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Giant cell tumor (GCT) of bone is essentially benign but locally aggressive, and the rate of local recurrence is high when the resection is not enough. En bloc resection is recommended as an ideal solution for GCT to decrease the risk of local recurrence, but it remains challenging for cervical GCT. In this technical case report, we present a case of extensively infiltrating GCT of the cervical spine completely encasing the vertebral artery (VA) on one side. The tumor was distributed to layers A-D, sectors 3-8 based on the Weinstein-Boriani-Biagini staging. Combined posterior and anterior surgical approach for the cervical spine was successfully performed and followed by postoperative adjuvant pharmacological therapy. This kind of multimodal management may be one of the solutions for advanced cervical GCT.

Spinal intramedullary tumors such as ependymoma or vascular lesions such as cavernous malformation are often at risk of intramedullary hemorrhage. Surgical procedures involving the high cervical spinal cord are often challenging. This technical note included four patients who presented with acute, subacute, or gradual onset of spinal cord dysfunction associated with intramedullary hemorrhage at the C1 or C1/2 level of the high cervical spine. The mean age was 46.3 years (16-74 years). All patients underwent posterior spinal cord myelotomy of the posterior median sulcus or posterolateral sulcus. It was not to exceed the caudal opening of the fourth ventricle (foramen of Magendie) and was assumed to be as high as the caudal medulla oblongata. Total removal of the intramedullary ependymoma or cavernous malformation occurred in three of four cases, and the remaining case had subtotal removal of the ependymoma. None of the patients showed postoperative deterioration of the neurological condition. Pathological examination of all cases revealed intramedullary hemorrhage was associated with ependymoma or cavernous malformation. Posterior spinal myelotomy should be limited to the caudal opening of the fourth ventricle (foramen of Magendie), that is the caudal medulla oblongata, to avoid the significant deterioration after surgery.

Spinal intramedullary metastasis is an extremely rare event that occurs in advanced cancer. The surgical indications for spinal intramedullary metastasis are highly limited because of surgical difficulty and poor prognosis. In this technical case report, we present a rare case of spinal intramedullary metastasis from the lung that recurred late after local radiation to the spinal cord. The patient progressively experienced relapsed buttock pain and developed gait and urination disorders late after treatment for lung cancer. Imaging examinations suggested the recurrence of spinal intramedullary metastasis in the conus medullaris. Systemic examinations revealed no apparent recurrence in other organs, including the primary lung lesions. Gross total resection of the tumor within the conus medullaris was safely performed using the unilateral posterolateral (PLS) approach and by addition of the contralateral PLS approach. To the best of our knowledge, this is the first case in which a spinal intramedullary metastatic tumor was successfully removed using a bilateral PLS approach.

Frameless stereotactic brain biopsy (FSB) with navigation system has been widely used. We reported preliminary experience of FSB with intraoperative computed tomography (iCT) and examined the usefulness of this novel adjuvant technique and real target registration error (rTRE) of FSB. The FSB with 5-aminolevulinic acid (5-ALA) and iCT was performed on 10 patients. The gadolinium-enhanced lesions on magnetic resonance image were defined as the biopsy target. In the procedure, iCTs were scanned twice, for autoregistration of the navigation system and for confirmation of the position of the actual inserted biopsy needle. The red fluorescence of the samples was observed under excitation with violet-blue light through a low-cut filter of neurosurgical microscope. The distance between the planned target and the tip of the biopsy needle in the image of iCT was calculated in a workstation for the assessment of rTRE. The median volume of the target was 12.13 mL (0.06-39.15 mL). We performed the surgical procedure in a prone position in four patients. None to faint 5-ALA-induced fluorescence was observed in six samples. There existed no sampling errors. The mean target distance between the planned and real targets of the mean rTRE of FSB was 2.7 ± 0.56 mm. The real TRE of FSB was first reported and was larger than the reported rTRE exactly calculated from the fiducial registration error. iCT guarantees accurate tumor sampling with autoregistration regardless of the surgical position and prevents inaccurate biopsy to occur even with ALA fluorescence assistance.

The aim of this study was to evaluate the influence of skin distortion due to surgical positioning on the clinical accuracy of the navigation system. The distance errors were measured in four fiducial markers (anterior, posterior, right, and left of the head) after the registration of the navigation system. The distance errors were compared between the surface-merge registration (SMR) method using preoperative imaging and the automatic intraoperative registration (AIR) method using intraoperative imaging. The comparison of the distance errors were performed in various surgical positions. The AIR method had the significant accuracy in the lateral markers than the SMR method (lateral position, 3.8 mm vs. 8.95 mm; p p = 0.0001; 5.2 mm vs. 11.5 mm; p = 0.0070). The smallest distance errors were obtained close to the surgical field in the AIR method (3.25–3.85 mm) and in the forehead in the SMR method (3.3–8.1 mm). The AIR method was accurate and recommended for all the surgical positions if intraoperative imaging was available. The SMR method was only recommended for the supine position, because skin distortion was frequently observed in the lateral region.

Boron neutron capture therapy (BNCT), which uses the capture reaction between neutrons and boron-10, an isotope of boron, is rapidly gaining interest. The reason for this is the successful development of a compact accelerator-type neutron generator that can be installed in a hospital and launched into the clinical setting. BNCT, which provides selective radiotherapeutic effects at the cellular level, is expected to be effective against invasive cancer. We have been investigating BNCT applications in various types of malignant brain tumors, especially malignant gliomas, as medical applications. Recently, we have conducted clinical trials using the developed accelerator neutron source. Research on pharmaceutical applications of compounds that transport boron to cancer cells is expected to be in even greater need. Currently, the only boron agent used in cancer therapy is BPA (Borofaran 10B), which takes advantage of the demand for essential amino acids, but the research and development of boron agents are an absolutely key technology to further improve the precision of this treatment modality. This chapter summarizes and discusses the results of BNCT in the treatment of brain tumors.

