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Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-β1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. 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.

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.

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: Neuronavigation systems have become essential tools in image-guided neurosurgery that aid in the accurate resection of brain tumors. Recent advancements to these devices can indicate the precise location of lesions but can also project an augmented reality (AR) image on the microscope eyepiece to facilitate a successful surgical operation. Although the transcortical approach is a very popular method in neurosurgery, it can lead to disorientation and can cause unnecessary brain damage when the distance from the brain surface to the lesion is long. Herein, we report on an actual case in which a virtual line from AR images was used to assist the transcortical approach. Methods: A virtual line connecting the entry point and the target point, which were set as the navigation route, was created using Stealth station S7® (Medtronic, Minneapolis, USA). This line was projected as an AR image on the microscope eyepiece. It was possible to reach the target point by proceeding through the white matter along the displayed virtual line. Results: The lesion was reached within a short duration using virtual line without disorientation. Conclusion: Setting a virtual line as an AR image using neuronavigation is a simple and accurate method that can effectively support the conventional transcortical approach.

BACKGROUNDS Recently, nuclear reactors have been replaced with accelerator-based neutron sources (ABNS) for boron neutron capture therapy (BNCT). High-grade meningiomas (HGM) are refractory, especially recurred after some radiotherapy. We are now applying randomized controlled trial (RCT) of “A phase II clinical trial using accelerator-based BNCT system for refractory recurrent high-grade meningioma”. STUDY DESIGN PMDA in Japan which is a counter part of FDA in USA suggested the importance of RCT even for this exploratory clinical trial for HGM. Along to this suggestion, we prepared 2 study groups, BNCT test treatment group and control best supportive care (BSC) group. Progression free survival (PFS) was set-up as primary endpoint. Rescue BNCT is allowed for control group patients, if they showed progress disease (PD) during observation. Two-dimensional modified Macdonald criteria is adopted for assessment. METHODS The trial started in August 2019. Eighteen subjects were enrolled and divided in 12 and 6 subjects for BNCT and control BSC group, respectively. Cyclotron-based ABNS system was used for neutron source. Neutron-irradiation time is determined not to exceed to 7.5 Gy-Eq for scalp dose which was referencing preceding phase I trial for malignant gliomas. The last patient-in was August 2021. INTERIM RESULTS (as of April 30, 2022): All 6 cases of control group were judges as PD. Seven out of 11 cases of BNCT group were judged as PD. One case of BNCT group dropped out from the study with withdrawal of consent. Median PFS were 8 and 64 weeks for control group and BNCT group, respectively. Log-rank test showed marked statistical difference with p-value of 0.000401 between these 2 groups. CONCLUSIONS This RCT showed a marked difference of PFS between accelerator-based BNCT group and control group, so far. We will keep on observation at least next 2 years for other endpoints.

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.

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.

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 Although boron neutron capture therapy has shown excellent survival data, previous studies have shown an increase in radiation necrosis against recurrent malignant glioma. Herein, we proposed that bevacizumab may reduce radiation injury from boron neutron capture therapy by re-irradiation. We evaluated the efficacy and safety of a boron neutron capture therapy and add-on bevacizumab combination therapy in patients with recurrent malignant glioma. Methods Patients with recurrent malignant glioma were treated with reactor-based boron neutron capture therapy. Treatment with bevacizumab (10 mg/kg) was initiated 1–4 weeks after boron neutron capture therapy and was administered every 2–3 weeks until disease progression. Initially diagnosed glioblastomas were categorized as primary glioblastoma, whereas other forms of malignant glioma were categorized as non-primary glioblastoma. Results Twenty-five patients (14 with primary glioblastoma and 11 with non-primary glioblastoma) were treated with boron neutron capture therapy and add-on bevacizumab. The 1-year survival rate for primary glioblastoma and non-primary glioblastoma was 63.5% (95% confidence interval: 33.1–83.0) and 81.8% (95% confidence interval: 44.7–95.1), respectively. The median overall survival was 21.4 months (95% confidence interval: 7.0–36.7) and 73.6 months (95% confidence interval: 11.4–77.2) for primary glioblastoma and non-primary glioblastoma, respectively. The median progression-free survival was 8.3 months (95% confidence interval: 4.2–12.1) and 15.6 months (95% confidence interval: 3.1–29.8) for primary glioblastoma and non-primary glioblastoma, respectively. Neither pseudoprogression nor radiation necrosis were identified during bevacizumab treatment. Alopecia occurred in all patients. Six patients experienced adverse events ≥grade 3. Conclusions Boron neutron capture therapy and add-on bevacizumab provided a long overall survival and a long progression-free survival in recurrent malignant glioma compared with previous studies on boron neutron capture therapy alone. The add-on bevacizumab may reduce the detrimental effects of boron neutron capture therapy, including pseudoprogression and radiation necrosis. Further studies of the combination therapy with a larger sample size and a randomized controlled design are warranted.

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 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.

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.

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.

