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

We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. The aim of this study was to further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their relatively benign clinical behavior. We compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. By comparing expression levels of genes of 19q-loss astrocytomas to those of 19q-intact astrocytomas, 102 up-regulated genes and 162 down-regulated genes were extracted. The down-regulated genes clustered heavily to 19q and 4p while the up-regulated genes clustered to 4q. It was noteworthy that fibroblast growth factor 1 associated with stem cell maintenance and multiple genes associated with glioma progression were down-regulated in 19q-loss astrocytomas, and these results were validated with the independent TCGA data set. On t-SNE analysis of the 19q-loss astrocytomas with other IDH-mutant glioma subgroups from the TCGA datasets, the expression pattern of the 19q-loss astrocytomas showed no shift toward oligodendrogliomas with 1p/19q codeletion but rather constituted a subgroup of astrocytoma. These findings suggested that 19q-loss in astrocytomas is more likely acquired event rather than an early event in oncogenesis like the 1p/19q-codeletion in oligodendrogliomas, and that the biological features of 19q-loss astrocytomas are possibly related to differentially expressed genes associated with stem cell maintenance and glioma progression.

Oligodendrogliomas with 1p/19q-codeletion are relatively slow progressive tumors that show good response to chemo-radiation therapy after resection. The median survival is about 15 years regardless of WHO grade, although recurrences are mostly inevitable and there is no standard treatment for recurrence. We experienced 5 oligodendroglioma cases who underwent re-radiation for recurrent tumors after chemo-radiation treatment. We retrospectively investigated those for response to re-radiation, the duration from first radiation to second radiation, and Karnofsky Performance Status (KPS) before and after the re-radiation. Patients were all male; the median radiation dose for primary tumor was 60Gy (54-60Gy), the median age at first radiation was 46 years (35-59), the median duration from the first radiation to re-radiation was 65 months (range 18-116 months), and the median follow-up period after re-radiation was 15 months (1-39 months). In all 5 cases, tumors showed good response to re-radiation. In 3 of the 5 cases, tumor recurred in corpus callosum and/or lateral side of cerebral hemisphere or basal ganglia contiguous with primary tumor sites and were radiated by IMRT (50Gy/25fr) . In 2 cases, tumors recurred around the fourth ventricle and posterior fossa and underwent conventional radiation (54Gy/30fr and 30Gy/10fr). In 2 of the 5 cases, the tumors re-recurred 24 months later after re-radiation, but the KPS were maintained until re-recurrence. For oligodendrogliomas, re-radiation therapy appears to be very effective to recurrent tumors after first chemo-radiation. Although evaluation for longer-term side effects is to be examined, re-radiation appears to be a good option for recurrent oligodendrogliomas after first chemo-radiation therapy.

Oligodendrogliomas are diffuse gliomas located in the cerebral hemisphere, and the MRI typically show swollen cortex and subcortical white matter by the tumor cells. IDH mutation and 1p/19q co-deletion define oligodendrogliomas in WHO classification, and these genetic alterations are associated with good response to chemo-radiation therapy and better prognosis compared to the IDH-mutant astrocytomas. We reviewed MRI findings of 60 oligodendrogliomas with 1p/19q co-deleted tumors which were diagnosed at Dokkyo Medical University since 1999. Of those, 3 cases showed highly infiltrating pattern in which tumors were more predominant in the white matter than the cortex and the infiltration involved multiple lobes. We retrospectively investigated those 3 cases for histological features, treatment, and clinical outcome. There were 2 males and 1 female. MRI showed faint-brushed Gd enhancement around the center of the tumor-infiltrated area in 1 case, while there was no enhancing lesion in other 2 cases. All three underwent stereotactic biopsy. Histologically, all 3 cases lacked typical oligodendroglioma morphology: the tumor cells have irregular round, oval to elongated nuclei without perinuclear halo and had dense, closed chromatin similar to astrocytoma. Two cases underwent chemotherapy (TMZ and PAV accordingly), without radiation and 1 case underwent chemotherapy with radiation as the primary treatment. Interestingly, all three tumors responded well not only to the primary treatments but also to the radiation therapy administered after recurrence, although all eventually succumbed to the tumor. PFS were 16, 37, 67 months and OS were 104, 70, 115 months for each, which were at the worse end as oligodendrogliomas but are apparently better than astrocytomas. Highly infiltrating oligodendrogliomas appeared to show significantly different MRI and histological features from typical oligodendrogliomas that primarily involve cerebral cortex. The underlying mechanism of such differences might involve specific genetic alterations and/or gene expression alterations that may not affect treatment response.

