally and subdurally. Spontaneous regression occurred at the same time as that of a lumbar lesion 3 months after biopsy. This unique course has never been reported, and the rate of regression in this case was remarkable. Case report

The RIVET: a novel technique involving absorbable fixation for hydroxyapatite osteosynthesis.

AbstractCranioplasty using custom-made hydroxyapatite (HAP) ceramic implants is a common procedure for the repair of skull defects. The advantages of using HAP are that it is nonmetallic, unlike titanium; biocompatible; and osteoconductive. Furthermore, it can be molded to any complex shape that may be needed. A disadvantage is that titanium screws and plates are in development for its fixation. We developed a technique for implant fixation using bioabsorbable screws and plates, and named this technique RIVET: resorbable immobilization for vacuolar en bloc technique.Before each operation, the implant was customized for the patient in question on the basis of models prepared using computed tomography data. The bioabsorbable plates were attached to the implant by drilling, tapping, and screwing, as shown in the video (http://links.lww.com/SCS/A43). The interior portion of the screw was then melted to flatten it against the internal surface of the implant, forming a rivet to join the plate and HAP implant.We used this technique for cranial reconstruction in 2 patients, with satisfying and functional results. We did not encounter any complications.In conclusion, the technique described here allows surgeons to fix implants and plates together more rigidly, giving a better result than possible with previous methods.