Endoscopic surgery, including endoscopic endonasal transsphenoidal surgery (ETSS), requires special psychomotor skills from surgeons. The learning curve in the acquisition of psychomotor skills varies among individuals, and studies about laparoscopy indicate that the difference can be predicted using spatial ability tests. We examined the association between the results of such tests and the learning curve in ETSS to determine the need for a personalized curriculum for ETSS skill training. A total of 30 fifth-year medical students from Kindai University School of Medicine (17 men, 13 women; mean age, 26 years) without ETSS experience completed the spatial orientation test (SOT) for the measurement of spatial visualization ability. They performed the dural incision task (DIT) twice on an ETSS training model for surgical psychomotor skill evaluation. The SOT scores (angle errors) exhibited substantial individual differences in spatial visualization ability, whereas the DIT scores significantly improved in the second trial (Wilcoxon signed-rank test, P = 0.0035). However, no significant difference was observed in the DIT scores between the smaller error and larger error groups of the SOT. The results indicated that two DIT trials were sufficient to acquire psychomotor skills for the DIT as the endoscope was almost fixed and learning only one viewpoint and line of sight combination was adequate. In conclusion, a personalized ETSS training program based on the trainee's spatial ability is not necessary for the DIT. Further research is warranted to determine the effect of spatial ability on more complex tasks, such as suturing in cranial base repair.

＜文献概要＞Point ●脳室とは,脳脊髄液(CSF)で満たされた脳内の空間のことである.左右一対の側脳室と正中に第三脳室・第四脳室が1つずつ存在し,合計計4つの脳室から成る.これらは相互に連絡があり,頭蓋内・脊髄腔内のくも膜下腔へと交通することで,CSFは脳室内,脳内,脊髄腔内を循環している.●CSFは主に脳内から排出される間質液から生成され,一部は脈絡叢から生成される.脈絡叢から生成されるCSFは人間の恒常性(ホメオスタシス)の維持の重要な役割を担っている.●CSFの産生と吸収機構の概念は100年間変わることがなかったが,2010年代に入って大きく変化し,新たな概念へと革新された.●新たな概念とは,脈絡叢や脳細胞から産生される間質液がCSFとなり,脳室とくも膜下腔に排出されるCSF,くも膜顆粒を介して静脈洞から吸収される経路だけではなく,硬膜リンパ管からも吸収されるということである.

BACKGROUND/AIM: Standard treatment options for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based drug therapy and whole-brain radiation therapy. However, there are many cases in which these standard treatment options are not tolerated for various reasons. In the present study, five cases of refractory/relapsed PCNSL that are difficult to treat with standard treatment were successfully treated by tirabrutinib. PATIENTS AND METHODS: A total of 5 patients (4 women, 1 man) with refractory (n=3) and relapsed (n=2) PCNSL were included. The patients had a median age of 76 years and a median Karnofsky performance status (KPS) of 40. The reasons why standard treatment cannot be given to these patients are the low KPS, renal dysfunction, and resistance to HD-MTX. Administration of a drug via the oral route was challenging in three patients; thus, these patients were administered tirabrutinib in suspension through a nasogastric tube. RESULTS: Imaging findings showed that the patients achieved a 100% response rate to tirabrutinib, with a median survival of 8 months. As symptoms improved, 2 of the 3 patients who were initially administered tirabrutinib via a nasogastric tube were able to receive the drug via the oral route. Three patients developed adverse reactions; however, treatment was not interrupted because they were manageable. CONCLUSION: Tirabrutinib was effective in the treatment of patients who were unable to receive standard treatment options. Tirabrutinib may be considered one of the novel treatment strategies that could improve the prognosis of PCNSL patients in the future.

ABSTRACT: A 20-year-old man had left visual impairment and homonymous hemianopsia. MRI findings suggested enlargement of an optic glioma, because optic glioma was indicated by MRI 14 years earlier without a definite pathological diagnosis. 11C-methionine (MET) PET showed high uptake in the tumor in the parasellar region. Transnasal endoscopic biopsy was performed, and an inflammatory pseudotumor (IPT) was diagnosed based on histopathological findings. High MET uptake in a parasellar IPT has apparently not been previously reported. Clinicians should be aware of the possibility of high MET uptake in IPT, because this image could provide an interpretation pitfall.

30代男性。咳嗽・胸痛・血痰を主訴に近医を受診し、胸部X線で両側肺野に瀰漫性スリガラス状陰影を認められ、当院に紹介された。胸部CTでスリガラス状陰影に加えて多発する結節影を認め、悪性疾患の鑑別のため気管支鏡検査目的に入院となった。気管支鏡で瀰漫性の出血所見を認め、左上葉の結節から生検を行ったが確定診断は得られなかった。悪性疾患等の鑑別が必要であるため胸腔鏡下肺部分切除術を施行し、術中・術後に合併症は認めなかったが、術後3日目に突然の頭痛・嘔吐が出現し、頭部CTで小脳出血を認めた。脳血管病変の精査のためCT angiographyを施行し、明らかな血管異常は認めなかったが、血腫が拡大したため緊急で開頭血腫除去術を施行した。血腫を吸引で除去したところ腫瘍性病変を認めたため、この病巣を摘出して病理組織学的検査を行い、血管肉腫と診断した。肺病変の病理組織学的診断も同様であり、肺血管肉腫原発の転移性脳腫瘍と診断した。

BACKGROUND/AIM: Leptomeningeal carcinomatosis (LMC) with hydrocephalus is particularly difficult to treat, and its prognosis is extremely poor. The therapeutic outcomes of 14 patients with LMC-associated hydrocephalus who were treated with cerebrospinal fluid shunting are reported. PATIENTS AND METHODS: The study subjects were 14 LMC patients with solid primary cancer who had developed hydrocephalus. RESULTS: Postoperatively, both symptoms and Karnofsky performance status improved in 100% of patients. Postoperative therapy consisted of whole-brain radiotherapy in 4 cases and molecular targeted therapy in 4, with 6 patients not receiving any postoperative treatment. Median overall survival was 3.7 months, with no significant difference between those who underwent postoperative therapy and those who did not. However, two of those who received molecular targeted therapy survived for more than one year. CONCLUSION: Cerebrospinal fluid shunting for LMC-associated hydrocephalus is an effective therapeutic procedure from the palliative viewpoint. Patients for whom molecular targeted therapy is indicated may have better long-term survival.

