Intraventricular mucin-producing glioblastoma arising in the septum pellucidum at the frontal horn of the lateral ventricle: A case report.

Glioblastoma (GBM) most commonly appears to be intraparenchymal tumor, and intraventricular GBMs are rarely reported. In previous reports, the sites of origin were not identified. Here, we report a rare case of intraventricular mucin-producing GBM in a 73-year-old woman who had a strongly enhancing tumor in the right anterior horn of the lateral ventricle. The tumor had previously been identified one and a half years ago as a small asymptomatic lesion attached to the septum pellucidum. It had been documented to gradually enlarge during subsequent follow-up examinations. The patient underwent a gross total resection of the tumor, and a soft and gelatinous mass was observed. The pathological diagnosis was compatible with GBM, and numerous tumor cells having cytoplasmic mucin vacuoles were observed. Genetic analysis revealed TP53 and NFKBIA deletions. The patient received postoperative concurrent chemotherapy with temozolomide and radiotherapy, followed by maintenance administration of temozolomide. A follow-up examination seven months later detected an asymptomatic local recurrent lesion, which was treated with gamma-knife therapy, followed by bevacizumab administration for six months. The patient has remained clinically well for five years following surgery. The origin of a rare tumor entity, intraventricular GBM, and the specific spatial and pathological findings in our case are discussed in this report.

Clinical implications of molecular analysis in diffuse glioma stratification.

The revised 4th edition of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) has introduced the integrated diagnostic classification that combines molecular and histological diagnoses for diffuse gliomas. In this study, we evaluated the molecular alterations for consecutive 300 diffuse glioma cases (grade 2, 56; grade 3, 62; grade 4, 182) based on this classification. Mutations in the isocitrate dehydrogenase (IDH) genes were common in lower grade glioma (LGG: grade2-3), and when combined with 1p/19q status, LGGs could be stratified into three groups except for four cases (Astrocytoma, IDH-mutant: 44; Oligodendroglioma, IDH-mutant and 1p/19q codeleted: 37; Astrocytoma, IDH-wildtype: 33). 1p/19q-codeleted oligodendrogliomas were clinically the most favorable subgroup even with upfront chemotherapy. In contrast, IDH-wildtype astrocytomas had a relatively worse prognosis; however, this subgroup was more heterogeneous. Of this subgroup, 11 cases had TERT promoter (pTERT) mutation with shorter overall survival than 12 pTERT-wildtype cases. Additionally, a longitudinal analysis indicated pTERT mutation as early molecular event for gliomagenesis. Therefore, pTERT mutation is critical for the diagnosis of molecular glioblastoma (WHO grade 4), regardless of histological findings, and future treatment strategy should be considered based on the precise molecular analysis.

Molecular diagnosis of diffuse glioma using a chip-based digital PCR system to analyze IDH, TERT, and H3 mutations in the cerebrospinal fluid.

PURPOSE: Conventional genetic analyzers require surgically obtained tumor tissues to confirm the molecular diagnosis of diffuse glioma. Recent technical breakthroughs have enabled increased utilization of cell-free tumor DNA (ctDNA) in body fluids as a reliable resource for molecular diagnosis in various cancers. Here, we tested the application of a chip-based digital PCR system for the less invasive diagnosis (i.e., liquid biopsy) of diffuse glioma using the cerebrospinal fluid (CSF). METHODS: CSF samples from 34 patients with diffuse glioma were collected from the surgical field during craniotomy. Preoperative lumbar CSF collection was also performed in 11 patients. Extracted ctDNA was used to analyze diagnostic point mutations in IDH1 R132H, TERT promoter (C228T and C250T), and H3F3A (K27M) on the QuantStudio® 3D Digital PCR System. These results were compared with their corresponding tumor DNA samples. RESULTS: We detected either of the diagnostic mutations in tumor DNA samples from 28 of 34 patients. Among them, we achieved precise molecular diagnoses using intracranial CSF in 20 (71%). Univariate analyses revealed that the World Health Organization (WHO) grade (p = 0.0034), radiographic enhancement (p = 0.0006), and Mib1 index (p = 0.01) were significant predictors of precise CSF-based molecular diagnosis. We precisely diagnosed WHO grade III or IV diffuse gliomas using lumbar CSF obtained from 6 (87%) of 7 patients with tumors harboring any mutation. CONCLUSION: We established a novel, non-invasive molecular diagnostic method using a chip-based digital PCR system targeting ctDNA derived from CSF with high sensitivity and specificity, especially for high-grade gliomas.

