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Objective: IDH-mutant lower-grade gliomas (LGGs, grade 2 or 3) eventually transform into secondary grade 4 astrocytomas (sAIDHmut/G4). Here, we sought to describe the transformation time, risk factors, and outcomes in malignant transformation of IDH-mutant LGGs. Methods: We screened data for 108 patients with sAIDHmut/G4 in the Chinese Glioma Genome Atlas who had initial IDH-mutant LGGs and underwent reoperation during 2005–2021. We evaluated the transformation time from IDH-mutant LGGs to sAIDHmut/G4, and associated risk factors and outcomes. Malignant transformation was defined as pathological confirmation of grade 4 astrocytoma. Results: The median age of the 108 patients with IDH-mutant LGGs was 35 years (range, 19–54); the median age at transformation was 40 years (range, 25–62); and the median follow-up time for all patients was 146 months (range, 121–171). The average transformation time was 58.8 months for all patients with LGGs (range, 5.9–208.1); 63.5 and 51.9 months for grade 2 and 3 gliomas, respectively; and 58.4 and 78.1 months for IDH-mutant/1p/19q-non-codeleted astrocytomas and IDH-mutant/1p/19q-codeleted oligodendrogliomas, respectively. Univariate and multivariate analysis indicated that radiotherapy [hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.137–0.595; P = 0.001] and non-A blood type (HR, 0.37; 95% CI, 0.203–0.680; P = 0.001) were protective factors against delayed malignant transformation. Radiotherapy was associated with improved survival after transformation (HR, 0.44; 95% CI, 0.241–0.803; P = 0.008), overall survival (HR, 0.50; 95% CI, 0.265–0.972; P = 0.041), and progression-free survival (HR, 0.25; 95% CI, 0.133–0.479; P < 0.0001) in patients with IDH-mutant gliomas. Conclusions: Radiotherapy is associated with delayed malignant transformation and improved survival in patients with IDH-mutant gliomas.

BACKGROUND The radiation dose for patients with low-grade gliomas (LGGs) is controversial. The objective of this study was to investigate the impact of the radiation dose on survival for patients with LGGs and especially for molecularly defined subgroups. METHODS Three hundred fifty-one patients with newly diagnosed LGGs from the multicenter Chinese Glioma Cooperative Group received postoperative radiotherapy (RT) in 2005-2018. The RT dose, as a continuous variable, was entered into a Cox regression model using penalized spline regression to allow for a nonlinear relationship between the RT dose and overall survival (OS) or progression-free survival (PFS). Inverse probability of treatment weighting (IPTW)-adjusted propensity scores were used to correct for potential confounders. Dose effects on survival within IDH mutation and 1p/19q codeletion defined subgroups were analyzed. RESULTS The risk of mortality and disease progression decreased sharply until 54 Gy. High-dose RT (≥54 Gy) was associated with significantly better 5-year OS (81.7% vs 64.0%; hazard ratio [HR], 0.33; P < .001) and PFS (77.4% vs 54.5%; HR, 0.46; P < .001) than low-dose RT (

BackgroundSkull base chordoma and chondrosarcoma are exceptionally rare bone tumors with high propensity for local recurrence. Different postoperative radiation modalities are often used to improve the clinical efficacy. Proton therapy (PT) might be among the most promising ones because of the unique ballistic characteristics of high-energy particles. However, previous meta-analysis often included studies with combined radiation techniques. No systematic review to date has directly analyzed the survival and toxicity of pure PT for these two types of malignancies.MethodsBy following the PRISMA guidelines, a systematic search of three databases was conducted. Articles were screened and data were extracted according to a prespecified scheme. R 4.2.0 software was used to conduct the meta-analysis. Normal distribution test was used for the incidence rate of each subgroup.ResultsA total of seven studies involving 478 patients were included in this analysis. The quality of included articles ranged from moderate to high quality. All patients were histopathologically diagnosed with chordoma or chondrosarcoma, and the follow-up time of the cohort ranged from 21 to 61.7 months. For PT planning, the median target volume ranged from 15 cc to 40 cc, and the administered median dose varied from 63 to 78.4 GyRBE at 1.8–2.0 GyRBE per fraction. The 1-, 2-, 3-, 5-, and 7-year local control and overall survival rates were 100%, 93%, 87%, 78%, and 68%, and 100%, 99%, 89%, 85%, and 68%, respectively. The late grade 3 or higher toxicities were reported in only two involved articles.ConclusionsUntil now, medical centers worldwide have exerted PT to improve outcomes of skull base chordomas and chondrosarcomas. PT not combined with other radiation modalities showed favorable local control and survival with a low incidence of severe radiation-induced toxicities, which manifests promising clinical benefits. However, high-quality evidence is still limited, requiring future clinical trials and prospective studies in selected patients.

