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Simple Summary: Therapeutic options for rare cancers are frequently limited and less effective than for common cancers. Therefore, novel therapeutic strategies to treat rare cancers are urgently required. Our clinical study on rare cancers showed that the biweekly WT1 Trio peptide vaccine comprising two WT1-cytotoxic T lymphocyte (CTL)-peptides and one WT1-helper T lymphocyte-peptide induced more robust immune responses targeting WT1 than the weekly WT1-CTL peptide (WT1-235) vaccine. In addition, the safety of WT1 Trio was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer (TC). Fifteen (33.3%) of the 45 patients with recurrent or advanced rare cancers, including malignant glioma, soft-tissue sarcoma, TC, and malignant pleural mesothelioma, achieved stable disease after 3 months of protocol treatment. Therefore, since WT1 is widely overexpressed in rare cancers, WT1-targeted immunotherapy may be a therapeutic strategy for rare cancers. No standard treatment has been established for most rare cancers. Here, we report a clinical trial of a biweekly WT1 tri-peptide-based vaccine for recurrent or advanced rare cancers. Due to the insufficient number of patients available for a traditional clinical trial, the trial was designed for rare cancers expressing shared target molecule WT1. The recruitment criteria included WT1-expressing tumors as well as HLA-A*24:02 or 02:01. The primary endpoints were immunoglobulin G (IgG) antibody (Ab) production against the WT1-235 cytotoxic T lymphocyte (CTL) epitope and delayed-type hypersensitivity (DTH) skin reactions to targeted WT1 CTL epitopes. The secondary endpoints were safety and clinical efficacy. Forty-five patients received WT1 Trio, and 25 (55.6%) completed the 3-month protocol treatment. WT1-235 IgG Ab was positive in 88.0% of patients treated with WT1 Trio at 3 months, significantly higher than 62.5% of the weekly WT1-235 CTL peptide vaccine. The DTH positivity rate in WT1 Trio was 62.9%, which was not significantly different from 60.7% in the WT1-235 CTL peptide vaccine. The WT1 Trio safety was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer. Fifteen (33.3%) patients achieved stable disease after 3 months of treatment. In conclusion, the biweekly WT1 Trio vaccine containing the WT1-332 helper T lymphocyte peptide induced more robust immune responses targeting WT1 than the weekly WT1-235 CTL peptide vaccine. Therefore, WT1-targeted immunotherapy may be a potential therapeutic strategy for rare cancers. [ABSTRACT FROM AUTHOR]

We have previously revealed the overexpression of Wilms' tumor gene 1 (WT1) in malignant glioma and developed WT1 peptide vaccine cancer immunotherapy. A phase II clinical trial indicated the clinical efficacy of the WT1 peptide vaccine for recurrent malignant glioma. Here, we aimed to investigate the immunological microenvironment in glioma tissues before and after WT1 peptide vaccine treatment. Paired tissue samples were obtained from 20 malignant glioma patients who had received the WT1 peptide vaccine for > 3 months and experienced tumor progression, confirmed radiographically and/or clinically, during vaccination. We discovered that the expression of WT1 and HLA class I antigens in the tumor cells significantly decreased after vaccination. Maintenance of WT1 expression, which is the target molecule of immunotherapy, in tumor cells during the vaccination period was significantly associated with a longer progression-free and overall survival. A high expression of HLA class I antigens and low CD4+/CD8+ tumor-infiltrating lymphocytes (TIL) ratio in pre-vaccination specimens, were also associated with a good prognosis. No statistically significant difference existed in the number of infiltrating CD3+ or CD8+ T cells between the pre- and post-vaccination specimens, whereas the number of infiltrating CD4+ T cells significantly decreased in the post-vaccination specimens. This study provides insight into the mechanisms of intra-tumoral immune reaction/escape during WT1 peptide vaccine treatment and suggests potential clinical strategies for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: An open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma. Methods: Patients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%. Results: Of the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27–66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4–17.7) and 1.5 (1.4–1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3–4 and 2.0% for Grade 5; most adverse events resolved and were manageable. Conclusions: The 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types. Clinical Trial Registration: JapicCTI-152967. [ABSTRACT FROM AUTHOR]

