[Show abstract][Hide abstract] ABSTRACT: TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%¿±¿8.7%, respectively (p¿<¿0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%¿±¿2% vs. 57.4%¿±¿1.8% (p¿<¿0.01)). In contrast, ß-catenin mutation sensitized TP53 mutant cells to radiation (p¿<¿0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%¿±¿1.5% in lithium treated cells vs. 56.6¿±¿3% (p¿<¿0.01)) accompanied by increased number of ¿H2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%¿±¿8% for lithium treated cells vs. 27%¿±¿3% for untreated controls (p¿=¿0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine if molecular alterations are associated with tumor location and radiological characteristics in anaplastic gliomas. We performed a retrospective analysis of 122 anaplastic gliomas for molecular alterations (IDH1/2 mutations, TP53 mutations, and 1p19q co-deletion) to compare MRI features (location and image characteristics). We observed that IDH mutation is strongly associated with frontal location (P = 0.001). However, 13 tumors not located in the cerebral cortex were IDH intact tumors (P < 0.0001). While IDH mutation and TP53 mutation are significantly associated with AA (p < 0.0001), IDH mutation and 1p19q co-deletion were significantly associated with AO/AOA (p < 0.0001). No tumors with IDH mutation and 1p19q co-deletion infiltrated the temporal lobe (P = 0.003). The tumors with 1p19q co-deletion and histologically diagnosed as AO/AOA were associated with contrast enhancement on MR images (p = 0.007, p = 0.002, respectively) and those with TP53 mutation had a weak association with sharp tumor borders (p = 0.043). MRI features might be useful to predict molecular profiles in anaplastic gliomas.
[Show abstract][Hide abstract] ABSTRACT: Nuclear factor erythroid 2-related factor 2 (NRF2) plays pivotal roles in cytoprotection. We aimed at clarifying the contribution of the NRF2 pathway to malignant glioma pathology.
[Show abstract][Hide abstract] ABSTRACT: Object Maximum resection of gliomas with minimum surgical complications usually leads to optimum outcomes for patients. Radical resection of insulo-opercular gliomas is still challenging, and selection of ideal patients can reduce risk and obtain better outcomes. Methods This retrospective study included 83 consecutively treated patients with newly diagnosed gliomas located at the insulo-opercular region and extending to the sylvian fissure around the primary motor and somatosensory cortices. The authors selected 4 characteristics as surgical indicators: clear tumor boundaries, negative enhancement, intact lenticulostriate arteries, and intact superior extremity of the central insular sulcus. Results Univariate analysis showed that tumors with clear boundaries were associated with higher rates of gross-total resection than were tumors with ambiguous boundaries (75.7% vs 19.6%). Tumors with negative enhancement compared with enhanced tumors were associated with lower frequency of tumor progression (32.0% vs 81.8%, respectively) and lower rates of surgical complications (14.0% vs 45.5%, respectively). Tumors with intact lenticulostriate arteries were associated with higher rates of gross-total resection than were tumors with involved lenticulostriate arteries (67.3% vs 11.8%, respectively). Tumors with intact superior extremity of the central insular sulcus were associated with higher rates of gross-total resection (57.4% vs 20.7%, respectively) and lower rates of surgical complications (18.5% vs 41.4%, respectively) than were tumors with involved anatomical structures. Multivariate analysis showed that clear tumor boundaries were independently associated with gross-total resection (p < 0.001). Negative enhancement was found to be independently associated with surgical complications (p = 0.005), overall survival times (p < 0.001), and progression-free survival times (p = 0.004). Independent associations were also found between intact lenticulostriate arteries and gross-total resection (p < 0.001), between intact lenticulostriate arteries and progression-free survival times (p = 0.026), and between intact superior extremity of the central insular sulcus and gross-total resection (p = 0.043). Among patients in whom all 4 indicators were present, prognosis was good (5-year survival rate 93.3%), resection rate was maximal (gross-total resection 100%), and surgical complication rate was minimal (6.7%). Also among these patients, overall rates of survival (p = 0.003) and progression-free survival (p = 0.005) were significantly higher than among patients in whom fewer indicators were present. Conclusions The authors propose 4 simple indicators that can be used to identify ideal candidates for radical resection of insulo-opercular gliomas, improve the outcomes, and promote maximum resection without introducing neurological complications. The indicators are clear tumor boundaries, negative enhancement, intact lenticulostriate arteries, and intact superior extremity of the central insular sulcus.