We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. The aim of this study was to further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their relatively benign clinical behavior.We compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis.By comparing expression levels of genes of 19q-loss astrocytomas to those of 19q-intact astrocytomas, 102 up-regulated genes and 162 down-regulated genes were extracted. The down-regulated genes clustered heavily to 19q and 4p while the up-regulated genes clustered to 4q. It was noteworthy that fibroblast growth factor 1 associated with stem cell maintenance and multiple genes associated with glioma progression were down-regulated in 19q-loss astrocytomas, and these results were validated with the independent TCGA data set. On t-SNE analysis of the 19q-loss astrocytomas with other IDH-mutant glioma subgroups from the TCGA datasets, the expression pattern of the 19q-loss astrocytomas showed no shift toward oligodendrogliomas with 1p/19q codeletion but rather constituted a subgroup of astrocytoma.These findings suggested that 19q-loss in astrocytomas is more likely acquired event rather than an early event in oncogenesis like the 1p/19q-codeletion in oligodendrogliomas, and that the biological features of 19q-loss astrocytomas are possibly related to differentially expressed genes associated with stem cell maintenance and glioma progression.

BACKGROUND In BIOMARK trial, patients with newly diagnosed glioblastoma were treated with standard chemoradiotherapy combined with first-line bevacizumab; a subset of patients continued bevacizumab beyond progression (BBP). Neurocognitive function (NCF), symptom burden, and health-related quality of life (HRQoL) were examined as secondary endpoints. PATIENTS AND METHODS In the primary protocol, newly diagnosed glioblastoma patients aged 20-75 received standard 6-week radiotherapy combined with temozolomide and bevacizumab followed by 4-week cycles of temozolomide plus bevacizumab, and then 2-3-week cycles of bevacizumab monotherapy. Upon recurrence, patients were subjected to the secondary protocol with 2-3-week cycles of bevacizumab monotherapy with or without other chemotherapeutic agents. NCF tests (Hopkins verbal learning test-revised, trail making test, and controlled oral word association), EORTC QLQ-C30/BN20, and MDASI-BT were completed by the patients. Time to deterioration (TTD) was defined as the time from randomization until a pre-specified change from baseline without further improvement or death. The Kaplan-Meier method and the log-rank test were used to assess TTD for each subscale of the above tests. RESULTS Overall, 94 patients were enrolled in the study. Analyses were based on the full analysis set cohort (N=90), excluding non-glioblastoma diagnosis by central review. The median overall survival (OS) and progression-free survival (PFS) were 25.0 and 14.9 months, respectively. Baseline HRQoL and symptom burden subscales (emotional functioning, symptom severity score, affective factor, and focal factor) were significantly associated with PFS. The median TTD was 8.7, 7.5, 8.1 months for global health status/QoL, symptom severity score, interference score, respectively. Among patients who experienced recurrence, disease progression was apparently preceded by deterioration in terms of symptom burden. CONCLUSIONS Detailed analysis of HRQoL and symptom burden may aid care of glioblastoma patients throughout the disease trajectory.

We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. To further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their clinical behavior, we compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. Comparing expression level of each genes between 19q-loss and 19q-intact astrocytomas,136 up-regulated genes and 203 down-regulated genes were extracted. Gene expression patterns of 19q-loss astrocytomas were partially different from that of 19q-intact astrocytomas. More down-regulated genes distributed on 19q and 4p, and more up-regulated genes distributed on 4q. Multiple genes associated with stem cell maintenance were down-regulated in 19q-loss astrocytomas, and genes associated with glioma progression were differentially expressed. Comparing expression patterns among 19q-loss astrocytomas and other IDH-mutant glioma subgroups using TCGA datasets by t-SNE analysis revealed that expression pattern of 19q-loss astrocytomas did not shift to that of oligodendrogliomas with 1p/19q codeletion but were a subgroup in astrocytomas. These results indicated that 19q-loss in astrocytomas was an acquired event different from 1p/19q codeletion in oligodendrogliomas, and better prognosis morphological features in 19q-loss astrocytomas were derived from differentially expressed genes associated with stem cell maintenance and glioma progression.