Radiation therapy (RT) modulates immune cells and cytokines, resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during RT for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described.The study population consisted of children (n = 83, aged 3~18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors (GCT), and central nervous system embryonal tumor-not otherwise specified), with or without residual or disseminated (R/D) diseases who were starting standard postoperative focal or craniospinal irradiation (CSI). Peripheral blood T lymphocyte subsets collected before and 4 weeks after RT were enumerated by flow cytometry. Plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A were measured by cytometric bead array.Patients with R/D lesions receiving CSI (n = 32) had a post-RT increase in the frequency of CD3+T and CD8+T cells, a decrease in CD4+T cells, and an increase in regulatory T cells (Tregs) and CD8+CD28- suppressor cells, which was more predominantly seen in these patients than in other groups. In the CSI group with such R/D lesions, consisting of patients with medulloblastoma and germ cell tumors, 19 experienced a complete response (CR) and 13 experienced a partial response (PR) on imaging at 4 weeks after RT. The post/pre-RT ratio of Tregs (P = .0493), IL-6 (P = .0111), and IL-10 (P = .0070) was lower in the CR group than in the PR group. Multivariate analysis revealed that the post/pre-RT ratios of Treg, IL-6, and IL-10 were independent predictors of CR (P.0001, P = .018, P.0001, respectively). The areas under the receiver operating curves and confidence intervals were 0.7652 (0.5831-0.8964), 0.7794 (0.5980-0.9067), and 0.7085 (0.5223-0.8552) for IL-6, IL-10, and Treg, respectively. The sensitivities of IL-6, IL-10, and Treg to predict radiotherapeutic responses were 100%, 92.3%, and 61.5%, and specificity was 52.6%, 57.9%, and 84.2%, respectively.CSI treatment to those with R/D lesions predominantly exerted an effect on antitumor immune response compared with both R/D lesion-free but exposed to focal or CSI RT and with R/D lesions and exposed to focal RT. Such CSI with R/D lesions group experiencing CR is more likely to have a decrease in immunoinhibitory molecules and cells than patients who only achieve PR. Measuring peripheral blood Treg, IL-6, and IL-10 levels could be valuable for predicting radiotherapeutic responses of pediatric brain tumors with R/D lesions to CSI for medulloblastoma and intracranial germ cell tumors.

Primary central nervous system lymphoma (PCNSL) is a type of central nervous system restricted non-Hodgkin lymphoma, whose histopathological diagnosis is majorly large B cell lymphoma. To provide specific, evidence-based recommendations for medical professionals and to promote more standardized, effective and safe treatment for patients with PCNSL, a panel of experts from the Chinese Neurosurgical Society of the Chinese Medical Association and the Society of Hematological Malignancies of the Chinese Anti-Cancer Association jointly developed an evidence-based consensus. After comprehensively searching literature and conducting systematic reviews, two rounds of Delphi were conducted to reach consensus on the recommendations as follows: The histopathological specimens of PCNSL patients should be obtained as safely and comprehensively as possible by multimodal tomography-guided biopsy or minimally invasive surgery. Corticosteroids should be withdrawn from, or not be administered to, patients with suspected PCNSL before biopsy if the patient’s status permits. MRI (enhanced and DWI) should be performed for diagnosing and evaluating PCNSL patients where whole-body PET-CT be used at necessary time points. Mini-mental status examination can be used to assess cognitive function in the clinical management. Newly diagnosed PCNSL patients should be treated with combined high-dose methotrexate-based regimen and can be treated with a rituximab-inclusive regimen at induction therapy. Autologous stem cell transplantation can be used as a consolidation therapy. Refractory or relapsed PCNSL patients can be treated with ibrutinib with or without high-dose chemotherapy as re-induction therapy. Stereotactic radiosurgery can be used for PCNSL patients with a limited recurrent lesion who were refractory to chemotherapy and have previously received whole-brain radiotherapy. Patients with suspected primary vitreoretinal lymphoma (PVRL) should be diagnosed by vitreous biopsy. PVRL or PCNSL patients with concurrent VRL can be treated with combined systemic and local therapy.

To follow the revision of the fourth edition of WHO classification and the recent progress on the management of diffuse gliomas, the joint guideline committee of Chinese Glioma Cooperative Group (CGCG), Society for Neuro-Oncology of China (SNO-China) and Chinese Brain Cancer Association (CBCA) updated the clinical practice guideline. It provides recommendations for diagnostic and management decisions, and for limiting unnecessary treatments and cost. The recommendations focus on molecular and pathological diagnostics, and the main treatment modalities of surgery, radiotherapy, and chemotherapy. In this guideline, we also integrated the results of some clinical trials of immune therapies and target therapies, which we think are ongoing future directions. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China and other countries.

