Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Clinical and molecular features of patients with IDH1 wild-type primary glioblastoma presenting unexpected short-term survival after gross total resection.

BACKGROUND: This study investigated the factors influencing short-term survivors (STS) after gross total resection (GTR) in patients with IDH1 wild-type primary glioblastoma. METHODS: We analyzed five independent cohorts who underwent GTR, including 83 patients from Kitasato University (K-cohort), and four validation cohorts of 148 patients from co-investigators (V-cohort), 66 patients from the Kansai Molecular Diagnosis Network for the Central Nervous System tumors, 109 patients from the Cancer Genome Atlas, and 40 patients from the Glioma Longitudinal AnalySiS. The study defined STS as those who had an overall survival ≤ 12 months after GTR with subsequent radiation therapy, and concurrent and adjuvant temozolomide (TMZ). RESULTS: The study included 446 patients with glioblastoma. All cohorts experienced unexpected STS after GTR, with a range of 15.0-23.9% of the cases. Molecular profiling revealed no significant difference in major genetic alterations between the STS and non-STS groups, including MGMT, TERT, EGFR, PTEN, and CDKN2A. Clinically, the STS group had a higher incidence of non-local recurrence early in their treatment course, with 60.0% of non-local recurrence in the K-cohort and 43.5% in the V-cohort. CONCLUSIONS: The study revealed that unexpected STS after GTR in patients with glioblastoma is not uncommon and such tumors tend to present early non-local recurrence. Interestingly, we did not find any significant genetic alterations in the STS group, indicating that such major alterations are characteristics of GB rather than being reliable predictors for recurrence patterns or development of unexpected STS.

Distant recurrence in the cerebellar dentate nucleus through the dentato-rubro-thalamo-cortical pathway in supratentorial glioma cases.

BACKGROUND: Distant recurrence can occur by infiltration along white matter tracts or dissemination through the cerebrospinal fluid (CSF). This study aimed to clarify the clinical features and mechanisms of recurrence in the dentate nucleus (DN) in patients with supratentorial gliomas. Based on the review of our patients, we verified the hypothesis that distant DN recurrence from a supratentorial lesion occurs through the dentato-rubro-thalamo-cortical (DRTC) pathway. METHODS: A total of 380 patients with supratentorial astrocytoma, isocitrate dehydrogenase (IDH)-mutant (astrocytoma), oligodendroglioma, IDH mutant and 1p/19q-codeleted (oligodendroglioma), glioblastoma, IDH-wild type (GB), and thalamic diffuse midline glioma, H3 K27-altered (DMG), who underwent tumor resection at our department from 2009 to 2022 were included in this study. Recurrence patterns were reviewed. Additionally, clinical features and magnetic resonance imaging findings before treatment, at the appearance of an abnormal signal, and at further progression due to delayed diagnosis or after salvage treatment of cases with recurrence in the DN were reviewed. RESULTS: Of the 380 patients, 8 (2.1%) had first recurrence in the DN, 3 were asymptomatic when abnormal signals appeared, and 5 were diagnosed within one month after the onset of symptoms. Recurrence in the DN developed in 8 (7.4%) of 108 cases of astrocytoma, GB, or DMG at the frontal lobe or thalamus, whereas no other histological types or sites showed recurrence in the DN. At the time of the appearance of abnormal signals, a diffuse lesion developed at the hilus of the DN. The patterns of further progression showed that the lesions extended to the superior cerebellar peduncle, tectum, tegmentum, red nucleus, thalamus, and internal capsule along the DRTC pathway. CONCLUSION: Distant recurrence along the DRTC pathway is not rare in astrocytomas, GB, or DMG at the frontal lobe or thalamus. Recurrence in the DN developed as a result of the infiltration of tumor cells through the DRTC pathway, not dissemination through the CSF.

Frontotemporal craniotomy with skin incision along the superior temporal line outside the hairline in bald male patients with temporal gliomas.

