Search

Supplementary figure 3. The Ceacam1L/STAT3 axis regulated the expression of stemness-related genes in NSCL61s

Supplementary figure 1. Expression of ceacam1 in mouse and human GIC lines and human glioma tissues

Supplementary figure 2. Knockdown efficiency of ceacam1 shRNAs

Supplementary figure 6. Ceacam1+/EGFR+ GBM cells associate with CD68+ microglia

Supplementary figure 5. Overexpression of ceacam1L made hGICs to be TMZ-resistance

Supplementary figure 4. Overexpression of ceacam1L kept the neurosphere formation activity of hGICs

Supplementary materials & methods and supplementary figure legends

The diagnosis of mosaicism is challenging in patients with neurofibromatosis type 2 (NF2) subset due to low variant allele frequency. In this study, we generated induced pluripotent stem cells (iPSCs) were generated from a patient clinically diagnosed with NF2 based on multiple schwannomas, including bilateral vestibular schwannomas and meningiomas. Genetic analysis of the patient's mononuclear cells (MNCs) from peripheral blood failed to detect NF2 alteration but successfully found p.Q65X (c.193C>T) mutation in all separate tumors with three intracranial meningiomas and one intraorbital schwannoma, and confirming mosaicism diagnosis in NF2 alteration using deep sequencing. Five different clones with patient-derived iPSCs were established from MNCs in peripheral blood, which showed sufficient expression of pluripotent markers. Genetic analysis showed that one of five generated iPSC lines from MNCs had the same p.Q65X mutation as that found in NF2. There was no significant difference in the expression of genes related to NF2 between iPSC clones with the wild-type and mutant NF2. In this case, clonal expansion of mononuclear bone marrow-derived stem cells recapitulated mosaicism's genetic alteration in NF2. Patient-derived iPSCs from mosaic NF2 would contribute to further functional research of NF2 alteration.

The study aimed to investigate the clinical implications and natural history of primary intraparenchymal lesions in patients with neurofibromatosis type 2. Radiological findings of 15 neurofibromatosis type 2 cases were retrospectively collected. Twenty-seven primary intraparenchymal lesions were observed in 7 out of 15 patients (47%). Cortical/subcortical T2 hyperintense lesions and enlarged Virchow–Robin spaces were the most common findings in five and four patients, respectively. During the follow-up period (median 84 months), one new primary intraparenchymal lesion was identified and increased lesions were observed in two cases on contrast-enhanced MRI. Surgical resection was performed in one case pathologically diagnosed with atypical meningioma. Twenty-five other lesions without contrast enhancement presented no apparent growth during follow-up. Although most primary intraparenchymal lesions are benign, a subset of cases would present newly developed or increased lesions on contrast-enhanced MRI. Careful monitoring is necessary for such cases, and pathological confirmation should be considered.

We conducted a prospective multicenter trial to compare the usefulness of C-11-methionine (MET) and F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both C-11-MET and F-18-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either C-11-MET or F-18-FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of C-11-MET PET and F-18-FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (P < .0001). The diagnostic accuracy of C-11-MET PET was significantly better than that of F-18-FDG PET (87.5% vs. 69.6%, P = .033). No examination-related adverse events were observed. The results of the study demonstrated that C-11-MET PET was superior to F-18-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis.

Bevacizumab (BEV) is a key anti-angiogenic agent used in the treatment for recurrent glioblastoma multiforme (GBM). The aim of this study was to investigate whether cytoreductive surgery prior to treatment with BEV contributes to prolongation of survival for patients with recurrent GBM. We retrospectively analyzed the treatment outcomes of 124 patients with recurrent GBM who were initially treated with the Stupp protocol between 2006 and 2019. Given that BEV has only been available in Japan since 2013, we grouped the patients into two groups according to the time of first recurrence: the pre-BEV group (N = 51) included patients who had recurrence before BEV approval, and the BEV group (N = 73) included patients with recurrence after BEV approval. The overall survival after first recurrence (OS-R) was analyzed according to the treatment strategy. Among 124 patients, 27 patients (19.4%) received cytoreductive surgery. There were nine cases in the pre-BEV group and 18 cases in the BEV group. Although the mean extent of resection for both groups was almost equal, OS-R was significantly different. The median OS-R was 8.1 m in the pre-BEV group and 16.3 m in the BEV group (P = 0.007). Multivariate analysis revealed that the unavailability of BEV postoperatively (P = 0.03) and decreasing performance status by surgery (P = 0.01) were significant poor prognostic factors for survival after surgery. With the advent of BEV, cytoreductive surgery might provide superior survival benefit at the time of GBM recurrence, especially in cases where surgery can be performed without deteriorating the patient's condition.