BACKGROUND In the previous studies, intracranial germ cell tumor (iGCTs) patients with pure choriocarcinoma or mixed germ cell tumors containing choriocarcinoma components showed similar dismal prognoses with median overall survival of 22 months and a one-year survival rate around 60%. However, those conclusions need update since radiotherapy, a milestone for this disease, was not applied to many patients in the published reports. Patients and METHODS Clinical data of iGCTs patients with histologically confirmed choriocarcinoma component and/or β-HCG > 500IU/L were collected from the archive of our institute and studied retrospectively. RESULTS Totally, 76 patients were eligible for the study. 11 patients took surgery as initial treatment, followed by chemoradiotherapy in terms of treatments. Sixty-one patients initiated their treatments with chemotherapy. Among them, twelve patients received second-look surgery due to residue disease. Subsequently, all received radiotherapy except for two early deaths. Four patients received radiotherapy initially, followed by chemotherapy. The median follow-up time was 63 months. The 5-year EFS and OS were 81.5% and 84.1%, respectively. Among patients who did not suffer from early death or progressed disease after induction chemotherapy (n = 68), multivariate analysis found chemotherapy cycles ( > 4 vs ≤ 4) (Hazard ratio [HR] for EFS 0.156, p = 0.021; HR for OS 0.110, p = 0.032), β-HCG level ( > 3000IU/L vs ≤ 3000IU/L) (HR for EFS 4.512, p = 0.052; HR for OS 6.604, p=0.028), and intertumoral hemorrhage (Yes vs No) (HR for EFS 23.177, p = 0.006; HR for OS 12.173, p = 0.081) were independent factors for survival. While radiation field (CSI vs non-CSI) was not proved to be a prognostic factor, either for EFS or OS. CONCLUSIONS iGCTs patients with choriocarcinoma component or β-HCG > 500IU/L showed improved survival with radiotherapy-based treatments. Patients with higher β-HCG levels and hemorrhage had a poorer prognosis. More chemotherapy cycles could bring additional survival benefits.

OBJECTIVES Given the increasing importance of patient’s perspective in adverse events reporting, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) has been proposed as new PRO measures in oncology; however, its implementation has not yet been evaluated in glioma patients, and standardized selection process of priority symptom terms has not been applied. METHODS A total of 16 experts (13 neurosurgeons, 2 radiotherapists, 1 psychiatrist) from 14 medical centers in China were invited to participate in a consensus-seeking 2-round online Delphi survey. Participants rated the level of their agreement with each symptom term likely to occur during adult diffuse gliomas treatment on a 5-point Likert scale. Terms not reaching consensus over the first round were modified in the second rounds. Consensus was defined as content validity index (CVI) > 0.78，coefficient of variation (CV)< 0.35 and average Likert score > 3.00. RESULTS Experts reached a consensus on 21 PRO-CTCAE™ symptom terms in the first Delphi round, and 10 terms in the second round. Likert scale scoring among all experts showed significant consistency (Round 1: Kendall’s W= 0.415，p＜0.001; Round 2: Kendall’s W = 0.351，P＜0.001). The 31 terms (38.75%) screened out of all 78 terms covered neurological symptoms(n=7), psychiatric symptoms(n=6), dermatological symptoms(n=6), gastrointestinal symptoms(n=5) and other common postoperative systemic symptoms of glioma patients. CONCLUSIONS We identified a customized PRO-CTCAE™ questionnaire containing a core set of priority symptom terms for the adult diffuse glioma through a 2-round Delphi survey. Next, a prospective, multi-center, real-word study would be performed to assess the validity, reliability and responsiveness of the customized PRO-CTCAE™ for adult diffuse glioma patients in Chinese population (VERONICA).

Background Cell division cycle 6 (CDC6) has been proven to be associated with the initiation and progression of human multiple tumors. However, it’s role in glioma, which is ranked as one of the common primary malignant tumor in the central nervous system and is associated with high morbidity and mortality, is unclear. Methods In this study, we explored CDC6 gene expression level in pan-cancer. Furthermore, we focused on the relationships between CDC6 expression, its prognostic value, potential biological functions, and immune infiltrates in glioma patients. We also performed vitro experiments to assess the effect of CDC6 expression on proliferative, apoptotic, migrant and invasive abilities of glioma cells. Results As a result, CDC6 expression was upregulated in multiple types of cancer, including glioma. Moreover, high expression of CDC6 was significantly associated with age, IDH status, 1p/19q codeletion status, WHO grade and histological type in glioma (all p p Conclusion In conclusion, high CDC6 expression may serve as a promising biomarker for prognosis and correlated with immune infiltrates, presenting to be a potential immune therapy target in glioma.