We report that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL). The patient was a 76-year-old woman who underwent endoscopic biopsy of multiple intracerebral masses, which resulted in the diagnosis of diffuse large B-cell lymphoma. The patient was diagnosed with PCNSL and was started on an induction regimen of systemic chemotherapy with rituximab in combination with high-dose methotrexate. However, after the second cycle of chemotherapy, the tumor grew rapidly, and the patient went into a coma. As a result, the treatment was changed to nasogastric tube administration of tirabrutinib suspension. After 1 week of tirabrutinib administration, the patient's level of consciousness improved, and furthermore, after 2 weeks of tirabrutinib administration, the patient was able to take tirabrutinib orally. Although oral administration is the standard route of administration for tirabrutinib, this case study showed that the nasogastric tube administration of tirabrutinib suspension is a therapeutic option for patients with impaired consciousness or dysphagia.

BACKGROUND/AIM: Recent advances in systemic chemotherapy, including molecularly targeted therapy, have dramatically improved survival for patients with advanced non-small cell lung cancer. We retrospectively analyzed the clinical outcomes of surgical resection for brain metastases of non-small cell lung cancer cases performed at the Department of Neurosurgery of Kindai University Hospital, Osaka, Japan. PATIENTS AND METHODS: Craniotomy and tumor resection were performed for 56 patients with brain metastases of non-small cell lung cancer. Adenocarcinoma was the most common histological type, appearing in 40 cases, of which 18 were positive for driver gene mutations. RESULTS: Median survival for all 56 patients was 14.5 months, and single brain metastasis and adenocarcinoma were identified as favorable prognostic factors. Analysis limited to the 40 cases of adenocarcinoma identified single brain metastasis as a favorable prognostic factor. Although no significant difference was found for systemic chemotherapy, patients who received molecularly targeted therapy showed a better prognosis than those who received cytotoxic chemotherapy. Analyses of both the entire group and of adenocarcinoma patients alone found that whole-brain radiotherapy showed no significant association with survival. CONCLUSION: Single brain metastasis and adenocarcinoma were identified as favorable prognostic factors, but did not confirm any benefit from whole-brain radiotherapy. These results suggest that multimodal treatment strategies utilizing various methods of treatment, including systemic chemotherapy, may help prolong patient survival in the future.

BACKGROUND: Brain metastasis (BM) is an uncommon complication of sarcomas with a poor prognosis. Little information is available about the feasibility and prognostic factors of surgical resection of BM from sarcomas. METHODS: This study involved a retrospective analysis of 22 patients with BM from sarcomas who underwent resection at six institutes in Japan. Prognostic factors were analyzed to develop a graded prognostic assessment (GPA) using the log-rank test and Cox regression analysis. For validation of this GPA, we collected data on 100 surgical cases from 48 published reports. RESULTS: Postoperative Karnofsky Performance Status (KPS) improved in 50% of our patients. Median overall survival (OS) was 21 months. Multivariate analysis showed age and alveolar soft part sarcoma (ASPS) were significant preoperative prognostic factors (P < 0.05). RTOG-RPA classification had no significant prognostic value. We developed a GPA system for OS after resection of BM. A score of 0 was assigned to patients aged 18-29 years with non-ASPS, 2 to patients aged 18-29 years with ASPS or 30-76 years with non-ASPS, and 4 to patients aged 30-76 years with ASPS. Median OS for patients with GPA scores of 0, 2, and 4 were 6.5, 16.0, and 44.0 months, respectively (P = 0.002). The results were validated by the data of 100 cases compiled (P < 0.001). CONCLUSION: Median OS of patients with BM from sarcomas was comparable to that from carcinomas after resection. A new sarcoma-specific GPA may help patients and clinicians to select resection as an option for treatment of BM from sarcomas.

Aplastic anemia is a rare blood disease characterized by the destruction of the hematopoietic stem cells (HSC) in the bone marrow that, in the majority of cases, is caused by an autoimmune reaction. Patients with aplastic anemia are treated with immunosuppressive drugs and some of them, especially younger individuals with a donor available, can be successfully treated with hematopoietic stem cell transplantation (HSCT). We report here a rare case of post-transplant lymphoproliferative disorder (PTLD) associated with Epstein-Barr virus (EBV) reactivation in a 30-year-old female patient who underwent allogeneic HSCT for severe aplastic anemia. The PTLD, which was diagnosed 230 days after transplantation, was localized exclusively in the central nervous system (specifically in the choroid plexus) and manifested with obvious signs of intracranial hypertension. After receiving three cycles of high dose methotrexate (HD-MTX) combined with rituximab, the patient achieved a complete clinical recovery with normalization of blood cell counts, no evidence of EBV reactivation, and no associated neurotoxicity.