The ORBEYE (ORB), an innovative 3-dimensional digital exoscope, is an equipped system for fluorescence-guided surgery with 5-aminolevulinic acid. Therefore, this study aimed to verify the characteristics of fluorescence-guided surgery with 5-aminolevulinic acid and excitation light source with ORB.The same operative field of glioblastoma was recorded under blue light (BL) excitation using a conventional microscope (MS) and ORB. For in vitro studies, the energy of 405-nm wavelength light in white light and BL modes of each scope was examined in various focal lengths. To examine the degree of photobleaching with BL for each scope, protoporphyrin IX-soaked filter papers were continuously exposed with BL of an MS and ORB, and the video-recorded red fluorescence intensity was analyzed.The color tone of tumor-induced red fluorescence was remarkably different under each scope. Furthermore, nonfluorescent normal structures without red fluorescence were well recognized under ORB. The energy of 405-nm wavelength light in BL was significantly higher in ORB than that in an MS, especially in the short focal length. With continuous BL excitation to filter papers, the relative red fluorescence intensity of filter papers was significantly decreased over time in ORB than in an MS. In low protoporphyrin IX concentration, the difference was more significant.With ORB, the good visibility due to BL energy as compared with an MS might improve the surgical manipulation even in BL mode. However, the weak fluorescent tissue and short focal length should be carefully considered because photobleaching might be critical for FGS.

Glioblastoma (GBM) is a high-grade, poor prognosis tumor that is resistant to standard treatment. The presence of a small number of glioma stem cells (GSCs) surviving in the harsh microenvironment is responsible for their refractoriness. This study aimed to investigate the effect of a hypoxic environment on the sensitivity of GSCs to photodynamic therapy with 5-aminolevulinic acid (ALA-PDT).Six human GSC lines, Mesenchymal types HGG13, HGG30, HGG1123, and Proneural types HGG146, HGG157, HGG528, were divided into two groups: normoxia (OHypoxia-GSCs showed higher mRNA levels of FECH (ferrochelatase), which is required for iron synthesis to convert PpⅨ to heme, compared with Normoxia-GSCs. Flow cytometry revealed that the accumulation of PpⅨ in Hypoxia-GSCs reduced upon incubation with ALA. However, Hypoxia-GSCs showed less reduction in sensitivity to ALA-PDT than Normoxia-GSCs.Hypoxia-GSCs had lower intracellular PpⅨ accumulation than Normoxia-GSCs due to increased gene expression of FECH, and that their sensitivity to ALA-PDT was reduced less, despite accumulating lower concentrations of PpⅨ. ALA-PDT is a potentially effective therapy for hypoxia-tolerant GSCs that exist in hypoxia at 5% oxygen concentration.

Background Although most patients with Rathke's cleft cysts (RCCs) remain asymptomatic throughout their lives, visual impairment in RCCs usually indicates surgical interventions, including endoscopic drainage of the cyst. We report a case of RCC with unique findings in the optic nerve root (ONR) by magnetic resonance imaging (MRI). Case Description A 58-year-old man admitted to our hospital complained of progressive left visual impairment. Preoperative computed tomography MRI revealed a suprasellar cystic lesion that extended anteriorly, and the bilateral ONRs were lateralized with the cyst and were partially enhanced with gadolinium administration. The cyst content was drained, and the cyst wall was partially removed by endoscopic transsphenoidal surgery. Postoperatively, the patient was administered corticosteroid intravenously for 3 days, and his visual acuity improved dramatically. Postoperative MRI revealed that the volume of the cyst decreased, and the position of the bilateral ONRs normalized. Additionally, enhancement of the ONRs with gadolinium administration was not observed. Histological examination of the surgical specimen revealed a ciliated single-layer columnar epithelium with inflammatory cell infiltration. Conclusions To our knowledge, we report the first case of a patient with RCC with ONR enhancement with gadolinium administration on MRI. This unique finding might prove that inflammation is one of the causes of visual impairment in RCC as in optic neuritis.

Background Endovascular embolization of the middle meningeal artery (MMA) is effective for recurrent chronic subdural hematoma (CSDH). CSDH associated with dural metastasis is generally refractory to burr hole surgery and has poor prognosis even if any interventions are applied. To the best of our knowledge, this study is the first to report a case of refractory CSDH associated with dural metastasis that was successfully treated with embolization of the MMA. Case Description A 66-year-old man with a 1-year history of lung adenocarcinoma had also undergone whole-brain irradiation for multiple brain metastases 5 months before presentation, surgical removal of relapse of brain metastases 3 months prior, and stereotactic radiotherapy for the relapses 1 month prior. He was admitted to our institution with speech disturbance, severe headache, and right-sided motor weakness. Head computed tomography on admission revealed left-sided CSDH, and emergency burr hole irrigation surgery was performed. However, CSDH recurred twice in a short period after hospitalization. Histological examination revealed adenocarcinoma cells in the dura mater and in hematoma samples during the first surgery; therefore, the patient was diagnosed with refractory CSDH associated with dural metastasis of lung adenocarcinoma. We performed endovascular embolization of the MMA, followed by systemic chemotherapy at 1 month after embolization, and no recurrence of the CSDH was observed. Conclusions Embolization of the MMA has few surgical risks and could be a treatment option for refractory CSDH associated with dural metastasis because it might prolong the therapeutic time window until radical therapies are administered.