BACKGROUND Mismatch Repair (MMR) Deficiency is common in recurrent gliomas from IDH-mutant and IDH-wild-type tumors. Emergence of MMR deficit is strongly associated with the chemotherapy using TMZ, and it is considered to be a key mechanism of acquiring resistance to TMZ. Several studies showed MMR protein loss detected by immunohistochemistry was well concordant with molecular genetics sequencing data, and sometimes even more reliable in detecting MMR functional deficit. Here we evaluated Mismatch Repair protein expression by immunohistrochemistry for the pairs of primary and recurrent gliomas. METHODS We investigated the expression of 4 MMR proteins (MLH1/MSH2/MSH6/PMS2) in 37 cases of paired primary-recurrent gliomas (7 grade II & III astrocytomas, 16 grade II & III oligodendrogliomas, and 14 glioblastomas). Clinical information including history of chemo-radiotherapy after primary surgery were collected retrospectively. RESULTS Except for one case of GBM, all primary tumors retained 4 MMR proteins. 10 of 37 recurrent tumors lost one or more MMR protein expression (4 GBM 3 astrocytoma, 3 oligodendroglioma), including one case in which primary tumor already had MSH2/MSH6 loss. 2 recurrent GBM lost MMR protein expression homogenously, while in other 8 tumors, the patterns of MMR protein loss were heterogenous. 8 of 10 tumors that lost MMR protein expression were recurrence after TMZ treatment. CONCLUSION Although the interpretation of the heterogenous loss of MMR protein expression is somewhat difficult, the immunohistochemical evaluation of MMR proteins appears to be feasible, and may be able to detect early phase of MMR deficiency and the rise of hypermutator phenotype.

Background The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed. Methods A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Results Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them. Conclusion All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.

Brain invasion by chronic lymphocytic leukemia (CLL) is very rare, and only a handful of cases have been reported. We here report a case of 61-year-old woman who had been treated for CLL for 14 years presenting with a progressive mental disturbance. Magnetic resonance imaging (MRI) showed discontinuous ring-enhancing lesions compatible with the "open ring" sign, which was considered a demyelinating disorder, in both the frontal lobes. However, on histological examination of the biopsied specimen, infiltration of small lymphocytes positive for CD5, CD20, and CD23, indicating brain invasion by CLL, was seen. The leukemia cells occupied the Virchow-Robin space and infiltrated into the brain parenchyma. The arterioles in the Virchow-Robin space were compressed and occluded with the tumor cells, while CD163-positive cells infiltrated the brain parenchyma. Myelin staining demonstrated myelinoclasis in the infiltrated brain tissue. The MRI findings in the present case probably reflected myelinoclasis, suggesting rare brain invasion by CLL. The possibility of lymphoma should not be eliminated based on the MRI findings.

Introduction A prospective study was designed to elucidate incidence and predictors of deep venous thrombosis (DVT) in patients undergoing craniotomies. Materials and Methods Ninety-two patients who underwent craniotomies received pre- and postoperative venous ultrasonography and/or contrast-enhanced spiral computed tomography for diagnosis of DVT. The primary endpoint was DVT occurrence. Serial levels of serum D-dimer, soluble fibrin, and thrombin–antithrombin complex (TAT) were analyzed. Results Twenty-four of 92 patients (26.1%) had DVT, of whom 10 (41.7%) were diagnosed preoperatively. In patients with preoperative DVT, age, incidence of decreased performance status and leg paresis, levels of D-dimer, soluble fibrin, and TAT were significantly greater. In patients with postoperative DVT, length of surgery, incidence of decreased postoperative performance status, levels of D-dimer on postoperative days (POD) 3, 7, and 14, and TAT on POD7 were significantly greater. Patients with postoperative DVT had elevated D-dimer levels on POD 7 compared with POD 3. The D-dimer cutoff of 2.65 μg/mL at POD 7 could be used to identify DVT with 85.7% sensitivity and 72.3% specificity. A cutoff of 5.25 μg/mL at POD 7 yielded a specificity of 96.9%. Decreased performance status and elevated D-dimer were independent predictors for preoperative DVT, prolonged operation time, and elevated D-dimer on POD 7 for postoperative DVT. Conclusions DVT frequently was observed in patients before and after undergoing craniotomies. Patients with decreased performance status should be preoperatively screened for DVT by checking D-dimer levels. Elevated D-dimer levels on POD 7 compared with POD 3 and D-dimer levels greater than 2.65 μg/mL at POD7 suggest the presence of DVT.

Intravascular lymphoma (IVL) has been characterized in many case reports by multiple white matter lesions reflecting ischemic changes. In contrast, there are very few case reports of cerebral or cerebellar hemorrhage resulting from IVL. A 56-year-old woman was referred to our department with two-week history of headache, nausea, and poor appetite. Gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) showed dilated veins on the cerebellar surface. No ischemic lesions were detected on diffusion-weighted images. Three days after admission, the patient had a large cerebellar hemorrhage, prompting emergency surgery. Unfortunately, the patient died on the 11th postoperative day. Massive CD20-positive lymphoma cells were recognized in the cerebellar veins, but not in the arteries or the parenchyma of the brain. This is the rare case report of a cerebellar hemorrhage complication from IVL that might have been caused by venous congestion. The dilated veins on the cerebellar surface recognized from the Gd-enhanced T1-weighted images were specific clues in this case.