BACKGROUND/AIM: High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein that exerts a range of proinflammatory actions when it is secreted extracellularly. We hypothesized that HMGB1 released from damaged cells in pituitary apoplexy would exacerbate the neurological symptoms due to acute inflammation. PATIENTS AND METHODS: All the patients included in this study suffered from non-functioning pituitary adenoma. Four patients with apoplexy and three patients without apoplexy were included in this study. They underwent endonasal transsphenoidal endoscopic surgery to resect the tumors. We conducted enzyme-linked immunosorbent assay (ELISA) to measure HMGB1 in the surgical specimens. RESULTS: Patients with apoplexy expressed HMGB1 at significantly higher levels than those in the non-apoplexy group (p=0.0478). CONCLUSION: HMGB1 may be involved in subacute inflammation of pituitary apoplexy. Further work is needed to elucidate the detailed biological significance of HMGB1 in this disease.

Intravascular lymphoma (IVL) is a malignant lymphoma that lacks the expression of cell surface adhesion molecules so that cells fluidly migrate within the blood vessels. The patient in the present study had restricted eye movement caused by IVL, mimicking a cavernous sinus tumor. Because the cavernous sinus lumen is divided into multiple compartments by trabeculae and venous channels, IVL tumor cells were trapped in these compartments, thus forming a mass, which subsequently extended into the contralateral cavernous sinus via the anterior and posterior intercavernous sinuses. This is a rare case of IVL forming a mass inside the cavernous sinus.

Background: Leptomeningeal metastases (LM) pose the most difficult form of cancer metastasis to treat and portend a poor prognosis. Standard treatment has yet to be established, and intrathecal chemotherapy and whole- brain radiotherapy are administered on an empirical basis. Case Description: We report on a 46-year-old woman with LM from human epidermal growth factor receptor 2 (HER2)-positive breast cancer. She was suffering from intractable headaches, severe nausea and vomiting, and cerebellar ataxia. Contrast-enhanced magnetic resonance imaging (MRI) revealed diffuse enhancement of the meninges, mainly in the posterior cranial fossa, and compression of the cerebellum by the profoundly thickened meninges. The first step in the treatment was decompression of the posterior cranial fossa to relieve intracranial hypertension. After surgery, her symptoms immediately improved. The second step was treatment with lapatinib at 1250 mg and capecitabine 1200 mg, which dramatically improved her symptoms and disappeared diffuse abnormal signal enhancement on MRI. Conclusion: We treated a patient with LM from primary HER2-positive breast cancer who responded well to lapatinib plus capecitabine.

INTRODUCTION: The introduction of systemic chemotherapy for advanced hepatocellular carcinoma in recent years has led to the prediction that cases of brain metastases from hepatocellular carcinoma will increase. However, because brain metastases from hepatocellular carcinoma are relatively rare, the characteristics of this pathology are poorly understood. METHODS: We carried out a multicenter retrospective study to verify the characteristics of brain metastases from hepatocellular carcinoma in Japan. RESULTS: A total of 38 patients were enrolled and patient characteristics were poor general condition in many patients due to the progression of primary cancers. Stereotactic radiosurgery/stereotactic radiotherapy alone was the most common treatment (39.5%), with best supportive care provided for 10.5%. Median survival was 6 months, the neurological death rate was 28%, and the rate of brain hemorrhage was high (39.5%). Overall survival was analyzed for correlations with age, etiology of chronic liver disease, albumin-bilirubin (ALBI) grade, RPA classification, control of the primary tumor, number of brain metastases, brain hemorrhage, surgical resection, and radiotherapy. In multivariate analysis, ALBI grade, number of brain metastases and brain hemorrhage showed statistically significant correlation. CONCLUSIONS: A multivariate analysis extracted three items-ALBI grade, number of brain metastases, and brain hemorrhage-as prognostic factors for survival of brain metastases from hepatocellular carcinoma.

BACKGROUND/AIM: Excessive extracellular glutamate activates AMPA-type glutamate receptors (AMPA receptors) and induces seizures. Antagonistic activation of AMPA receptors inhibits epilepsy and glioma growth in in vitro and in vivo studies. This study was conducted to evaluate the clinical impacts of perampanel (PER), a novel AMPA receptor antagonist, on seizures and tumor progression in glioma patients with uncontrollable epilepsy. PATIENTS AND METHODS: Twelve glioma patients with uncontrollable epilepsy were treated with PER. Seizure response, PER concentration, and tumor volume were assessed. RESULTS: Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free. Median plasma concentrations of PER were 296 ng/ml in those with 4 mg/day PER treatment and 518 ng/ml in those with 8 mg/day PER treatment. High-intensity lesions in fluid-attenuated inversion recovery of magnetic resonance imaging (MRI) were volumetrically assessed to analyze tumor size. Volume reduction was detected within 6 months in correlation with increased plasma levels of PER. CONCLUSION: PER treatment was effective in uncontrollable epilepsy with gliomas. MRI images showed the inhibition of tumor growth.

Patients with malignant brain tumors are possibly at increased risk for surgical site infections (SSIs) considering the various medical situations associated with the disease. However, the actual rate of SSI after malignant brain tumor resection has not been well established, despite the potential impact of SSI on patient outcome. To investigate the incidence of SSI following malignant brain tumor surgery, we performed a retrospective study in 3 neurosurgical units. Subsequently, aiming at the reduction of incidence of SSI, we performed a prospective study using a care bundle technique in the same units. The SSI incidence in the retrospective (n = 161) and prospective studies (n = 68) were 4.3% and 4.4%, respectively, similar to the previously reports on general craniotomies. A care bundle does not appear to enhance prevention of SSI. However, future, large studies with a new care bundle should be planned based on a zero tolerance policy.

