Bevacizumab beyond Progression for Newly Diagnosed Glioblastoma (BIOMARK): Phase II Safety, Efficacy and Biomarker Study.

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.

Transcriptome and methylome analysis of CNS germ cell tumor finds its cell-of-origin in embryogenesis and reveals shared similarities with testicular counterparts.

BACKGROUND: CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. METHODS: We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. RESULTS: Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. CONCLUSIONS: These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.

Low tumor cell content predicts favorable prognosis in germinoma patients.

BACKGROUND: Germinoma preferentially occurs in pediatric and young adult age groups. Although they are responsive to treatment with chemotherapy and radiation, the treatment may cause long-term sequelae in their later lives. Here, we searched for clinical and histopathological features to predict the prognosis of germinoma and affect treatment response. METHODS: A total of 114 germinoma cases were included in the analysis. We investigated the association between clinical factors, tumor cell content, and progression-free survival (PFS). RESULTS: The tumor cell content was widely distributed from <5% to 90% in the specimens, with a median value of 50%. Female patients showed higher tumor cell content in the specimens (P = .002). Cases with lesions at atypical sites showed shorter PFS than those with lesions at other sites (P = .03). Patients with a higher tumor cell content (≥50%) showed shorter PFS than those with a lower tumor cell content (<50%) (P = .03). In multivariate analysis, tumor cell content was the only statistically significant prognostic factor (P = .04). Among the 7 cases treated with local radiation and chemotherapy, all 3 cases that recurred (2 outside of the radiation field, 1 unknown) had tumor cell content of ≥50% in the original specimen, whereas all 4 cases without recurrence had tumor cell contents of <50%. CONCLUSIONS: We found that tumor cell content significantly affected the prognosis of germinomas. Although validation of these results using an independent and larger cohort is necessary, this potentially opens the possibility of leveraging this pathological factor in future clinical trials when stratifying the treatment intensity.

Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.

PURPOSE: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonß (IFNß) plus temozolomide (TMZ) with that of TMZ alone. EXPERIMENTAL: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. RESULTS: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNß + Radiotherapy (RT) group were found. CONCLUSION: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNß addition were identified.

Integrated clinical, histopathological, and molecular data analysis of 190 central nervous system germ cell tumors from the iGCT Consortium.

BACKGROUND: We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management. METHODS: Data from the Intracranial Germ Cell Tumor Genome Analysis (iGCT) Consortium were reviewed. A total of 190 cases were classified as primary germ cell tumors (GCTs) based on central pathological reviews. RESULTS: All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker positive and 6.1% of non-germinomatous GCTs were marker negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better progression-free survival than those at atypical sites (P = 0.03). A molecular clinical association study revealed frequent mitogen-activated protein kinase (MAPK) pathway mutations in males (51.4% vs 14.3%, P = 0.007), and phosphatidylinositol-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway mutations in basal ganglia cases (P = 0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance. CONCLUSIONS: The in-depth findings of this study regarding clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.

Effects of Surgery With Salvage Stereotactic Radiosurgery Versus Surgery With Whole-Brain Radiation Therapy in Patients With One to Four Brain Metastases (JCOG0504): A Phase III, Noninferiority, Randomized Controlled Trial.