Mesenchymal glioblastoma-induced mature de-novo vessel formation of vascular endothelial cells in a microfluidic device.

High vascularization is a biological characteristic of glioblastoma (GBM); however, an in-vitro experimental model to verify the mechanism and physiological role of vasculogenesis in GBM is not well-established. Recently, we established a self-organizing vasculogenic model using human umbilical vein endothelial cells (HUVECs) co-cultivated with human lung fibroblasts (hLFs). Here, we exploited this system to establish a realistic model of vasculogenesis in GBM. We developed two polydimethylsiloxane (PDMS) devices, a doughnut-hole dish and a 5-lane microfluidic device to observe the contact-independent effects of glioblastoma cells on HUVECs. We tested five patient-derived and five widely used GBM cell lines. Confocal fluorescence microscopy was used to observe the morphological changes in Red Fluorescent Protein (RFP)-HUVECs and fluorescein isothiocyanate (FITC)-dextran perfusion. The genetic and expression properties of GBM cell lines were analyzed. The doughnut-hole dish assay revealed KNS1451 as the only cells to induce HUVEC transformation to vessel-like structures, similar to hLFs. The 5-lane device assay demonstrated that KNS1451 promoted the formation of a vascular network that was fully perfused, revealing the functioning luminal construction. Microarray analysis revealed that KNS1451 is a mesenchymal subtype of GBM. Using a patient-derived mesenchymal GBM cell line, mature de-novo vessel formation could be induced in HUVECs by contact-independent co-culture with GBM in a microfluidic device. These results support the development of a novel in vitro research model and provide novel insights in the neovasculogenic mechanism of GBM and may potentially facilitate the future detection of unknown molecular targets.

Base-resolution methylomes of gliomas bearing histone H3.3 mutations reveal a G34 mutant-specific signature shared with bone tumors.

Two recurrent mutations, K27M and G34R/V, in H3F3A, encoding non-canonical histone H3.3, are reported in pediatric and young adult gliomas, whereas G34W mutation is prevalent in bone tumors. In contrast to K27M mutation, it remains elusive how G34 mutations affect the epigenome. Here we performed whole-genome bisulfite sequencing of four G34R-mutated gliomas and the G34V-mutated glioma cell line KNS-42 for comparison with gliomas harboring K27M and no mutations in H3F3A and with G34W-mutated bone tumors. G34R-mutated gliomas exhibited lower global methylation levels, similar CpG island (CGI) methylation levels, and compromised hypermethylation of telomere-proximal CGIs, compared to the other two glioma subgroups. Hypermethylated regions specific to G34R-mutated gliomas were enriched for CGIs, including those of OLIG1, OLIG2, and canonical histone genes in the HIST1 cluster. They were notably hypermethylated in osteosarcomas with, but not without, G34W mutation. Independent component analysis revealed that G34 mutation-specific components shared a significant similarity between glioma and osteosarcoma, suggesting that G34 mutations exert characteristic methylomic effects regardless of the tumor tissue-of-origin. CRISPR/Cas9-mediated disruption of G34V-allele in KNS-42 cells led to demethylation of a subset of CGIs hypermethylated in G34R-mutated gliomas. These findings will provide a basis for elucidating epigenomic roles of G34 oncohistone in tumorigenesis.

First-line bevacizumab contributes to survival improvement in glioblastoma patients complementary to temozolomide.

