A recent study reported on mutations in the active site of the isocitrate dehydrogenase 1 (IDH1) gene in several types of gliomas. All mutations detected resulted in an amino acid exchange at position 132. We analyzed the genomic region spanning wild-type R132 of IDH1 by direct sequencing in 125 glial tumors. A total of 39 IDH1 mutations were observed. Mutations of the IDH2 gene, homologous to IDH1, were often detected in gliomas without IDH1 mutations. In the present study, R172 mutation of the IDH2 gene was detected in one anaplastic astrocytoma. IDH1 or IDH2 mutations were frequently in oligodendrogliomas (67%), anaplastic astrocytomas (62%), anaplastic oligoastrocytomas (75%), anaplastic oligodendrogliomas (50%), secondary glioblastomas (67%), gangliogliomas (38%), and anaplastic gangliogliomas (60%). Primary glioblastomas were characterized by a low frequency of mutations (5%) at amino acid position 132 of IDH1. Mutations of the IDH1 or IDH2 genes were significantly associated with improved outcome in patients with anaplastic astrocytomas. Our data suggest that IDH1 or IDH2 mutation plays a role in early tumor progression of several types of glioma and might arise from a common glial precursor. The infrequency of IDH1 mutation in primary glioblastomas revealed that these subtypes are genetically distinct entities from other glial tumors. (Cancer Sci 2009; 100: 1996-1998) G liomas are the most common primary brain tumors and are grouped into four grades according to the World Health Organization (WHO) criteria.(1) This group of tumors includes specific histological subtypes; the most common are astrocytomas, oligodendrogliomas, and ependymomas. Glioblastomas (GBM; WHO grade IV), the most malignant glioma, may manifest rapidly de novo (primary GBM), or develop slowly from low-grade diffuse or anaplastic astrocytoma (secondary GBM). (2) Recent genomewide mutational analysis revealed somatic mutations of cytosolic NADP + -dependent isocitrate dehydrogenase (IDH1) in approximately 12% of GBM.(3) Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate thereby leading to NADPH production.(4) Mutations affected the amino acid arginine at position 132 of the amino acid sequence, which is evolutionarily highly conserved, and is located in the binding site of isocitrate.(5) In the vast majority of the cases, wild-type arginine at position 132 was replaced by histidine ( R132H).The IDH2 gene is homologous to IDH1, which uses NADP + as an electron receptor. Gliomas without IDH1 mutations were often found to have mutations at the analogous amino acid (R172) of the IDH2 gene.(6) Both IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. (6) In recent analyses from North American and European groups, IDH1 mutations were more frequent in secondary GBM than primary GBM.(6-8) Similarly, high frequencies of IDH1 mutations were found in diffuse (WHO grade II) or anaplastic astrocytomas ( WHO grade III), oligodendrogliomas ( WHO grade II), and anaplastic oligoden...

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.

Background. We conducted a phase III trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)-A24+ recurrent glioblastoma to develop a new treatment modality. Methods. We randomly assigned 88 recurrent glioblastoma patients to receive PPV (n = 58) or the placebo (n = 30) at a 2-to-1 ratio. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebos were injected 1×/week for 12 weeks. Results. Our trial met neither the primary (overall survival [OS]) nor secondary endpoints. Unfavorable factors for OS of 58 PPV patients compared with 30 placebo patients were SART2-93 peptide selection (n = 13 vs 8, hazard ratio [HR]: 15.9), ≥70 years old (4 vs 4, 7.87), >70 kg body weight (10 vs 7, 4.11), and performance status (PS)3 (8 vs 2, 2.82), respectively. Consequently, the median OS for PPV patients without SART2-93 selection plus one of these 3 favorable factors (<70 y old, ≤70 kg, or PS0-2) was significantly longer than that for the corresponding placebo patients (HR: 0.49, 0.44, and 0.51), respectively. Preexisting immunity against both all 12 warehouse peptides besides SART2-93 and the other cytotoxic T lymphocyte epitope peptides was significantly depressed in the patients with SART2-93 selection (n = 21) compared with that of the patients without SART2-93 selection (n = 67). Biomarkers correlative for favorable OS of the PPV patients were a lower percentage of CD11b+CD14+HLA-DR low A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma 349 Narita et al. Recurrent GBM and peptide vaccination: phase III trial Neuro-Oncologyimmunosuppressive monocytes and a higher percentage of CD4+CD45RA− activated T cells, the intermediate levels of chemokine C-C ligand 2 (CCL2), vascular endothelial growth factor, interleukin (IL)-6, IL-17, or haptoglobin, respectively. Conclusion. This phase III trial met neither the primary nor secondary endpoints. Key Points1. This trial of personalized peptide vaccination did not meet the primary endpoint.2. Personalized peptide vaccination shortened the OS of certain patients.3. Intermediate CCL2 level was a biomarker correlative for favorable OS.The overall survival (OS) of recurrent glioblastoma (rGBM) patients is very poor, although bevacizumab has been reported to improve the progression-free survival (PFS) of rGBM patients. [1][2][3] Many clinical studies failed to provide clinical benefits for rGBM in the past decade. [4][5][6] This failure may be partly due to the unique and diverse immunological features of GBM. 4-10 GBM tumor cells produce many cytokines and chemokines as potential autocrine growth factors and subsequent immune regulators, which might in turn influence the self-proliferation in most patients. 4-10 Among the GBM-producing cytokines, granulocyte-monocyte stimulating factor (GM-CSF) and the chemokine (C-C motif) ligand 2 (CCL2) are the two major factors for immune regulation. [6][7][8][9] GM-CSF forms a cytokine network with in...

Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0630-1) contains supplementary material, which is available to authorized users.