BACKGROUND: Although newly diagnosed high-grade glioma patients in Japan can receive bevacizumab (BEV) as first-line chemotherapy. randomized clinical trials have not shown a survival benefit for BEV for these patients. In this study, we investigated whether selective add-on BEV for patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA) improves prognosis, in cases where tumors were continuously growing during radiotherapy concomitant with temozolomide (TMZ). METHODS: We conducted a retrospective survey of the overall survival (OS) of patients with GBM;AAs who were treated in our institution between 2006 and 2016. Patients whose tumors were continuously growing regardless of radiotherapy were categorized as the "progressive" group; remaining patients were categorized as the "non-progressive" group. Since 2013, patients in the "progressive" group received add-on BEV therapy with the Stupp regimen during or just after radiotherapy. RESULTS: Of 151 GBM/AA patients, 34 (22.5%) were categorized in the "progressive" group. Median OSs of the "progressive" and "nonprogressive" groups were 13.2 months and 25.3 months, respectively (P

The aim of this study was to analyze the clinical and radiological characteristics of glioblastomas (GBMs) harboring a BRAF mutation. Sequencing analysis of BRAF, IDH1/2, and TERT promoters was performed on GBM samples of patients older than 15 years. The clinical, pathological, and radiological data of patients were retrospectively reviewed. Patients were classified into three groups according to their BRAF and IDH1/2 status: BRAF group, IDH group, and BRAF/IDH-wild-type (WT) group. Among 179 GBM cases, we identified nine cases with a BRAF mutation and nine with IDH mutation. The WT group had 161 cases. Age at onset in the BRAF group was significantly lower compared to the WT group and was similar to the IDH group. In cases with negative IDH1-R132H staining and age < 55 years, 15.2% were BRAF-mutant cases. Similar to the IDH group, overall survival of the BRAF group was significantly longer compared with the WT group. Among nine cases in the BRAF group, three cases had hemorrhagic onset and prior lesions were observed in two cases. In conclusion, age < 55 years, being IDH1-R132H negative, with hemorrhagic onset or the presence of prior lesions are factors that signal recommendation of BRAF analysis for adult GBM patients.

OBJECTIVEThe authors aimed to investigate genetic alterations in low-grade gliomas (LGGs) in pediatric and young adult patients presenting with spontaneous hemorrhage.METHODSPatients younger than 30 years of age with a pathological diagnosis of World Health Organization (WHO) grade I or II glioma and who had undergone treatment at the authors’ institution were retrospectively examined. BRAF V600E, FGFR1 N546/K656, IDH1 R132, IDH2 R172, and KIAA1549-BRAF (K-B) fusion genetic alterations were identified, and the presence of spontaneous tumoral hemorrhage was recorded.RESULTSAmong 66 patients (39 with WHO grade I and 27 with grade II tumors), genetic analysis revealed K-B fusion in 18 (27.3%), BRAF V600E mutation in 14 (21.2%), IDH1/2 mutation in 8 (12.1%), and FGFR1 mutation in 4 (6.1%). Spontaneous hemorrhage was observed in 5 patients (7.6%); 4 of them had an FGFR1 mutation and 1 had K-B fusion. Univariate analysis revealed a statistically significant association of an FGFR1 mutation and a diencephalic location with spontaneous hemorrhage. Among 19 diencephalic cases including the optic pathway, hypothalamus, and thalamus, an FGFR1 mutation was significantly associated with spontaneous hemorrhage (p < 0.001). Four FGFR1 mutation cases illustrated the following results: 1) a 2-year-old female with pilomyxoid astrocytoma (PMA) harboring the FGFR1 K656E mutation presented with intraventricular hemorrhage (IVH); 2) a 6-year-old male with PMA harboring FGFR1 K656E and D652G mutations presented with intratumoral hemorrhage (ITH); 3) a 4-year-old female with diffuse astrocytoma harboring FGFR1 K656M and D652G mutations presented with IVH; and 4) a young adult patient with pilocytic astrocytoma with the FGFR1 N546K mutation presented with delayed ITH and IVH after 7 years of observation.CONCLUSIONSAlthough the mechanism remains unclear, the FGFR1 mutation is associated with spontaneous hemorrhage in pediatric and young adult LGG.