A head skin incision is inevitable in neurosurgical procedures and is usually concealed within the hairline. Androgenetic alopecia (AGA) is a progressive hair loss disorder or baldness highly prevalent in men. Therefore, if bald male patients require neurosurgical procedures, skin incisions cannot be concealed, but this subject is yet to be discussed in the literature. This study presents a frontotemporal craniotomy using a skin incision along the superior temporal line, ignoring the hairline in bald male patients. Thirty-three patients with temporal gliomas underwent surgical removal between 2015 and 2022. They were divided into three groups: bald male patients with skin incisions not concealed in the hairline (minimum group, n = 13), bald and non-bald male patients with skin incisions concealed in the hairline (male group, n = 11), and female patients with skin incisions concealed in the hairline (female group, n = 9). In the minimum group, patients had no complaints regarding the incision scar. Cosmetic outcome was excellent, and no cases showed surgical site infection or peripheral facial nerve palsy. Compared with the male and female groups, the minimum group had the shortest skin incision length; however, the craniotomy size and extent of resection were similar. Skin incision for frontotemporal craniotomy cannot be hidden in bald male patients, and the preferred location for the incision is unknown. The skin incision along the superior temporal line is a cosmetically favorable, feasible, and safe procedure.

Angiographic evaluation of the distance from the top of the jugular bulb to the inferior petrosal sinus-internal jugular vein junction: simple classification and identification method for the orifice of the non-visualized inferior petrosal sinus during neuroendovascular surgery.

BACKGROUND: The inferior petrosal sinus (IPS) is the transvenous access route for neurointerventional surgery that is occasionally undetectable on digital subtraction angiography (DSA) because of blockage by a clot or collapse. This study was aimed at analyzing the distance from the jugular bulb (JB) to the IPS-internal jugular vein (IJV) junction and proposing a new anatomical classification system for the IPS-IJV junction to identify the non-visualized IPS orifice. METHODS: DSA of 708 IPSs of 375 consecutive patients were retrospectively investigated to calculate the distance from the top of the JB to the IPS-IJV junction, and a simple classification system based on this distance was proposed. RESULTS: The median distance from the top of the JB to the IPS-IJV junction was 20.8 ± 14.7 mm. Based on the lower (10.9 mm) and upper (31.1 mm) quartiles, IPS-IJV junction variants were: type I, 0-10 mm (22.3%); type II, 11-30 mm (45.8%); type III, > 31 mm (23.9%); and type IV, no connection to the IJV (8.0%). Bilateral distances showed a positive interrelationship, with a correlation coefficient of 0.86. The bilateral symmetry type (visualized IPSs bilaterally) according to our classification occurred in 267 of 300 (89.0%) patients. CONCLUSIONS: In this study, the IPS-IJV junction was located far from the JB (types II and III), with a higher probability (69.6%). This distance and the four-type classification demonstrated high degrees of homology with the contralateral side. These results would be useful for identifying the non-visualized IPS orifice.

[Glioblastoma, IDH-Wildtype].

The 5th edition of the WHO Classification of Central Nervous System Tumours(WHO2021)emphasizes the importance of molecular classification. A significant update was that glioblastoma IDH-mutant from WHO2016 was renamed and classified as astrocytoma IDH-mutant WHO grade 4 in WHO2021. This review describes the current updates to the glioblastoma classification, and discusses the essential knowledge regarding daily practice, especially for young neurosurgeons.

A functional role of S100A4/non-muscle myosin IIA axis for pro-tumorigenic vascular functions in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most aggressive form of brain tumor and has vascular-rich features. The S100A4/non-muscle myosin IIA (NMIIA) axis contributes to aggressive phenotypes in a variety of human malignancies, but little is known about its involvement in GBM tumorigenesis. Herein, we examined the role of the S100A4/NMIIA axis during tumor progression and vasculogenesis in GBM. METHODS: We performed immunohistochemistry for S100A4, NMIIA, and two hypoxic markers, hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase 9 (CA9), in samples from 94 GBM cases. The functional impact of S100A4 knockdown and hypoxia were also assessed using a GBM cell line. RESULTS: In clinical GBM samples, overexpression of S100A4 and NMIIA was observed in both non-pseudopalisading (Ps) and Ps (-associated) perinecrotic lesions, consistent with stabilization of HIF-1α and CA9. CD34(+) microvascular densities (MVDs) and the interaction of S100A4 and NMIIA were significantly higher in non-Ps perinecrotic lesions compared to those in Ps perinecrotic areas. In non-Ps perinecrotic lesions, S100A4(+)/HIF-1α(-) GBM cells were recruited to the surface of preexisting host vessels in the vascular-rich areas. Elevated vascular endothelial growth factor A (VEGFA) mRNA expression was found in S100A4(+)/HIF-1α(+) GBM cells adjacent to the vascular-rich areas. In addition, GBM patients with high S100A4 protein expression had significantly worse OS and PFS than did patients with low S100A4 expression. Knockdown of S100A4 in the GBM cell line KS-1 decreased migration capability, concomitant with decreased Slug expression; the opposite effects were elicited by blebbistatin-dependent inhibition of NMIIA. CONCLUSION: S100A4(+)/HIF-1α(-) GBM cells are recruited to (and migrate along) preexisting vessels through inhibition of NMIIA activity. This is likely stimulated by extracellular VEGF that is released by S100A4(+)/HIF-1α(+) tumor cells in non-Ps perinecrotic lesions. In turn, these events engender tumor progression via acceleration of pro-tumorigenic vascular functions. Video abstract.