This article reviews the existing approaches to determining the

Cancer cells with stem cell-like features are generally more resistant to chemotherapy and radiotherapy than differentiated tumor cells. Thus, these cells tend to increase the propensity for tumor recurrence and metastasis. This study investigated the efficacy of 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) in destructing glioma stem cells (GSCs), including the mesenchymal subtype (MES-GSCs) demonstrated to have the lowest radio- and chemosensitivity.Five high-grade glioma (HGG) GSC lines and derived differentiated glioma cell (DGC) lines were examined for protoporphyrin-IX (PpIX) expression using fluorescence-activated cell sorting (FACS) and then assessed for ALA-PDT sensitivity using cell viability assays. MES-GSCs surviving ALA-PDT were then isolated and evaluated for stem cell and mesenchymal marker expression levels (CD44, ALDH1A3, KLF4, nestin) by qRT-PCR. The ability of these surviving cells to form tumors was then examined using colony forming and by xenograft tumor assays in athymic mice. Finally, the relationship between PpIX expression level (high versus low) and ALA-PDT sensitivity was examined by FACS and colony forming assays.ALA-PDT was effective against all GSC lines including MES-GSCs. MES-GSC lines exhibited higher PpIX expression than derived DGCs. Surviving MES-GSCs demonstrated lower stem cell marker expression and tumor forming potential than naive MES-GSCs. Higher PpIX production capacity by MES-GSCs was associated with greater colony forming ability, and ALA-PDT was more effective against MES-GSCs with greater PpIX accumulation.ALA-PDT may be clinically effective against HGG by targeting GSCs, including MES-GSCs.

Integrin αvβ3 is more highly expressed in high-grade glioma cells than in normal tissues. In this study, a novel boron-10 carrier containing maleimide-functionalized closo-dodecaborate (MID), serum albumin as a drug delivery system, and cyclic arginine-glycine-aspartate (cRGD) that can target integrin αvβ3 was developed. The efficacy of boron neutron capture therapy (BNCT) targeting integrin αvβ3 in glioma cells in the brain of rats using a cRGD-functionalized MID-albumin conjugate (cRGD-MID-AC) was evaluated. F98 glioma cells exposed to boronophenylalanine (BPA), cRGD-MID-AC, and cRGD + MID were used for cellular uptake and neutron-irradiation experiments. An F98 glioma-bearing rat brain tumor model was used for biodistribution and neutron-irradiation experiments after BPA or cRGD-MID-AC administration. BNCT using cRGD-MID-AC had a sufficient cell-killing effect in vitro, similar to that with BNCT using BPA. In biodistribution experiments, cRGD-MID-AC accumulated in the brain tumor, with the highest boron concentration observed 8 h after administration. Significant differences were observed between the untreated group and BNCT using cRGD-MID-AC groups in the in vivo neutron-irradiation experiments through the log-rank test. Long-term survivors were observed only in BNCT using cRGD-MID-AC groups 8 h after intravenous administration. These findings suggest that BNCT with cRGD-MID-AC is highly selective against gliomas through a mechanism that is different from that of BNCT with BPA.

Background Glioblastoma is a highly malignant brain tumor refractory to standard treatment and its refractoriness is attributed to the presence of a small number of glioma stem cells (GSCs) that survive in a harsh microenvironment. The aim of this study was to investigate the effect of hypoxic conditions on the sensitivity of GSCs to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). Materials and Methods Six human GSClines: three GSCs classified as Mesenchymal subtype and three GSCs classified as Proneural subtype, were divided into normoxia-GSCs (O2: 21%) and hypoxia-GSCs (O2: 5%) groups. To compare the effects of different oxygen partial pressures on protoporphyrin-IX (PpIX) biosynthetic activity, the expression levels of PpIX biosynthetic enzymes and transporters were examined by qRT-PCR and intracellular PpIX concentration was measured by flow cytometry. In addition, the sensitivity of these two cell groups to ALA-PDT was assessed in vitro. Results Hypoxia-GSCs showed higher mRNA levels of FECH (ferrochelatase), which is required for iron synthesis to convert PpIX to haem, compared to Normoxia-GSCs. Flow cytometry revealed that the accumulation of PpIX from exogenous ALA in Hypoxia-GSCs was reduced compared to in Normoxia-GSCs. Despite this, no Hypoxia-GSC lines showed significantly reduced sensitivity to ALA-PDT compared to Normoxia-GSCs. Conclusion Hypoxia-GSCs had lower intracellular PpIX accumulation than Normoxia-GSCs due to increased gene expression of FECH, and that their sensitivity to ALA- PDT was reduced less, despite accumulating lower concentrations of PpIX. ALA-PDT is at least a potentially effective therapy for hypoxia-tolerant GSCs that exist in hypoxia at 5% oxygen concentration.

Background We previously reported a phase II trial of accelerator-based boron neutron capture therapy (BNCT) for patients with malignant glioma, which showed a long median overall survival of 18.9 months. However, median progression-free survival was 0.9 months. In this trial, bevacizumab was permitted to use after progressive disease. The reason of discrepance between a short progression-free survival and a long overall survival was speculated that progression disease included pseudoprogression. But, efficacy of add-on bevacizumab on overall survival was not ignored. Methods The present study was approved by the Osaka Medical and Pharmaceutical University certificated review board and registered for Japan Registry of Clinical Trial (jRCTs051220019). Twenty-one patients who had malignant glioma refractory to bevacizumab treatment were planned to enroll in the study. The primary endpoint was a response rate of boronophenylalanine positron emission tomography. The secondary endpoints were a response rate of magnetic resonance image and safety. Conclusion Patients have been enrolled from June 2022. The efficacy of BNCT for malignant glioma could be elucidated by PET evaluation of tumor viability after BNCT.

Background Glioblastoma is a highly malignant brain tumor refractory to standard treatment and its refractoriness is attributed to the presence of a small number of glioma stem cells (GSCs) that survive in a harsh microenvironment. The aim of this study was to investigate the effect of hypoxic conditions on the sensitivity of GSCs to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). Materials and Methods Six human GSClines: three GSCs classified as Mesenchymal subtype and three GSCs classified as Proneural subtype, were divided into normoxia-GSCs (O2: 21%) and hypoxia-GSCs (O2: 5%) groups. To compare the effects of different oxygen partial pressures on protoporphyrin-IX (PpIX) biosynthetic activity, the expression levels of PpIX biosynthetic enzymes and transporters were examined by qRT-PCR and intracellular PpIX concentration was measured by flow cytometry. In addition, the sensitivity of these two cell groups to ALA-PDT was assessed in vitro.Results:Hypoxia-GSCs showed higher mRNA levels of FECH (ferrochelatase), which is required for iron synthesis to convert PpIX to haem, compared to Normoxia-GSCs. Flow cytometry revealed that the accumulation of PpIX from exogenous ALA in Hypoxia-GSCs was reduced compared to in Normoxia-GSCs. Despite this, no Hypoxia-GSC lines showed significantly reduced sensitivity to ALA-PDT compared to Normoxia-GSCs.Conclusion:Hypoxia-GSCs had lower intracellular PpIX accumulation than Normoxia-GSCs due to increased gene expression of FECH, and that their sensitivity to ALA- PDT was reduced less, despite accumulating lower concentrations of PpIX. ALA-PDT is at least a potentially effective therapy for hypoxia-tolerant GSCs that exist in hypoxia at 5% oxygen concentration.