Background Patients with lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations have a high risk of brain metastasis (BM). Mitogen-activated protein kinase (MAPK) is an important mediator of EGFR/c-MET crosstalk, which is involved in development of BM in non-small cell lung cancer. Here, we investigated the association of MAPK genetic variations with the risk of BM in patients with lung adenocarcinoma. Methods Patients with pathologically confirmed lung adenocarcinoma from two Hospitals (n=120, discovery cohort; n=213, validation cohort) were enrolled. Magnetic resonance imaging (MRI) was employed for BM follow-up after the completion of planned therapy. Single nucleotide polymorphisms (SNPs) of MAPK pathway genes were tested with blood samples. Results After adjustment for sex, age, staging, smoking status, surgery, and thoracic radiotherapy, extracellular signal-regulated kinase 2 (ERK2) rs6928 and rs5999521 SNPs were found to be associated with increased risk of BM. The rs6928 GG and CG genotypes were associated with 2.033-fold (P=0.033) and 1.910-fold (P=0.012) increases in the risk of developing BM compared with the CC genotype. For rs5999521, the risk of developing BM was increased by 1.993-fold (P=0.037) in patients with the GG genotype and 1.834-fold (P=0.019) in patients with the AG genotype compared with patients with the AA genotype. Furthermore, patients with genotypes of higher risk of BM showed higher EGFR mutation rates and tended to have >1 BM lesions. Conclusions In patients with lung adenocarcinoma, ERK2 rs6928 and rs5999521 SNPs contributed to BM risk, particularly in patients with specific genotypes.

BackgroundGlioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. GBM with primitive neuronal component (GBM-PNC) is an aggressive variant identified in 0.5% of GBMs. Extracranial metastasis from GBM-PNC is a rare and challenging situation.MethodsA special case of early-onset GBM with systemic bone metastasis was enrolled. Clinical data, including patient characteristics, disease course, and serial radiological images were retrieved and analyzed. Tumor tissues were obtained by surgical resections and were made into formalin-fixed paraffin-embedded sections. Histopathological examinations and genetic testing were performed for both the primary and metastatic tumor specimens.ResultsA 20-year-old man suffered from GBM with acute intratumoral hemorrhage of the left temporal lobe. He was treated by gross total resection and chemoradiotherapy following the Stupp protocol. Seven months later, he returned with a five-week history of progressive neck pain and unsteady gait. The radiographic examinations identified vertebral collapse at C4 and C6. Similar osteolytic lesions were also observed at the thoracolumbar spine, pelvic, and left femur. Anterior spondylectomy of C4 and C6 was performed. The resected vertebral bodies were infiltrated with greyish, soft, and ill-defined tumor tissue. One month later, he developed mechanical low-back pain and paraplegia caused by thoracolumbar metastases. Another spine surgery was performed, including T10 total en-bloc spondylectomy, T7-9, L2-3, and L5-S1 laminectomy. After the operation, the patient’s neurological function and spinal stability remained stable. However, he finally succumbed to the rapidly increased tumor burden and died 15 months from onset because of cachexia and multiple organ failure. In addition to typical GBM morphology, the histological examinations identified monomorphic small-round cells with positive immunohistochemical staining of synaptophysin and CD99, indicating the coexistence of PNC. The next-generation sequencing detected pathogenic mutations in TP53 and DNMT3A. Based on above findings, a confirmed diagnosis of systemic metastases from GBM-PNC (IDH-wild type, WHO grade IV) was made.ConclusionsThe present case highlights the occurrence and severity of extensive axial skeletal metastases from GBM-PNC. This rare variant of GBM requires aggressive multimodal treatment including surgery and chemoradiotherapy targeting PNC. The pathological screening of PNC is recommended in patients with early-onset GBM and intratumoral hemorrhage. Surgery for spinal metastasis is appropriate in patients with chemoradioresistance and relatively good general status, with the objectives of restoring spinal stability and relieving spinal cord compression.

Whereas evidences of single-cell studies have suggested the cellular diversity of medulloblastoma, the most common malignant brain tumor in childhood, the understanding of spatial status for specific cell populations and gene modules remains rudimentary. Herein, we comprehensively analyze single-nucleus RNA expression, chromatin accessibility and spatial transcriptomic profiling from 52 human medulloblastomas spanning four molecular subgroups, complemented with the bulk whole genome and RNA sequencing data across 300 samples. We comprehensively interrogated the composition of medulloblastoma microenvironment and spatially described the developmental trajectory from progenitor-like to differentiated malignant cells. Furthermore, distinct heterogeneity within molecular subgroups leads to the identification of twelve subtypes of medulloblastoma, which unfortunately lacks the cellular biology. By deciphering the copy number variation and transcriptional programs at single-cell resolution, we in-depth characterized medulloblastoma and mapped the activity of gene expression and transcription factor binding according to individual subtype. The WNT-β, SHH-γ, Group 3-β and Group 4-γ were observed in early differentiation stage. Harmony alignment revealed subtype-dependent modules recapitulated the neurodevelopmental gene enrichment, strongly correlating to clinical outcomes. Collectively, our findings provide spatiotemporally resolved insights into transcriptome and epigenome of twelve-subtype medulloblastoma allowing further refinement regarding clinical risk stratification strategies.