Ventricular opening and cerebrospinal fluid circulation accelerate the biodegradation process of carmustine wafers suggesting their immunomodulation potential in the human brain.

PURPOSE: Opening the ventricular system during glioblastoma surgery is often necessary, but the consequent effect on the tumor microenvironment of glioblastoma remains unknown. Implantation of carmustine wafer enables direct drug delivery to the tumor site; however, the exact mechanism of the wafer's biodegradation process is unclear, and the available data is limited to in vivo non-human mammalian studies. We hypothesized that the ventricular opening affects the degradation process of the wafer and the glioblastoma tumor microenvironment. METHODS: This study included 30 glioblastoma patients. 21 patients underwent carmustine wafer implantation during initial surgery. All patients underwent repeated surgical resection upon recurrence, allowing for pathological comparison of changes associated with wafer implantation. Immunohistochemical analyses were performed using CD68, TMEM119, CD163, IBA1, BIN1, and CD31 antibodies to highlight microglia, macrophages, and tumor vascularity, and the quantitative scoring results were correlated with clinical, molecular, and surgical variables, including the effect of the ventricular opening. RESULTS: The carmustine wafer implanted group presented significantly less TMEM119-positive microglia within the tumor (P = 0.0002). Simple and multiple regression analyses revealed that the decrease in TMEM119-positive microglia was correlated with longer intervals between surgeries and opened ventricular systems. No correlation was observed between age, methylated O6-methylguanine DNA methyltransferase promoter expression, and the extent of surgical resection. CONCLUSIONS: Our study findings strongly suggest that biomaterials may possess immunomodulation capacity, which is significantly impacted by the ventricular opening procedure. Furthermore, our data highlights the pathophysiological effects of the ventricular opening within the surrounding human brain, especially after the wafer implantation.

Safety and efficacy of depatuxizumab mafodotin in Japanese patients with malignant glioma: A nonrandomized, phase 1/2 trial.

INTELLANCE-J was a phase 1/2 study of a potent antibody-drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux-M), as a second- or first-line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second-line arms, patients with EGFR-amplified recurrent WHO grade III/IV glioma received Depatux-M plus chemotherapy (temozolomide) or Depatux-M alone regardless of EGFR status. In first-line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux-M plus chemoradiotherapy. The study was halted following lack of survival benefit with first-line Depatux-M in the global trial INTELLANCE-1. The primary endpoint was 6-month progression-free survival (PFS) in patients with EGFR-amplified tumors receiving second-line Depatux-M plus chemotherapy. Common nonocular treatment-emergent adverse events (TEAEs) with both second-line and first-line Depatux-M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second-line Depatux-M plus chemotherapy and all patients receiving second-line Depatux-M alone or first-line Depatux-M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6-month PFS estimate was 25.6% (95% confidence interval [CI] 11.4-42.6), and median PFS was 2.1 months (95% CI 1.9-3.9) with second-line Depatux-M plus chemotherapy in the EGFR-amplified subgroup. This study showed acceptable safety profile of Depatux-M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263).

An analysis of the demographic history of the risk allele R4810K in RNF213 of moyamoya disease.