Boron neutron capture therapy (BNCT) is a particle therapy that can target tumors at the cellular level. BNCT has been developed for the treatment of malignant gliomas with widely infiltrated tumors, but as the indication for BNCT was expanded to include the whole body, the focus shifted to borophalan-10B (BPA), which is based on the essential amino acid phenylalanine, as a candidate agent. We started BNCT for brain tumors in 2002 with a protocol combining two compounds (BPA, BSH) that had been clinically used, but later, with the development of an accelerator-based system, we conducted a clinical study of a single agent of BPA with a modified administration protocol in a nuclear reactor. In this report, we analyze the clinical studies of BNCT for recurrent malignant glioma using the reactor as a neutron source, and discuss the possibility of BNCT using multiple drugs in combination. The median survival with BSH+BPA was 11.0 months (n=29) overall, and the MST with BPA alone was 11.1 months (n=24), with similar results for BPA alone. The blood boron levels at the time of irradiation were 46.3 and 27.3 μg/ml, respectively, which were higher with the addition of BSH. The irradiation doses converted to X-rays (Gy) equivalent were calculated to be 69 and 76 Gy-Eq for the maximum tumor, 37 and 40 Gy-Eq for the minimum, and 10.9 and 10.5 Gy-Eq for the normal brain, respectively. The biological effectiveness ratios for tumor and normal tissue from neutron capture reactions with boron compounds and tissue boron concentrations were factored into these calculations, and since BPA and BSH have different target systems (BPA in the infiltration zone and BSH in the contrast zone, respectively), we believe that their combined use may improve therapeutic efficacy and attenuate adverse events.

Background Virtual reality (VR) and mixed reality (MR) are now widely applied for preoperative simulation and intraoperative navigation. Methods We developed an MR-based simulator for endoscopic transnasal surgery (ETNS) with a head-mounted display HoloLens and evaluated its usefulness. This simulator consisted of MR images of patients and an MR endoscope. HoloLens was used for projection of MR images and recognition of markers. The MR images were reconstructed from the preoperative images of patients and superimposed onto the endoscopic training model of the head. The MR endoscope was superimposed onto a three-dimensional (3D) printed replica of an endoscope. The MR endoscopic images from the replica of the endoscope were projected in the operator’s visual field. The MR images followed the manipulation of the replica of the endoscope through a nasal cavity on the training model. To evaluate the developed simulator, the MR endoscopic images were compared with video-recorded actual operative endoscopic views. And face validity and content validity of the simulator were evaluated by senior residents, using a 5-point Likert scale. Result The 3D MR images through HoloLens correlated well with the actual intraoperative views. Although there was an innate learning curve with the simulator, the face validity and the content validity demonstrated effective simulation of an operative field of view with real-time characteristics of the surgical procedure. Conclusions Our developed simulator for ETNS will contribute to learning the unique and the limited surgical fields through the narrow surgical corridor with endoscope, particularly for novice surgeons.

Background Glioblastoma (GBM) is a highly malignant lethal brain cancer. Accumulated evidence suggests that elevated resistance of GBM to both chemo- and radio-therapy is, at least in part, due to the presence of a small population of glioma stem cells (GSC). In the present study, we aimed to determine the sensitivity of GSCs to 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT). Methods For this purpose, we established GSC-enriched cell cultures (termed glioma stem-like cells or GSLCs) from A172 human GBM cell line. Under our cultivation conditions, GSLCs formed floating spheroid clusters that contained increased population of CD133/Sox2 expressing cells. Firstly, to compare the activity of protoporphyrin IX (PpIX) biosynthesis in the GSLCs and the parental A172 glioma cells, we examined the expression levels of biosynthesis enzymes and transporters for PpIX using qRT-PCR, and investigated the intracellular levels of PpIX with use of flow cytometry analysis. Then, we evaluated the sensitivity of these cells to ALA-PDT in vitro. Finally, to confirm the therapeutic impact of ALA-PDT on GSLCs with more clinically relevant model, we performed the same experiment using three different patient-derived glioma sphere lines, which cultivated them either in stem cell media or under differentiation conditions in the presence of serum. Results and Conclusion GSLCs expressed higher mRNA levels of PpIX biosynthesis enzymes and its transporters PEPT1/2 and ABCB6, when compared to the parental A172 glioma cells. Consistently, flow cytometry analysis revealed that upon incubation with ALA, GSLCs accumulate a higher level of PpIX. Finally, we showed that GSLCs were more sensitive to ALA-PDT than the original A172 cells, and confirmed that all patient-derived glioma sphere lines also showed significantly increased sensitivity to ALA-PDT if cultivated under the pro-stem cell condition. Our data indicate that ALA-PDT has potential as a novel clinically useful treatment that might eliminate GBM stem cells that are highly resistant to current chemo- and radio-therapy.