Chronic inflammation promotes the progression of diabetic nephropathy (DN). However, the role of TNF-α remains unclear. The objectives of the present study were to examine whether TNF-α inhibition with a soluble TNF receptor (TNFR)2 fusion protein, i.e., etanercept (ETN), improves the early stage of DN in the type 2 diabetic model of the KK-Ay mouse and to also investigate which TNF pathway, TNFR1 or TNFR2, is predominantly involved in the progression of this disease. ETN was injected intraperitoneally into mice for 8 wk. Renal damage was evaluated by immunohistochemistry, Western blot analysis, and/or real-time PCR. In vitro, mouse tubular proximal cells were stimulated by TNF-α and/or high glucose (HG) and treated with ETN. ETN dramatically improved not only albuminuria but also glycemic control. Renal mRNA and/or protein levels of TNFR2, but not TNF-α and TNFR1, in ETN-treated KK-Ay mice were significantly decreased compared with untreated KK-Ay mice. mRNA levels of ICAM-1, VCAM-1, and monocyte chemoattractant protein-1 and the number of F4/80-positive cells were all decreased after treatment. Numbers of cleaved caspase-3- and TUNEL-positive cells in untreated mice were very few and were not different from ETN-treated mice. In vitro, stimulation with TNF-α or HG markedly increased both mRNA levels of TNFRs, unlike in the in vivo case. Furthermore, ETN partly recovered TNF-α-induced but not HG-induced TNFR mRNA levels. In conclusion, it appears that ETN may improve the progression of the early stage of DN predominantly through inhibition of the anti-inflammatory action of the TNF-α-TNFR2 pathway.

By multivariate analysis, we found that a younger age and MGMT promoter methylation were significant favorable factors in patients with glioblastoma.

The prognosis of patients with WHO grade III gliomas is highly dependent on their genomic status such as the isocitrate dehydrogenase (IDH) 1/2 mutation and1p/19q co-deletion. However, difficulties have been associated with determining which tumors have certain genomic profiles by preoperative radiographical modalities, and the role of surgical resection in achieving better outcomes remains unclear. This retrospective study included 124 consecutive patients with newly diagnosed grade III gliomas. The genomic status of IDH1/2 and 1p/19q was analyzed in these patients. Tumors were then divided into 3 subgroups based on their genomic status; the IDH 1/2 mutation with the 1p/19q co-deletion (1p/19q co-del), the IDH 1/2 mutation without the 1p/19q co-deletion (non-1p/19q co-del), and the IDH 1/2 wild type (IDH wt). Survival times were compared between patients who underwent gross total resection and those who did not (GTR versus non-GTR). The relationships between genomic statuses and MR imaging characteristics such as ring-like or nodular enhancements by gadolinium, and very low intensity on T1-weighted images with blurry enhancements (T1VL) were also examined. Among all patients with grade III gliomas, GTR patients had longer median survival and progression-free times than those of non-GTR patients (undefined versus 87 months, p = 0.097, and 124 versus 34 months, p = 0.059, respectively). No significant differences were observed in survival between GTR and non-GTR patients in the 1p/19q co-del group (p = 0.14), or between GTR and non-GTR patients in the IDH wt group (26 and 27 months, p = 0.29). On the other hand, in non-1p/19q co-del group, survival was significantly longer in GTR patients than in non-GTR patients (undefined versus 77 months, p = 0.005). Radiographically, T1VL was detected in most tumors in the non-1p/19q co-del group (78.2 %), but only 6 (21.4 %) and 17 (41.5 %) tumors in the 1p/19q co-del and IDH wt groups, respectively. A correlation was not found between other genomic subgroups and MR imaging findings. Strict surgical removal is important to improve the prognosis of patients with grade III gliomas, especially for tumors with the IDH 1/2 mutation without the 1p/19q co-deletion. The MR finding of T1VL can be used to select candidates for more radical resection.

Object This study retrospectively analyzed the long-term outcomes of 108 consecutive patients to establish the classification and optimal treatment strategy for each subgroup of newly diagnosed germ cell tumors (GCTs). Methods A retrospective review of medical records from the authors' department between April 1989 and March 2007 identified 108 patients with newly diagnosed intracranial GCT. The diagnoses were germinoma in 83 patients, and nongerminomatous GCT (NGGCT) in 25 patients. Results In patients with germinoma, the 10-year overall and progression-free survival (PFS) rates at a median follow-up period of 99 months were 86 and 74%, respectively. Recurrences developed during a range of 6 to 153 months (median 26 months) after starting the initial therapy. Patients treated only with chemotherapy demonstrated a shorter PFS rate, and patients treated with chemotherapy followed by reduced-dose radiation therapy to the whole ventricle, whole brain, or craniospinal axis showed significantly better PFS than patients treated with only radiation or reduced-dose radiation therapy to the focal field. Nongerminomatous GCTs were divided into good, intermediate, and poor prognosis groups as proposed by the Japanese Pediatric Brain Tumor Study Group. In the good and intermediate prognosis groups, the 10-year overall and PFS rates were 100 and 93%, respectively. In the poor prognosis group, the 3-year overall and PFS rates were 56 and 29%, respectively. All patients with NGGCTs, in whom the lesions on MR imaging disappeared after combination therapies consisting of resection, radiation therapy, and chemotherapy, remained alive. Conclusions Chemotherapy followed by reduced-dose radiation therapy covering the whole ventricle improves the prognosis for patients with germinoma. Combined therapy of radiation therapy, chemotherapy, and radical resection as an initial or salvage treatment achieved excellent tumor control in the intermediate prognosis NGGCT group. The outcomes were still dismal in the poor prognosis NGGCT group, so initial therapy should target complete disappearance of all lesions on MR imaging.