Background: Glioblastoma multiforme (GBM) is a malignant brain tumor with an extremely poor prognosis. GBM tissues frequently express mesenchymal-epithelial transition factor (MET), which induces cell division, growth and migration. In addition, angiogenesis is a significant feature of GBM, attributable to the overexpression of vascular endothelial growth factor (VEGF). Although the VEGF inhibitor bevacizumab was recently highlighted as the second-line drug for GBM treatment, GBMs often recur even with bevacizumab therapy. Based on these findings, we hypothesized that inhibition of both MET and VEGF would exhibit a synergistic effect on MET-overexpressing GBM. Materials and Methods: As we observed MET expression at high levels in some patients with GBM, we designed GL261 murine glioma-based experiments. GL261 cells were transfected with siRNAs specific for MET and VEGF in vitro, and the cell growth ratios were evaluated. Simultaneously, transfected GL261 cells were transplanted into the brain of C57BL/6 mice, and their survival was monitored. Results: GBM tissues frequently overexpressed MET protein at high levels compared with lower-grade gliomas. These GBMs at first responded to bevacizumab, but often eventually recurred. When GL261 cells were co-transfected with both MET-specific siRNA and VEGF-specific siRNA, the in vitro tumor cell growth significantly decelerated compared to single siRNA transfection. Consistently, when mice were transplanted with co-transfected GL261 cells, their survival was significantly prolonged compared to those given cells transfected with single siRNA. Conclusion: The current data indicate that the inhibition of both MET and VEGF exhibits efficient therapeutic effects of GBM-bearing hosts.

Background: The prevalence of brain metastases (BM) from uterine cancer has recently increased because of the improvement of overall survival (OS) of patients with uterine cancer due to its early detection and improved local control as a result of new effective treatments. However, little information is available regarding their clinical characteristics and prognosis, because oncologists have encountered BM from uterine cancer on rare occasions. Methods: Records from 81 patients with uterine BM were collected from 10 institutes in Japan. These were used in a multi-institutional study to identify prognostic factors and develop a graded prognostic assessment (GPA) for patients with BM from uterine cancer. Results: Median OS after the development of BM was 7 months (95% confidence interval, 4 to 10 months). Multivariate analysis revealed that there were survival differences according to the existence of extracranial metastases and number of BM. In the present uterine-GPA, a score of 0 was assigned to those patients with >= 5 BM and extracranial metastasis, a score of 2 was assigned to those patients with one to four BM or without extracranial metastasis, and a score of 4 was assigned to those patients with one to four BM and without extracranial metastasis. The median OS for patients with a uterine-GPA scores of 0, 2, and 4 was 3, 7, and 22 months, respectively. A survival analysis confirmed the presence of statistically significant differences between these groups (p < 0.05). The results were validated by data obtained from the National Report of Brain Tumor Registry of Japan. Conclusion: Uterine GPA incorporates two simple clinical parameters of high prognostic significance and can be used to predict the expected survival times in patients with BM from uterine cancer. Its use may help in determining an appropriate treatment for individual patients with BM.

IntroductionThe concept of oligometastasis has emerged as a basis on which to identify patients with stage IV non-small cell lung cancer (NSCLC) who might be most amenable to curative treatment. Limited data have been available regarding the survival of patients with node-negative oligometastatic NSCLC. Patients and methodsConsecutive patients with advanced NSCLC who attended Kindai University Hospital between January 2007 and January 2016 were recruited to this retrospective study. Patients with regional lymph node-negative disease and a limited number of metastatic lesions (5) per organ site and a limited number of affected organ sites (1 or 2) were eligible. ResultsEighteen patients were identified for analysis during the study period. The most frequent metastatic site was the central nervous system (CNS, 72%). Most patients (83%) received systemic chemotherapy, with only three (17%) undergoing surgery, for the primary lung tumor. The CNS failure sites for patients with CNS metastases were located outside of the surgery or radiosurgery field. The median overall survival for all patients was 15.9months, with that for EGFR mutation-positive patients tending to be longer than that for EGFR mutation-negative patients. ConclusionCure is difficult to achieve with current treatment strategies for NSCLC patients with synchronous oligometastases, although a few long-term survivors and a smaller number of patients alive at last follow-up were present among the study cohort. There is an urgent clinical need for prospective evaluation of surgical resection as a treatment for oligometastatic NSCLC, especially negative for driver mutations.

Background: Glioblastoma multiforme (GBM) is the most frequent and the most malignant tumor among adult brain tumors. Previous reports led us to hypothesize that the protooncogene mesenchymal-epithelial transition (MET) expressed in glioma stem cell-like cells (GSCs) would be a potent therapeutic target for GBM. Patients and Methods: To address this question, we analyzed 113 original samples of tumors from patients based on immunohistochemistry. During this process, we were able to establish GSC lines from patients with GBM that were MET-positive and MET-negative. Using these cells, we tested the therapeutic impact of a MET inhibitor, crizotinib, both in vitro and in vivo. Results: Patients with MET-positive GBM exhibited poor survival. GSC-based experiments revealed that treatment with crizotinib, both in vitro and in vivo, exhibited therapeutic efficacy particularly against MET-positive GSCs. Conclusion: Based on these findings, we conclude that MET expressed in GSCs might be a potent therapeutic target for GBM.