Background Dural reconstruction after transpetrosal approaches is complicated because complete primary closure of presigmoid dura mater is difficult to achieve. To address this problem, we use biocompatible polyglycolic acid (PGA) felt (Durawave) to reconstruct dural defects. To evaluate the use of PGA felt in dural reconstruction, we compared these results with those after conventional duraplasty using autologous fascia grafts. Methods We retrospectively surveyed all cases involving a transpetrosal approach reported since 2013. In the conventional procedure, autologous fascia was fixed over the dural defect using stay sutures; any remaining dead space was obliterated by placing abdominal fat grafts. Since April 2017, we have used PGA felt instead of fascia. Results Of the 37 cases identified, 27 were reconstructed according to the conventional procedure, and the remaining 10 cases were reconstructed using PGA felt. Among the 27 conventional cases, 8 involved cerebrospinal fluid (CSF)-related complications, including 3 cases of rhinorrhea and 5 cases of subcutaneous fluid collection, and 2 cases (7%) required repair surgery. Of the 10 cases involving PGA felt, 1 case (10%) involved subcutaneous fluid collection and required repair surgery, and whereas the remaining 9 cases had no evidence of CSF leakage. In addition, the median dural reconstruction time using PGA felt was 9 minutes, significantly shorter than that when autologous fascia was used (median, 44 minutes). Conclusions Using PGA felt for presigmoid dura simplifies dural reconstruction because it obviates the need to suture in a deep field. PGA felt has the potential to prevent CSF-related complications after transpetrosal approaches.

18F-fluoromisonidazole (18F-FMISO) is the most widely used positron emission tomography (PET) tracer for imaging tumor hypoxia. Previous reports suggested that the time from injection to the scan may affect the assessment of 18F-FMISO uptake. Herein, we directly compared the images at 2 h and 4 h after a single injection of 18F-FMISO. Twenty-three patients with or suspected of having a brain tumor were scanned twice at 2 and 4 h following an intravenous injection of 18F-FMISO. We estimated the mean standardized uptake value (SUV) of the gray matter and white matter and the gray-to-white matter ratio in the background brain tissue from the two scans. We also performed a semi-quantitative analysis using the SUVmax and maximum tumor-to-normal ratio (TNR) for the tumor. At 2 h, the SUVmean of gray matter was significantly higher than that of white matter (median 1.23, interquartile range (IQR) 1.10–1.32 vs. 1.04, IQR 0.95–1.16, p

The study aimed to investigate the clinical implications and natural history of primary intraparenchymal lesions in patients with neurofibromatosis type 2. Radiological findings of 15 neurofibromatosis type 2 cases were retrospectively collected. Twenty-seven primary intraparenchymal lesions were observed in 7 out of 15 patients (47%). Cortical/subcortical T2 hyperintense lesions and enlarged Virchow-Robin spaces were the most common findings in five and four patients, respectively. During the follow-up period (median 84 months), one new primary intraparenchymal lesion was identified and increased lesions were observed in two cases on contrast-enhanced MRI. Surgical resection was performed in one case pathologically diagnosed with atypical meningioma. Twenty-five other lesions without contrast enhancement presented no apparent growth during follow-up. Although most primary intraparenchymal lesions are benign, a subset of cases would present newly developed or increased lesions on contrast-enhanced MRI. Careful monitoring is necessary for such cases, and pathological confirmation should be considered.

We conducted a prospective multicenter trial to compare the usefulness of 11C‐methionine (MET) and 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both 11C‐MET and 18F‐FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty‐one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either 11C‐MET or 18F‐FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow‐up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of 11C‐MET PET and 18F‐FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85‐0.99) and 0.48 (16/33, 95% CI: 0.33‐0.65), respectively, and the difference was statistically significant (P, This prospective multicenter study using positron emission tomography (PET) demonstrated the uptake of 11C‐methionine at a significantly higher sensitivity with brain tumor recurrence after radiotherapy than that of 18F‐fluorodeoxyglucose, based on histopathological evidence. The 11C‐methionine PET can be a useful diagnostic tool for the detection of tumor recurrence, distinguishable from radiation‐induced necrosis after radiotherapy in brain tumors.