Background: One of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden. Methods: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI. Results: Among the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0–231.0). The median CSI dose was 18 Gy (15.0–24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38–99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03–29.11, p value 0.044 for overall survival). Conclusion: Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment. [ABSTRACT FROM AUTHOR]

Meningiomas are often reported to be sensitive to progesterone, but it is not clear how pregnancy and childbirth affect this. A 41-year-old woman experienced two pregnancies and two deliveries. During the first pregnancy, her right visual acuity was impaired, but it recovered after delivery. However, during the second pregnancy, the right visual acuity was impaired again and did not recover after the second delivery. The magnetic resonance imaging revealed a right optic nerve sheath meningioma (ONSM). Surgical resection of the intracranial extension of the tumor was performed to prevent tumor invasion of the left optic nerve and optic chiasm. Pathological examination diagnosed meningioma with positive immunostaining for progesterone receptor. The present study provided clinical features of ONSM associated with pregnancy. ONSM may present with increased tumor growth and impaired vision with pregnancy. [ABSTRACT FROM AUTHOR]

To investigate the safety of combined Wilms tumor 1 peptide vaccination and temozolomide treatment of glioblastoma, a phase I clinical trial was designed. Seven patients with histological diagnosis of glioblastoma underwent concurrent radiotherapy and temozolomide therapy. Patients first received Wilms tumor 1 peptide vaccination 1 week after the end of combined concurrent radio/temozolomide therapy, and administration was continued once per week for 7 weeks. Temozolomide maintenance was started and performed for up to 24 cycles, and the observation period for safety encompassed 6 weeks from the first administration of maintenance temozolomide. All patients showed good tolerability during the observation period. Skin disorders, such as grade 1/2 injection-site reactions, were observed in all seven patients. Although grade 3 lymphocytopenia potentially due to concurrent radio/temozolomide therapy was observed in five patients (71.4 %), no other grade 3/4 hematological or neurological toxicities were observed. No autoimmune reactions were observed. All patients are still alive, and six are on Wilms tumor 1 peptide vaccination without progression, yielding a progression-free survival from histological diagnosis of 5.2-49.1 months. Wilms tumor 1 peptide vaccination was stopped in one patient after 12 injections by the patient's request. The safety profile of the combined Wilms tumor 1 peptide vaccination and temozolomide therapy approach for treating glioblastoma was confirmed. [ABSTRACT FROM AUTHOR]