Background: This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy for malignant brain tumors affect the recurrence and progression of glioma. Methods: 3 months after the same 65-Gy irradiation had been applied to the right hemisphere. Irradiated Fisher rats were divided into three groups for in vitro assay as follows. IR/Ipsi-brain; the right-hemisphere tissue was used for experiments. IR/Contra-brain; the left-hemisphere tissue was used. Sham-IR/Brain; sham-irradiation was applied to the brain, and the right-hemisphere tissue was used. The effects of proteins extracted from the brains directly or indirectly affected by irradiation on the growth of F98 cells, the effect on tube formation, the influence on tumor biology, and the influence on cytokine production were investigated. Additionally, irradiated animals were divided into three groups for in vivo assay as follows. IR/Ipis-tumor; F98 cells (a glioma cell line) were transplanted to the right hemisphere. IR/Contra-tumor; F98 cells were transplanted to the left hemisphere. Sham-IR/Tumor; F98 cells were transplanted to the right hemisphere without irradiation. The median survival time of F98 transplanted rats was also examined. Results: X-ray irradiation promoted the secretion of cytokines such as TNFα, TGF-β1, VEGF-A, and CXCL12 from the irradiated brain. F98 glioma cells implanted in the irradiated brains showed significantly high proliferation and angiogenesis ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group.Conclusions: These results indicate that the up-regulation of CXCL12-CXCR4 axis by radiotherapy could promote tumor proliferation. Radiation therapy is a standard treatment for malignant gliomas including glioblastoma multiforme, but the current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.

Malignant gliomas are highly invasive tumors. Accurate identification of tumor tissue is essential for enabling tumor resection as much as possible without damaging important neurological functions. One of the methods is intraoperative fluorescence imaging. This method visualizes in real time the boundary between the tumor and normal brain, which cannot be identified using conventional surgical microscope under white light. Although many fluorescent dyes have been reported for intraoperative fluorescence imaging of brain tumors, only 5-aminolevulinic acid(5-ALA)is approved by Ministry of Health, Labour and Welfare in Japan. After the oral administration of 5-ALA, fluorescence is emitted by protoporphyrin Ⅸ, a metabolite of 5-ALA in tumor cells(red fluorescence with a peak at 635 nm, induced by an excitation light of 405 nm). The intensity of fluorescence is correlated with tumor cell density, proliferation rate, and vascular density. In a multicenter randomized controlled study in Germany, compared with white light imaging, fluorescence imaging with 5-ALA increased the tumor resection rate and significantly prolonged progression-free survival at 6 months. However, no difference was observed in overall survival. Regarding other fluorescent substances, fluorescein sodium is a dye that leaks from tumor vessels without the blood-brain barrier, like contrast media used for computed tomography and magnetic resonance imaging(green fluorescence with a peak at 520 nm, induced by an excitation light of 493 nm). This dye spreads in the interstitial tissue of the tumor to visualize the tumor area. Indocyanine green emits a near-infrared light of 820-920 nm, induced by an excitation light of 760- 810 nm. This dye was expected to be useful for visualizing deep tumors as it emits light with high tissue permeability; however, it does not leak out of blood vessels because of its large molecular weight. Subsequently, this dye is used for intraoperative angiography of highly vascularized tumors. Talaporfin sodium was originally developed for photodynamic therapy in Japan and is readily taken up by tumor cells. This substance is also used for intraoperative fluorescence imaging because it emits the fluorescence of 672 nm, induced by an excitation light of 664 nm. Here, we review various fluorescent dyes used for intraoperative imaging of brain tumors.

BACKGROUNDCalcifications in pituitary adenomas are rare, being found in only 5.4%–25% of reported cases. These are divided into eggshell-like calcifications around the tumor and nodular calcifications at the center of the tumor, the latter of which are called “pituitary stones” (PSs).OBSERVATIONSThe authors report the case of a 60-year-old male with a nonfunctional pituitary adenoma with PSs and asymptomatic ventricular dilatation who presented with spontaneous cerebrospinal fluid (CSF) rhinorrhea and rapid visual aggravation without an increase in tumor size over the course of 4 years. After endoscopic transnasal surgery, his visual acuity immediately improved temporarily. It was believed that the increased intracranial pressure due to secondary hydrocephalus resulted in visual aggravation; thus, a ventriculoperitoneal (VP) shunt was created. After creation of the VP shunt, the patient’s visual acuity improved gradually and completely. Histological findings showed that adenoma cells were observed among the lamellar bone trabeculae. To the best of the authors knowledge, this is the first report of osteoid metaplasia–type PSs in nonfunctioning pituitary adenoma.LESSONSPSs formed near the sellar floor and caused spontaneous CSF rhinorrhea due to direct mechanical stress on the dura mater and optic nerves, which may have caused meningitis and secondary hydrocephalus that resulted in visual impairment independent of tumor size.

Background: Nocardia is an aerobic Gram-negative bacillus belonging to actinomycetes and has been reported to be an infectious disease in healthy individuals. However, more than 60% have some underlying illnesses and are said to be opportunistic infections. Case Description: The case was a 69-year-old man who had been on long-term steroids for systemic lupus erythematosus. He developed with nausea and gait disturbance and was suspected of having a brain abscess by imaging. Abscess drainage detects actinomycetes that appear to belong to the genus Nocardia and brain abscess by Nocardia thailandica using matrix-assisted laser desorption/ionization time-of-flight mass analysis (MALDITOFMS) I was diagnosed. He died during the course of the treatment, and his organs did not detect his N. thailandica at necropsy, so he concluded that bacterial death from long-term administration of antibiotics was the cause of death. Conclusion: N. thailandica is a very rare bacterium belonging to Nocardia asteroides and is said to easily form brain lesions. In immunocompromised patients, prophylaxis with antibiotics and detailed examination of lung lesions for surveillance were considered necessary. This paper is the first report of a brain abscess caused by N. thailandica, including a review of the literature.