Oligodendrogliomas are defined by mutation in isocitrate dehydrogenase (NADP(+)) (IDH)1/2 genes and chromosome 1p/19q codeletion. World Health Organisation diagnosis endorses testing for 1p/19q codeletion to distinguish IDH mutant (Mut) oligodendrogliomas from astrocytomas because these gliomas require different treatments and they have different outcomes. Several methods have been used to identify 1p/19q status; however, these techniques are not routinely available and require substantial infrastructure investment. Two recent studies reported reduced immunostaining for trimethylation at lysine 27 on histone H3 (H3K27me3) in IDH Mut 1p/19q codeleted oligodendroglioma. However, the specificity of H3K27me3 immunostaining in this setting is controversial. Therefore, we developed an easy-to-implement immunohistochemical surrogate for IDH Mut glioma subclassification and evaluated a validated adult glioma cohort. We screened 145 adult glioma cases, consisting of 45 IDH Mut and 1p/19q codeleted oligodendrogliomas, 30 IDH Mut astrocytomas, 16 IDH wild-type (Wt) astrocytomas, and 54 IDH Wt glioblastomas (GBMs). We compared immunostaining with DNA sequencing and fluorescent in situ hybridization analysis and assessed differences in H3K27me3 staining between oligodendroglial and astrocytic lineages and between IDH1-R132H and non-canonical (non-R132H) IDH1/2 Mut oligodendroglioma. A loss of H3K27me3 was observed in 36/40 (90%) of IDH1-R132H Mut oligodendroglioma. In contrast, loss of H3K27me3 was never seen in IDH1-R132L or IDH2-mutated 1p/19q codeleted oligodendrogliomas. IDH Mut astrocytoma, IDH Wt astrocytoma and GBM showed preserved nuclear staining in 87%, 94%, and 91% of cases, respectively. A high recursive partitioning model predicted probability score (0.9835) indicated that the loss of H3K27me3 is frequent to IDH1-R132H Mut oligodendroglioma. Our results demonstrate H3K27me3 immunohistochemical evaluation to be a cost-effective and reliable method for defining 1p/19q codeletion along with IDH1-R132H and ATRX immunostaining, even in the absence of 1p/19q testing. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01194-7.

The outcomes of intensity-modulated proton craniospinal irradiation (ipCSI) are unclear. We evaluated the clinical benefit of our newly developed ipCSI system that incorporates two gantry-mounted orthogonal online X-ray imagers with a robotic six-degrees-of-freedom patient table. Nine patients (7–19 years old) were treated with ipCSI. The prescribed dose for CSI ranged from 23.4 to 36.0 Gy (relative biological effectiveness) in 13–20 fractions. Four adolescent and young adult (AYA) patients (15 years or older) were treated with vertebral-body-sparing ipCSI (VBSipCSI). Myelosuppression following VBSipCSI was compared with that of eight AYA patients treated with photon CSI at the same institution previously. The mean homogeneity index (HI) in the nine patients was 0.056 (95% confidence interval: 0.044–0.068). The mean time from the start to the end of all beam delivery was 37 min 39 s ± 2 min 24 s (minimum to maximum: 22 min 49 s – 42 min 51 s). The nadir white blood cell, hemoglobin, and platelet levels during the 4 weeks following the end of the CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0071, 0.0453, 0.0024, respectively). The levels at 4 weeks after the end of CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0023, 0.0414, 0.0061). Image-guided ipCSI was deliverable in a reasonable time with sufficient HI. Using VBSipCSI, AYA patients experienced a lower incidence of serious acute hematological toxicity than AYA patients treated with photon CSI.

Purpose5-aminolevulinic acid (5-ALA) fluorescence-guided surgery (FGS) appears to be a promising treatment for glioma. However, 5-ALA-mediated fluorescence cannot always be detected in grade II/III gliomas. We hypothesized that gene expression patterns in the Protoporphyrin IX (PpIX) synthesis pathway may be associated with intraoperative fluorescence status of grade II/III gliomas, and then attempted to identify the key molecule of 5-ALA-mediated fluorescence.MethodsUsing 50 surgically obtained specimens, which were diagnosed as grade II and III gliomas, we analyzed gene expression within the PpIX synthesis pathway to identify candidate molecules according to intraoperative 5-ALA-mediated fluorescence status. The most likely candidate gene was selected and confirmed by protein expression analysis. To evaluate the biological function of the molecule in PpIX synthesis, functional analysis was performed using specific, small interference (si)RNA in the SW-1783human grade III glioma cell line.ResultsAmong the genes involved in the porphyrin synthesis pathway, the mRNA expression of Peptide transporter 2 (PEPT2) in FGS fluorescence-positive gliomas was significantly higher than that in fluorescence-negative gliomas. Protein expression of PEPT2 was also significantly higher in the fluorescence-positive gliomas, which was confirmed by western blot analysis and immunofluorescence analysis. The siRNA-mediated downregulation of the mRNA and protein expression of PEPT2 led to decreased PpIX fluorescence intensity, as confirmed by fluorescence spectrum analysis.ConclusionsThe results suggest PEPT2 is an important candidate molecule in 5-ALA-mediated FGS in grade II/III gliomas. As the overexpression of PEPT2 was associated with higher PpIX fluorescence intensity, PEPT2 may improve fluorescence-guided resection in grade II/III gliomas.

