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Rebleeding from a ruptured intracranial aneurysm has poor outcomes. Although numerous factors are associated with rebleeding, studies on computational fluid dynamics (CFD) on hemodynamic parameters associated with early rebleeding are scarce. In particular, no report of rebleeding in ultra-early phase exists. We aimed to elucidate the specific hemodynamic parameters associated with ultra-early rebleeding using CFD. In this study, the rebleeding group included patients with aneurysmal subarachnoid hemorrhage (aSAH) that rebled within 6 h from the onset. The control group included patients without rebleeding, observed for >10 h following the initial rupture. Clinical images after initial rupture and before rebleeding were used to build 3D vessel models for hemodynamic analysis focusing on the following parameters: time-averaged wall shear stress (WSS), normalized WSS, low shear area, oscillatory shear index, relative residence time, pressure loss coefficient, and aneurysmal inflow rate coefficient (AIRC). Five and 15 patients in the rebleeding and control groups, respectively, met the inclusion criteria. The World Federation of Neurosurgical Surgeons grade was significantly higher in the rebleeding group (p = 0.0088). Hemodynamic analysis showed significantly higher AIRC in the rebleeding group (p = 0.042). The other parameters were not significantly different between groups. There were no significant differences or correlations between SAH severity and AIRC. AIRC was identified as a hemodynamic parameter associated with ultra-early rebleeding of ruptured intracranial aneurysms. Thus, AIRC calculation may enable the prediction of ultra-early rebleeding.

Abstract We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

Transsylvian selective amygdalohippocampectomy (TSA) is one of the predominant surgical options for drug-resistant mesial temporal lobe epilepsy. The purpose of this article is to highlight the unique features of TSA and determine the setting to perform safe and secure TSA with special reference to the optimal head position. TSA should be performed via a small surgical corridor in the temporal stem that contains functionally important fiber tracts, including the uncinate fasciculus, the inferior fronto-occipital fasciculus, and the optic radiation. Graphical simulations proposed that low-degree (

To assess the clinicopathological features and prognostic factors of pediatric intracranial ependymomas and to explore the current diagnostic practice, we analyzed clinical data from the Brain Tumor Registry of Japan (BTRJ). Data of fifty children under 18 years of age diagnosed with intracranial ependymoma were extracted from the BTRJ database. Cases were reviewed for overall survival (OS) and progression-free survival (PFS), with attention to gender, preoperative Karnofsky performance status score, location of the tumor, the extent of resection, World Health Organization (WHO) histopathological grading, and adjuvant therapy. The median age at diagnosis was 6.1 years, ranging from 7 months to 17.6 years. Based on the WHO histopathological grading, 27 patients were classified under grade 2 (54%) and 23 patients were classified under grade 3 (46%). Gross total resection (GTR) was achieved in 30 patients (60%). The median follow-up time was 65 months. Five-year PFS and OS were 47.2 ± 7.3% and 73.3 ± 6.7%, respectively. GTR was associated with longer OS (P = 0.02). The histopathological grading was not an independent prognostic factor for the OS. Mitosis and microvascular proliferation were higher among patients with grade 3 than in those with grade 2, which aided in deciding the WHO grade. This nationwide study revealed the characteristics and outcomes of patients with childhood ependymomas. GTR was the factor most consistently associated with improved survival. In contrast, the histopathological grading in this cohort was not a significant prognostic factor. More reproducible and practical criteria for the diagnosis of intracranial ependymomas should be further pursued in future studies.

Abstract Background Brain metastasis of colorectal cancer is infrequent, and isolated brain metastases are more infrequent. Thus, when neurological symptoms, such as paralysis or disturbance of consciousness appear, there is a high probability that the cancer has spread to other organs. Case presentation Here, we present a 64-year-old man with a progressive headache, decreased motivation, and aphasia who was diagnosed with a brain tumor in the left frontal region. He underwent a craniotomy, and the brain tumor was diagnosed as adenocarcinoma. We performed a colonoscopy and diagnosed rectal cancer without other distant metastases. After whole-brain radiotherapy (WBRT), low anterior resection for primary rectal tumor was performed using a robotic system. The patient was discharged in good condition and received postoperative adjuvant therapy for rectal cancer. He showed no signs of recurrence after 1 year of follow-up. Conclusions We described a rare case of rectal cancer that was diagnosed after resection of isolated brain metastasis. A good prognosis was achieved with surgery and WBRT.