This article reviews the existing approaches to determining the TERT promoter mutational status in patients with various tumoral diseases of the central nervous system. The operational characteristics of the most common methods and their transferability in medical practice for the selection or monitoring of personalized treatments based on the TERT status and other related molecular biomarkers in patients with the most common tumors, such as glioblastoma, oligodendroglioma, and astrocytoma, are compared. The inclusion of new molecular markers in the course of CNS clinical management requires their rapid and reliable assessment. Availability of molecular evaluation of gliomas facilitates timely decisions regarding patient follow-up with the selection of the most appropriate treatment protocols. Significant progress in the inclusion of molecular biomarkers for their subsequent clinical application has been made since 2016 when the WHO CNS classification first used molecular markers to classify gliomas. In this review, we consider the methodological approaches used to determine mutations in the promoter region of the TERT gene in tumors of the central nervous system. In addition to classical molecular genetical methods, other methods for determining TERT mutations based on mass spectrometry, magnetic resonance imaging, next-generation sequencing, and nanopore sequencing are reviewed with an assessment of advantages and disadvantages. Beyond that, noninvasive diagnostic methods based on the determination of the mutational status of the TERT promoter are discussed.

BACKGROUND Spinal catheter insertion in lumboperitoneal (LP) shunt surgery for idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with technical difficulties especially in patients with obesity and elderly patients with vertebral deformities. OBJECTIVE To elucidate the accuracy and safety of image-guided spinal catheter placement using a paramedian approach (PMA). METHODS We retrospectively analyzed 39 consecutive iNPH patients treated by LP shunting with spinal catheter insertion via the PMA. The success rate of catheter placement and the number of changes in puncture location were evaluated. Accuracy of catheter insertion was assessed by measuring both vertical and horizontal deviations in the point of catheter dural penetration from the center of the interlaminar space. RESULTS The success rate of catheter placement was 100% (39/39). The difficulty rate for catheter insertion, measured by the number of changes in puncture location, was 2.6% (1/39). No bloody punctures or surgical infections were observed. Accuracy of catheter insertion, measured as the degree of deviation, was 0.5 ± 1.9 mm horizontally and 0.0 ± 2.4 mm vertically. The rates of minor complications, including caudal catheter insertion, transient low-pressure headache, and root pain, were 5.1% (2/39), 10.4% (4/39), and 0% (0/43), respectively. Subdural hematoma requiring surgical intervention occurred in 1 case (2.6%). During the mean follow-up period of 36 mo, spinal catheter rupture at the level of the spinous processes was not observed. CONCLUSION Fluoroscopic-guided spinal catheter placement via the PMA was safe, accurate, and reliable, even for use in geriatric and obese patients.

This study is intended to objectively clarify the relationship between the fluorescence intensity emitted by protoporphyrin IX (PpIX), which is a metabolite of 5-aminolevulinic acid (ALA), and histological findings during glioblastoma surgery.ALA is widely used for the intraoperative detection of tumors. There are several reports about the fluorescence of PpIX and the histological findings of tumors, but judgments about the fluorescence intensity depend largely on the subjective sense of each surgeon.We quantified the PpIX fluorescence intensity emitted from tissue specimens using a spectroradiometer and evaluated the relationship between a spectral radiance of 635 nm and the histopathological features of surgical specimens of glioblastoma. Surgical samples from glioblastoma patients consist of a strongly fluorescent area (SFA) or vaguely fluorescent area (VFA). Hematoxylin and eosin staining, immunohistochemical Ki-67, and CD31 staining were performed to evaluate the cell density, MIB-1 index, and vascularity, respectively. The fluorescence intensities of each sample were compared with each histopathological parameter.Cell density, MIB-1 index, and total vascular area were significantly correlated with PpIX fluorescence radiance. 87.5% of SFA were judged to be tumor bulk consisting mostly of tumor cells and 12.5% peritumoral invaded brain. In the VFA, 100% of specimens were judged to be peritumoral invaded brain.ALA-induced PpIX fluorescence has quantitatively correlated well with histopathological malignant features both in SFA and VFA. These findings suggest that not only SFA but also VFA should be removed to the highest extent that does not cause neurological symptoms.

Background Oral 5-aminolevulinic acid (ALA) induces biosynthesis/accumulation of the natural photo-sensitizer protoporphyrin IX (PpIX) in cancer cells. ALA is used widely in photodynamic diagnosis (PDD) and therapy (PDT) during malignant glioma surgery, but few studies have examined the effects of photodynamics plus ALA on normal brain tissue in vivo. We investigated the effects of ALA-mediated PDD and PDT on normal brain tissue. Methods We established a rat model in which the brain surface was irradiated through the skull by light-emitting diode (635 nm) after ALA administration. Using this model, we investigated the effects of various amounts of light irradiation with various ALA doses on brain tissue. Results Neurological symptoms developed with administration of ALA at 240 or 120 mg/kg accompanied by irradiation at 100 or 400 J/cm2, respectively. Dye leakage occurred due to disruption of the blood–brain barrier (BBB) at 90 mg/kg and 100 J/cm2, respectively. Thickness of the cortex increased significantly at 240 mg/kg and 400 J/cm2, respectively. The number of neurons appeared to decrease at 200 mg/kg plus 400 J/cm2, respectively, and there was an increase in the number of cells that were positive for terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) staining. Conclusions ALA-mediated PDT is safe at doses of 90 mg/kg or less followed by light irradiation of 100 J/cm2 in rat brains. At doses above this threshold, ALA-PDT led to irreversible BBB and brain damage in rats.

Background Fluorescence image guided surgery (FIGS) with 5-aminolevulinic acid for malignant gliomas improves surgical outcome. One of the problems during FIGS is photobleaching under surgical microscopic white light. A solid laser-based white light source for neurosurgery that we developed does not include light with a wavelength of around 405 nm, which is strongly absorbed by protoporphyrin IX. In the present study, we examined the efficacy of this light source to prevent the photobleaching of protoporphyrin IX-induced fluorescence. Methods Filter papers transfused with protoporphyrin IX solution and a coronally sectioned F98 glioma rat model pretreated with 50 mg/kg 5-aminolevulinic acid were continuously exposed to white light. One group was exposed to conventional xenon-based white light and another group was exposed to laser-based white light. Fluorescence at a wavelength of 635 nm was measured with a radiospectrometer (in vitro study) and the relative fluorescence brightness was also measured in digital images (in vivo study) under excitation from violet blue light emitted from diodes every 5 min. Results and conclusion Estimated time for 50% photobleaching was prolonged about two times in the laser-based white light exposure group compared with that in the xenon-based white light exposure group (9.1/18.7 min). In the brain tumor rat model, it was also prolonged about 2.7 times (15.1/40.7 min). A laser-based white light source may inhibit photobleaching during FIGS for malignant gliomas. This light source for neurosurgical microscopy has the potential to prolong the prognosis of malignant glioma patients.