Glioblastoma multiforme (GBM) often infiltrates surrounding tissues, an action which is known as a clinical characteristic of this deadly disease. In contrast, extracranial metastases of GBM rarely occur. Consequently, the underlying mechanisms and prognosis of GBM metastasis remain unclear. In this regard, we here present a case of GBM with pleural metastases and discuss the relevant literature. The patient was a 62-year-old male who was originally diagnosed with GBM in the right temporal lobe and underwent craniotomy for tumor removal. Gross total resection was successfully performed. The patient received postoperative chemoradiotherapy with temozolomide, followed by maintenance chemotherapy with temozolomide alone. He showed a good postoperative course until a small recurrence occurred in the resection cavity at 17 months after the surgery. At 21 months, the patient developed thoracodorsal pain due to a large volume of pleural effusion with pleural masses. An intrathoracic biopsy revealed that the pleural lesions were metastases of the GBM. Simultaneously, intracranial imaging studies indicated tumor spread into the right cavernous sinus. These findings suggest that the GBM may have infiltrated into the cavernous sinus via the dura surrounding the cavernous sinus adjacent to the resection cavity and metastasized hematogenously to the pleural cavity

We verified the effectiveness of training in endoscopic endonasal transsphenoidal surgery (eETSS) techniques using chicken eggs and a skull model. We verified the area of eggshell removed by drilling when five residents and four experts used the chicken eggs and a skull model. When residents performed drilling on 10 eggs, a mean (+/- standard deviation [SD]) area of 31.2 +/- 17.5 mm2 was removed from the first egg, and 104.8 +/- 3.3 mm2 from the tenth and final egg, representing an increase in area and a decrease in SD. The experts performed the same drilling operation on a single egg, and removed a mean area of 257 +/- 31.7 mm2. These results demonstrated that skills improved as a result of this training, and suggested that this method was also capable of overcoming the initial individual differences in the amount of force applied and ability. An obvious difference between residents and experts was seen in the area removed (p = 0.00011); however, this was attributed to differences in endoscopic manipulation, rather than drilling skill. Our findings suggest that this training method could be adequate for acquiring eETSS techniques. Although experts showed superior endoscopic manipulation, residents may also be able to acquire adequate endoscopic skills through further training, and our training method appears to offer an effective means of improving eETSS techniques.

Background: An outstanding issue regarding the surgical treatment of cyst-type metastatic brain tumors is the incomplete resection of cyst walls. Herein we propose a novel surgical technique that can overcome this issue. During a surgical procedure for cystic tumors, autologous fibrin glue is to be injected into the tumor cysts, which solidifies the cyst lumens and cyst walls en bloc with reducing the tumor size. As a result, tumor masses and cyst walls can be removed completely in an en bloc fashion in all cases. Copyright: Methods: The illustrative case presented in this report is a patient with metastatic brain tumors in the frontal lobe. When we reached the tumor wall surgically, we first suctioned out the cyst content and subsequently injected autologous fibrin glue into the cyst lumen. The autologous fibrin glue solidified the tumor en bloc, and we resected the tumor mass and the cyst walls in an en bloc fashion. Results: We have applied this technique to four cases with cyst-type metastatic brain tumors. This approach made it possible to perform ideal en bloc resection in all cases. There were no adverse events due to the autologous fibrin glue. Conclusion: We developed a novel surgical technique to solidify cyst-type metastatic brain tumors using autologous fibrin glue, which allows en bloc resection of tumor masses and cyst walls quite safely using inexpensive materials. Given these advantages, it appears a promising surgical strategy for cyst-type metastatic brain tumors.

[Abstract] Current evidence indicates that glioma stem cell-like cells (GSC_S) in humans play critical roles in the pathogenesis of carcinogenesis ofglioblastoma (GBM ). The GSC_S are known to overexpress members of the adenosine triphosphate-binding cassette (ABC) family transporters to exhibit multidrug resistance. Eradication of the GSC compartment is therefore essential to achieve a stable and long-lasting remission of GBM. To elucidate the characteristics of GSC_S in detail, we generated murine GSC lines from Sleeping Beauty transposon-mediated spontaneous GBM . Using these several cell lines, we evaluated the significance of ABC transporters in the GSC kinetics by cell morphology assays, flow cytometry, and quantitativeRT-PCR for mRNA expressions. As a consequence, we show that siRNA-mediated ABCG2 inhibition enhances the sensitivity of GSC_S to temozolomide (TMZ) and in turn reduces their spheroid-forming capability. Furthermore, we show that GSC_S treated with Abcg2-specific siRNA become sensitive to TMZ and reduce their spheroid-forming capability. In conclusion, our data suggest that targeting of drug transporters in GSC_S is a promising strategy to enhance their chemo-sensitivity for achieving a longlasting remission of GBM .

BACKGROUND: An outstanding issue regarding the surgical treatment of cyst-type metastatic brain tumors is the incomplete resection of cyst walls. Herein we propose a novel surgical technique that can overcome this issue. During a surgical procedure for cystic tumors, autologous fibrin glue is to be injected into the tumor cysts, which solidifies the cyst lumens and cyst walls en bloc with reducing the tumor size. As a result, tumor masses and cyst walls can be removed completely in an en bloc fashion in all cases. METHODS: The illustrative case presented in this report is a patient with metastatic brain tumors in the frontal lobe. When we reached the tumor wall surgically, we first suctioned out the cyst content and subsequently injected autologous fibrin glue into the cyst lumen. The autologous fibrin glue solidified the tumor en bloc, and we resected the tumor mass and the cyst walls in an en bloc fashion. RESULTS: We have applied this technique to four cases with cyst-type metastatic brain tumors. This approach made it possible to perform ideal en bloc resection in all cases. There were no adverse events due to the autologous fibrin glue. CONCLUSION: We developed a novel surgical technique to solidify cyst-type metastatic brain tumors using autologous fibrin glue, which allows en bloc resection of tumor masses and cyst walls quite safely using inexpensive materials. Given these advantages, it appears a promising surgical strategy for cyst-type metastatic brain tumors.