Purpose Whereas whole-brain radiotherapy (WBRT) has been the standard treatment of brain metastases (BMs), stereotactic radiosurgery (SRS) is increasingly preferred to avoid cognitive dysfunction; however, it has not been clearly determined whether treatment with SRS is as effective as that with WBRT or WBRT plus SRS. We thus assessed the noninferiority of salvage SRS to WBRT in patients with BMs. Patients and Methods Patients age 20 to 79 years old with performance status scores of 0 to 2-and 3 if caused only by neurologic deficits-and with four or fewer surgically resected BMs with only one lesion > 3 cm in diameter were eligible. Patients were randomly assigned to WBRT or salvage SRS arms within 21 days of surgery. The primary end point was overall survival. A one-sided α of .05 was used. Results Between January 2006 and May 2014, 137 and 134 patients were enrolled in the WBRT and salvage SRS arms, respectively. Median overall survival was 15.6 months in both arms (hazard ratio, 1.05; 90% CI, 0.83 to 1.33; one-sided P for noninferiority = .027). Median intracranial progression-free survival of patients in the WBRT arm (10.4 months) was longer than that of patients in the salvage SRS arm (4.0 months). The proportions of patients whose Mini-Mental Status Examination and performance status scores that did not worsen at 12 months were similar in both arms; however, 16.4% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction after 91 days postenrollment, whereas only 7.7% of those in the SRS arm did ( P = .048). Conclusion Salvage SRS is noninferior to WBRT and can be established as a standard therapy for patients with four or fewer BMs.

Employment status and termination among survivors of pediatric brain tumors: a cross-sectional survey.

BACKGROUND: Some childhood cancer survivors experience employment difficulties. This study aimed to describe pediatric brain-tumor survivors' employment status. METHODS: A cross-sectional, observational study was conducted, with questionnaires distributed to 101 pediatric brain-tumor survivors (aged 15 years or older) and their attending physicians from nine institutions in Japan. We compared category and time-series histories for participants' first-time employment using national census information. Factors related to delayed employment or early employment termination were examined using survival-time analyses. RESULTS: Excluding students and homemakers, 38 brain-tumor survivors (median age 27 years, with 15 years since diagnosis) were of working age. Of these, 12 (32%) were unemployed and 9 (24%) had never been employed. First-time employment occurred later for brain-tumor survivors than the general population, particularly in those with lower educational levels. The number of brain-tumor survivors whose first job was terminated within the first year was higher than that for the general population, particularly in male survivors and germ cell-tumor survivors. Brain-tumor survivors described their working patterns (irregular), job types (specialist or professional), reasons for early termination (unsuitable job), and thoughts about working (they wished to serve their communities but lacked confidence). CONCLUSION: Brain-tumor survivors are associated with high unemployment rates and multiple unemployment-related factors. Education and welfare systems should identify individual methods of social participation for this group.

Primary spinal cord astroblastoma: case report.

Astroblastoma is a rare tumor that is thought to occur exclusively in the cerebrum. To the authors' knowledge, no cases of spinal cord astroblastoma have been reported. A 20-year-old woman presented with numbness in her legs. MRI demonstrated a 2-cm intramedullary enhancing lesion in the spinal cord at the T-1 level. The patient declined to undergo resection of the tumor because she was able to walk unassisted; however, she returned for surgery 1 month later because she had developed paraplegia with bladder and rectal dysfunction, and MRI showed enlargement of the tumor. Intraoperatively, the border between the tumor and normal tissue was poorly defined. Biopsy samples were obtained for histopathological examinations, and a diagnosis of astroblastoma with a Ki-67 index of 5% was made. Considering the rapid tumor growth on MRI and remarkable deterioration in her symptoms, the patient was treated with a combination of radiation therapy, temozolomide (TMZ), and bevacizumab. After completion of the combined treatment, she was able to move her toes, and oral TMZ and bevacizumab injections were continued. Six months later, definite tumor shrinkage was identified on MRI, and the patient was able to stand up from a wheelchair without assistance and walk by herself. No therapeutic regimens for residual astroblastoma are established; however, in this case the authors' therapeutic strategy was successful in treating the spinal cord astroblastoma.

JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonß plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma.

PURPOSE: This study explored the superiority of temozolomide (TMZ) + interferonß (IFNß) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design. EXPERIMENTAL DESIGN: Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ + radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m2, daily) followed by TMZ maintenance (100-200 mg/m2/day, days 1-5, every 4 weeks) for 2 years. Patients in the TMZ + IFNß + RT arm intravenously received IFNß (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ + RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8). RESULTS: Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ + RT and TMZ + IFNß + RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65-1.55; one-sided log rank P = 0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85-1.84). The incidence of neutropenia with the TMZ + RT and the TMZ + IFNß + RT (grade 3-4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%. CONCLUSIONS: TMZ + IFNß + RT is not considered as a candidate for the following phase III trial, and TMZ + RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

A Case of Breast Cancer Brain Metastasis with a 16-Year Time Interval without Evidence of Cancer Recurrence.