BACKGROUND: The extent of tumor resection is acknowledged as 1 of the prognostic factors for glioma. 5-Aminolevulinic acid (5-ALA)-induced fluorescence guidance and neuronavigation integrated with 11C-methionine positron emission tomography (PET) are widely utilized under the expectation of improving the extent of resection. These 2 novel approaches are beneficial for glioma resections, and the combination of these approaches appears rational. However, biological characteristics reflecting 5-ALA-induced fluorescence and 11C-methionine uptake have not been clearly elucidated, and studies about the relationship between 5-ALA-induced fluorescence and 11C-methionine uptake have been limited. The present study aimed to clarify this issue. METHODS: Data from 11 consecutive patients harboring astrocytic tumors were analyzed: 2 grade II and 2 grade III, and 7 grade IV tumors were included. Thirty samples from these patients were obtained from the relative periphery of each tumor. Relationships among histology, 5-ALA-induced fluorescence and 11C-methionine uptake were analyzed by stereotactic sampling and image analysis. RESULTS: Uptake of 11C-methionine correlated with cell density ( R2 = 0.322, P = .0059). Cell density was higher in fluorescence-positive areas than in negative areas (2760 ± 1080 vs 1450 ± 1380/mm2, P = .0132). Although both 11C-methionine uptake and fluorescence seemed to correlate with cell density, no significant difference in 11C-methionine uptake was seen between fluorescence-positive and -negative areas ( P = .367). Multiple linear regression analysis revealed 11C-methionine uptake and 5-ALA-induced fluorescence as independent indices for tumor cell density. CONCLUSIONS: These results indicate that 5-ALA fluorescence and 11C-methionine PET image are separate index markers for cytoreduction surgery of gliomas. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: There have been few studies investigating neuro-oncologists' attitudes toward the disclosure of the diagnosis. This study aimed to determine the current status of disclosure to glioma patients in Japan and to analyze the factors associated with disclosure. Methods: A set of questionnaires about disclosure to patients with malignant glioma was distributed by e-mail to 191 physicians participating in the 27th Annual Meeting of the Japan Society for Neuro-Oncology. Results: The response rate was 73.8% (141/191). Of these, 44.3% disclosed the correct diagnosis to glioblastoma patients aged <60 years and 41.4% disclosed the correct diagnosis to those aged ≥70 years; for anaplastic astrocytoma patients, these proportions were 61.5 and 51.9%, respectively. Physicians working at facilities performing surgery on more than 50 cases of glioma per year, those in metropolitan areas, and those with other patient psychosocial support systems available disclosed the diagnosis and prognosis more frequently. The physicians' gender and postgraduate period of practice did not influence disclosure. When the family opposed disclosing the diagnosis to the patient, more than half of the physicians respected the family's wishes. Conclusions: This survey revealed that most of the physicians told at least the malignant nature of the disease to patients with malignant glioma, but they did not always tell the exact diagnosis. Physicians tended to modify their attitudes toward disclosing a diagnosis or prognosis of glioma depending on the histopathological grading, the hospital volume of cases, the location, the availability of patient psychological support systems, and the patient's family's wishes. [ABSTRACT FROM AUTHOR]

Meningiomas are the most frequent primary brain tumors. The long-term natural history of asymptomatic meningiomas remains unclear and difficult to predict accurately, however. The purpose of this study was to determine the subsequent course of asymptomatic meningiomas preceded by 5 years of no treatment. We retrospectively studied patients with radiologically suspected intracranial asymptomatic meningiomas preceded by 5 years of no treatment. We volumetrically measured the lesions' chronological changes during the initial 5 years to obtain the 5-year tumor doubling time (5y-TdT). A total of 201 cases met the inclusion criteria. They were further divided into 3 subgroups: those who remained asymptomatic (group A; 174 cases), those who developed neurological symptoms and underwent treatment (group B; 8 cases), and those who received intentional intervention for a preventative reason (group C; 19 cases). 5y-TdT of group B (median: 46.5 months) was significantly shorter than that of group A (median: 216.3 months) (P < 0.001). Progression-free survival (PFS) was significantly different between tumors that exhibited 5y-TdT ≥ 98.8 months and <98.8 months (P < 0.001). When we combined groups B and C and set the PFS endpoint as either disease progression or treatment, we found that more than 20% of patients would require treatment within 15 years. The present study revealed the subsequent course of asymptomatic meningiomas after 5 years of no treatment and demonstrated that 5y-TdT is useful to detect patients who may require treatment. [ABSTRACT FROM AUTHOR]

Cluster of differentiation (CD) 166 or activated leukocyte cell adhesion molecule (ALCAM) is a transmembrane molecule known to be an intercellular adhesion factor. The expression and function of ALCAM in medulloblastoma (MB), a pediatric brain tumor with highly advanced molecular genetics, remains unclear. Therefore, this study aimed to clarify the significance and functional role of ALCAM expression in MB. ALCAM expression in 45 patients with MB was evaluated by immunohistochemical analysis of formalin-fixed paraffin-embedded clinical specimens and the relationship between ALCAM expression and pathological type/molecular subgroup, such as WNT, SHH, Group 3, and Group 4, was examined. Eight ALCAM positive (18%), seven partially positive (16%), and 30 negative (67%) cases were detected. All seven cases of the WNT molecular subgroup were ALCAM positive and ALCAM expression strongly correlated with this subgroup (P < 0.0001). In addition, functional studies using MB cell lines revealed ALCAM expression affected proliferation and migration as a positive regulator in vitro. However, ALCAM silencing did not affect survival or the formation of leptomeningeal dissemination in an orthotopic mouse model, but did induce a malignant phenotype with increased tumor cell invasion at the dissemination sites (P = 0.0029). In conclusion, our results revealed that ALCAM exhibited highly specific expression in the WNT subgroup of MB. Furthermore, we demonstrated that the cell kinetics of MB cell lines can be altered by the expression of ALCAM. [ABSTRACT FROM AUTHOR]