The aim of this study was to identify the location associated with primitive sentence processing. Processing related to generation and comprehension of sentences ("sentence processing") is postulated to be largely divided into syntactic processing (processing related to the formation of sentences and to verb reflection and particles) and verb information (argument structure and thematic role). Numerous lesion studies and functional brain imaging studies on unimpaired individuals have suggested that the left inferior frontal gyrus (IFG) is involved in syntactic processing. In addition, some studies have reported that the area from the left parietal lobe to the posterior superior temporal gyrus is involved in processing information such as argument structure and thematic role. However, studies on sentence processing using functional brain imaging have used complex sentences as tasks, raising the possibility that the results show the demands on not only language processing, but also on working memory. To clarify the brain areas involved in basic sentence processing in human language, there is a need to examine tasks involved in sentence processing that assume more primitive processing with minimal demands on working memory. The present study used sentence-completion tasks in the Japanese language that include basic sentence processing. The results showed activation in the left IFG and left parietal lobe, suggesting that these areas are involved in sentence processing. We then investigated the proportion of patients showing impaired sentence processing from among patients with aphasia and a lesion in the left IFG or from the parietal lobe to the posterior superior temporal gyrus. Four of 5 patients (80%) with lesions mostly in the left IFG showed impaired sentence processing, suggesting that this site plays a critical role in sentence processing. Of the 4 patients with lesions mostly in the area from the left parietal lobe to the posterior superior temporal gyrus, 1 patient (25%) showed impaired sentence processing. Unlike the other 3 subjects, this subject exhibited impaired recalling of verbs. This area is mainly involved in lexical-semantics and the present results suggest that verb information within that field became impaired, in turn causing impaired sentence processing. (C) 2013 Elsevier Ltd. All rights reserved.

We have developed a technique of fluorescence-guided surgery using high-dose fluorescein sodium (20 mg/kg) with excitation and barrier filters for glioblastoma multiforme surgery. This technique was used in 10 patients, with surgery proceeding as expected in all patients. There were no complications or permanent side effects. This method uses filters to help distinguish between the usually invisible tumor and the brain surface, as well as allowing a detailed assessment of the positional relationships with tumor vessels and the surrounding normal vessels. As sufficient yellow staining was present even without filters, delicate microsurgery was also possible under a normal white-light microscope. Both environments could be used as necessary during surgery according to the requirements of resection, thereby improving the reliability and safety of surgery. (C) 2012 Elsevier Ltd. All rights reserved.

Recently, endoscopic pituitary surgery is increasingly being used in pituitary surgery. Compared to conventional microscopic pituitary surgery, outcomes have been non-inferior, so endoscopic pituitary surgery has become an established surgical technique. However, this is a highly specialized surgery and sophisticated surgical techniques are required. We report our development of a training model for endoscopic endonasal transsphenoidal surgery. Our training model is constructed using a skull model and eggs. The sella turcica of the skull model is hollowed out and an egg is placed. The bottom of the egg simulates the sella turcica floor and the egg contents simulate a tumor. Training is conducted using this model in an actual operating room with actual surgical instruments. This model is highly realistic and is within acceptable limits as a surgical simulation. Since practice can be repeated, this model is effective for familiarization with endoscopic imaging and to increase technical skills such as drilling and curetting. In addition, variations in eggs, ranging from raw eggs to boiled eggs, can be used to simulate various tumors for training. This training model using a skull model and eggs is useful to improve surgical techniques in endoscopic endonasal transsphenoidal surgery.

We aimed to demonstrate the effectiveness of fluorescence-guided surgery of metastatic brain tumors using fluorescein sodium. The study comprised 38 patients with metastatic brain tumors who underwent tumor resection after intravenous injection of fluorescein sodium. The local recurrence rate was investigated in 36 of the 38 patients, and compared for patients who had undergone surgery only and surgery plus whole-brain radiotherapy (WBRT). In 31 of 36 patients, the tumors had been completely resected using fluorescence-guided surgery. Postoperative WBRT was not performed in 20 of the 31 patients who underwent gross total resection. Although the recurrence rate for these 20 patients was 20%, compared to 9.1% for the 11 patients who also underwent postoperative WBRT, the difference was not statistically significant. Use of fluorescein sodium in metastatic brain tumor surgery may reduce the rate of local recurrence, and thus help improve the quality of life for these patients. (C) 2009 Elsevier Ltd. All rights reserved.

Background: Many metastatic brain tumors have a distinct border with normal brain tissue, which facilitates tumor removal. However, residual tumor tissue may be present after surgery when metastatic brain tumors are of cystic type. We have developed a method using hydrofiber dressing to transform cystic-type into solid-type tumors. Methods: Hydrofiber dressing is a sodium carboxymethylcellulose hydrocolloid polymer with high fluid-absorptive capacity. This material was originally used as a dressing for exudative wounds. Hydrofiber dressing was used for 8 patients with cystic-type metastatic brain tumor. Tumor removal was performed after hydrofiber dressing was inserted into the cyst cavity to transform the tumor into a solid-type tumor. Results: Transformation of cystic-type metastatic brain tumors into smaller solid-type tumors using hydrofiber dressing facilitated en bloc resection of tumor. The dressing also absorbed residual cyst fluid and was thus also effective in preventing intraoperative dissemination of tumor cells. This approach enabled ideal en bloc resection in all patients. There were no adverse events. Conclusions: These findings suggest hydrofiber dressing may be useful in surgery for cystic-type metastatic brain tumors. (C) 2009 Elsevier Inc. All rights reserved.