INTRODUCTION: First-line bevacizumab (BEV) is now available as a treatment option for glioblastoma patients with severe clinical conditions in Japan. However, the survival benefits remain controversial. To elucidate these potential survival benefits, we retrospectively analyzed survival in glioblastoma patients receiving BEV. METHODS: We analyzed survival in 120 patients with IDH-wild type glioblastoma treated from 2002 to 2018. Overall survival (OS) was assessed in three treatment era subgroups [pre-temozolomide (TMZ), TMZ, and TMZ-BEV], and the correlations of prognostic factors with survival were evaluated. RESULTS: An improvement in survival was observed after BEV approval (median OS in the pre-TMZ, TMZ, and TMZ-BEV eras: 14.6, 14.9, and 22.1 months, respectively). A Cox proportional hazards model identified extent of resection and MGMT methylation status as significant prognostic factors in the TMZ era; however, these factors were not significant in the TMZ-BEV era. In subgroup analyses, patients with MGMT methylation had improved OS after TMZ introduction (pre-TMZ vs. TMZ, 18.5 vs. 28.1 months; P = 0.13), and those without MGMT methylation had significantly increased OS after BEV approval (TMZ vs. TMZ-BEV, 12.2 vs. 16.7 months; P = 0.04). CONCLUSIONS: Our findings imply that optional first-line administration of BEV can overcome the impact of conventional risk factors and prolong survival complementary to TMZ. The patient subgroups benefitting from TMZ and BEV did not seem to overlap, and stratification based on risk factors, including MGMT methylation status, might be effective for selecting patients in whom BEV should be preferentially used as a first-line therapy.

Relevance of calcification and contrast enhancement pattern for molecular diagnosis and survival prediction of gliomas based on the 2016 World Health Organization Classification.

OBJECTIVES: The significance of conventional neuroimaging features for predicting molecular diagnosis and patient survival based on the updated World Health Organization (WHO) classification remains uncertain. We assessed the relevance of neuroimaging features (ring enhancement [RE], non-ring enhancement [non-RE], overall gadolinium enhancement [GdE], and intratumoral calcification [IC]) for molecular diagnosis and survival in glioma patients. PATIENTS AND METHODS: We evaluated 234 glioma patients according to the updated WHO classification. Isocitrate dehydrogenase (IDH), H3F3A, BRAF hotspot mutations, TERT promotor mutation, and chromosome 1p/19q co-deletion were examined. RE, non-RE, GdE, and IC were evaluated as significant neuroimaging findings. Kaplan-Meier analyses were performed to evaluate overall survival (OS) and the correlations of prognostic factors were evaluated by log-rank tests. Univariate and multivariate analyses were performed to detect prognostic factors for OS. RESULTS: A total of 207 patients were eligible. In 110 patients presenting RE, 102 (93%) were glioblastoma (GBM), IDH-wild type. In 97 patients without RE, presence of GdE or IC were not significantly different between IDH-mutant and -wild type tumors, whereas presence of GdE was a significant indicator of higher WHO grades. IC was the only significant finding for 1p/19q co-deleted tumors. TERT promoter mutation was observed in 7/17 patients with diffuse astrocytic glioma, IDH-wild type; recently-defined as "molecular GBM." IC, RE, and GdE were observed with lower prevalence in molecular GBMs. While presence of RE, GdE, and absence of IC were significant factors of OS in overall cohort, presence of GdE was not significant in OS in cases without RE, and IDH-mutant tumors. IC was a significant predictor of favorable OS in cases without RE and IDH-wild type tumors. Multivariate analysis also validated these findings. CONCLUSION: GdE alone is not a significant predictor of IDH mutation status, but the pattern of enhancement is a significant predictor with RE demonstrating high sensitivity and specificity for GBM, IDH-wild type. Predicting "molecular GBM" by conventional neuroimaging is difficult. Moreover, GdE is not a significant factor of survival analyzed with pattern of enhancement or molecular stratifications. IC is an important radiographic finding for predicting molecular diagnosis and survival in glioma patients.

Microsurgical Anatomy of the Jugular Process as an Anatomical Landmark to Access the Jugular Foramen: A Cadaveric and Radiological Study.

BACKGROUND: The jugular process forms the posteroinferior surface of the jugular foramen and is an important structure for surgical approaches to the foramen. However, its morphological features have not been well described in modern texts. OBJECTIVE: To elucidate the microsurgical anatomy of the jugular process and examine its morphological features. METHODS: Five adult cadaveric specimens were dissected in a cadaveric study, and computed tomography data from 31 heads (62 sides) were examined using OsiriX (Pixmeo SARL, Bernex, Switzerland) to elucidate the morphological features of the jugular process. RESULTS: The cadaveric study showed that it has a close relationship with the sigmoid sinus, jugular bulb, rectus capitis lateralis, lateral atlanto-occipital ligament, and lateral and posterior condylar veins. The radiographic study showed that 9/62 sigmoid sinuses protruded inferiorly into the jugular process and that in 5/62 sides, this process was pneumatized. At the entry of the jugular foramen, if the temporal bone has a bulb-type jugular bulb, and if surgery concerns the right side of the head, the superior surface of the jugular process is more likely to be steep. CONCLUSION: The jugular process forms the posteroinferior border of the jugular foramen. Resection of the jugular process is a critical step for opening the jugular foramen from the posterior and lateral aspects. Understanding the morphological features of the jugular process, and preoperative and radiographical examination of this process thus help skull base surgeons to access the jugular foramen.