Primary intracranial spindle cell sarcoma is an extremely rare mesenchymal tumor, the molecular pathogenesis of which is poorly understood. Because of the lack of specific markers, diagnosis sometimes relies on ruling out all possible differential diagnoses, often making it difficult to reach a definitive diagnosis. In this case study, we report a 69 year-old female patient for whom the integration of multi-layered molecular analyses contributed to making the diagnosis. The disease exhibited aggressive clinical behavior, requiring two sequential surgeries because of rapid regrowth within a short period. Primary and recurrent tumors exhibited similar histological features, in which spindle-shaped cells arranged in interlacing fascicles without any specific architectures, implicating sarcomatous tumors. In immunohistochemistry testing, tumor cells were immunopositive for vimentin but lacked any specific findings that contribute to narrowing down the differential diagnoses. Seeking further diagnostic clues, we performed DNA methylation-based analysis. The copy number analysis revealed MDM2 gene amplification and loss of heterozygosity of 22q. Moreover, dimension reduction clustering analysis implicated a methylation pattern comparable to aggressive types of sarcomas. In addition, an in-house next-generation sequencing panel (“Todai-OncoPanel”) analysis identified somatic mutations in DICER1, NF2 , and ATRX genes. Taken all together, we finally made the diagnosis of primary intracranial spindle cell sarcoma, DICER1 -mutant, with MDM2 gene amplification. This case report suggests that even for the tumors with insufficient morphological and immuno-histological diagnostic clues, integration of multi-layered molecular analyses can contribute to making the diagnoses as well as to understanding the rare tumors by elucidating unexpected genetic and epigenetic features.

Neurofibromatosis type 2 (NF2) causes bilateral vestibular schwannomas (VSs), leading to deafness. VS is treated by surgery or radiation, but neither treatments prevent hearing loss. Bevacizumab was found to be effective in suppressing the tumor’s growth and may help to improve hearing. We are conducting a randomized, double-blind, multicenter clinical trial to verify the efficacy and safety of bevacizumab in NF2-related VS. The primary objective is to evaluate the efficacy of bevacizumab in improving hearing in the affected ear. One of the secondary objectives is to evaluate bevacizumab’s efficacy in rechallenge treatment in relapsed cases. Sixty patients will randomly receive either bevacizumab or a placebo and will be clinically observed for 48 weeks in the initial intervention phase. In the first half (24 weeks), they will receive either 5 mg/kg of bevacizumab or a placebo drug. In the second half, all patients will receive 5 mg/kg of bevacizumab. If hearing function deteriorated in a patient who had shown improvement during the first phase, a rechallenge dose with bevacizumab would be offered.

Summary: 2-Methylthio-N6-isopentenyl modification of adenosine (ms2i6A) is an evolutionally conserved modification found in mitochondrial (mt)-tRNAs. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) specifically converts N6-isopentenyladenosine (i6A) to ms2i6A at position A37 of four mt-DNA-encoded tRNAs, and the modification regulates efficient mitochondrial translation and energy metabolism in mammals. Here, we report that the ms2 conversion mediated by CDK5RAP1 in mt-tRNAs is required to sustain glioma-initiating cell (GIC)-related traits. CDK5RAP1 maintained the self-renewal capacity, undifferentiated state, and tumorigenic potential of GICs. This regulation was not related to the translational control of mt-proteins. CDK5RAP1 abrogated the antitumor effect of i6A by converting i6A to ms2i6A and protected GICs from excessive autophagy triggered by i6A. The elevated activity of CDK5RAP1 contributed to the amelioration of the tumor-suppressive effect of i6A and promoted GIC maintenance. This work demonstrates that CDK5RAP1 is crucial for the detoxification of endogenous i6A and that GICs readily utilize this mechanism for survival. : Biological Sciences; Molecular Biology; Cell Biology; Stem Cells Res earch; Cancer Subject Areas: Biological Sciences, Molecular Biology, Cell Biology, Stem Cells Research, Cancer

We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab.