Journal of Neurosurgery 08/2014; · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Optic pathway cavernous malformations (CMs) are extremely rare, accounting for less than 1 % of all intracranial CMs. We report a case of optic pathway CM mimicking optic glioma because the initial magnetic resonance (MR) images did not disclose hemorrhagic findings such as popcorn-like lesion or hemosiderin ring.
Child s Nervous System 07/2014; · 1.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intracranial germ cell tumors (iGCTs) are rare in the Western countries, however they are the second most common brain tumors in patients under 14 in Japan. Unlike other common pediatric brain tumors, the biology of iGCTs is largely unknown.
[Show abstract][Hide abstract] ABSTRACT: Glioblastoma carries a poor prognosis primarily because of its high rate of recurrence. Similarly, anaplastic gliomas without IDH mutation present poor prognosis similar to glioblastoma. The ability to predict the recurrence pattern and timing would be highly useful for determining effective treatment strategies. We here examined high grade glioma to determine their recurrence pattern and the expression of CD133, a cell surface marker of glioma stem cells.
[Show abstract][Hide abstract] ABSTRACT: Diagnosis of WHO grade III anaplastic gliomas does not always correspond to its clinical outcome because of the isocitrate dehydrogenase (IDH) gene status. Anaplastic gliomas without IDH mutation result in a poor prognosis, similar to grade IV glioblastomas. However, the malignant features of anaplastic gliomas without IDH mutation are not well understood. The aim of this study was to examine anaplastic gliomas, in particular those without IDH mutation, with regard to their malignant features, recurrence patterns, and association with glioma stem cells.
[Show abstract][Hide abstract] ABSTRACT: Abstract In cases of malignant brain tumors, infiltrating tumor cells that exist at the tumor-surrounding brain tissue always escape from cytoreductive surgery and, protected by blood-brain barrier (BBB), survive the adjuvant chemoradiotherapy, eventually leading to tumor recurrence. Local interstitial delivery of chemotherapeutic agents is a promising strategy to target these cells. During our effort to develop effective drug delivery methods by intra-tumoral infusion of chemotherapeutic agents, we found consistent pattern of leakage from the tumor. Here we describe our findings and propose promising strategy to cover the brain tissue surrounding the tumor with therapeutic agents by means of convection-enhanced delivery. First, the intracranial tumor isograft model was used to define patterns of leakage from tumor mass after intra-tumoral infusion of the chemotherapeutic agents. Liposomal doxorubicin, although first distributed inside the tumor, distributed diffusely into the surrounding normal brain once the leakage happen. Trypan blue dye was used to evaluate the distribution pattern of peri-tumoral infusions. When infused intra- or peri-tumorally, infusates distributed robustly into the tumor border. Subsequently, volume of distributions with different infusion scheduling; including intra-tumoral infusion, peri-tumoral infusion after tumor resection, peri-tumoral infusion without tumor removal with or without systemic infusion of steroids, were compared with Evans-blue dye. Peri-tumoral infusion without tumor removal resulted in maximum volume of distribution. Prior use of steroids further increased the volume of distribution. Local interstitial drug delivery targeting tumor surrounding brain tissue before tumor removal should be more effective when targeting the invading cells.
[Show abstract][Hide abstract] ABSTRACT: Object Intraoperative diagnosis is important in determining the strategies during surgery for glioma. Because the mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes have diagnostic, prognostic, and predictive values, the authors assessed the feasibility and significance of a simplified method for the intraoperative detection of IDH1 and IDH2 gene mutations. Methods Rapid DNA extraction, amplification with conventional polymerase chain reaction (PCR) or co-amplification at lower denaturation temperature PCR (COLD-PCR), and fluorescence melting curve analysis with adjacent hybridization probes were performed for the intraoperative detection of IDH1 and IDH2 mutations in 18 cases of suspected nonneoplastic lesions and low- and high-grade gliomas and in 3 cases of radiation necrosis. Results DNA extraction for detection of the mutation took 60-65 minutes. The results of this assay showed complete correlation with that of Sanger sequencing. The sensitivity for detection of mutations in a background of wild-type genes was 12.5% and 2.5% in conventional PCR and COLD-PCR, respectively. The diagnosis of glioma was established in 3 of 5 cases in which definitive diagnosis was not obtained using frozen sections, and information was obtained for the discrimination of glioblastoma or glioblastoma with an oligodendroglioma component from anaplastic glioma or secondary glioblastoma. This assay also detected a small fraction of tumor cells with IDH1 mutation in radiation necrosis. Conclusions These methods provide important information for establishing the differential diagnosis between low-grade glioma and nonneoplastic lesions and the diagnosis for subtypes of high-grade glioma. Although tumor cells in radiation necrosis were detected with a high sensitivity, further investigation is necessary for clinical application in surgery for recurrent glioma.