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.

髄膜腫は最も頻度の多い脳腫瘍で，その多くは手術摘出後に再発が稀な腫瘍であるが，一部ではより高い増殖能を示すものがある．組織学的には異型性髄膜腫に分類されるもので，その頻度は診断基準であるWHO分類の変遷に伴い1993年当初数％であったものが，最近30％程度にまで増加している．しかし，臨床的には髄膜腫全体での再発率や悪性度が高くなっている証拠はない．一つの可能性として異型性髄膜腫と診断される比率が増えたことが考えられる．我々は異型性髄膜腫の組織像を詳細に検討し，臨床経過と併せて検討を行った．対象症例は2009年1月〜2014年7月における64例で，WHO grade Iが37例，異型性髄膜腫が27例であった．異型性髄膜腫は組織像によって，局所での核分裂像を示すⅡa群と，全体的での核分裂像もしくは脳浸潤を伴うⅡb群に分けることが可能であり，Ⅱa群は10例，Ⅱb群は17例であった．臨床像はⅡb群が grade I/Ⅱa群より，高齢(中央値Ⅰ：57，Ⅱa：50，Ⅱb：69歳)で男性に多く，MIB-1 labeling indexがより高値(中央値Ⅰ：3.0，Ⅱa：2.1，Ⅱb：10.3％)であった．追跡期間中にgradeⅠで1 例，Ⅱb群で5例が再発した．Ⅱa群の臨床経過は，grade Iに類似しており，臨床像としてはⅡb群が異型性髄膜腫のような，より再発を認めやすい一群であると考えられる．

Hemangioblastoma is usually amenable to total surgical resection, but indication for surgery can be hampered by its location, multiplicity, or repeated recurrences frequently observed in patients with von Hippel Lindau disease (VHLD). Stereotactic radiosurgery (SRS) has been administered for such cases as an alternative therapeutic option with generally favorable clinical response, but the effect of SRS has not been underscored by histological examination of the treated hemangioblastoma. Here we present histology of VHLD-associated hemangioblastoma tissue resected three months after SRS because of cyst enlargement. It confirmed that hemangioblastoma cells totally disappeared after SRS with a marginal dose of 20 Gy. Furthermore, Electron microscope revealed that endothelial cells of the vascular structure disappeared while maintaining the basement membranes, and leakage of intraluminal contents was observed around the structure. We showed the SRS was effective for hemangioblastoma pathologically at least with the marginal dose of 20 Gy. Leakage of intraluminal contents from the damaged vascular structure losing the endothelial cells is one possible mechanism for the cyst enlargement, and it may be a reason of poor control rate of SRS for the cystic hemangioblastoma.

BACKGROUND Clinical benefit of continuing bevacizumab beyond progression is unknown in glioblastomas. A biomarker analysis of the AVAglio trial suggested that proneural subtype of IDH-wildtype glioblastoma patients may receive an OS benefit from a first-line bevacizumab. This study explored biomarkers that may predict survival of glioblastoma patients treated with concurrent irradiation, temozolomide (TMZ) and bevacizumab (BEV) followed by BEV beyond progression (BBP). METHODS In the primary protocol, newly diagnosed GBM patients aged 20–75 received concurrent TMZ (75 mg/m2, D1-42), irradiation (2 Gy x 5 QW x6) and BEV (10 mg/kg Q2W x 3) followed by ≤12 4-week cycles of TMZ (150–200 mg/m2, D1-5) plus BEV (10 mg/kg, D1 and 15) and then 2 or 3-week cycles of BEV monotherapy (15 or 10 mg/kg). Upon PD/recurrence during the primary protocol, the patients were subjected to the secondary protocol with 2-3-week cycles of BEV monotherapy with or without other chemotherapeutic agents (BBP). The primary endpoint was 2-year survival rate in patients receiving BBP. Fresh-frozen tumor specimen were subjected to genome-wide methylation, copy number, expression and mutation analysis. A subset of the control cohort of the AVAglio study was used as BEV-negative control. RESULTS A total of 94 GBM patients were enrolled at 39 centers between June 2015 and January 2017. Efficacy analyses were based on the full analysis set (FAS) cohort (N=90), excluding non-GBM diagnosis by central review. The median time to PD/recurrence was 453 days in the FAS and 348 days in patients receiving BBP (N=27). The 2-year survival rate (90% CI) was 52.4% (43.3–60.8%) and 28.8% (15.4–43.7%), respectively. The 2-year survival rate in GBM patients receiving BBP was lower than expected (50%). That of proneural and mesenchymal IDH-wt GBM in the biomarker cohort (n=83) were 52.9% (31.7–70.3%) and 56.6% (41.6–69.1%), respectively. A full biomarker analysis will be presented.