Background: In neurosurgery, it is important to inspect the spatial correspondence between the preoperative medical image (virtual space), and the intraoperative findings (real space) to improve the safety of the surgery. Navigation systems and related modalities have been reported as methods for matching this correspondence. However, because of the influence of the brain shift accompanying craniotomy, registration accuracy is reduced. In the present study, to overcome these issues, we developed a spatially accurate registration method of medical fusion 3-dimensional computer graphics and the intraoperative brain surface photograph, and its registration accuracy was measured. Methods: The subjects included 16 patients with glioma. Nonrigid registration using the landmarks and thin-plate spline methods was performed for the fusion 3-dimensional computer graphics and the intraoperative brain surface photograph, termed mixed-reality computer graphics. Regarding the registration accuracy measurement, the target registration error was measured by two neurosurgeons, with 10 points for each case at the midpoint of the landmarks. Results: The number of target registration error measurement points was 160 in the 16 cases. The target registration error was 0.72 ± 0.04 mm. Aligning the intraoperative brain surface photograph and the fusion 3-dimensional computer graphics required ∼10 minutes on average. The average number of landmarks used for alignment was 24.6. Conclusions: Mixed-reality computer graphics enabled highly precise spatial alignment between the real space and virtual space. Mixed-reality computer graphics have the potential to improve the safety of the surgery by allowing complementary observation of brain surface photographs and fusion 3-dimensional computer graphics.

A 36-year-old male suffered from a sudden headache. Computed tomography (CT) showed a subarachnoid hemorrhage (SAH). CT angiography demonstrated an aneurysm arising from the duplicate origin of the right posterior communicating artery (PcomA). The aneurysm was at the junction of the internal carotid artery and the distal branch of the PcomA duplication. Frontotemporal craniotomy and neck clipping were performed for the ruptured aneurysm. The patient’s post-operative course was uneventful and without symptomatic vasospasm. Post-operative angiography revealed the total duplication of the PcomA. The ophthalmic artery originating from cavernous portion anomalously. Although the relationship between the frequency of aneurysms and PcomA duplication is unclear, the PcomA duplication-in addition to the ophthalmic artery's anomalous origin-was speculated to be an anomaly related to the developmental processes of cerebral arteries.

Background: Intraoperative rupture is the most fatal and catastrophic complication of surgery for unruptured intracranial aneurysms (UIAs); thus, it is extremely useful to predict reddish and thin-walled regions of the UIA before surgery. Although several studies have reported a relationship between the hemodynamic characteristics and intracranial aneurysm wall thickness, a consistent opinion is lacking. We aimed to investigate the relationship between objectively and quantitatively evaluated bleb wall color and hemodynamic characteristics using phase-contrast magnetic resonance angiography (PC-MRA). Methods: Ten patients diagnosed with UIA who underwent surgical clipping and preoperative magnetic resonance imaging along with PC-MRA were included in this study. Bleb wall color was evaluated from an intraoperative video. Based on the Red (R), Green, and Blue values, bleb wall redness (modified R value; mR) was calculated and compared with the hemodynamic characteristics obtained from PC-MRA. Results: The wall redness distribution of 18 blebs in 11 UIAs in 10 patients was analyzed. Bleb/neck inflow velocity ratio (Vb/Va: r = 0.66, P = 0.003) strongly correlated with mR, whereas bleb/neck inflow rate ratio (r = 0.58, P = 0.012) correlated moderately. Multivariate regression analysis revealed that only Vb/Va (P = 0.017) significantly correlated with mR. There was no correlation between wall shear stress and mR. Conclusions: The bleb redness of UIAs and Vb/Va, calculated using PC-MRA, showed a significantly greater correlation. Thus, it is possible to predict bleb thickness noninvasively before surgery. This will facilitate more detailed pre- and intraoperative strategies for clipping and coiling for safe surgery.