Intra-cranial germ cell tumors (iGCTs) are classified into two pathological subtypes Germinomas (GEs) and nongerminomatous germ cell tumors (NGGCTs). Accurate preoperative determination of iGCT subtypes is essential to guide clinical decision making and prognosis assessment. This study aims to develop a deep-learning algorithm to automatically segment iGCTs and classify subtypes using preoperative T2-weighted (T2W) images. Brain MR imaging and corresponding pathologic information were retrospectively obtained from 594 subjects including 269 GEs and 325 NGGCTs from Beijing Tiantan Hospital between January 1, 2008, and October 31, 2020, and subdivided into training (n=416) and test (n=178) sets for iGCTs segmentation, and classification using 3D nnU-Net based on T2W images. An internal validation cohort (including 56 GEs and 17 NGGCTs) and two external validation cohorts (Center 1 including 13 GEs and 12 NGGCTs；Center 2 including 17 GEs and 12 NGGCTs) were prospectively designed as an independent sets for testing the iGCT-net. Dice scores were computed to assess tumor segmentation. Accuracy and area under the curve (AUC) were calculated to assess the GEs and NGGCTs classification. Additionally, sensitivity analysis of different tumor location (suprasellar, pineal and basal ganglia regions) was performed to access the classification accuracy. The iGCT-net for tumor segmentation achieved a mean dice score of 0.80 in all cohorts. For tumor classification, the iGCT-net achieved the mean accuracy of 90.96% of all cohorts, which was superior to that using demographics and morphologic features (mean = 67.50%, p< 0.01). For different tumor location (suprasellar region, pineal region, and basal ganglia region), the iGCT-net showed an mean accuracy of 87.94%, 89.38% and 65.74% in test set, internal validation set and external validation cohorts. A fully automatic deep learning algorithm to segment iGCT and discriminate GEs and NGGCTs with high accuracy based on only T2W images from a large dataset is successfully developed.

BackgroundChoroid plexus carcinomas (CPCs) are rare pediatric tumors commonly associated with Li-Fraumeni syndrome (LFS), which involves a germline mutation of the tumor suppressor gene TP53.Materials and MethodsWe retrospectively analyzed the corresponding information of 12 cases, including the effects of surgery and radiotherapy and TP53 germline mutations, to analyse the management strategies. Kaplan-Meier curves and the log-rank test were used to evaluate the progression-free survival (PFS).ResultsTwelve CPC patients were included, of which TP53 germline mutations were found in eight cases. All patients underwent surgical resection, and six patients received radiotherapy following with operation after initial diagnosis, one patient received radiotherapy following relapse. It was significantly different (P=0.012 and 0.028) that patients with TP53 germline mutation receiving the gross total resection (GTR) without radiotherapy showed survival advantages. Without TP53 germline mutations also showed survival advantages, but there is no statistical significance (P=0.063)ConclusionsThese findings provide evidence for the therapeutic strategy that radiotherapy should not be considered for patients with TP53 germline mutations.

Background: Hypoxia-inducible factor 1α (HIF1A), the principal regulator of hypoxia, is involved in the suppression of antitumor immunity. We aimed to describe the T-cell exhaustion status of gliomas under different levels of HIF1A expression.Methods: In this study, 692 patients, whose data were collected from the Chinese Glioma Genome Atlas (CGGA) database, and 669 patients, whose data were collected from The Cancer Genome Atlas database, were enrolled. We further screened the data of a cohort of paired primary and recurrent patients from the CGGA dataset (n = 50). The abundance of immune cells was calculated using the transcriptome data. The association between HIF1A and T-cell exhaustion-related genes and immune cells was investigated.Results: According to the median value of HIF1A expression, gliomas were classified into low-HIF1A-expression and high-HIF1A-expression groups. The expression levels of PDL1 (CD274), FOXO1, and PRDM1 in the high-HIF1A-expression group were significantly higher in both glioblastoma (GBM) and lower-grade glioma. The abundance of exhausted T cells and B cells was significantly higher in the high-HIF1A-expression group, while that of macrophage, monocyte, and natural killer cell was significantly higher in the low-HIF1A-expression group in both GBM and lower-grade glioma. After tumor recurrence, the expression of HIF1A significantly increased, and the correlation between HIF1A expression levels and exhausted T cells and induced regulatory T cells became stronger.Conclusion: In diffuse gliomas, the levels of T-cell exhaustion-associated genes and the abundance of immune cells were elevated under high HIF1A expression. Reversing hypoxia may improve the efficacy of immunotherapy.