Classification of gliomas, first established by Cushing and Bailey in early 20th century, has been based on histological features that were associated with clinical behavior of the tumor fairly well. However, inter-observer variation in the diagnosis and heterogeneous clinical outcome within a single entity have been problematic in some cases. Accumulation of molecular information of gliomas over the past two to three decades gradually elucidated the mechanism of oncogenesis and progression of gliomas at the molecular level, and it now appears to be possible to classify gliomas by the molecular markers, especially in adult diffuse gliomas that constitute ~25-30% of the primary intracranial tumors. Most powerful molecular markers to classify those tumors are those that appear to be involved in the early phases of oncogenesis, including IDH1/2, TP53, TERT, ATRX and 1p/19q co-deletion. Interesting tight negative and positive correlations among those molecular genetic alterations enable clearer definition of entities and better prognosis prediction in adult diffuse gliomas.

We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. To further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their relatively benign clinical behavior, we compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. By comparing expression levels of genes of 19q-loss astrocytomas to those of 19q-intact astrocytomas,136 up-regulated genes and 203 down-regulated genes were extracted. Down-regulated genes in the 19q-loss astrocytomas were heavily clustered to 19q and 4p, and up-regulated genes to 4q. It was noted that fibroblast growth factor 1 associated with stem cell maintenance was down-regulated in 19q-loss astrocytomas and genes associated with glioma progression were differentially expressed, these results were validated with the independent TCGA data set. On t-SNE analysis of the 19q-loss astrocytomas with other IDH-mutant glioma subgroups from the TCGA datasets, 19q-loss astrocytomas did not shift to oligodendrogliomas with 1p/19q codeletion but were a subgroup in astrocytomas. These results indicated that 19q-loss in astrocytomas is more likely to be an acquired event rather than early event in oncogenesis like 1p/19q codeletion in oligodendrogliomas, and the biological and morphological features of 19q-loss astrocytomas were possibly related to differentially expressed genes associated with stem cell maintenance and glioma progression.

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. We carried out a multicenter retrospective study to verify the characteristics of brain metastases from hepatocellular carcinoma in Japan. 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. 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.

We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas (Otani et al. Cancer Sci 2018). The purpose of the present study was to reveal how 19q-loss contributed to better prognosis and the morphology in the subgroup. We compared expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. 136 up-regulated genes and 203 down regulated genes were extracted in 19q-loss astrocytomas compared with 19q-intact astrocytomas. Significantly changed genes distributed throughout all chromosomes, but more down-regulated genes were on 19q and 4p, and more up-regulated genes were on 4q. Genes associated with apoptosis, cell adhesion, and antigen presentation were up-regulated, and genes associated with Ras signaling pathway were down-regulated. These changes could result in better prognosis. By contrast, there was few expression changed gene associated with oligodendroglioma-like morphology although up-regulation of genes associated with axon guidance and down-regulation of genes associated with cell shape might result in the morphology or neuronal differentiation. Expression pattern of 19q-loss astrocytomas indicated no tendency of oligodendroglial differentiation. Better prognosis of 19q-loss astrocytomas was derived from expression changes associated with tumor proliferation and tumor immunity.

Brain metastasis is associated with worse prognosis in patients with non-small cell lung cancer (NSCLC). However, recent advances in molecular targeted therapy are rapidly changing the treatment strategy for NSCLC. Here, we conducted a retrospective study to clarify the prognosis and risk factors in NSCLC patients with synchronous brain metastasis. Seventy-four patients who were treated at our institute between Jan 2013 and Apr 2019 were included. The association between overall survival (OS) and clinicopathological features, such as neurological symptoms at diagnosis, histology, EGFR and ALK mutation status, number of intracranial metastases, extracranial systemic metastasis, Karnofsky performance status (KPS) at diagnosis, and initial therapy, were examined. OS was calculated from the day of diagnosis with brain metastasis or NSCLC. Of the 51 men and 23 women enrolled (median 70.0 years of age, range 40–84), 26 patients (35.1%) exhibited neurological symptoms at diagnosis. EGFR and ALK mutations were present in 24 (32.4%) patients. The median OS for all patients was 23.0 months. Factors significantly associated with worse OS in univariate analysis were symptomatic lesions and the absence of a driver mutation. Driver mutation status was only an independent prognosis factor in multivariate analysis. On lung-mol GPA score, the patients greater than or equal to 2.5 were significantly better prognosis compared with less than 2.5 (median OS: 40.0 VS 10.0 months, respectively). Our cohort of 74 NSCLC patients with synchronous brain metastasis had a median OS of 23.0 months. This much longer OS may reflect recent advances in treatment, particularly the availability of molecular targeted drugs. Lung-mol GPA score was considered as a useful tool to estimate the prognosis; thus, the information of KPS score, extracranial metastasis, brain metastases numbers, and driver mutation status are essential to build a treatment strategy for synchronous brain metastasis from NSCLC.