Temporal muscle abscess in children usually occurs from acute otitis media, and rapid progression and concomitant infectious disease often make it easy to diagnose. We report a rare case of a nine-month-old infant who showed right temporal mass with no evidence of infection. Computed tomography showed an osteolytic round mass, and magnetic resonance imaging revealed heterogenous enhancement with a high apparent diffusion coefficient. Malignant tumor was first suspected, but an open biopsy revealed the swelling to be temporal muscle abscess. It should be noted that temporal abscess may mimic the features of a malignant tumor, and multiple examinations should be performed for an accurate diagnosis.

Background Myelocystoceles, which are classified as closed neural tube defects, are usually covered by skin and rarely complicated by hydrocephalus. We encountered an unusual case of a terminal myelocystocele with hydrocephalus with clinical characteristics of a myelomeningocele. Case Description Severe hydrocephalus and a lumbosacral lesion were detected in the fetus of a gravid 34-year-old woman. Cesarean section was performed at 37 weeks. The neonate presented with a lumbosacral mass with a partial skin defect. As myelomeningocele was suspected, the neonate underwent surgery on the day of birth. The intraoperative findings pointed to a myelocystocele rather than a myelomeningocele. After insertion of a ventriculoperitoneal shunt, the neonate was discharged without any neurologic deficits. Conclusions Presence of skin abnormalities, hydrocephalus, and lumbosacral mass strongly suggests a diagnosis of myelomeningocele. However, such cases should be differentiated from myelocystocele, especially when associated with severe hydrocephalus.

Background Bevacizumab (BEV) is a key anti-angiogenic agent in the treatment for recurrent glioblastoma multiforme (GBM). The aim of this study was to investigate whether cytoreductive surgery prior to treatment with BEV contributes to prolongation of survival for patients with recurrent GBM. Methods We retrospectively analyzed the treatment outcomes of 124 patients with recurrent GBM who were initially treated with the Stupp protocol in our institution between 2006 and 2019. Given that BEV has only been available in Japan since 2013, we grouped the patients into 2 groups according to the time of first recurrence: the pre-BEV group (N = 51) included patients who had a recurrence before BEV approval, and the BEV group (N = 73) included patients with recurrence after BEV approval. The overall survival after first recurrence (OS-R) according to treatment strategy was analyzed. In addition, multivariate analysis using Cox’s proportional hazards model was used to evaluate the impact of clinical factors on OS-R after cytoreductive surgery in the patients with recurrent GBM. Results Among 124 patients, 27 patients (19.4%) received cytoreductive surgery: 9 cases in the pre-BEV group and 18 cases in the BEV group. Although the mean extent of resection of both groups was almost equal (92.2% pre-BEV group and 93.3% BEV group), OS-R was significantly different: median OS-R was 8.1 m in the pre-BEV group and 16.3 m in the BEV group, respectively (P = 0.007). Multivariate analysis revealed that the unavailability of BEV postoperatively (P = 0.03) and decreasing performance status caused by surgery (P = 0.01) were significant poor prognostic factors for survival after cytoreductive surgery in the patients with recurrent GBM. Conclusions With the advent of BEV, cytoreductive surgery might provide superior survival benefit at the time of GBM recurrence, especially in cases where surgery can be performed without deteriorating the patient’s condition.

Background: WHO grade 2 and 3 adult gliomas are nowadays getting together as lower-grade gliomas (LrGGs), but we had been recognized grade 3 (G3) tumors as high-grade and grade 2 (G2) tumors as low-grade. In this report, we investigate the treatment and prognosis of the patients with LrGG harboring IDH mutations in our institutions. Methods:We retrospectively review primary treatments and their prognosis for LrGG patients with IDH mutation since 2003. They categorized as astrocytomas and oligodendrogliomas according to 1p/19q loss-of-heterozygosity status. Prognosis were evaluated by overall survival. Postoperative primary treatments applied chemo-radiotherapy (CRT), radiotherapy only (RT), chemotherapy only (CT), and observation (Ob). Results: 36 astrocytomas and 60 oligodendrogliomas were identified. In astrocytomas, the patients with G3 (N=16) were treated by CRT (N=14) or CT (N=2), and the patients with G2 (N=20) were treated by CRT (N=2), RT (N=3), CT (N=3), or Ob (N=12). In oligodendrogliomas, the patients with G3 (N=34) were treated by CRT (N=32) or CT (N=2), and the patients with G2 (N=26) were treated by CRT (N=3), RT (N=1), CT (N=5), or Ob (N=17). 10-year survival rate (10yOS) of astrocytomas and oligodendrogliomas are 54% and 90%, respectively (p=0.002). According to histological malignancy, 10yOS of G3 and G2 astrocytomas were 54% and 54%, respectively (p=0.97) and that of G3 and G2 oligodendrogliomas were 86% and 100%, respectively (p=0.64). In both group, there are no different of prognosis according to histological malignancy. Discussion: There was no prognostic different between G2 and G3 astrocytomas in our institution. Since the treatment intensity for G2 and G3 astrocytomas were clearly different, the primary treatment for G2 astrocytomas might be insufficient. On the other hand, there were no prognostic different between G2 and G3 oligodendrogliomas in our institution, as with recent reports, so the primary treatment intensity for oligodendrogliomas should be appropriate.