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

Brain Tumor Image Analysis (BraTumIA) is a fully automated segmentation tool dedicated to detecting brain tumors imaged by magnetic resonance imaging (MRI). BraTumIA has recently been applied to several clinical investigations; however, the validity of this novel method has not yet been fully examined. The present study was conducted to validate the quality of tumor segmentation with BraTumIA in comparison with results from 11C-methionine positron emission tomography (MET-PET). A total of 45 consecutive newly diagnosed high-grade gliomas imaged by MRI and MET-PET were analyzed. Automatic tumor segmentation was conducted by BraTumIA and the resulting segmentation images were registered to MET-PET. Three-dimensional conformal association between these two modalities was calculated, considering MET-PET as the gold standard. High underestimation and overestimation errors were observed in tumor segmentation calculated by BraTumIA compared with MET-PET. Furthermore, when the tumor/normal ratio threshold was set at 1.3 from MET-PET, the BraTumIA false-positive fraction was ~0.4 and the false-negative fraction was 0.9. By tightening this threshold to 2.0, the BraTumIA false-positive fraction was 0.6 and the false-negative fraction was 0.6. Following comparison of segmentation performance with BraTumIA with regard to glioblastoma (GBM) and World Health Organization (WHO) grade III glioma, GBM exhibited better segmentation compared with WHO grade III glioma. Although BraTumIA may be able to detect enhanced tumors, non-enhancing tumors and necrosis, the spatial concordance rate with MET-PET was relatively low. Careful interpretation is therefore required when using this technique. [ABSTRACT FROM AUTHOR]

Purpose: The safety and clinical efficacy of WT1 human leukocyte antigen (HLA) class I peptide vaccine have been established, but the safety of a cocktail vaccine of WT1 HLA class I and II peptides has not. To verify its safety, we performed a phase I clinical trial for patients with recurrent malignant gliomas and assessed the immunological responses and survival data.Patients and methods: Fourteen HLA-A*24:02-positive patients with recurrent malignant glioma (2 with grade 3, 12 with grade 4) were enrolled. Every week, the patients received alternately a vaccine containing 3 mg of WT1 HLA-A*24:02-restricted (HLA class I) peptide and a cocktail vaccine of the HLA class I peptide and one of 0.75, 1.5 or 3 mg of the WT1 HLA class II peptide. For patients who showed no significant adverse effects within 6 weeks, the WT1 vaccine was continued at 2-4-week intervals.Results: Eleven of the 14 patients completed WT1 vaccination for 6 weeks, while 3 patients dropped out earlier due to disease progression. All patients showed grade I level of skin disorders at the injection sites. No grade III/IV toxicity or dose-limiting toxicity was observed for any dose of WT1 HLA class II peptide. Six of the 14 patients had stable disease at 6 weeks. Median OS and 1-year OS rates were 24.7 weeks and 36%, respectively.Conclusion: The safety of a cocktail vaccine of WT1 HLA class I and II peptides for malignant gliomas was verified. This vaccine is, therefore, considered promising for patients with recurrent malignant glioma. [ABSTRACT FROM AUTHOR]