Journal of Neurosurgery 04/2014; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.
[Show abstract][Hide abstract] ABSTRACT: Survivors of pediatric brain tumors are often affected by late effects, such as motility disturbance of limb(s), seizure, ocular/visual impairment, endocrine abnormality, and higher brain dysfunction, resulting from the disease and its treatment. Appropriate provision of supportive care will require understanding the effects of these experiences on survivors' health-related quality of life (HRQOL).
The aim of this study was to identify the relationships between late effects and specific aspects of the HRQOL of pediatric brain tumor survivors.
We distributed questionnaires for measuring HRQOL to 138 survivors and their parents at 8 hospitals and 1 clinic in Japan and simultaneously surveyed late effects using information provided by the survivors' attending physicians. We compared the HRQOL of survivors with and survivors without specific late effects.
A total of 106 survivors and their parents returned the questionnaires to the researchers. The HRQOL of survivors 18 years or older was negatively affected by all 5 late effects, indicating that their higher impairment was associated with diminished HRQOL. The HRQOL of survivors aged 12 to 17 years was negatively affected by 2 late effects (ocular/visual impairment and motility disturbance of the limbs). A part of the HRQOL subdomain (motor and cognitive functioning) of survivors aged 12 to 17 years was positively related to ocular/visual impairment.
Five late effects influenced the HRQOL of pediatric brain tumor survivors.
Nurses and other health professionals should provide specific care designed to support aspects of HRQOL affected by late effects. For example, survivors with ocular/visual impairment may be expected to require additional emotional support, and those with seizures or endocrine abnormalities may be expected to require additional support for sleep disorders.
[Show abstract][Hide abstract] ABSTRACT: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.
Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.
Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.
Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
Journal of Clinical Oncology 02/2014; · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 15 in Japan. The pathogenesis of iGCTs is largely unexplored. Although a subset of iGCTs is known to have KIT mutation, its impact on the biology and patients' survival has not been established. In this study, we investigated genes involved in the KIT signaling pathway. 65 iGCTs (30 pure germinomas, 14 teratomas, 18 mixed GCTs, 2 yolk sac tumors, 1 choriocarcinoma) were screened for mutation of KIT, KRAS, NRAS, HRAS, BRAF, PDGFRA, and IDH1 by direct sequencing. KIT expression was examined by immunohistochemistry and quantitative PCR. Chromosomal status was analyzed by array-comparative genomic hybridization (aCGH). Somatic mutations were detected only in KIT and RAS, which were frequently observed in pure germinomas (60.0 %), but rare in non-germinomatous GCTs (NGGCTs) (8.6 %). All KIT/RAS mutations were mutually exclusive. Regardless of the mutation status or mRNA expression, the KIT protein was expressed in all germinomas, while only in 54.3 % of NGGCTs. Amplification of KIT was found in one pure germinoma by aCGH. In pure germinomas, high expression of KIT mRNA was associated with the presence of KIT/RAS alterations and severe chromosomal instability. Our results indicate that alterations of the KIT signaling pathway play an important role in the development of germinomas. Pure germinomas may develop through two distinct pathogeneses: one with KIT/RAS alterations, elevated KIT mRNA expression and severe chromosomal instability, and the other through yet an unidentified mechanism without any of the above abnormalities.
[Show abstract][Hide abstract] ABSTRACT: Autoimmune hypophysitis very rarely spreads to nearby organs outside the pituitary tissue, for unknown reasons, with only 5 reported cases of hypophysitis spreading over the cavernous sinus.
Three patients presented with cases of non-infectious hypophysitis spreading outside the pituitary tissue over the cavernous sinus. All three cases were diagnosed with histological confirmation by transsphenoidal surgery, and the patients showed remarkable improvement with postoperative pulse dose steroid therapy, including disappearance of abnormal signal intensities in the bilateral hypothalami on magnetic resonance imaging, resolution of severe stenosis of the internal carotid artery, and normalization of swollen pituitary tissues. Two of 3 cases fulfilled the histological criteria of immunoglobulin G4-related disease, although none of the patients had high serum immunoglobulin G4 level.
The true implications of such unusual spreading of hypophysitis to nearby organs are not fully understood, but the mechanism of occurrence might vary according to the timing of inflammation in this unusual mode of spreading. Pulse dose steroid therapy achieved remarkably good outcomes even in the patient with progressive severe stenosis of the internal carotid artery and rapid visual deterioration.