The long-term prognosis of cognitive function in patients with idiopathic normal pressure hydrocephalus (iNPH) remains unclear. This study aimed to determine the long-term prognosis of cognitive function in patients with iNPH, as well as the factors related to it. It included 48 patients with iNPH who were treated with cerebrospinal fluid shunting between January 2015 and December 2017 at Osaka Medical College Hospital, with follow-up evaluation of their cognitive function for >2 years. Cognitive function was measured using the Mini-Mental State Examination (MMSE) preoperatively and at 3 months, 1 and 2 years post-operatively. The mean MMSE score (22.4 ± 5.4 preoperatively) improved at 3 months [23.8 ± 5.0 (p = 0.0002)] and 1 year [23.7 ± 4.8 (p = 0.004)] post-operatively. At 2 years post-operatively, they were able to maintain their preoperative level (22.6 ± 5.3). The patients were classified in to the cognitive decline group [11 (23%) patients; a decrease in the MMSE score by ≥ 2 points 2 years after surgery] and the maintenance/improvement group [37 (77%) patients]. Univariate and receiver operating characteristic analyses were performed for the two groups to identify factors associated with cognitive prognosis. In both groups, the patients who were younger (p = 0.009) or had milder symptoms (p = 0.035) had a better long-term prognosis of cognitive function. The cutoffs for age and disease severity (idiopathic normal-pressure hydrocephalus grading scale; INPHGS) were 78 years (area under the curve = 0.77) and 5 points (area under the curve = 0.71), respectively. In conclusion, most patients (77%) were able to improve and maintain cognitive function for at least 2 years after surgery. The fact that disease severity and age are associated with cognitive prognosis suggests that early iNPH intervention is desirable to improve cognitive prognosis.

Background The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. Methods We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. Results The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95% CI: 0–94.6) than intratumoral macrophages (27.5%; 95% CI: 0–81.1, p = 0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p = 0.0429), with very low coefficient correlation (ρ = 0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p = 0.0008; better MSKCC score, p = 0.0103; peritumoral macrophages: low proportion of LDH elevation, p = 0.0064) and longer OS (for intratumoral macrophages: high PD-L1 = 60 months, 95% CI = 30–132.6; low PD-L1 = 24 months, 95% CI = 11–48; p = 0.032; for peritumoral macrophages: high PD-L1 = 60 months, 95% CI = 30.7–NR; low PD-L1 = 14 months, 95% CI = 3–26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR = 0.30, 95% CI = 0.12–0.77, p = 0.0129). Conclusions Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.

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.

Introduction: Near-Infrared Photoimmunotherapy (NIR-PIT) is a recently developed hybrid cancer therapy based on photodynamic cytotoxicity and anti-tumor immunopotentiation, utilizing a photosensitive antibody drug (PSAD). A global Phase III trial of NIR-PIT with an anti-EGFR-PSAD in patients with recurrent head and neck squamous cell carcinoma (HNSCC) is already underway, and NIR-PIT is expected to have therapeutic applications also in malignant gliomas. Methods: In this study, monoclonal antibodies to EGFR and IL13Rα2 were conjugated to the photosensitive dye IRDye700DX (IR700) to produce PSADs (EGFR-Ab/IR700 and IL13Rα2-Ab/IR700) and in vitro PDT assays using these PSADs were performed on four human glioma cell lines (U87MG, U251, U138, A172).Five groups were studied: EGFR-Ab/IR700 monotherapy: 5 μg/ml or 10 μg/ml, IL13Rα2-Ab/IR700 monotherapy: 5 μg/ml or 10 μg/ml, and EGFR-Ab/IR700: 5 μg/ml + IL13Rα2-Ab/IR700: 5 μg/ml combination therapy. The cytotoxic activity of each group was compared after irradiation with 690 nm light at 16 J/cm2. Results: Significantly higher cytotoxic activity was observed in all four glioma cell lines when EGFR-Ab/IR700 and IL13Rα2-Ab/IR700 were used in combination at 5 μg/ml each, than when each PSAD was treated with a doubled dose (10 μg/ml).Conclusion: Malignant gliomas show extensive cellular heterogeneity with diverse expression of cell surface antigens. The present results suggest that a therapeutic strategy using several different photosensitive antibodies simultaneously may lead to the release of tumor antigens from a greater number of tumor cells, resulting in a more efficient host immune response for therapeutic purposes.

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.

Background Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is a promising real-time navigation method in the surgical resection of malignant gliomas. In order to determine whether this method is applicable to metastatic brain tumors, we evaluated the usefulness of intraoperative fluorescence patterns and histopathological features in patients with metastatic brain tumors. Methods We retrospectively reviewed the cases of 16 patients with metastatic brain tumors who underwent intraoperative 5-ALA fluorescence-guided resection. Patients were given 20 mg/kg of 5-ALA orally 2 h prior to the surgery. High-powered excitation illumination and a low-pass filter (420, 450, or 500 nm) were used to visualize the fluorescence of protoporphyrin IX (PpIX), the 5-ALA metabolite. We evaluated the relationships between the fluorescence and histopathological findings in both tumoral and peritumoral brain tissue. Results Tumoral PpIX fluorescence was seen in only 5 patients (31%); in the remaining 11 patients (69%), there was no fluorescence in the tumor bulk itself. In 14 patients (86%), vague fluorescence was seen in peritumoral brain tissue, at a thickness of 2–6 mm. The histopathological examination found cancer cell invasion of adjacent brain tissue in 75% of patients (12/16), at a mean ± SD depth of 1.4 ± 1.0 mm (range 0.2–3.4 mm) from the microscopic border of the tumor. There was a moderate correlation between vague fluorescence in adjacent brain tissue and the depth of cancer cell invasion (P = 0.004). Conclusion Peritumoral fluorescence may be a good intraoperative indicator of tumor extent, preceding more complete microscopic gross total resection. Trial registration Institutional Review Board of Osaka Medical College No. 42, registered February 17, 1998, and No. 300, registered April 1, 2008. They were retrospectively registered.

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.