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients’ treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P

Near-infrared spectroscopy (NIRS) has proven to be useful for the evaluation of language lateralization in healthy subjects, infants, and epileptic patients. This study for the first time investigated the expressive and receptive language functions separately, using NIRS in presurgical glioma patients. We also describe a special case with dissociated pattern of language functions. Ten glioma patients were examined. Using NIRS, the hemodynamic changes during a verb generation task or story listening task were measured in the cerebral hemisphere on either side covering the language areas. Following the NIRS study, the Wada test was performed in all the patients. The NIRS study revealed increases of oxyhemoglobin and decreases of deoxyhemoglobin in the language areas elicited by both tasks. In 9 patients, who were all right-handed, the expressive and receptive language functions were lateralized to the left hemisphere. The results of the NIRS study were completely consistent with those of the Wada test. In the remaining 1 patient with a right sided insular glioma, who was right-handed, the NIRS study revealed stronger activation of the right inferior frontal region during the verb generation task, and stronger activation of the left superior temporal region during the story listening task. This dissociated language function was validated by the Wada test and the postoperative neurological course. These results demonstrate that a NIRS study using our technique is extremely valuable for preoperative assessment of the language functions and exemplifies how a preoperative NIRS study can allow detection of unforeseen language lateralization.

Immunohistochemical staining is important for histological diagnosis of brain tumors; however, its intraoperative application has rarely been reported. Herein, we describe our methods and four successfully diagnosed cases. Between January 2008 and April 2010, intraoperative immunohistochemical analysis was performed in 43 patients undergoing brain tumor surgery at our institute. The time for rapid histological diagnosis was 70 min. MIB-1 immunostaining was performed; staining index (SI) was 0.8-76.2% (median, 2.5%) in rapid diagnoses and 0.6-83.9% (median, 7.7%) in permanent diagnoses. There was no discrepancy in low- or high-grade tumors between intraoperative and final pathological diagnosis. The antibodies used for staining were MIB-1 in all cases, L26 in 8 cases, UCHL-1 in 6 cases, GFAP in 4 cases, AFP in 3 cases, and PLAP in 5 cases. The staining patterns were similar between rapid and permanent diagnoses. We think that immunohistochemical examination is indicated under the following conditions: (1) preoperative radiologic differential diagnosis includes both high- and low-grade tumors, (2) intraoperative assessment is necessary to determine the extent of excision, and (3) quick and accurate pathological diagnosis is necessary for early initiation of treatment after surgery.

Angiocentric glioma (AG) is an epileptogenic benign cerebral tumor primarily affecting children and young adults, and characterized histopathologically by an angiocentric pattern of growth of monomorphous bipolar cells with features of ependymal differentiation (WHO grade I). We report an unusual cerebral glial tumor in a 66-year-old woman with generalized tonic-clonic seizure; the patient also had a 6-year history of headache. On MRI, the tumor appeared as a large T2-hyperintense lesion involving the right insular gyri-anterior temporal lobe, with post-contrast enhancement in the insula region. Histopathologically, the tumor involving the insular cortex-subcortical white matter was composed of GFAP-positive glial cells showing two different morphologies: one type had monomorphous bipolar cytoplasm and was angiocentric with circumferential alignment to the blood vessels, with dot-like structures positive for epithelial membrane antigen and a Ki-67 labeling index of 5%. In the anterior temporal lobe, a diffuse increase in the number of astrocytic cells was evident in part of the cortex and subcortical white matter. On the basis of these findings, we considered whether the present tumor may represent an unusual example of AG with infiltrating astrocytic cells showing primary anaplastic features (AG with anaplastic features), or anaplastic astrocytoma showing primary vascular-associated ependymal differentiation (anaplastic astrocytoma with angiocentric ependymal differentiation). At present, the latter appears to be the more appropriate interpretation.