BACKGROUND: Ring finger protein 213 (RNF213) is a susceptibility gene of moyamoya disease (MMD). A previous case-control study and a family analysis demonstrated a strong association of the East Asian-specific variant, R4810K (rs112735431), with MMD. Our aim is to uncover evolutionary history of R4810K in East Asian populations. METHODS: The RNF213 locus of 24 MMD patients in Japan were sequenced using targeted-capture sequencing. Based on the sequence data, we conducted population genetic analysis and estimated the age of R4810K using coalescent simulation. RESULTS: The diversity of the RNF213 gene was higher in Africans than non-Africans, which can be explained by bottleneck effect of the out-of-Africa migration. Coalescent simulation showed that the risk variant was born in East Asia 14,500-5100 years ago and came to the Japanese archipelago afterward, probably in the period when the known migration based on archaeological evidences occurred. CONCLUSIONS: Although clinical data show that the symptoms varies, all sequences harboring the risk allele are almost identical with a small number of exceptions, suggesting the MMD phenotypes are unaffected by the variants of this gene and rather would be more affected by environmental factors.

Postcentral gyrus resection of opercular gliomas is a risk factor for motor deficits caused by damaging the radiologically invisible arteries supplying the descending motor pathway.

BACKGROUND: Postoperative motor deficits are among the worst morbidities of glioma surgery. We aim to investigate factors associated with postoperative motor deficits in patients with frontoparietal opercular gliomas. METHODS: Thirty-four patients with frontoparietal opercular gliomas were retrospectively investigated. We examined the postoperative ischemic changes and locations obtained from MRI. RESULTS: Twenty-one patients (62%) presented postoperative ischemic changes. Postoperative MRI was featured with ischemic changes, all located at the subcortical area of the resection cavity. Six patients had postoperative motor deficits, whereas 28 patients did not. Compared to those without motor deficits, those with motor deficits were associated with old age, pre- and postcentral gyri resection, and postcentral gyrus resection (P = 0.023, 0,024, and 0.0060, respectively). A merged image of the resected cavity and T1-weighted brain atlas of the Montreal Neurological Institute showed that a critical area for postoperative motor deficits is the origin of the long insular arteries (LIAs) and the postcentral gyrus. Detail anatomical architecture created by the Human Connectome Project database and T2-weighted images showed that the subcortical area of the operculum of the postcentral gyrus is where the medullary arteries supply, and the motor pathways originated from the precentral gyrus run. CONCLUSIONS: We verified that the origin of the LIAs could damage the descending motor pathways during the resection of frontoparietal opercular gliomas. Also, we identified that motor pathways run the subcortical area of the operculum of the postcentral gyrus, indicating that the postcentral gyrus is an unrecognized area of damaging the descending motor pathways.

[Anterior Interosseous Nerve Palsy with Isolated Flexion Palsy of the Thumb or Index Finger as an Initial Symptom:Two Case Reports].

Case 1: A 73-year-old man who had undergone neurolysis for right cubital tunnel syndrome complained of difficulty using chopsticks. Froment's sign test showed that the interphalangeal(IP)joint of the right thumb that had flexed preoperatively was extended. This finding was considered to indicate recovery from ulnar neuropathy, and the patient was closely followed up. One year later, the patient was unable to push a camera shutter button and was unable to flex the IP joint of the thumb and the distal interphalangeal(DIP)joint of the index finger, a characteristic symptom of anterior interosseous nerve(AIN)palsy. Therefore, the patient underwent AIN neurolysis and subsequently reported slight improvement in his condition. Case 2: A 60-year-old woman reported difficulty performing computer mouse clicks with her right hand. As flexing the index finger DIP joint was difficult, a local lesion was suspected, and the patient was closely followed up. One year later, the patient was unable to push the button of a ballpoint pen with her thumb. Extension of the thumb and index finger indicated AIN palsy. The patient refused treatment and was only followed up. The following year, the patient reported that the weakness improved. Simultaneous flexion palsy of the thumb and index finger can lead to a diagnosis of AIN palsy. However, flexion palsy of a single finger in incomplete AIN palsy, as reported here, is often overlooked because of its similarity to the flexor tendon rupture. Awareness regarding this incomplete form of AIN palsy is needed for early and correct diagnosis.

Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.

PURPOSE: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonß (IFNß) plus temozolomide (TMZ) with that of TMZ alone. EXPERIMENTAL: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. RESULTS: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNß + Radiotherapy (RT) group were found. CONCLUSION: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNß addition were identified.

[Surgical Removal of a Superior Medial Midbrain Cavernous Angioma through the Anterior Interhemispheric Transcallosal Transforaminal Approach:A Case Report].