We report effective treatment with nivolumab of a patient with recurrent primary central nervous system lymphoma (PCNSL) after multiple therapies. A 41-year-old woman with a right parietal PCNSL underwent treatment with high-dose methotrexate and radiotherapy. After recurrence in the left frontal lobe, the patient received several chemotherapies, including methotrexate and rituximab, and underwent surgery. The tumor was refractory to these treatments, and the patient then underwent intensity-modulated radiotherapy (IMRT). Multiple small, new recurrent tumors appeared in the right frontal lobe and the left frontoparietal region 2 months after IMRT. The patient received nivolumab 3 mg/kg with dendritic cell vaccination. Complete remission of the tumors was achieved after six cycles of nivolumab, and remission was maintained for 10 months after the initiation of nivolumab. Nivolumab could be a novel treatment for intractable recurrent PCNSL in the future.

Endoscopic third ventriculostomy(ETV)is the first-line treatment for fourth ventricle outlet obstruction(FVOO)-associated hydrocephalus. However, because FVOO is difficult to diagnose in the acute stage, ventriculoperitoneal shunt(VPS)is also used. Herein, we report two cases of shunted FVOO resulting in overdrainage or slit ventricle syndrome(SVS)that were treated successfully with the shunt-clamp system. In addition, we discuss the efficacy of the shunt-clamp system for FVOO-associated hydrocephalus. CASE 1:A 79-year-old man complained of severe postural headaches. One year earlier, he underwent VPS for secondary hydrocephalus associated with hemorrhagic cerebellar infarction. CT revealed that the ventricle had become slit-like. Although the shunt valve adjusted the maximum pressure, his complaint and the ventricle shape did not improve. After the on-off valve was inserted in the shunt system and clamped, his symptoms were resolved and the ventricle size was normalized. CASE 2:A 21-year-old man who complained of drowsiness, diplopia, and severe intermittent retroocular pain was admitted to our hospital. One year earlier, he underwent VPS with the shunt-clamp system for a secondary hydrocephalus after surgery for medulloblastoma. CT on admission revealed ventricle dilatation;however, the shape of the ventricle became slit-like 3 days after admission. We made a diagnosis of SVS and planned ETV. Owing to the difficulty in approaching the lateral ventricle, the shunt system was clamped 8 hours before the operation. After confirming ventricle dilatation, ETV was successfully performed. After the operation, the symptoms were resolved, and magnetic resonance imaging confirmed that the ventricle size was normalized.

Searching key words for RQ1 (conventional radiological image) and RQ2 (nuclear medicine image). (DOCX 13 kb)

Detail information about included studies in each radiological image. (DOCX 196 kb)

Background Brain radiation necrosis (BRN) can be a complication of radiotherapy for primary and secondary brain tumors, as well as head and neck tumors. Since vascular endothelial growth factor (VEGF) is also a vascular permeability factor in the brain, bevacizumab, a humanized antibody that inhibits VEGF, would be expected to reduce perilesional edema that often accompanies BRN. Methods Patients with surgically untreatable, symptomatic BRN refractory to conventional medical treatments (eg, corticosteroid, anticoagulants, or hyperbaric oxygen therapy) were enrolled. We judged that a major cause of perilesional edema with a lesion-to-normal brain ratio ≤1.8 on 11C-methionine or ≤2.5 on 18F-boronophenylalanine PET was BRN, not tumor recurrence, and 6 cycles of biweekly bevacizumab (5 mg/kg) were administered. The primary endpoint was a ≥30% reduction from the patients' registration for perilesional edema continuing for ≥1 month. Results Of the 41 patients enrolled, 38 were fully eligible for the response assessment. The primary endpoint was achieved in 30 of the 38 (78.9%) patients at 3.0 months (median) after enrollment. Sixteen patients (42.1%) experienced improvement of their Karnofsy Performance Score. Corticosteroid use could be reduced in 29 patients (76.3%). Adverse events at grade ≥3 occurred in 10 patients (24.4%). Conclusions Bevacizumab treatment offers certain clinical benefits for patients with surgically untreatable, symptomatic BRN. The determination of BRN using amino-acid PET, not biopsy, is adequate and less invasive for determining eligibility to receive bevacizumab.

The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas.

Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl–closo-dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)—a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 ± 29.6 µg B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21–24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26–36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25–37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28–40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects.

Background The frequency of the occurrence of adverse events associated with carotid artery stenting (CAS) is usually low, but serious adverse events such as cerebral hyperperfusion syndrome (CHS) may occur. Real-time monitoring is ideal for the early detection of adverse events during the surgical procedure. This study aimed to evaluate continuous blood glucose (BG) monitoring for the detection of adverse events during CAS. Methods Forty patients undergoing scheduled CAS were prospectively enrolled. An artificial pancreas was used for continuous BG monitoring (once per minute), using venous blood extracted at a rate of 2 mL/hr during CAS. The primary endpoint was a correlation between BG change and adverse events. Results CAS was discontinued in 1 patient, and BG was not measured in 5 patients (12.5%) because of the inability to extract blood. Among 34 evaluable patients, no patient developed CHS, but 3 patients (9%) experienced carotid occlusion intolerance. During CAS, BG was significantly higher in patients with carotid occlusion intolerance (median: 5 mg/dL) than in patients without carotid occlusion intolerance (median: 0 mg/dL) (P = 0.0221). A cutoff BG value ≥4 mg/dL during CAS showed 50% sensitivity and 100% specificity for the detection of carotid occlusion intolerance. There was no significant correlation between BG change and other adverse events. Conclusions BG elevation may help detect carotid occlusion intolerance although it is still unknown whether BG monitoring can detect CHS. Further studies should validate that a cutoff BG elevation value of ≥4 mg/dL during CAS indicates carotid occlusion intolerance.