This paper describes a new system to match the impedance automatically for a re-entrant resonant cavity applicator during brain tumor hyperthermia treatments non-invasively. We have already discussed the effectiveness of the heating method using a manual impedance matching controller with heating experiments of an agar phantom and computer simulations. With this heating method, to generate heating power in the cavity, it is necessary to match the impedance and to tune the resonant frequency. In the initial prototype heating system, both were manually adjusted. However, it was difficult to match the impedance and to tune the frequency especially using a high resonant frequency. To overcome this problem, we developed the automatic impedance matching system (AIMS). It is known that reflected power is generated when the impedance matching is not complete. In this system, to reduce the reflected power which is fed back to the computer, the stepping motor to turn the dial of the variable capacitors is controlled by developed software. To evaluate the developed AIMS, the heating experiments of the agar phantom, using several electromagnetic modes, were performed. The VSWRs are 1.05 and 1.01 using manual matching and AIMS, respectively. From these results, we found that the temperature rise in the agar phantom using AIMS was about 180% (with TM012-like mode) and about 110% (with TM010-like mode) more than using the manual type controller under the same heating condition. It was found that the proposed system was very effective for hyperthermia treatment using the resonant cavity applicator even when the resonant frequency was high.

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic tumor that usually occurs in the superficial cerebral hemispheres of children and young adults and has a relatively favorable prognosis. We report an unusual case of supratentorial, intraventricular tumor in a 52-year-old man. The tumor was composed of pleomorphic cells, including giant cells, most of which were multinucleated, and small cells. In addition, frequent xanthic changes in the cytoplasm of the tumor cells, and widespread reticulin deposits and lymphocytic infiltrates in the stroma were characteristic features. Large areas of necrosis were also evident. However, mitotic figures were rare (1-2 mitoses per 10 high-power fields). Many tumor cells were positive for GFAP, and a number were positive for neurofilament protein and synaptophysin, indicating their neuronal differentiation. In addition, occasional tumor cells were positive for CD34. p53 protein was entirely negative in the tumor cells. In diagnosing this tumor histopathologically, differentiation between PXA and giant cell glioblastoma (GCG), a rare variant of glioblastoma, was problematic. However, considering the overall histopathological picture, a final diagnosis of PXA with anaplastic features was made. The present case indicates that PXA can occur as an intraventricular tumor, and suggests that in some instances, it would be very difficult to differentiate PXA and GCG histopathologically.

This 15-year-old boy with a tentorial cavernous angioma reported occasional headache and scintillation in his left visual field. Magnetic resonance imaging revealed a well-demarcated, homogeneously enhanced tumor originating from the right cerebellar tentorium and extending into both the supratentorial and infratentorial spaces. Although a meningioma was suspected, vertebral artery angiography revealed a thickened meningeal branch originating from the right posterior inferior cerebellar artery and flecked tumor stain with pooling of contrast medium until the late venous phase. A cavernous angioma of the tentorium was suspected based on this finding, and as expected from the radiological findings, profuse bleeding was encountered during tumor removal. The histological diagnosis was a cavernous angioma. A cavernous angioma of the tentorium is extremely rare but should be differentiated from a meningioma preoperatively given that a cavernous angioma of dural origin tends to bleed massively during removal.

This paper describes a new heating method used to expand the heating area of a needle applicator by using a needle applicator made of a shape memory alloy (SMA) for brain tumor hyperthermia treatment. The purpose of the study described here is to show the ability of the method to expand a defined heating region. One major disadvantage of RF interstitial hyperthermia treatment is that this heating method has a small heating area. To overcome this problem, a new type of needle made of a SMA was developed. The thermal properties of this proposed method, when applied to agar phantoms, were calculated with computer simulations and these properties were checked experimentally with the current physical version of the heating system. The calculated temperatures were in close agreement with the measured temperatures with an error of 10% or less. In both the numerical calculations and experimental results the proposed SMA needle heat treatment expanded the heating area to approximately 300% of that of a non-SMA needle heat treatment. These results suggest that the proposed heating method using the SMA needle applicator is capable of being used for invasive brain tumor hyperthermia treatments.