A 33-year-old male presented with sudden onset of dysarthria. MRI showed a single round lesion containing hematomas in varying stages combined with venous malformation in the superior midline portion of the midbrain, indicating a midbrain cavernous angioma. Serial follow-up MRI revealed enlargement of the angioma concomitant with worsening of the dysarthria, ataxia, and intention tremor. Preoperative MRI suggested that the angioma consisted of a cystic hemorrhagic lesion with an 18-mm diameter without hydrocephalus. Since the angioma was located just beneath the floor of the midline portion of the third ventricle, we chose an anterior interhemispheric transcallosal transforaminal approach. After callosotomy, the foramen of Monro was widened by dissecting the choroidal fissure, enabling entry into the third ventricle. The lower part of the massa intermedia was cut;the median floor of the third ventricle was dissected and the angioma was removed. After the surgery, only a transient complication of seesaw nystagmus was observed, caused by damage to the interstitial nucleus of Cajal. As the anterior interhemispheric transcallosal transforaminal approach does not damage both forces, this technique may be a safe and useful approach for superior medial midbrain lesions, located just beneath the floor of the third ventricle.

[Lymphorrhea at the Site of Repeated Fascia Lata Harvesting:A Case Report].

This 74-year-old man had undergone a third re-operation for anaplastic meningioma in the convexity six weeks before he was referred to us. He presented with a bulge on the lateral aspect of the left thigh. We observed a fresh fascia lata harvesting scar that extended peripherally from an old proximal scar. The bulge was colorless. The aspirated subcutaneous fluid(more than 200mL)was watery and yellowish;there was no evidence of abscess or hematoma. Although the bulge shrank after aspiration and the placement of a compression bandage, it recurred in three days. Surgery-associated lymphorrhea was the diagnosis given. Goreisan, a herbal medicine for hydrostatic modulation, was administered. One week later, the bulge diminished in size. Harvesting of the fascia lata in the lateral aspect of the thigh is usually safe. However, additional dissection and peripheral extension due to repeated harvesting risks damaging the superficial lymphatic pathways because of scar formation after earlier surgeries and the hyperdense distribution of the lymphatic pathways in the peripheral part. When subcutaneous fluid collection after fascia lata harvesting is refractory, lymphorrhea must be considered in the differential diagnosis.

[Cerebral Amyloid Angiopathy-related Inflammation Demonstrating Early Venous Filling on Digital Subtraction Angiography:A Case Report].

Cerebral amyloid angiopathy-related inflammation(CAA-RI)is a rare condition thought to be caused by an inflammatory response to amyloid beta(Aß)protein in the walls of the small arteries and capillaries of the cerebral cortex. A 73-year-old female presented with left hemiparesis and dysarthria. Fluid-attenuated inversion recovery(FLAIR)imaging disclosed progressive enlargement of infiltrative white matter abnormalities in the right temporo-occipito-parietal lobes. Interestingly, digital subtraction angiography(DSA)demonstrated early venous filling. Pathological examination of the biopsy specimen demonstrated lymphocytes infiltration surrounding the blood vessels and in the thickened walls with amyloid-beta deposition. The diagnosis given was CAA-RI. The patient was successfully treated with high dose corticosteroids and clinical improvement was associated with shrinkage of the high intensity lesion on FLAIR imaging. Early venous filling resolved on the follow-up DSA. Most patients with CAA-RI can be treated with corticosteroids. However, the clinical condition will worsen without appropriate treatment. Early diagnosis is the key. If an expanding disease of the white matter appears in an elderly patient, we should exclude other cerebrovascular diseases by DSA, followed by biopsy without delay. The present case demonstrated that early venous filling on DSA may appear until inflammation is resolved by the treatment of CAA-RI.

[A Case of Familial Schwannomatosis Occurring as Intraorbital Schwannoma].

A 67-year-old male presenting with left exophthalmos and progressive visual disturbance was referred to our department. Tumors at the supraclavicular fossa and dorsal femoral region were resected at ages 27 and 45 years. His father and son had both been diagnosed with spinal tumors, and his son's tumor was pathologically diagnosed as a schwannoma. Brain MRI of his son demonstrated no intracranial tumor. Brain MRI of the patient revealed a multilobular tumor of 2 cm diameter compressing the optic nerve medially within the left muscle cone, and no other intracranial tumors. However, large masses lateral to the pharynx and intercostal nerve, as well as multiple spinal tumors were detected. Transcranial total resection of the intraorbital tumor was performed. The pathological diagnosis was consistent with a schwannoma. These clinical characteristics fulfilled the diagnostic criteria of familial schwannomatosis. The postoperative course was uneventful. His visual dysfunction and eye movement disorder resolved completely. The intraorbital tumor was believed to originate from the lacrimal nerve. Sequencing of all exons for SMARCB1 and LZTR1 using DNA extracted from the tumor did not reveal any mutations. This case is the third report on familial schwannomatosis in Japan.