Gliosarcoma arising from oligodendroglioma (Oligosarcoma): A case report with genetic analyses.

Gliosarcomas are a type of bimorphic tumor composed of glial and sarcomatous elements, and are considered to be a variant of glioblastoma, WHO grade IV. To date, only rare cases of gliosarcoma with oligodendroglial components (oligosarcoma) have been reported. We report a case of oligosarcoma consisting of gliosarcoma arising from recurrent oligodendroglioma. A 53-year-old man, who had undergone a gross total resection of oligodendroglioma (WHO grade II) 11 years earlier, presented with a local tumor recurrence. The patient underwent a second gross total resection, whereupon a histopathological examination further revealed residual features of classical oligodendroglioma, and newly-developed sarcomatous characteristics. Both the primary and recurrent tumors showed 1p/19q co-deletion and mutation of the isocitrate dehydrogenase 1 (IDH1) gene, consistent with being oligodendroglial in nature. Loss of heterozygosity (LOH) of chromosome 1p/19q and IDH1 mutation have seldom been analyzed in previous reports of oligosarcomas. We report a rare case study supported by the results of genetic analyses. Our analyses have revealed that the sarcomatous component represents a metaplastic change occurring in the oligodendroglial element.

An elderly case of malignant small cell glioma with hemorrhage coexistent with a calcified pilocytic astrocytoma component in the cerebellar hemisphere.

Pilocytic astrocytoma is a less aggressive form of glial tumor that commonly occurs in the pediatric population, and its malignant transformation is extremely rare. Here, we report an elderly case of malignant small cell glioma with hemorrhage coexistent with a calcified pilocytic astrocytoma component. An 80-year-old male was found to have a right cerebellar non-enhanced tumor with hematoma adjoining a calcified nodule. The lesion was surgically removed, and a histological examination verified that the tumor was a malignant small cell glioma with hemorrhagic change and the calcified nodule showed features of pilocytic astrocytoma. Genetic analyses revealed no glioma-relevant genetic alterations such as IDH and BRAF mutations. Although calcification is generally observed in slowly growing gliomas, the aggressive clinical course of calcified cerebellar pilocytic astrocytoma has been previously reported. Our extremely rare case shows that careful follow-up is necessary even for calcified pilocytic astrocytomas.

Pediatric ganglioglioma with an H3 K27M mutation arising from the cervical spinal cord.

The 2016 edition of the World Health Organization Classification of Tumors of the Central Nervous System introduced "diffuse midline glioma H3 K27M mutant" as a new diagnostic entity. These tumors predominately affect pediatric patients and arise from midline structures such as the brainstem, thalamus and spinal cord. Here, we report a rare patient with spinal ganglioglioma carrying an H3 K27M mutation. A 10-year-old boy presented with an intramedullary tumor in the cervical spinal cord. The lesion was partially removed and histologically diagnosed as ganglioglioma. After the remnant tumor grew within 3 months after surgery, the patient underwent radiotherapy. Genetic analyses revealed an H3F3A K27M mutation but no other genetic alterations such as IDH and BRAF mutations. This case may point to pathological heterogeneity in gliomas with H3 K27M mutations.

The Effectiveness of Salvage Treatments for Recurrent Lesions of Oligodendrogliomas Previously Treated with Upfront Chemotherapy.