A 5-year-old boy underwent biopsy of an intra-axial calcified tumor in the hypothalamus, which was incidentally found. Based on the presence of ganglion-like cells combined with glial cell element, the pathological diagnosis was ganglioglioma. Because the tumor grew gradually in size over the next 2 years, he underwent chemotherapy with temozolomide. However, at 8 years of age, the boy developed hydrocephalus and the cystic lesion had re-grown. Endoscopic cyst fenestration and tumor biopsy was performed, and pathological diagnosis was tentatively oligodendroglioma based on the presence of tumor cells with a perinuclear halo. At 10 years of age, hydrocephalus recurred and the cystic lesion had re-grown. A second round of endoscopic cyst fenestration and tumor biopsy led to a pathological diagnosis of pilocytic astrocytoma due to a biphasic appearance with areas of dense tumor cells and microcystic areas, tumor cells with eosinophilic processes, and the presence of an eosinophilic granular body. Genetic analysis of the first biopsy successfully identified the BRAF V600E mutation. Because pathological diagnosis of diencephalic low-grade glioma harboring BRAF V600E would be sometimes difficult due to pathological variations, pathological diagnosis should be performed under the consideration of molecular diagnosis of BRAF V600E for optimal diagnosis and treatment.

Object: Surgical resection is not the standard of treatment for primary central nervous system lymphoma (PCNSL). Some recent studies suggest that resection might be beneficial. The aim of this study was to examine the effect of surgical treatment in terms of the time from surgery to chemotherapy. Methods: We retrospectively analyzed all patients with PCNSL treated at Hokkaido University Hospital between 2001 and 2018 to assess the effect of selection for resection on the response of Methotrexate chemotherapy. We identified the days from surgery to chemotherapy, complications, the response of Methotrexate (CR/CRu rate) and prognostic factors including progression free survival (PFS) and overall survival (OS). Results: A total 105 patients were identified. 84 patients underwent biopsy and 21 patients underwent surgical resection. Their median age were 63 [31–78] and 68 [44–77], respectively. Their Karnofsky Performance Status (KPS) were 70 [30–100] and 70 [40–100]. There were any significant difference. Patients undergoing biopsy and those undergoing resection had comparable rates of complications for all complication type. Overall, 4 biopsy patients and 5 resection patients experienced at least one complication. They were composed of 2 asymptomatic bleeding, 1 wound abscess, 1 hydrocephalus in biopsy patients, 1 epidural abscess, 1 epilepsy, 1 chronic subdural hematoma, 2 temporary hemiparesis. Although the days from surgery to chemotherapy were significantly shorter in patients underwent biopsy than in those underwent resection (P=0.0015), PFS was significantly longer in patients underwent resection than in those underwent biopsy (P=0.0403), whereas there was no difference in OS. Discussion: Resection could delay the postoperative treatment. In this study, there was a significant delay of postoperative treatment in resection patients, however, CR/CRu rate after MTX was significantly better in those underwent resection than biopsy. We can see that resection for PCNSL might not necessarily worsen the prognosis.