A number of studies have revealed the usefulness of multimodal imaging in gliomas. Although the results have been heavily affected by the method used for region of interest (ROI) design, the most discriminatory method for setting the ROI remains unclear. The aim of the present study was to determine the most suitable ROI design for 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) positron emission tomography (PET), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) obtained by diffusion tensor imaging (DTI) from the viewpoint of grades of non-enhancing gliomas. A total of 31 consecutive patients with newly diagnosed, histologically confirmed magnetic resonance (MR) non-enhancing gliomas who underwent FDG-PET, MET-PET and DTI were retrospectively investigated. Quantitative measurements were performed using four different ROIs; hotspot/tumor center and whole tumor, constructed in either two-dimensional (2D) or three-dimensional (3D). Histopathological grading of the tumor was considered as empirical truth and the quantitative measurements obtained from each ROI was correlated with the grade of the tumor. The most discriminating ROI for non-enhancing glioma grading was different according to the different imaging modalities. 2D-hotspot/center ROI was most discriminating for FDG-PET (P=0.087), ADC map (P=0.0083), and FA map (P=0.25), whereas 3D-whole tumor ROI was best for MET-PET (P=0.0050). In the majority of scenarios, 2D-ROIs performed better than 3D-ROIs. Results from the image analysis using FDG-PET, MET-PET, ADC and FA may be affected by ROI design and the most discriminating ROI for non-enhancing glioma grading was different according to the imaging modality. [ABSTRACT FROM AUTHOR]

Reports have suggested that tumor textures presented on T2-weighted images correlate with the genetic status of glioma. Therefore, development of an image analyzing framework that is capable of objective and high throughput image texture analysis for large scale image data collection is needed. The current study aimed to address the development of such a framework by introducing two novel parameters for image textures on T2-weighted images, i.e., Shannon entropy and Prewitt filtering. Twenty-two WHO grade 2 and 28 grade 3 glioma patients were collected whose pre-surgical MRI and IDH1 mutation status were available. Heterogeneous lesions showed statistically higher Shannon entropy than homogenous lesions (p = 0.006) and ROC curve analysis proved that Shannon entropy on T2WI was a reliable indicator for discrimination of homogenous and heterogeneous lesions (p = 0.015, AUC = 0.73). Lesions with well-defined borders exhibited statistically higher Edge mean and Edge median values using Prewitt filtering than those with vague lesion borders (p = 0.0003 and p = 0.0005 respectively). ROC curve analysis also proved that both Edge mean and median values were promising indicators for discrimination of lesions with vague and well defined borders and both Edge mean and median values performed in a comparable manner (p = 0.0002, AUC = 0.81 and p < 0.0001, AUC = 0.83, respectively). Finally, IDH1 wild type gliomas showed statistically lower Shannon entropy on T2WI than IDH1 mutated gliomas (p = 0.007) but no difference was observed between IDH1 wild type and mutated gliomas in Edge median values using Prewitt filtering. The current study introduced two image metrics that reflect lesion texture described on T2WI. These two metrics were validated by readings of a neuro-radiologist who was blinded to the results. This observation will facilitate further use of this technique in future large scale image analysis of glioma. [ABSTRACT FROM AUTHOR]

One of the challenges in glioblastoma (GBM) imaging is to visualize non-enhancing tumor (NET) lesions. The ratio of T1- and T2-weighted images (rT1/T2) is reported as a helpful imaging surrogate of microstructures of the brain. This research study investigated the possibility of using rT1/T2 as a surrogate for the T1- and T2-relaxation time of GBM to visualize NET effectively. The data of thirty-four histologically confirmed GBM patients whose T1-, T2- and contrast-enhanced T1-weighted MRI and 11C-methionine positron emission tomography (Met-PET) were available were collected for analysis. Two of them also underwent MR relaxometry with rT1/T2 reconstructed for all cases. Met-PET was used as ground truth with T2-FLAIR hyperintense lesion, with >1.5 in tumor-to-normal tissue ratio being NET. rT1/T2 values were compared with MR relaxometry and Met-PET. rT1/T2 values significantly correlated with both T1- and T2-relaxation times in a logarithmic manner (p < 0.05 for both cases). The distributions of rT1/T2 from Met-PET high and low T2-FLAIR hyperintense lesions were different and a novel metric named Likeliness of Methionine PET high (LMPH) deriving from rT1/T2 was statistically significant for detecting Met-PET high T2-FLAIR hyperintense lesions (mean AUC = 0.556 ± 0.117; p = 0.01). In conclusion, this research study supported the hypothesis that rT1/T2 could be a promising imaging marker for NET identification. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) reactivation during anticancer chemotherapy or immunosuppressive therapy in chronic carriers can lead to fatal liver failure. We report a rare case of severe HBV reactivation during postoperative radiotherapy with concomitant and adjuvant temozolomide (TMZ) for malignant glioma. A 49-year-old Japanese woman with a history of HBV carrier status with positive results for hepatitis B surface antigen presented with persistent headache due to a tumor in the left frontal lobe. The tumor was partially resected and anaplastic astrocytoma was diagnosed. Postoperative liver function was normal and radiotherapy plus concomitant and adjuvant TMZ was started. Impaired liver function became apparent just before administration of adjuvant TMZ, and acute liver failure developed. Antiviral therapy including entecavir, a nucleoside analog, led to a successful outcome and the patient survived. This case underlines the possibility of HBV reactivation due to TMZ and suggests the utility of HBV screening and antiviral prophylaxis before administration of TMZ to patients with malignant glioma. [ABSTRACT FROM AUTHOR]