Incidence of initial spinal metastasis in glioblastoma patients and the importance of spinal screening using MRI.

PURPOSE: Intracranial glioblastomas with simultaneous spinal lesions prior to chemoradiation therapy or craniotomy, defined as initial spinal metastasis, are not well understood. Herein, we investigated intracranial glioblastoma and demonstrated the importance of spinal screening using gadolinium enhanced spinal magnetic resonance imaging (Gd-MRI). METHODS: Consecutive adult patients with intracranial glioblastoma were treated between 2010 and 2014 and received spinal screening using Gd-MRI. Spinal screening was performed regardless of spine-related symptoms, and patients presenting with and without initial spinal metastasis (spinal and non-spinal groups, respectively) were compared based on patient demographics, tumor characteristics, radiological and molecular features, and overall survival (OS). RESULTS: During the study period, 116 glioblastoma cases were treated and 87 of these (76%) underwent spinal screening. Among these patients, 11 (13%) were included in the spinal group, and 76 (87%) were included in the non-spinal group. All patients of the spinal group were free of symptoms related to spinal lesions. Compared with the non-spinal group, intracranial lesions of the spinal group presented higher incidences of intracranial dissemination and were located at subventricular zones (P = 0.0012 and 0.020, respectively). MIB-1 labeling index, molecular alterations such as IDH1 mutation, TERT promoter mutation, and immunoreactivity of ATRX and MGMT did not differ between two groups. OS was significantly shorter in the spinal group than in the non-spinal group (P = 0.0054). CONCLUSIONS: This study revealed a relatively high incidence of spinal metastasis. A subset of glioblastoma patients benefited from spinal screening, through which early detection of asymptomatic spinal metastasis was achieved.

A multicenter randomized phase III study for newly diagnosed maximally resected glioblastoma comparing carmustine wafer implantation followed by chemoradiotherapy with temozolomide with chemoradiotherapy alone; Japan Clinical Oncology Group Study JCOG1703 (MACS study).

A randomized phase III trial in Japan commenced in June 2019. The present standard treatment for newly diagnosed glioblastoma is maximal resection followed by chemoradiotherapy with temozolomide. The purpose of this study is to confirm the superiority of maximal resection with carmustine wafer implantation followed by chemoradiotherapy with temozolomide over the standard maximal resection followed by chemoradiotherapy with temozolomide in terms of overall survival for newly diagnosed glioblastoma. A total of 250 patients will be accrued from 35 Japanese institutions in 5.5 years. Patients with >90% surgical resection will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is overall survival and the secondary endpoints are progression-free survival, loco-regional progression-free survival and incidence of adverse events. This trial has been registered in the Japan Registry of Clinical Trial, as jRCT1031190035 [https://jrct.niph.go.jp/en-latest-detail/jRCT1031190035].

Idiopathic spinal cord herniation: consideration of its pathogenesis based on the histopathology of the dura mater.

INTRODUCTION: We present a patient with idiopathic spinal cord herniation (ISCH) whose dura mater was histopathologically examined to elucidate its pathogenesis. CASE REPORT: A 33-year-old previously healthy man presented with progressive walking difficulty, spasticity of the right lower leg, and hyperesthesia below the right chest. Neuroimaging revealed right ventral displacement of the spinal cord at T5-6. The diagnosis was ISCH and he underwent release of the herniation from the ventral dural opening. Dural biopsy at the edge of the ventral opening and in the dorsal durotomy was performed. Postoperatively, his gait was improved. Histopathological examination of the ventral dural specimen showed non-specific degeneration, i.e., loose arrangements of collagen fibers, edematous changes, minor inflammatory cell infiltration, and angiogenesis. The specimen from the dorsal durotomy was normal. CONCLUSION: It is unclear whether the observed degeneration besides the ventral opening was the primary cause of ISCH or reflected secondary changes resulting from cumulative damage due to pulsation of the herniated spinal cord. However, the degeneration limited to the ventral opening suggests that ISCH was a local event in an individual with a normal dural theca.