Abstract Background Standard sampling methods to evaluate the proliferative ability of meningioma have not been established. Methods This prospective study was conducted to evaluate the effectiveness of intraoperative rapid flow cytometry (iFC) using raw samples for the quantitative assessment of proliferative ability in meningioma cells and to investigate intratumoral heterogeneity. Proliferation index (PI) was defined as the ratio of aneuploid cells with an abnormal number of chromosomes to the total cells. Results From 50 patients, 118 specimens were analyzed. There was a statistically significant correlation between the postoperative MIB‐1 labeling index (LI) and PI (R = 0.59, P

Background: Much effort is required to dissect the adhesion in the surgical trajectory in reoperation via the lateral suboccipital retrosigmoid approach. Lumbar drainage is a standard procedure in neurosurgical practice; its usefulness during reoperation has not been reported. The purpose of this study is to elucidate whether pretreatment with lumbar drainage is effective in enabling a more straightforward lateral suboccipital approach during reoperation. Methods: There were 13 reoperations among 115 lateral suboccipital craniotomies performed by a single surgeon between April 2016 and March 2018 at our institution. Lumbar drainage was performed prior to reoperations when tight adhesion was anticipated by preoperative neuroimaging. We retrospectively inspected 11 reoperations in which the video recordings were available. Results: After lumber drainage, the cerebellum was slack by the start of the dural incision. The total approach time, defined as the time between starting dural incision and reaching the cerebellopontine cistern, in the group with lumbar drainage (47 min. 45 sec., n = 6) was 13 min. 46 sec. shorter than that of the group without drainage (61 min. 31 sec., n = 5) (p = 0.09). The number of times hemostasis was required in the group with drainage (4 ± 1.4) was significantly lower than that of the group without drainage (7 ± 1.4) (p

Supratentorial acute subdural hematoma (SASDH) after surgery for an infratentorial lesion is rare. Most cases are experienced after microvascular decompression surgery. To our knowledge, there has been only one reported case of SASDH after surgery for an infratentorial lesion including a vestibular schwannoma. Here, we present a rare case of SASDH after removal of vestibular schwannoma, in which the hematoma was successfully removed immediately after the initial suboccipital surgery. During the craniotomy, a small abnormal blood vessel formation was identified on the brain surface as a possible source of the subdural bleeding.

Medical care-related decision-making among patients with malignant brain tumors has not been sufficiently discussed. This study aimed to develop a framework for understanding patients’ experiences in the decision-making process. Semi-structured interviews with 14 patients were analyzed using a grounded theory approach, focusing on their 48 decision-making points. Additionally, interviews with two family members and seven healthcare providers, and participant observations were used to gain contextual insight into patients’ experiences. Patients faced decisions while they struggled in vulnerability under shock, fear, and anxiety while hoping. Under this context, they showed four decision-making patterns: (1) led by the situation , (2) controlled by others , (3) entrusted someone with the decision , and (4) myself as a decision-making agent . Across these patterns, the patients were generally satisfied with their decisions even when they did not actively participate in the process. Healthcare providers need to understand patients’ contexts and their attitudes toward yielding decision-making to others.

Glioblastoma (GBM) usually develops in adult brain white matter. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo-radioresistance. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and periphery by miRNA microarray. The top three of miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathologically oligodendrocyte lineage cells were increased in the border, where macrophages and microglia also colocalized. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, similar to that produced by FGF1, EGF and HB-EGF, IL-1β, corresponding to OPCs and macrophages, respectively. Thus, OPCs and macrophages/microglia may form a glioma stem cell niche at the tumor border, representing a promising target for prevention of recurrence. Keywords: Oligodendrocyte progenitor cell, Macrophage, Microglia, Stemness, Chemoradioresistance, Recurrence, Border niche, Glioblastoma, Glioma stem cells niche, microRNA

Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.