Background: The extent of tumor resection is acknowledged as 1 of the prognostic factors for glioma. 5-Aminolevulinic acid (5-ALA)-induced fluorescence guidance and neuronavigation integrated with (11) C-methionine positron emission tomography (PET) are widely utilized under the expectation of improving the extent of resection. These 2 novel approaches are beneficial for glioma resections, and the combination of these approaches appears rational. However, biological characteristics reflecting 5-ALA-induced fluorescence and (11) C-methionine uptake have not been clearly elucidated, and studies about the relationship between 5-ALA-induced fluorescence and (11) C-methionine uptake have been limited. The present study aimed to clarify this issue.Methods: Data from 11 consecutive patients harboring astrocytic tumors were analyzed: 2 grade II and 2 grade III, and 7 grade IV tumors were included. Thirty samples from these patients were obtained from the relative periphery of each tumor. Relationships among histology, 5-ALA-induced fluorescence and (11) C-methionine uptake were analyzed by stereotactic sampling and image analysis.Results: Uptake of (11) C-methionine correlated with cell density (R(2) = 0.322, P = .0059). Cell density was higher in fluorescence-positive areas than in negative areas (2760 ± 1080 vs 1450 ± 1380/mm(2) , P = .0132). Although both (11) C-methionine uptake and fluorescence seemed to correlate with cell density, no significant difference in (11) C-methionine uptake was seen between fluorescence-positive and -negative areas (P = .367). Multiple linear regression analysis revealed (11) C-methionine uptake and 5-ALA-induced fluorescence as independent indices for tumor cell density.Conclusions: These results indicate that 5-ALA fluorescence and (11) C-methionine PET image are separate index markers for cytoreduction surgery of gliomas. [ABSTRACT FROM AUTHOR]

Abstract: 11C-methionine positron emission tomography (11C-methionine PET) provides accurate detection of brain tumors. Several reports have analyzed the correlation between uptake of 11C-methionine and Ki-67 index or microvessel density non-stereotactically and suggested that 11C-methionine uptake reflects both proliferation potential and angiogenic capability in gliomas. As gliomas possess heterogeneous histological architecture, non-stereotactic comparison of the histology and 11C-methionine PET image may not be accurate. In the present study, the correlation between 11C-methionine uptake and cell or microvessel density was analyzed using histological specimens obtained by stereotactic biopsy, and an exact local comparison of 11C-methionine PET image and histological specimens was conducted. The tumor/normal tissue (T/N) ratio of 11C-methionine positron emission tomography was found to correlate better with cell density (R =0.747, p =0.000042) and Ki-67 index (R =0.675, p =0.00041) than with microvessel density (R =0.467, p =0.025) in a histological comparison using a stereotactic image. Furthermore, multiple linear regression analysis revealed that cell density was the key determinant for predicting 11C-methionine level while microvessel density was not. These results suggest that cell density contributes more to 11C-methionine uptake than microvessel density in glioma tissues and that the previously reported correlation of 11C-methionine uptake and microvessel density in glioma patients requires reevaluation. [Copyright &y& Elsevier]