PurposeCurrent studies and guidelines suggest that the biobehavior of IDH-wild type (IDH-wt) lower-grade glioma (LGG, WHO II-III) is similar to IDH-wt glioblastoma (GBM). However, differences in their clinical and molecular characteristics have not been reported. This study aimed to analyze the clinical and genetic information of gliomas with IDH-wt.Methods389 patients with IDH-wt were enrolled in the study (LGG=165, GBM=224), and their clinical and genetic information was collected from the Chinese Glioma Genome Atlas (CGGA). We conducted an analysis of this information between the two groups of patients and drew conclusions thereof.ResultsThe median age of the LGG patients was 42 (18–74) years, whereas that of the GBM patients was 51 (18–79) years (P < 0.010). GBM patients were more likely to undergo total resection (P = 0.018) and had fewer epileptic seizure symptoms (P < 0.001). The median overall survival (OS) was 55 months for the LGG patients and only 14.83 months for the GBM patients (P < 0.01). The median progression-free survival (PFS) was 44 months for the LGG patients and only 9.767 months for the GBM patients (P < 0.001). GBM patients were more prone to PETN mutations (P = 0.010). Transcriptome analysis showed that the differentially expressed genes in LGG patients were mainly enriched in metabolic pathways and pathways in cancer and in the function of signal transduction and positive regulation of GTPase activity, whereas in GBM patients, they were mainly enriched in the PI3K-Akt signaling pathway and in the functions of apoptotic process and oxidation-reduction process.ConclusionsOur data indicate that these two groups of patients should be re-evaluated and treated differently, despite both having IDH wild type.

Medulloblastoma is the most common malignant childhood tumor type with distinct molecular subgroups. While advances in the comprehensive treatment have been made, the mortality in the high-risk group is still very high, driven by an incomplete understanding of cellular diversity. Here we use single-nucleus RNA expression, chromatin accessibility and spatial transcriptomic profiling to generate an integrative multi-omic map in 40 human medulloblastomas spanning all molecular subgroups and human postnatal cerebella, which is supplemented by the bulk whole genome and RNA sequences across 300 cases. This approach provides spatially resolved insights into the medulloblastoma and cerebellum transcriptome and epigenome with identification of distinct cell-type in the tumor microenvironment. Medulloblastoma exhibited three tumor subpopulations including the quiescent, the differentiated, and a stem-like (proliferating) population unique to cancer, which localized to an immunosuppressive-vascular niche. We identified and validated mechanisms of stem-like to differentiated process among the malignant cells that drive tumor progression. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing stem-like malignant cells as a hub for intercellular communication. Multiple features of potential immunosuppression and angiogenesis were observed, including Treg cells and endothelial cells co-localization in compartmentalized tumor stroma. Collectively, our study provides an integrative molecular landscape of human medulloblastoma and represents a reference to advance mechanistic and therapeutic studies of pediatric neuro-oncological disease.

e14048 Background: To explore the clinical characteristics and treatment outcomes of patients with intracranial germ cell tumors (iGCTs). Methods: Clinical data of 1448 patients who were diagnosed with iGCTs based on histology and/or tumor marker elevation between 1990 and 2019 at Beijing Tiantan Hospital were studied retrospectively. Results: The median age was 12 years, and 74.3% of patients were male. In total, 32.6% of patients were of sellar origin, 32.3% were of pineal origin, 20.4% were of basal ganglia (BG) origin, and 14.7% were others. In nonmetastatic germinoma patients, multivariate analysis found that both whole-brain radiotherapy (p < 0.001) and craniospinal irradiation (p = 0.040) could significantly reduce the risk of relapse compared with focal radiotherapy. In nonmetastatic NGGCT patients, the disease control rate was similar among the above three radiation volumes. Among 87 relapsed patients, those with germinoma (n = 35) showed a significantly higher out-field relapse rate than patients with NGGCTs (54.3% vs. 32.7%, p = 0.003). In patients with NGGCTs (n = 52), the in-field (36.5%) and out-field (32.7%) relapse rates were similar. In terms of relapse sites, relapse at the parenchyma (36.4%) was documented only in patients with BG region involvement. In patients with sellar or pineal origin, > 80% of relapses were documented in ventricles and/or the spine. Conclusions: iGCT patients in our series showed unique characteristics. Considering both efficacy and potential adverse effects, the optimal radiation strategy in nonmetastatic germinoma patients should be minimum coverage of at-risk areas. In patients with nonmetastatic NGGCTs, the optimal radiation strategy needs further investigation.