Machine learning models for automated magnetic resonance image segmentation may be useful in aiding glioma detection. However, the image differences among facilities cause performance degradation and impede detection. This study proposes a method to solve this issue. We used the data from the Multimodal Brain Tumor Image Segmentation Benchmark (BraTS) and the Japanese cohort (JC) datasets. Three models for tumor segmentation are developed. In our methodology, the BraTS and JC models are trained on the BraTS and JC datasets, respectively, whereas the fine-tuning models are developed from the BraTS model and fine-tuned using the JC dataset. Our results show that the Dice coefficient score of the JC model for the test portion of the JC dataset was 0.779 ± 0.137, whereas that of the BraTS model was lower (0.717 ± 0.207). The mean Dice coefficient score of the fine-tuning model was 0.769 ± 0.138. There was a significant difference between the BraTS and JC models (p < 0.0001) and the BraTS and fine-tuning models (p = 0.002); however, no significant difference between the JC and fine-tuning models (p = 0.673). As our fine-tuning method requires fewer than 20 cases, this method is useful even in a facility where the number of glioma cases is small.

Summary: The development of cancer is driven not only by genetic mutations but also by epigenetic alterations. Here, we show that TET1-mediated production of 5-hydroxymethylcytosine (5hmC) is required for the tumorigenicity of glioblastoma cells. Furthermore, we demonstrate that chromatin target of PRMT1 (CHTOP) binds to 5hmC. We found that CHTOP is associated with an arginine methyltransferase complex, termed the methylosome, and that this promotes the PRMT1-mediated methylation of arginine 3 of histone H4 (H4R3) in genes involved in glioblastomagenesis, including EGFR, AKT3, CDK6, CCND2, and BRAF. Moreover, we found that CHTOP and PRMT1 are essential for the expression of these genes and that CHTOP is required for the tumorigenicity of glioblastoma cells. These results suggest that 5hmC plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of cancer-related genes. : The development of cancer is driven not only by genetic mutations but also by chromatin and DNA modification changes. Takai et al. now show that proneural glioblastomas contain high levels of 5hmC and TET1. Production of 5hmC is required for the tumorigenicity of glioblastoma cells. Furthermore, 5hmC recruits the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of cancer-related genes.

Objective: We report here an atypical case of cavernous sinus dural arteriovenous fistula (CSDAVF) with a septation that separates the cavernous sinus (CS) into two components, namely, normal cerebral venous drainage and shunted blood drainage into the superior ophthalmic vein (SOV) alone. The CSDAVF was successfully treated by selective transvenous embolization (TVE) through the septum with the trans-inferior petrosal sinus (IPS) approach. Case Presentation: A 74-year-old woman presented with right exophthalmos and tinnitus on the right side. Neuroradiological examination showed CSDAVF mainly supplied by multiple feeders from the bilateral ascending pharyngeal artery and meningohypophyseal trunk with a shunted pouch located medial-dorsally to the right CS. Blood from the CSDAVF drained via the anterior component of the CS to the right SOV only. Normal cerebral venous blood from the right superficial middle cerebral vein drained through the dorsolateral component of the right CS into the right IPS. These findings suggest that a septal barrier exists between the outflow tract of the dural arteriovenous fistula and the normal cerebral venous outflow tract within the CS. The CSDAVF was successfully treated by selective TVE through the septum with the trans-IPS approach after detailed evaluation of 3D rotational angiography (3DRA) and MRA/MR venography (MRV) cross-sectional images. The patient's symptoms improved, and she was discharged uneventfully. Conclusion: Septation within the CS can completely separate the drainage route of the CSDAVF from the normal cerebral drainage route. Successful catheterization to the shunted pouch through the septum with the IPS approach and selective embolization were possible with detailed evaluation of anatomy on MRA/MRV cross-sectional images and 3DRA images. [ABSTRACT FROM AUTHOR]