Abstract: Multimodal imaging is one of the necessary steps in the treatment of malignant brain tumors, and use of magnetic resonance imaging (MRI) and positron emission tomography (PET) are the current gold standard technique for the morphological and biological assessment of malignant brain tumors. In addition, fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) and 11C-methionine PET are useful to determine the tumor border at the tumor and white matter interface. Although there is no question of their value, a universally accepted cut-off value to discriminate normal and abnormal tissue has not been established. In this study we attempted to calculate and determine the cut-off values in FA and 11C-methionine PET that will allow delineation of the tumor border at the tumor and white matter interface by combining these two modalities. We were able to determine individual cut-off values for 11 patients, and then found an average cut-off value in the T/N ratio of 11C-methionine PET of 1.27 and in FA of 0.26, values similar to those previously confirmed by histological study. Moreover, reconstructing images delineating the tumor border was possible combining these two imaging modalities. We propose that the combined analysis of DTI and 11C-methionine PET has the potential to improve tumor border imaging in glioma patients, providing important information for establishing neurosurgical strategies. [Copyright &y& Elsevier]

Abstract: A noninvasive technique for assessing tumor tissue characteristics is required to assist preoperative surgical planning for malignant brain tumors. Preoperative information on tumor cell density within a tumor would help better define the target for tumor biopsy, resulting in more accurate diagnosis and grading of malignant brain tumors. One possible source of this information is diffusion tensor imaging (DTI), although to date studies have focused on its ability to delineate white matter fiber tracks by fiber-tracking and to detect tumor infiltration around the tumor and normal white matter interface. However, the use of DTI for providing information on cell density has also been examined, although with the controversial results. In addition the exact relationships between cell density and the two key values that DTI provides, namely fractional anisotropy (FA) and mean diffusivity (MD), still need to be investigated. In the present study we performed a retrospective investigation of tumor cell density and FA and MD values in biopsy cases. We found that FA has a good positive correlation (R =0.75) and MD has a good negative correlation (R =0.70) with tumor cell density within the tumor core. Similar correlation was observed between the Ki-67 labeling index and FA (R =0.71) and MD (R =0.62). Thus, measurement of both FA and MD within the tumor core has a potential to provide detailed information on tumor cell density within the tumor. Although data obtained from DTI should be interpreted carefully and comprehensively with other imaging modalities such as positron emission tomography, DTI seems to be informative for planning the best biopsy target containing the highest cell density. [Copyright &y& Elsevier]

Abstract: Background: Although craniopharyngiomas have a histologically benign nature, their treatment can be difficult. The correlation among clinical, proliferative, and immunohistologic features of female sex hormone receptors was determined in craniopharyngiomas to analyze whether they influence the growth of the tumor. Methods: The study subjects were 43 patients with previously untreated craniopharyngioma who underwent surgery at our department over the past 15 years. Serial tissue sections were immunostained with the antibodies against estrogen receptor (ER), progesterone receptor (PR), and Ki-67. Results: The Ki-67 labeling index was significantly higher in patients with regrowth (7.8%) than without regrowth (3.9%). ER and PR were detected in 9 of 30 (30%) craniopharyngiomas, and the incidence of postoperative tumor regrowth was significantly higher in patients negative for ER and PR (29%) than in those positive for both receptors (11%). Conclusions: A high Ki-67 labeling index suggests a high possibility of tumor regrowth, and the presence of ER and PR is suggestive of a high tissue differentiating potential. ER and PR assay may be useful for determining the indication for additional radiation therapy in craniopharyngioma patients treated by incomplete resection. [Copyright &y& Elsevier]