This paper describes the possibility of a new heating method with a needle applicator made of a shape memory alloy (SMA) to expand the heating area for interstitial brain tumor hyperthermia treatments. The purpose of the study described here is to show the capability of the method to expand a defined heating region with the developed three-dimensional (3-D) anatomical human head model using the finite element method (FEM). One major disadvantage of RF interstitial hyperthermia treatment is that this heating method has a small heating area. To overcome this problem, a new type of needle made of a SMA was developed. The specific absorption rate (SAR) distributions of this proposed method, when applied to the 3-D anatomical human head model reconstructed from two-dimensional (2-D) MRI and X-ray CT images, were calculated with computer simulations. The calculated SAR distributions showed no unexpected hot spots within the model. The heated area was localized around the tumor. These results suggest that the proposed heating method using the SMA needle applicator and the developed method for reconstructing a 3-D anatomical human head model are capable of being used for invasive brain tumor hyperthermia treatments.

我々はこの20年間における1施設での, 視床ならびに被殻部の悪性神経膠腫症例をステージ分類し, この部位における温熱治療症例の臨床的特徴について報告する. 対象は, 新潟大学において治療を受けた基底核部 (視床を含む) のグレード3および4の悪性グリオーマ43例である. 病期分類は, 視床並びに被殻部の腫瘍の大きさを基に行った. すなわち, ステージ1 (2cm未満), ステージ2 (2―4cm), ステージ3 (4cm以上) とし, 腫瘍が被殻や視床を超えて他部位へ進展しているものをステージ4, 脳室への進展例 (播種例) をステージ5として分類した. 当科における温熱治療は, 腫瘍内に電極を局所麻酔下に生検する際に同時に埋め込んでくるもので, 通常の外照射60Gyとともに週2回計3ないし4回の加温を行うものである. 化学療法はACNUまたはMCNUを温熱放射線治療中に静注もしくは動注しているが, 高齢者においては併用していない. その結果, ステージ4症例は全症例の30％を占め, ステージ5症例も含めると40％にもなった. 摘出術施行例は43例中14例で, 残りの29例は生検術症例である. そのうちの14例は生検術とともに温熱治療のための針電極を留置し, 放射線治療とともに温熱治療を行った. 平均生存期間は11ヶ月であった (視床部では17ヶ月, 被殻部で11ヶ月). 視床部の悪性グリオーマは被殻部の症例に比し, 若年である傾向が認められ, 予後も若干良好であった. 温熱症例の平均生存期間は22か月で, 非温熱治療, 生検術群の9ヶ月に比べ, 生存期間延長の傾向が認められた. 基底核部悪性グリオーマは深部であるため, 摘出術が可能であることが少なく予後不良であったが, 温熱治療により有効例も認められるようになっている.

Adenoviral replacement of the p53 gene has already been proved effective for the treatment of various tumours, including malignant gliomas. However, it is difficult to treat malignant glioma with p53 gene therapy alone because of problems with resistance or a less-than-satisfactory response to the treatment. This study investigated whether heat shock at 43 degrees C (mild hyperthermia) augments the cytotoxic effect of p53 gene transfer on malignant glioma cells expressing wild-type p53 (D54) or mutant p53 (U373-MG and U251-MG). The combination of mild hyperthermia and adenoviral p53 over-expression had an additive inhibitory effect on cellular proliferation in all three cell lines studied. Further, both cell cycle analysis and a DNA fragmentation assay showed that apoptosis was induced by p53 over-expression alone but not by heat shock at 43 degrees C alone. However, p53 over-expression followed by mild hyperthermia additively increased the proportion of cells in which apoptosis was induced, regardless of the endogenous p53 status of the tumour cells. Interestingly, a caspase-independent mechanism was observed to be involved in the p53-induced apoptosis in U251-MG and D54 cells. Taken together, the findings showed that combining adenoviral p53 transfer with mild hyperthermia inhibits the proliferation of malignant glioma cells in an additive manner, irrespective of their endogenous p53 status, suggesting a novel treatment strategy for this malignancy.

We report a basal ganglion hamartoma in a 10-year-old boy in whom the major clinical feature was precocious puberty. Endocrinological evaluation showed a gonadotropin reaction to luteinizing hormone-releasing hormone with no elevation of the human chorionic gonadotropin beta-subunit level in the serum or cerebrospinal fluid. Neuroimaging studies showed a small, calcified, nonenhanced mass lesion with some cystic components in the right basal ganglion. Histopathological examination of specimens removed by stereotactic needle biopsy revealed disorganized neuronal and glial elements in the calcified gray matter-like lesion. In addition, although the presence of microcalcifications was not conspicuous, similar neuroglial lesions of various sizes were scattered in the surrounding white matter. Immunostaining for Ki-67 antigen (MIB-1) showed very low proliferative potential of the glial cells in all the lesions. To our knowledge, this is the first reported occurrence of an intracranial hamartoma located in a site other than the hypothalamus and causing precocious puberty. The possible mechanisms underlying the development of precocious puberty in this patient are discussed.