Leptomeningeal carcinomatosis is a serious complication leading to a fatal outcome in patients with gastric cancer. We tried to treat leptomeningeal carcinomatosis from gastric cancer with intrathecal chemotherapy using methotrexate (MTX) and cytosine arabinoside (Ara-C). We described and discussed the therapeutic strategy. Six patients with leptomeningeal carcinomatosis from gastric cancer were admitted in our institution from March 2004 to July 2007. Three of 6 patients were accepted for intrathecal chemotherapy. They received intraventricular injections of MTX (5 mg) and Ara-C (20 mg) through the Ommaya reservoir. The other 3 patients who rejected the therapy were conservatively treated with betamethasone, carbamazepine and glyceol. Two of the intrathecal chemotherapy group received whole-brain radiotherapy after the initial intrathecal chemotherapy. The mean survival time was 122. 3 days (median survival time 35. 0 days). The survival of the intrathecal chemotherapy group was from 39 to 367 days, whereas the survival of the conservative treatment group was from 10 to 31 days. The intrathecal chemotherapy improved not only survival but also clinical symptoms dramatically. Intrathecal chemotherapy is thus recommended for leptomeningeal carcinomatosis from gastric cancer.

Lymphomatoid granulomatosis (LYG) is a systemic granulomatous disease characterized by B-cell proliferation of uncertain malignant potential. It most frequently affects the lungs but also occasionally affects the central nervous system. Its pathophysiology is unclear in numerous respects, thus making it difficult to diagnose and treat. We recently encountered a case of LYG that was followed clinically and histologically for 14 months. A 55-year-old man was hospitalized with multiple brain tumors for which the final diagnosis was not made until the second surgery, 14 months after the first intervention. Following the diagnosis, he was treated with steroid pulse therapy. At present, 3.5 years after the onset of LYG, the patient is in good condition with no signs of tumor recurrence. Although LYG is usually graded on the basis of histological findings, this patient showed no histological changes or any increase in disease grade during the 14-month follow-up period.

As for the surgical treatment of glioma, the recent employment of fluorescence-guided resection using 5-aminolevulinic acid (5-ALA) or high-dose fluorescein sodium has increased the rate of radical tumor resection. On the other hand, there is no specific technique for metastatic brain tumor surgery. We have used a fluorescence-guided tumor resection procedure with the aid of high-dose fluorescein sodium in surgery for metastatic brain tumor. Fluorescein sodium has been used in 13 cases, and achieved effective stainability in all cases. Fluorescein sodium is inexpensive, highly safe, and comparatively easy to use, and does not require any special equipment. We believe that the use of fluorescein sodium is beneficial for resection of the metastatic brain tumor.

A transcranial approach is frequently employed for the closure of cerebrospinal fluid (CSF) rhinorrhea, occurring after skullbase surgery or associated with anterior skull base fracture. However, the site of CSF rhinorrhea is usually most distant from the site of craniotomy and, because securing of an adequate operative field is difficult, elimination of this type of CSF rhinorrhea tends to be insufficient. We have attempted to reconstruct the anatomical structures with an extended transsphenoidal approach for a case with CSF rhinorrhea from the planum sphenoidale, and have succeeded in achieving a more physiological and reliable elimination of CSF rhinorrhea. This technique is presented, with a representative example.

Chronic cerebrospinal fluid (CSF) leaks associated with skull base fractures are rare but intractable and patients may be subjected to numerous operations. We present a 30-year-old man with a 13-year history of chronic CSF rhinorrhea following a cranial trauma. Computed tomography (CT) showed a bone defect in the planum sphenoidale. CT cisternography revealed a leak from the defect and CSF malabsorption. The absence of symptoms of CSF malabsorption may be attributable to external leakage of excess CSF. After closing the leak via the extended transsphenoidal approach we placed a ventriculoperitoneal shunt for occult hydrocephalus. We discuss the clinical symptoms of chronic CSF leakage and present therapeutic strategies dictated by the mechanisms underlying the leak. © Georg Thieme Verlag KG Stuttgart.

The authors report a case of hemichorea-hemiballism (HC-HB) that was successfully treated using deep brain stimulation (DBS). A 65-year-old right-handed man exhibited a sudden onset of right HC-HB without a diabetic coma. At admission T-1-weighted magnetic resonance (MR) images revealed a high-intensity signal in the left striatum, contralateral to the patient's involuntary movements. The HC-HB continued for 5 months after onset of the condition despite medical treatment and a decreased intensity of the signal on T-1-weighted MR images. The patient underwent placement of a quadripolar DBS electrode in the left thalamus, including the left ventral oralis (VO) anterior and posterior nuclei (the VO complex). Postoperatively, the right-sided HC-HB disappeared rapidly during electrical stimulation and there were no neurological deficits. The authors demonstrate that DBS can be an effective treatment for medically refractory HC-HB. This is the first case of HC-HB that has been successfully treated with DBS.

A 40-year-old man with intractable meningitis was transferred to our hospital 6 weeks after onset. On admission, he showed consciousness disturbance, meningeal signs and right oculomotor nerve palsy. MRI demonstrated prominent cisternal enhancement and hydrocephalus. We suspected tuberculous meningitis as the diagnosis, and treated with antituberculotics, though he died of midbrain infarction day 11 of the treatment. Before and during the admission, bacterial cultures, PCR, smear examination of cerebrospinal fluid (CSF) were repeated. But no evidence of tuberculosis was obtained. Cultures of the brainstem fragments detected mycobacterium, which was finally confirmed by a PCR method after his death. PCR provides a rapid and reliable diagnosis of tuberculous meningitis, although there is a potential for false-negative. Thus the clinical, radiological and CSF findings should be stressed. Corticosteroids treatment should be considered in cases with ischemic lesions.