[Show abstract][Hide abstract] ABSTRACT: Surgical resection is identified as an important prognostic factor for survival in patients undergoing initial resection of glioblastoma (GBM). However, in patients with tumor recurrence, the benefits of repeat surgery remain unclear. Recent reports have stated that the association between initial surgery for GBM and subventricular zone (SVZ) influences survival. The current study examined the relationship of SVZ involvement in recurrent GBM to survival time after reoperation. We conducted a retrospective review of 61 consecutive patients who had undergone repeat surgery for recurrent GBM at our institution between 1997 and 2010. Survival after repeat surgery were compared between patients with (n = 29) and without (n = 32) SVZ involvement at recurrence using univariate analysis with known prognostic factors, including sex, age, Karnofsky Performance Status (KPS) score at recurrence, recurrent tumor size, initial SVZ involvement, and adjuvant therapy after repeat surgery, as variables. All 26 SVZ-positive tumors at initial diagnosis recurred as SVZ-positive tumors, while 32 of 35 SVZ-negative tumors at initial diagnosis remained SVZ-negative at recurrence; the remaining three were SVZ-positive at recurrence. Survival after repeat surgery was decreased in patients with recurrent GBM involving the SVZ at recurrence (p = 0.022). No other prognostic factors for survival after repeat surgery were identified in this study. This finding may have prognostic and therapeutic significance.
[Show abstract][Hide abstract] ABSTRACT: Convection-enhanced delivery (CED) has been developed as a potentially effective drug-delivery strategy into the central nervous system. In contrast to systemic intravenous administration, local delivery achieves high concentration and prolonged retention in the local tissue, with increased chance of local toxicity, especially with toxic agents such as chemotherapeutic agents. Therefore, the factors that affect local toxicity should be extensively studied. New METHOD: With the assumption that concentration-oriented evaluation of toxicity is important for local CED, we evaluated the appearance of local toxicity among different agents after delivery with CED and studied if it is dose dependent or concentration dependent.
Local toxicity profile of chemotherapeutic agents delivered via CED indicates BCNU was dose-dependent, whereas that of ACNU was concentration-dependent. On the other hand, local toxicity for doxorubicin, which is not distributed effectively by CED, was dose-dependent. Local toxicity for PLD, which is extensively distributed by CED, was concentration-dependent. Comparison with Existing METHOD: Traditional evaluation of drug induced toxicity was dose-oriented. This is true for systemic intravascular delivery. However, with local CED, toxicity of several drugs exacerbated in concentration-dependent manner. From our study, local toxicity of drugs that are likely to distribute effectively tended to be concentration-dependent.
Concentration rather than dose may be more important for the toxicity of agents that are effectively distributed by CED. Concentration-oriented evaluation of toxicity is more important for CED.
Journal of neuroscience methods 11/2013; · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent advances in diagnostic imaging and experience with germinomas may allow for the differentiation of central nervous system germinomas from other tumors based on clinical information, without histological verification. We retrospectively analyzed clinically diagnosed germinoma-like tumors of the pineal and/or suprasellar regions. This was done to evaluate the efficacy of our strategy of defining germinoma-compatible tumors based on good responses to initial chemotherapy. The responses to chemotherapy and survival of 34 consecutive patients with germinoma-like tumors who underwent initial treatment from July 2001 to October 2010 were analyzed. The minimum apparent diffusion coefficient (minADC) value and proton magnetic resonance spectroscopy (MRS) were evaluated in recent patients. Twelve patients with histologically verified germinomas and 18 with germinoma-compatible tumors showed early logarithmic decreases in tumor volume in response to initial chemotherapy, typical low minADC values and typical MRS characteristics, including increased choline/creatine ratios, decreased N-acetylasparate/creatine ratios, and large lipid peaks. These patients had good progression-free survival. The other four patients, with histologically verified non-germinomas, showed no response to chemotherapy, and one patient with a pineoblastoma showed a similar minADC value and MRS characteristics to those of patients with germinomas. The response to initial chemotherapy can be used to distinguish germinoma-compatible tumors from non-germinoma in patients with germinoma-like tumors of the pineal and/or suprasellar regions. The evaluation of minADC and proton MRS are useful for distinguishing germinomas from other tumors. However, a subset of non-germinomas may show similar characteristics to germinomas. The benefit of bypassing unnecessary surgical intervention can be achieved, at least in Asian populations with a high incidence of germinomas.
Journal of Clinical Neuroscience 11/2013; · 1.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Carmustine (BCNU) implants (Gliadel® Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.