BACKGROUND: We previously reported a favorable outcome in a case series of patients with oligodendrogliomas treated with upfront chemotherapy; however, their progression-free survival (PFS) was relatively short considering their long-term overall survival (OS). This suggests that salvage treatments after progression were effective. However, the clinical impact of salvage treatments on outcomes of patients with recurrent oligodendrogliomas has not been precisely investigated. METHODS: Our case series included 28 patients with newly diagnosed isocitrate dehydrogenase-mutant and 1p/19q-codeleted oligodendroglial tumors treated with upfront procarbazine, nimustine, and vincristine. Clinical outcomes and patterns of recurrence were reviewed retrospectively. RESULTS: The median follow-up period of enrolled patients was 90.2 months. Disease progression occurred in 15 patients (53.6%), whereas the cancer appeared as local relapse alone in 14 (93.3%) patients. Salvage treatments were performed for all local relapses; thereafter, most of the subsequent progressions also appeared as resectable local relapses. The 5-year PFS and OS rates from the first progression were 30.3% and 92.9%, respectively. These relatively short PFS and favorable OS indicated the effectiveness of salvage treatment even after multiple progression. Thus far, 9 (60%) of 15 patients are deterioration-free with locally controlled lesions or complete remission; however, clinical deterioration was observed in 6 patients, and 4 of them experienced dissemination. CONCLUSIONS: In isocitrate dehydrogenase-mutant and 1p/19q-codeleted oligodendrogliomas, most of the tumors that demonstrated early progression appeared as local, nonlethal lesions, which have been well-controlled by salvage treatments. A precise diagnosis of oligodendrogliomas using molecular parameters is crucial to receive the best benefit from salvage treatment.

Relationship Between the Horizontal Part of the Sigmoid Sinus and the Line Through the Digastric Point and Posterior Edge of the Condyle: An Anatomic and Radiologic Study.

OBJECTIVE: This study aims to determine whether the line between the digastric point and posterior edge of the occipital condyle (DC line) could be a new surface landmark for the posterior margin of the horizontal part of the sigmoid sinus. METHODS: Cadaveric specimens were used to show the relationship between the DC line and retrosigmoid craniotomy. Three-dimensional computed tomography angiography images of adult heads (56 sides) were analyzed to measure the distance between the DC line and the horizontal part of the sigmoid sinus at the digastric point, posterior edge of the condyle, and midpoint of the line. RESULTS: The DC line was roughly parallel and posterior to the posterior margin of the sigmoid sinus. The distance between the DC line and the posterior edge of the sigmoid sinus at the digastric point, condyle, and midpoint of the line measured 4.7 ± 3.3 mm, 5.9 ± 2.6 mm, and 1.3 ± 2.2 mm, respectively. All sigmoid sinuses coursed anterior to the digastric point and condyle but in 17.9% (10/56 sides) the posterior edge of the sigmoid sinus extended a maximum of 4.1 mm posterior to the midpoint of the DC line. CONCLUSIONS: The DC line can be used as a new surface landmark for estimating the position of the horizontal part of the sigmoid sinus. The posterior edge of the sinus may extend posterior to the line at the midpoint; thus, care should be taken to prevent sinus injury when drilling around the midpoint of the line.

Reclassification of 400 consecutive glioma cases based on the revised 2016WHO classification.

In this study, we reclassified 400 consecutive glioma cases including pediatric cases, using the revised 2016 WHO classification with samples collected from the Kyushu University Brain Tumor Bank. The IDH1/2, H3F3A, key genetic markers in the 2016 classification, were analyzed using high-resolution melting, with DNA extracted from frozen tissues. The 1p/19q codeletions were evaluated using a microsatellite-based loss of heterozygosity analysis, with 18 markers, to detect loss of the entire chromosome arm. In the integrated diagnosis, 29 oligodendroglioma cases and 28 anaplastic oligodendroglioma cases were diagnosed as "IDH-mutant and 1p/19q-codeleted," while 2 oligodendroglioma cases and 5 anaplastic oligodendroglioma cases were diagnosed as not otherwise specified (NOS). These "NOS" cases were either IDH-mutants or 1p/19q-codeleted, although characteristic oligodendroglial features were evident histologically. Better overall survival of patients with oligodendroglioma correlated with the molecular characteristic of "IDH-mutant and 1p/19q-codeleted," rather than the WHO grade. Eleven "glioblastoma, IDH-wild-type" cases were classified as "1p/19q-codeleted", however, chromosome 10 loss was also detected in 10 out of 11 cases. The 2016 WHO criteria for glioma classification leads to better diagnosis of patients. However, there are technical pitfalls and problems to be solved in the molecular analysis of routine diagnostics.

Surgical Anatomy of the Eustachian Tube for Endoscopic Transnasal Skull Base Surgery: A Cadaveric and Radiologic Study.