2021 年度は肺癌血行性脳転移マウスモデルの脳組織を採取し、フローサイトメトリー法を用いてマクロファージ分画上の B7-H3 および B7-H5 発現レベルを確認した。同時に脳腫瘍組織より M2 マクロファージを単離して mRNA を抽出し、DNA マイクロアレイを用いたトランスクリプトーム解析を行った。さらにマルチプレックスサイトカイン測定も導入し、限定された臨床検体サンプルから相当量のサイトカイン/ケモカインデータの取得を行なっている。 他者の先行研究では肺癌細胞上に B7-H3 が発現することが示され、B7-H3 を標的とした治療薬が治験レベルで用いられるようになった。そこで我々真相学習アルゴリズムを用いた病理組織解析システム Cu-Cyto を用いて、腫瘍組織中の B7-H3 発現を解析した。上記知見と同様、一部の転移性肺癌細胞は B7-H3 を発現しており、かつ腫瘍組織に浸潤するマクロファージ上にも B7-H3 発現がみられた。 近年腫瘍組織近傍に三次リンパ節様構造物 (Tertiary Lymphoid Structures: TLS または Tertiary Lymphoid Organs: TLO) が形成され、腫瘍増殖あるいは腫瘍制御に関わることが示されている。そこで我々は Cu-Cyto システムを用いて上記腫瘍組織中での TLS/TLO を検索し、これらの発現頻度等を調べた。

WT1 based cancer immunotherapy is a therapy, in which HLA class I binding 9-mer WT1 peptide is administered intradermally, to induce WT1-specific cellular immune responses. We investigated the safety and immune response of vaccine therapy of WT1 against grade 2/3 glioma. Glioma cells in the animal model showed expressions of WT1, and immune cells were accumulated focally, but the response of WT1 vaccination was poor. In patients of malignant glioma, accumulation of WT1-specific immune response was detected but WT1-specific killer T cells were poor on the surface of tumor cells. Immunohistochemical analysis of skin specimens, where WT1 peptide was administered intradermally, revealed reactive proliferation of macrophages with giant cell formation and infiltration of CD4+ and CD8+T, and CD20+B lymphocytes in the lower dermis. These findings provide basic information about local immune responses elicited in the vaccination site.

It was recognized that the immune system mainly on the M2 macrophage participated in mechanism of the metastasis to brain onset in the lung cancer. Furthermore, I was able to identify the gene cluster which could become the treatment target of this M2 macrophage in microarray analysis. In addition, this immunoresponse proved that the metabolism product which intestinal bacteria produced participated. The possibility that a new treatment strategy to prevent metastasis to brain was provided was suggested in future.

WT1 based cancer immunotherapy is a therapy, in which HLA class I-binding 9-mer WT1 peptide is administered intradermally, to induce WT1-specific cellular immune responses. We investigated the safety and immune-response of vaccine therapy of WT1 against metastatic brain tumors. Metastatic brain tumor cells in the animal model showed expression of WT1, and immune cells during vaccination were accumulated focally, but the response of WT1 vaccination was poor. In patients of metastatic brain tumors-breast cancer, accumulation of WT1-specific immune response and WT1-specific killer T cells were poor on the surface of tumor cells. Immunohistochemical analysis on skin specimens, where WT1 peptide was administered intradermally, revealed reactive proliferation of macrophages with giant cell formation and infiltration of CD4+ and CD8+ T, and CD20+ B lymphocytes in the lower dermis. These findings provide basic information about local immune responses elicited in the vaccination site.

Associations between the regular use of NSAIDs and reduced cancer risks in human have been shonw. NSAIDs function as COX-2 inhibitors that prevent the production of PGE2, which induces MDSCs in cancer-bearing hosts. We thus hypothesized that COX-2 blockade would suppress brain metastasis of cancers by inhibiting MDSC development and their chemokine-mediated accumulation in the tumor microenvironment (TME). In both mouse and human brain metastasis cases, the expression levels of COX-2 and CCL2, a chemokine primarily attracting MDSCs, were increased in the tumor tissues compared with the periphery or normal brain. Concomitantly, the infiltration of MDSCs was observed at high levels in the tumor tissues. In the mouse brain tumor models using LL/2 murine lung cancer cell line, treatment with NSAIDs inhibited brain metastasis formation with the suppression of MDSCs. Our findings show that the COX-2 pathway promotes brain metastases of lung cancers by development and accumulation of MDSCs.

神経膠芽腫の摘出標本を用いた免疫染色を行った。術前にインターフェロンを静脈内投与、局所投与したものと投与なしで比較すると、局所投与した群にのみ誘導型一酸化窒素合成酵素(iNOS)の発現が認められた。このiNOSの発現細胞は二重染色の結果、脳内マクロファージであるミクログリアと判明、インターフェロンでの直接刺激によるものと考えられた。また高濃度のiNOSは大量の一酸化窒素(NO)を誘導することが判明している。次に神経膠芽腫の培養細胞を用いてNO負荷による抗腫瘍効果をDNAマイクロアレイを用いて解析した。NO負荷を与えた群と負荷なしの群で比較したところ、NO負荷では明らかな腫瘍増殖抑制関連の遺伝子が発現増加しており、また腫瘍増殖効果をもつ関連遺伝しの発現低下がみられた。これらの結果より、従来の報告ではインターフェロンの抗腫瘍効果はp53を介したものとされていたが、神経膠芽腫の場合、大量のNO誘導による新たな経路が生じている可能性がある。特に大量のNOによりEGFR-JAK/STAT経路を介している可能性が判明した。さらに培養細胞を用いてインターフェロンによる大量NO誘導療法を増強させるため、リポポリサッカライドを追加し、検討している。またEGFRの分子標的薬剤も追加し、抗腫瘍効果の増強を検討している。神経膠芽腫の新規化学療法としてアルキル化剤のTemozolomideが使用されているが、本薬剤はインターフェロンの併用によりMGMTの不活化が促進された結果、抗腫瘍効果の増強が予想される。このため、現在、全国規模で治験が行われている。これより、本研究結果も合わせてインターフェロンの静脈内投与+局所投与により、抗腫瘍効果が増強され、神経膠芽腫治療が進歩する可能性がある。