The median time of brain metastasis from the diagnosis of breast cancer is approximately 3 years. In this case report, a 69-year-old woman demonstrated cerebellar ataxia. Brain magnetic resonance imaging revealed enhanced lesions in bilateral cerebellar hemispheres. She had undergone surgery, radiation, and chemotherapy for uterine and breast cancer 24 years prior and 16 years prior, respectively. Although she had not received any anticancer treatment for 10 years, no recurrences were identified using whole body scans. A partial tumor resection was performed and the histological diagnosis was an adenocarcinoma from breast cancer. As no extracranial lesions were found, gamma-knife irradiation was performed, without additional systemic chemotherapy. One month posttreatment, the tumors dramatically reduced in size and the patient completely recovered from cerebellar ataxia. Systemic chemotherapy is not always required for brain metastasis from breast cancer with a long interval period, as long as no evidence of extracranial recurrence is detected.

Glioblastoma multiforme versus pleomorphic xanthoastrocytoma with anaplastic features in the pathological diagnosis: a case report.

BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) with anaplastic features should be strictly distinguished from glioblastoma multiforme (GBM). CASE PRESENTATION: A case of PXA that was initially diagnosed as GBM is presented. A 42-year-old man visited our clinic because of right hemiparesis and total aphasia. Head magnetic resonance imaging demonstrated enhanced multiple cystic lesions in the left temporal lobe suggesting an intra-parenchymal brain tumor. The lesion was partially removed and GBM with a Ki-67 index of 20 % was diagnosed by pathological examination of the resected specimen. Despite receiving radiation and chemotherapy, the patient died 6 months after the first admission. At autopsy, the boundary between the tumor and normal brain tissue was clear. Large parts of the tumor demonstrated typical features of PXA, including pleomorphism, clear xanthomatous cells with foamy cytoplasm, positive silver staining, and a Ki-67 index of less than 1 %. DISCUSSION AND CONCLUSIONS: GBM should be diagnosed only when the majority of the tumor cells are undifferentiated. Although the operative specimen appeared typical GBM histologically, the diagnosis of GBM was subsequently excluded by the autopsy finding that much of the tumor had the characteristic features of a benign PXA. Therefore, the final diagnosis in this case was PXA with anaplastic features. PXA with anaplastic features should be carefully distinguished from GBM to facilitate appropriate decisions concerning treatment.

Working Conditions and Lifestyle of Female Surgeons Affiliated to the Japan Neurosurgical Society: Findings of Individual and Institutional Surveys.

To investigate the working conditions of female neurosurgeons in Japan, two surveys were conducted by The Japan Neurosurgical Society: one involving female neurosurgeons themselves and the other involving the chiefs of neurosurgical departments. The responses were received from 224 (43.8%) female neurosurgeons and 496 (61.2%) departmental chiefs. About half (50.2%) of the female neurosurgeons were married and 39.2% had children (average number of children, 1.27). Their work was full-time in 80.6% of cases; on average, they worked 51.9 h per week, had night duty 2.8 times per month, and had 5.7 days off per month. Many of them stated that they were satisfied with their job status, but about half of them reported difficulty in maintaining a correct work-life balance. Among the institutions surveyed, 29% had female neurosurgeons. The survey of departmental chiefs revealed that the proxies for maternity leave were not available at most institutions, and that there was only limited availability of night child care (41%) or sick child care (39%); female neurosurgeons did not appear to be well-informed of these support systems. These findings suggest that apart from systematic approaches already in place, female neurosurgeons would prefer to have more understanding from their peers and chiefs.

Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy.

Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs.

Tree Based Method for Aggregate Survival Data Modeling.

In many scenarios, a patient in medical research is treated as a statistical unit. However, in some scenarios, we are interested in treating aggregate data as a statistical unit. In such situations, each set of aggregated data is considered to be a concept in a symbolic representation, and each concept has a hyperrectangle or multiple points in the variable space. To construct a tree-structured model from these aggregate survival data, we propose a new approach, where a datum can be included in several terminal nodes in a tree. By constructing a model under this condition, we expect to obtain a more flexible model while retaining the interpretive ease of a hierarchical structure. In this approach, the survival function of concepts that are partially included in a node is constructed using the Kaplan-Meier method, where the number of events and risks at each time point is replaced by the expectation value of the number of individual descriptions of concepts. We present an application of this proposed model using primary brain tumor patient data. As a result, we obtained a new interpretation of the data in comparison to the classical survival tree modeling methods.

The necessity of long-term follow-up including spinal examination after successful initial treatment of intracranial germinoma: case reports.

INTRODUCTION: Intracranial germinomas seldom recur at spinal space following whole-brain or whole-ventricular (WV) radiotherapy. The majority of the spinal recurrence takes place within 5 years after treatment; therefore, late spinal failure beyond 5 years after successful initial treatment is rare. CASE PRESENTATIONS: We describe the cases of two patients with intracranial germinoma, who developed spinal recurrence 7 and 9 years after the initial treatment with WV radiotherapy combined with and without chemotherapy, respectively. In both cases, spinal recurrent tumors were histologically diagnosed as germinoma and they were successfully treated with chemotherapy and local radiotherapy without tumor recurrence for 11 years and 11 months, respectively. CONCLUSION: Intracranial germinomas may potentially present with spinal recurrence many years after successful initial WV radiotherapy. Physicians must be aware of patients' symptoms during the clinical examination. Regular long-term monitoring, including spinal examination, is necessary for 5-10 years or longer.

Glioblastomas with IDH1/2 mutations have a short clinical history and have a favorable clinical outcome.

OBJECTIVE: Glioblastomas with isocitrate dehydrogenase 1/2 mutations comprise a biologically distinct subgroup of glioblastomas. We studied isocitrate dehydrogenase 1/2 mutant glioblastomas at the clinical, molecular and radiological levels to define their clinical features, including the prognostic value of isocitrate dehydrogenase 1/2 mutations compared with isocitrate dehydrogenase 1/2 wild-type glioblastomas. METHODS: We investigated 128 newly diagnosed glioblastoma patients who were treated at our institute between January 2005 and May 2013. Isocitrate dehydrogenase 1/2 mutation status was determined using pyrosequencing. O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation and 1p/19q co-deletions were also analyzed using pyrosequencing and multiplex ligation-dependent probe amplification, respectively. RESULTS: Isocitrate dehydrogenase 1/2 mutations were detected in 10 of 128 patients (7.8%). Isocitrate dehydrogenase 1/2 mutations were correlated with a younger age, the presence of an oligodendroglial component and 1p/19q co-deletions and a longer survival time. The interval from initial symptom to initial operation did not differ according to isocitrate dehydrogenase 1/2 mutation status (median interval: 2.3 versus 1.2 months; P = 0.13). Two of three isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions had an oligodendroglial component and were associated with a prolonged survival time. Multivariate analysis of 90 patients treated with temozolomide-based chemoradiotherapy indicated that age, extent of resection, postoperative Karnofsky performance score and O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation were correlated with better survival. Isocitrate dehydrogenase 1/2 mutations showed a trend for improved survival (P = 0.068). CONCLUSIONS: Most isocitrate dehydrogenase 1/2 mutant glioblastomas have a short clinical history, and some isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions behave like oligodendroglial tumors. Isocitrate dehydrogenase 1/2 mutations may have a positive prognostic impact on the Japanese population.