OBJECTIVE: The endoscopic endonasal approach to the anatomically complex lateral skull base presents technical challenges. The use of the eustachian tube as a landmark to identify the petrous internal carotid artery has recently been reported, and this study aims to define the anatomic relationship between the eustachian tube and its surrounding structures using cadaveric dissection and radiologic analysis. METHODS: To clarify the relationship of the eustachian tube with its surrounding structures, we performed endoscopic and microscopic dissection of 4 adult cadaveric heads and analyzed computed topography scans from 20 patients. RESULTS: The eustachian tube is divided into the osseous and cartilaginous parts. The cartilaginous part can be further subdivided into the posterolateral, middle, and anteromedial parts, based on its relationship to the skull base. The eustachian tube is closely related to the pterygoid process of the sphenoid bone, the foramen lacerum, and the petrosal apex and is directed away from the oblique sagittal plane almost parallel to the vidian canal at 12.2° ± 6.2° (mean ± standard deviation). The relationship between the course of the vidian canal and the eustachian tube can aid the estimation of the anatomic course of the horizontal segment of the petrous carotid artery. CONCLUSIONS: The eustachian tube is a useful landmark for predicting the course of the internal carotid artery when accessing the lateral skull base regions via an endonasal route. A profound understanding of the relationship between the eustachian tube and the surrounding skull base structures is important for endoscopic endonasal skull base surgeries.

High-resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas.

Craniopharyngioma consists of adamantinomatous and papillary subtypes. Recent genetic analysis has demonstrated that the two subtypes are different, not only in clinicopathological features, but also in molecular oncogenesis. Papillary craniopharyngioma (pCP) is characterized by a BRAF mutation, the V600E (Val 600 Glu) mutation. Adamantinomatous craniopharyngioma (aCP) can be distinguished by frequent ß-catenin gene (CTNNB1) mutations. Although these genetic alterations can be a diagnostic molecular marker, the precise frequency of these mutations in clinical specimens remains unknown. In this study, we first evaluated BRAF V600E and CTNNB1 mutations in four and 14 cases of pCP and aCP, respectively, using high-resolution melting analysis followed by Sanger sequencing. The results showed that 100% (4/4) of pCP cases had BRAF V600E mutations, while 78% (11/14) of the aCP cases had CTNNB1 mutations, with these genetic alterations being subtype-specific and mutually exclusive. Second, we evaluated BRAF V600E and CTNNB1 mutations by immunohistochemical analysis (IHC). All pCP cases showed positive cytoplasmic staining with the BRAF V600E-mutant antibody (VE-1), whereas 86% (12/14) of aCP cases showed positive cytoplasmic and nuclear staining for CTNNB1, suggesting a CTNNB1 mutation. Only one case of wild-type CTNNB1 on the DNA analysis showed immunopositivity on IHC. We did not detect a coexistence of BRAF V600E and CTNNB1 mutations in any single tumor, which indicated that these genetic alterations were mutually exclusive. We also report our modified IHC protocol for VE-1 staining, and present the possibility that BRAF V600E mutations can be used as a diagnostic marker of pCP in the differentiation of Rathke cleft cyst with squamous metaplasia.

Effective Intraluminal Shunt in Carotid Endarterectomy for Carotid Artery Near Occlusion: Technical Report.

BACKGROUND: Carotid artery near occlusion is a critical degree of stenosis whereby blood flow is decreased and the distal cervical and intracranial internal carotid arteries (ICAs) are prone to collapse. Considering the diminished perfusion and risk of progression to total occlusion and periocclusive embolism, we performed carotid endarterectomy for carotid artery near occlusion. METHODS: Accurate evaluation of tandem stenosis or patency of the poststenotic ICA in carotid artery near occlusion is often difficult preoperatively. Thus we performed carotid endarterectomy in a hybrid operating room where intraoperative digital subtraction angiography (DSA) and endovascular angioplasty or stenting for distal lesions can be performed if necessary. In addition, to evaluate the distal ICA intraoperatively, we used an intraluminal shunt for shunt angiography, with injection of contrast material through the shunt tube, as a replacement for conventional DSA. Furthermore, an intraluminal shunt held the collapsed lumen open and provided a scaffold for suturing, which prevented postoperative stenosis of the distal ICA. CONCLUSION: The present report is intended to underline the merits of intraluminal shunt as a replacement for conventional DSA and as a scaffold for suturing.