We have investigated the vortex phase diagram of YBa2Cu4O8 single crystals of intermediate c-axis anisotropy by means of the magnetic torque, the DC magnetization, and the AC susceptibility. The single crystals have been grown by a self-flux method under high-pressure. The magnetization curve shows a second peak. The torque also shows the multiple peak effects. The central peak is due to the intrinsic pinning. The first torque peak at θca≃90±10° requires the existence of the field component parallel to the CuO2 planes. The second torque peak at θca∼90±30° roughly correlates with the second peak in magnetization. We summarize the vortex melting line and the lines for the various peaks in the HT diagram. We find that vortex phase diagram of YBa2Cu4O8 in H&par;c is very different from those for the YBa2Cu3O7−δ and Bi2Sr2CaCu2O8+δ. [Copyright &y& Elsevier]

We have investigated the vortex phase diagram of YBa2Cu4O8 single crystals of intermediate c-axis anisotropy by means of the magnetic torque, the DC magnetization, and the AC susceptibility. The single crystals have been grown by a self-flux method under high-pressure. The magnetization curve shows a second peak. The torque also shows the multiple peak effects. The central peak is due to the intrinsic pinning. The first torque peak at θca≃90±10° requires the existence of the field component parallel to the CuO2 planes. The second torque peak at θca∼90±30° roughly correlates with the second peak in magnetization. We summarize the vortex melting line and the lines for the various peaks in the HT diagram. We find that vortex phase diagram of YBa2Cu4O8 in H&par;c is very different from those for the YBa2Cu3O7−δ and Bi2Sr2CaCu2O8+δ. [ABSTRACT FROM AUTHOR]

The diagnosis and prognostication of glioblastoma (GBM) remain to be solely dependent on histopathological findings and few molecular markers, despite the clinical heterogeneity in this entity. To address this issue, we investigated the prognostic impact of copy number alterations (CNAs) using two population-based IDH-wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). The molecular disproportions between these cohorts were dissected in light of cohort differences in GBM. The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The somatic landscape around CNAs was analyzed for 212 KNBTG cases and 359 TCGA cases. Next, the clinical impacts of CNA profiles were investigated for 140 KNBTG cases and 152 TCGA cases treated by standard adjuvant therapy using temozolomide-based chemoradiation. The comparative profiling indicated unequal distribution of specific CNAs such as EGFR, CDKN2A, and PTEN among the two cohorts. Especially, the triple overlap CNAs in these loci (triple CNA) were much higher in frequency in TCGA (70.5%) than KNBTG (24.3%), and its prognostic impact was independently validated in both cohorts. The KNBTG cohort significantly showed better prognosis than the TCGA cohort (median overall survival 19.3 vs 15.6 months). This survival difference between the two cohorts completely resolved after subclassifying all cases according to the triple CNA status. The prognostic significance of triple CNA was identified in IDH-wild-type GBM. Distribution difference in prognostic CNA profiles potentially could cause survival differences across cohorts in clinical studies. [ABSTRACT FROM AUTHOR]

The diagnosis and prognostication of glioblastoma (GBM) remain to be solely dependent on histopathological findings and few molecular markers, despite the clinical heterogeneity in this entity. To address this issue, we investigated the prognostic impact of copy number alterations (CNAs) using two population-based IDH-wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). The molecular disproportions between these cohorts were dissected in light of cohort differences in GBM. The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The somatic landscape around CNAs was analyzed for 212 KNBTG cases and 359 TCGA cases. Next, the clinical impacts of CNA profiles were investigated for 140 KNBTG cases and 152 TCGA cases treated by standard adjuvant therapy using temozolomide-based chemoradiation. The comparative profiling indicated unequal distribution of specific CNAs such as EGFR, CDKN2A, and PTEN among the two cohorts. Especially, the triple overlap CNAs in these loci (triple CNA) were much higher in frequency in TCGA (70.5%) than KNBTG (24.3%), and its prognostic impact was independently validated in both cohorts. The KNBTG cohort significantly showed better prognosis than the TCGA cohort (median overall survival 19.3 vs 15.6 months). This survival difference between the two cohorts completely resolved after subclassifying all cases according to the triple CNA status. The prognostic significance of triple CNA was identified in IDH-wild-type GBM. Distribution difference in prognostic CNA profiles potentially could cause survival differences across cohorts in clinical studies. [ABSTRACT FROM AUTHOR]