2069 Background: Medulloblastoma is the most common malignant childhood tumor type with distinct molecular subgroups. While advances in the comprehensive treatment have been made, the mortality in the high-risk group is still very high, driven by an incomplete understanding of cellular diversity. Methods: We use single-nucleus RNA expression, chromatin accessibility and spatial transcriptomic profiling to generate an integrative multi-omic map in 40 human medulloblastomas spanning all molecular subgroups and human postnatal cerebella, which is supplemented by the bulk whole genome and RNA sequences across 300 cases. Results: This approach provides spatially resolved insights into the medulloblastoma and cerebellum transcriptome and epigenome with identification of distinct cell-type in the tumor microenvironment. Medulloblastoma exhibited three tumor subpopulations including the quiescent, the differentiated, and a stem-like (proliferating) population unique to cancer, which localized to an immunosuppressive-vascular niche. We identified and validated mechanisms of stem-like to differentiated process among the malignant cells that drive tumor progression. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing stem-like malignant cells as a hub for intercellular communication. Multiple features of potential immunosuppression and angiogenesis were observed, including Treg cells and endothelial cells co-localization in compartmentalized tumor stroma. Conclusions: Our study provides an integrative molecular landscape of human medulloblastoma and represents a reference to advance mechanistic and therapeutic studies of pediatric neuro-oncological disease.

Purpose Whether craniospinal irradiation (CSI) could be replaced by limited-field radiation in non-metastatic bifocal germinoma remains controversial. We addressed the issue based on the data from our series and the literature. Materials and methods Data from 49 patients diagnosed with non-metastatic bifocal germinoma at our hospital during the last 10 years were collected. The Pediatric Quality of Life Inventory 4.0 was used to evaluate health-related quality of life (HRQOL). Additionally, 81 patients identified from the literature were also analyzed independently. Results In our cohort, 34 patients had tumors in the sellar/suprasellar (S/SS) plus pineal gland (PG) regions and 15 in the S/SS plus basal ganglia/thalamus (BG/T) regions. The median follow-up period was 52 months (range, 10 to 134 months). Our survival analysis showed that patients treated with CSI (n=12) or whole-brain radiotherapy (WBRT; n=34) had comparable disease-free survival (DFS; p=0.540), but better DFS than those treated with focal radiotherapy (FR; n=3, p=0.016). All 81 patients from the literature had tumors in the S/SS+PG regions. Relapses were documented in 4/45 patients treated with FR, 2/17 treated with whole-ventricle irradiation, 0/4 treated with WBRT, and 1/15 treated with CSI. Survival analysis did not reveal DFS differences between the types of radiation field (p=0.785). HRQOL analysis (n=44) in our cohort found that, compared with S/SS+PG germinoma, patients with BG/T involvement had significantly lower scores in social and school domains. However, HRQOL difference between patients treated with CSI and those not treated with CSI was not significant. Conclusion In patients with non-metastatic bifocal germinoma, it is rational that CSI could be replaced by limited-field radiation. HRQOL in patients with BG/T involvement was poorer.

BACKGROUND Growth problems are common in patients with intracranial germ cell tumours. However, the characteristics were not fully profiled, especially when stratified by orientation. Thus, we conducted this study. METHODS Patients newly diagnosed, ≤19 years, with confirmed pathology or tumour markers elevation were included. Patients with bifocal lesions or lost to follow-up were excluded. WHO AnthroPlus software, which was developed for the global application of the WHO Reference 2007 to monitor growth in children aged 5–19 years, was used. Based on age, sex, and height, the Z-scores of height(ZSOH) were calculated. A ZSOH< -1 indicates a slower physical development than that in peers, while a ZSOH >1 indicates faster growth than peers. RESULTS Among the 200 included patients, 75 had primary lesions originating from the sellar/suprasellar region(S/SS), 73 from the pineal gland(PG), and 52 from the basal ganglia/thalamus region(BG/T). At initial diagnosis, the median ZSOH in S/SS was -0.66(-3.76–3.05), which was significantly lower than that in PG(0.76,-2.23–5.19) and BG/T(0.64,-3.05–5.32)(p=0.001). However, the difference in ZSOH between PG and BG/T was comparable(p=0.61). In patients with S/SS who had paired data(n=36), the median ZSOH decreased from -0.22(-3.76–3.05) at diagnosis to -1.01(-3.42–1.89) at the last follow-up(p=0.001). The median ZSOHs in PG(n=38) and BG/T(n=28) remained in the normal range at last follow-up although the changes were statistically significant(p< 0.001). Linear regression analysis showed that, in S/SS, age at diagnosis(β=0.115,p=0.033), sex(β=1.337,p=0.002), radiotherapy dose(β=-0.061,p=0.007), and number of chemotherapy cycles(β=-0.177,p=0.038) were correlated with changes in median ZSOH. In BG/T, only the radiotherapy dose(β=-0.064,p=0.041) and number of chemotherapy cycles(β=-0.551,p=0.026) were correlated. However, none of the above were validated in PG. CONCLUSIONS Compared to intracranial germ cell tumours in the PG or BG/T, the growth problems in S/SS was more prominent and aggravated after treatments, especially in those with younger age, female sex, higher radiotherapy dose, and more chemotherapy cycles.