This study noninvasively examined the electrical conductivity (σ) characteristics of diffuse gliomas using MRI and tested its validity. MRI including a 3D steady-state free precession (3D SSFP) sequence was performed on 30 glioma patients. The σ maps were reconstructed from the phase images of the 3D SSFP sequence. The σ histogram metrics were extracted and compared among the contrast-enhanced (CET) and noncontrast-enhanced tumour components (NCET) and normal brain parenchyma (NP). Difference in tumour σ histogram metrics among tumour grades and correlation of σ metrics with tumour grades were tested. Validity of σ measurement using this technique was tested by correlating the mean tumour σ values measured using MRI with those measured ex vivo using a dielectric probe. Several σ histogram metrics of CET and NCET of diffuse gliomas were significantly higher than NP (Bonferroni-corrected p ≤ .045). The maximum σ of NCET showed a moderate positive correlation with tumour grade (r = .571, Bonferroni-corrected p = .018). The mean tumour σ measured using MRI showed a moderate positive correlation with the σ measured ex vivo (r = .518, p = .040). Tissue σ can be evaluated using MRI, incorporation of which may better characterise diffuse gliomas. • This study tested the validity of noninvasive electrical conductivity measurements by MRI. • This study also evaluated the electrical conductivity characteristics of diffuse glioma. • Gliomas have higher electrical conductivity values than the normal brain parenchyma. • Noninvasive electrical conductivity measurement can be helpful for better characterisation of glioma.

von Hippel-Lindau (VHL) disease is a hereditary tumor disease in which tumors develop in multiple organs, not only as hemangioblastomas (HBs) in the central nervous system, but also as kidney tumors, pheochromocytomas, and so on. Much about the epidemiology of VHL disease remained unknown until fairly recently in Japan, leading to calls for the establishment of a VHL disease epidemiological database in Japanese. To elucidate its epidemiology in Japan, the Japanese Ministry of Health, Labour and Welfare created the VHL Disease Study Group, which was put in charge of carrying out a nationwide epidemiological survey. The survey found close to 400 Japanese VHL disease patients throughout the country. Based on those results, the VHL Disease Study Group created the VHL Disease Treatment Guideline and also a severity classification. It is thought that the prognosis of VHL disease patients can be improved by performing genetic diagnosis and careful follow-up. Accordingly, the University of Tokyo Hospital put in place an in-hospital system for implementing genomic medicine for VHL disease based on genetic diagnosis. For that system, it was especially important to establish (I) accurate genetic diagnostic techniques, (II) genetic counseling capabilities for the patients and their families, and (III) a system of cooperation among multiple departments, including urology departments, and so on. Further elucidation of the epidemiology and the development of genomic medicine are needed to improve the treatment results of VHL disease in Japan.

Background Compared with surgical resection, endoscopic transsphenoidal surgery (TSS) for cholesterol granuloma (CG) in the petrous apex (PA) is associated with local recurrence due to obstruction of the drainage route. We present a detailed procedure of an endoscopic TSS using pedicle vascularized nasoseptal flap (PVNF). Methods A 40-year-old woman with a history of repeated surgery for left tympanitis was referred to our institution. Neurological examination revealed severe hearing loss in the left ear. Radiologic examination presented a round mass in the left PA and significant fluid collection in the mastoid air cells of the left temporal bone. CG was strongly suspected, and endoscopic TSS using PVNF was performed. Prior to endoscopic drainage, a PVNF was harvested from the mucosa of the ipsilateral nasal septum, with an attempt to preserve the sphenopalatine artery in the flap. Following this, puncture and adequate irrigation of the lesion was performed by endoscopic TSS, with neuro-navigation system assistance; the apex of PVNF was then placed into the lesion to prevent the obstruction of the drainage route. An absorbable polyglycolic acid sheet and fibrin glue were applied on the flap to prevent spontaneous deviation from the lesion. Results The patient was discharged without any further neurological complications. Eight-month postoperative computed tomography images showed no recurrence; the drainage route was patent and the fluid collection in the left mastoid air cells was resolved. Moreover, hearing loss was improved. Conclusions Endoscopic TSS using PVNF may be one of available surgical options for PACG.

Background To evaluate the accuracy of tumor size by maximum diameter, ABC/2 formula, and planimetry method using thick-slice and thin-slice magnetic resonance imaging (MRI). Methods Maximum diameter and tumor volume calculated using ABC/2 formula (V1) and planimetry method with thick-slice MRI (V2) and thin-slice MRI (V3) were examined in 83 meningiomas. Form factor (FF) analysis was performed to assess irregularity of the tumor. V3 values were considered as real tumor volumes. The accuracy of V1 and V2 was evaluated using ratio and difference from V3. Meningiomas were categorized by tumor locations: skull base (anterior, middle, and posterior) and non–skull base (calvaria and other sites). Results Correlation between maximum diameter and V3 was statistically significant ( r = 0.91), but the error was significant in tumors with longer maximum diameters. Correlation between V1 and V3 was significant ( r = 0.97). However, V1 tended to be larger in middle skull base meningiomas or in tumors with low FF values ( R 2 = 0.21). V2 represented relatively accurate volumes in both groups except in the case of small meningiomas. When tumors were demonstrated within 3 fractions on thick-slice MRI, the ratio of V2 to V3 showed significant variability. Conclusions Using the ABC/2 formula, the volume of meningiomas in the middle skull base or meningiomas with low FF value might be calculated larger than the real tumor volume. The planimetry method with thick-slice MRI demonstrated relatively accurate volumes if the tumor was fractionated in >4 slices.