Prevalence and clinicopathological features of H3.3 G34-mutant high-grade gliomas: a retrospective study of 411 consecutive glioma cases in a single institution.

A recurrent glycine-to-arginine/valine alteration at codon 34 (G34R/V) within H3F3A, a gene that encodes the replication-independent histone variant H3.3, reportedly occurs exclusively in pediatric glioblastomas. However, the clinicopathological and biological significances of this mutation have not been completely elucidated; especially, no such data exist for tumor samples from Japanese patients. We analyzed 411 consecutive glioma cases representing patients of all ages. Our results demonstrated that 14 patients (3.4%) harbored H3F3A mutations, of which four had G34R mutations and 10 had K27M mutations. G34R-mutant tumors were located in the parietal region in two patients and the basal ganglia in one patient. One patient showed multi-lobular extension similar to the pattern observed in gliomatosis cerebri. Regarding neuroradiological features, intratumoral calcification was evident in two cases and all cases showed no or scarce contrast enhancement on MRI. Histopathologically, the four G34R-mutant cases included three glioblastomas and one astroblastoma. We have also investigated alterations in histone methylation including H3K27me3, H3K9me3, and H3K4me3 in G34R-mutant samples by immunohistochemistry. These results indicate that G34R-mutant tumors are likely to show extensive infiltration and alterations in global histone trimethylation might also play an important role in G34R mutant tumors.

Add-on bevacizumab can prevent early clinical deterioration and prolong survival in newly diagnosed partially resected glioblastoma patients with a poor performance status.

PURPOSE: The AVAglio trial established the beneficial effect of add-on bevacizumab (BEV) for the treatment of newly diagnosed glioblastomas (nd-GBMs) that led to the approval of BEV for the treatment of these patients in Japan. However, the rationality of using BEV as a first-line treatment for nd-GBMs remains controversial. The purpose of this study was to analyze the outcomes of a case series of nd-GBM patients. PATIENTS AND METHODS: The outcomes of 69 nd-GBM patients treated after 2006 were retrospectively analyzed. Clinical and genetic analyses were performed, and estimates of progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Since add-on BEV therapy was only used for partially resected GBMs (pr-GBMs) after its approval in 2013, the patients were subdivided into 3 treatment groups: Type I, partial removal with temozolomide (TMZ)/BEV and concurrent radiotherapy (CCRT); Type II, partial removal with TMZ and CCRT; and Type III, gross total removal with TMZ and CCRT. RESULTS: The PFS rate of Type I patients was significantly higher than that of Type II patients (P=0.014), but comparable to that of Type III patients. Differences in OS rates between Type I and Type II patients were less apparent (P=0.075), although the median OS of Type I patients was ~8 months higher than that of Type II patients (17.4 vs 9.8 months, respectively). The clinical deterioration rate during initial treatment was significantly (P=0.024) lower in Type I than in Type II patients (7.7% vs 47.4%, respectively). Differences in OS rates between Type I and Type II patients with a poor performance status (PS) were significant (P=0.017). CONCLUSION: Our findings suggest that add-on BEV can prevent early clinical deterioration of pr-GBM patients and contribute to a prolonged survival, especially for those with a poor PS.

Insular primary glioblastomas with IDH mutations: Clinical and biological specificities.

Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations. The median overall survival of these five patients was 29 months (range: 4 to >40 months), which is considered good prognoses. Clinical and radiographic characteristics were distinct from IDH-wildtype (IDH-wt) pGBMs. IDH-mutant (IDH-mut) tumors consistently involved insular lesions and were subdivided into: (i) the two cases of elderly patients with long clinical histories and features implying multistep tumor development; and (ii) the three cases of younger patients with diffusely swelling insular tumors, slight contrast enhancement and no necrosis. Genetic and expression analyses of IDH-mut pGBMs were similar to those of sGBMs, suggesting that they are indeed distinct from their IDH-wt counterparts. TERT promoter mutation, a genetic marker of oligodendroglial derivation, was detected in one long-surviving case, but genetic alterations in the astrocyte-sGBM pathway were generally prevalent in IDH-mut pGBMs. Our results present a unique phenotype of IDH-mut pGBMs arising from insular cortex region, the molecular backgrounds of which are similar to sGBMs.