[Background]Boron neutron capture therapy (BNCT) is a unique particle radiation therapy based on the nuclear capture reactions in boron-10. We developed a novel boron-10 containing sodium borocaptate (BSH) derivative, 1-amino-3-fluorocyclobutane-1-carboxylic acid (ACBC)-BSH. ACBC is a tumor selective synthetic amino acid. The purpose of this study was to assess the biodistribution of ACBC-BSH and its therapeutic efficacy following Boron Neutron Capture Therapy (BNCT) of the F98 rat glioma. [Methods]We evaluated the biodistribution of three boron-10 compounds, ACBC-BSH, BSH and boronophenylalanine (BPA), in vitro and in vivo, following intravenous (i.v.) administration and intratumoral (i.t.) convection-enhanced delivery (CED) in F98 rat glioma bearing rats. For BNCT studies, rats were stratified into five groups: untreated controls, neutron-irradiation controls, BNCT with BPA/i.v., BNCT with ACBC-BSH/CED, and BNCT concomitantly using BPA/i.v. and ACBC-BSH/CED. [Results]In vitro, ACBC-BSH attained higher cellular uptake F98 rat glioma cells compared with BSH. In vivo biodistribution studies following i.v. administration and i.t. CED of ACBC-BSH attained significantly higher boron concentrations than that of BSH, but much lower than that of BPA. However, following convection enhanced delivery (CED), ACBC-BSH attained significantly higher tumor concentrations than BPA. The i.t. boron-10 concentrations were almost equal between the ACBC-BSH/CED group and BPA/i.v. group of rats. The tumor/brain boron-10 concentration ratio was higher with ACBC-BSH/CED than that of BPA/i.v. group. Based on these data, BNCT studies were carried out in F98 glioma bearing rats using BPA/i.v. and ACBC-BSH/CED as the delivery agents. The corresponding mean survival times were 37.4 ± 2.6d and 44.3 ± 8.0d, respectively, and although modest, these differences were statistically significant. [Conclusions]Our findings suggest that further studies are warranted to evaluate ACBC-BSH/CED as a boron delivery agent.

Carmustine (BCNU) implants (Gliadel® Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.

Telomerase reverse transcriptase (TERT) is up-regulated in a variety of human neoplasms. Mutations in the core promoter region of the TERT gene, which increases promoter activity, have been reported in melanomas and a variety of human neoplasms, including gliomas. In the present study, we screened for TERT promoter mutations by direct DNA sequencing in a population-based collection of 358 glioblastomas. TERT promoter mutations (C228T, C250T) were detected in 55 % glioblastomas analysed. Of these, 73 % had a C228T mutation, and 27 % had a C250T mutation; only one glioblastoma had both C228T and C250T mutations. TERT promoter mutations were significantly more frequent in primary (IDH1 wild-type) glioblastomas (187/322; 58 %) than in secondary (IDH1 mutated) glioblastomas (10/36, 28 %; P = 0.0056). They showed significant inverse correlations with IDH1 mutations (P = 0.0056) and TP53 mutations (P = 0.043), and a significant positive correlation with EGFR amplification (P = 0.048). Glioblastoma patients with TERT mutations showed a shorter survival than those without TERT mutations in univariate analysis (median, 9.3 vs. 10.5 months; P = 0.015) and multivariate analysis after adjusting for age and gender (HR 1.38, 95 % CI 1.01-1.88, P = 0.041). However, TERT mutations had no significant impact on patients' survival in multivariate analysis after further adjusting for other genetic alterations, or when primary and secondary glioblastomas were separately analysed. These results suggest that the prognostic value of TERT mutations for poor survival is largely due to their inverse correlation with IDH1 mutations, which are a significant prognostic marker of better survival in patients with secondary glioblastomas.

Bevacizumab is effective in treating radiation necrosis; however, radiation necrosis was not definitively diagnosed in most previous reports. Here we used amino acid positron emission tomography to diagnose radiation necrosis for the application of bevacizumab in treating progressive radiation necrosis. Lesion/normal tissue ratios of

Chromosomal 7q34 duplication and BRAF-KIAA1549 fusion is a characteristic genetic alteration in pilocytic astrocytomas. 7q34 gain appears to be common in diffuse astrocytomas, but its significance is unclear. We assessed BRAF gain and BRAF mutations in 123 low-grade diffuse gliomas, including 55 diffuse astrocytomas, 18 oligoastrocytomas and 50 oligodendrogliomas. Quantitative polymerase chain reaction (PCR) revealed BRAF gain in 17/50 (34%) oligodendrogliomas, a significantly higher frequency than in diffuse astrocytomas (7/55; 13%; P = 0.0112). BRAF gain was common in low-grade diffuse gliomas with 1p/19q loss (39%) and those lacking any of the genetic alterations analyzed (31%), but was rare in those with TP53 mutations (2%). Logistic regression analysis showed a significant positive association between 1p/19q loss and BRAF gain (P = 0.0032) and a significant negative association between TP53 mutations and BRAF gain (P = 0.0042). Fluorescence in situ hybridization (FISH) analysis of 26 low-grade diffuse gliomas with BRAF gain additionally revealed BRAF-KIAA1549 fusion in one oligodendroglioma. Sequencing of cDNA in 17 low-grade diffuse gliomas showed BRAF-KIAA1549 fusion in another oligodendroglioma. A BRAF(V600E) mutation was also detected in one oligodendroglioma, and a BRAF(A598V) in one diffuse astrocytoma. These results suggest that low-grade diffuse gliomas with 1p/19q loss have frequent BRAF gains, and a small fraction of oligodendrogliomas may show BRAF-KIAA1549 fusion.