Objective: Although microvascular decompression (MVD) is a reliable treatment for hemifacial spasm (HFS), the postoperative course is varied. We retrospectively analyzed the resolution pattern of the spasm and specified predictors for delayed cure after MVD. Methods: This study included 114 consecutive patients with typical HFS. All of them were followed-up for at least one year after operation. Patients were divided into three groups depending on the postoperative course: immediate cure, delayed cure, and failure. To identify the predictive factors for delayed cure after MVD, logistic regression analyses were applied using candidate clinical factors, such as duration of symptom, the tendency of the spasm, preoperative medical treatment and offending vessels. Results: Among the 114 patients, 107 patients were cured. For those cured, 65 patients were classified as immediate cure and 42 patients were classified as delayed cure. Cumulative spasm free rate after one week, one month, and 3 months after MVD were 70%, 88%, and 97%, respectively. No predictive factors between the cured and failure groups were observed. According to multivariate analysis, preoperative anticonvulsant therapy was found to be the sole significant predictive factor for delayed cure after MVD (p = 0.025). Conclusions: A significant correlation between delayed cure and preoperative anticonvulsant therapy was found in our study, which suggests that hyperexcitation of the facial nucleus plays an important role in pathogenesis of delayed cure. Therefore, if a patient demonstrating a positive response to preoperative anticonvulsant therapy showed a persistent spasm after MVD, reoperation should be delayed for at least 3 months after the initial operation.

Background Glioblastoma-initiating cells (GICs) comprise a tumorigenic subpopulation of cells that are resistant to radio- and chemotherapies and are responsible for cancer recurrence. The aim of this study was to identify novel compounds that specifically eradicate GICs using a high throughput drug screening approach. Methods We performed a cell proliferation/death-based drug screening using 10 560 independent compounds. We identified dihydroorotate dehydrogenase (DHODH) as a target protein of hit compound 10580 using ligand-fishing and mass spectrometry analysis. The medical efficacy of 10580 was investigated by in vitro cell proliferation/death and differentiation and in vivo tumorigenic assays. Results Among the effective compounds, we identified 10580, which induced cell cycle arrest, decreased the expression of stem cell factors in GICs, and prevented tumorigenesis upon oral administration without any visible side effects. Mechanistic studies revealed that 10580 decreased pyrimidine nucleotide levels and enhanced sex determining region Y–box 2 nuclear export by antagonizing the enzyme activity of DHODH, an essential enzyme for the de novo pyrimidine synthesis. Conclusion In this study, we identified 10580 as a promising new drug against GICs. Given that normal tissue cells, in particular brain cells, tend to use the alternative salvage pathway for pyrimidine synthesis, our findings suggest that 10580 can be used for glioblastoma therapy without side effects. Key Points 1. Chemical screening identified 10580 as a novel GIC-eliminating drug that targets DHODH, an essential enzyme for the de novo pyrimidine synthesis pathway. 2. Compound 10580 induced cell cycle arrest, apoptosis, and differentiation in GICs.

Twenty-three patients with or suspected of having a brain tumor were scanned twice at 2 and 4 h following an intravenous injection ofAt 2 h, the SUVmean of gray matter was significantly higher than that of white matter (median 1.23, interquartile range (IQR) 1.10-1.32 vs. 1.04, IQR 0.95-1.16, p 0.0001), whereas at 4 h, it significantly decreased to approach that of the white matter (1.10, IQR 1.00-1.23 vs. 1.02, IQR 0.93-1.13, p = NS). The gray-to-white matter ratio thus significantly declined from 1.17 (IQR 1.14-1.19) to 1.09 (IQR 1.07-1.10) (p 0.0001). All 7 patients with glioblastoma showed significant increases in the SUVmax (2.20, IQR 1.67-3.32 at 2 h vs. 2.65, IQR 1.74-4.41 at 4 h, p = 0.016) and the TNR (1.75, IQR 1.40-2.38 at 2 h vs. 2.34, IQR 1.67-3.60 at 4 h, p = 0.016).In the assessment of hypoxic tumors