Our previous data showed that WHO grade II/III gliomas with isocitrate dehydrogenase wide-type (IDH-wt) and telomerase reverse transcriptase promoter mutation (TERTp-mut) have dismal prognosis as glioblastoma. This study compared concurrent chemoradiotherapy(CRT) with radiotherapy(RT) alone on the outcome of these patients. Between September 2016 and November 2018, 30 eligible grade II/III glioma patients with IDH-wt and TERTp-mut were randomly assigned to receive either RT (60 Gy in 30 daily fractions for 6 weeks) alone (n=15) or concurrent CRT with daily temozolomide and adjuvant temozolomide (n=15). The median follow-up duration was 15.5 months. The median age was 51 years (range, 24–66 years). The median Karnofsky performance status (KPS) score at randomization was 80 (range, 60–80). Surgery was the primary treatment. The characteristics of the two treatment groups were well balanced at baseline. The 1-year OS rate was significant difference between CRT group (92.3%; 95% CI: 77.8–100) and RT alone group(71.1%; 95% CI: 47.0–95.2) (p = 0.019). Local, distant, and combined tumor recurrence patterns were observed in 4 (26.7%), 1 (6.7%), and 3 patients (20%) in the CRT group and 4 (26.7%), 3 (20%), and 3 patients (20%) in the RT alone group. Those treated with RT alone had shorter median PFS (9 vs 18 months, HR: 0.517; 95% CI: 0.193 to 1.386; p = 0.19). CRT with temozolomide and extent of resection were statistically significant predictors for survival on univariate analysis. Multivariate analysis showed that CRT was associated with a significantly better OS compared with RT alone (OR=0.195; 95% CI, 0.044 to 0.867; p=0.032). Consequently, concurrent CRT with daily temozolomide and adjuvant temozolomide for newly diagnosed IDHwt/TERTp-mut grade II/III gliomas had significantly better OS compared with RT alone. A large multi-center prospective randomized trial is warranted. The trial has been registered at ClinicalTrials.gov (NCT02766270).

We previously reported a novel fusion gene PTPRZ1-MET in 15% of secondary GBM (sGBM). Subsequent studies showed that ZM fusion indicates a significantly worse prognosis and promotes glioma progression by increasing MET activity. We have demonstrated hyper-activation of MAPK and STAT3 signaling and elevated angiogenesis activities in patients and subcutaneous tumors with ZM fusion. However, the angiogenesis mechanism regulated by ZM is still unclear. In this study, 66 up-regulated and 66 down-regulated genes were identified on 8 sGBMs with ZM fusion comparing gene expression with 135 negative sGBMs (fold-change >2.5 & p.value < 0.05). ZM-harboring U87 MG xenograft models were conducted and RNA sequencing was performed in 3 subcutaneous tumors with ZM-harboring U87 MG and 3 negative control. 384 up-regulated and 698 down-regulated genes were identified on 3 ZM-harboring samples comparing gene expression with 3 negative control samples (fold-change >2.5 & p.value < 0.05. Three subcutaneous tumors with ZM-harboring U87 MG were treated by a MET kinase inhibitor, PLB-1001. Finally, the expression of 13 up-regulated gene decreased and 10 down-regulated genes increased after treatment by PLB-1001. We overlapped the candidate genes between patient samples and subcutaneous tumors and 5 up-regulated and 4 down-regulated genes was appeared and most associated with ZM fusion. Prognostic analysis of 9 candidate genes on sGBM revealed that a higher expression of IGF2BP3 indicates a worse prognosis. In further study, we found that IGF2BP3 can be secreted out of the gliomas stem cells (GSCs) and promote proliferation of vascular endothelial cells and the expression of CD31. IGF2BP3 siRNA can block this pathway and inhibit the angiogenesis. Conclusion, our study demonstrated a new pathway promoting angiogenesis in gliomas. But the regulating mechanism between ZM fusion gene and IGF2BP3 deserves to do further research.

High grade gliomas (HGGs: anaplastic gliomas and GBM) are the most lethal type of primary brain tumor. Maximal resection and postoperative concurrent chemoradiotherapy, and followed with adjuvant chemotherapy is the standard treatment. But patients with HGGs have a relapse rapidly and short survival. Studies have identified many clinical characteristics and biomarkers were associated with progression free survival (PFS) and over survival (OS). However, there has not yet a comprehensive study on the effects of these factors to survival after the first progression (SAP). 319 patients with HGGs were conducted maximum resection followed by radiotherapy and/or temozolomide chemotherapy and have been confirmed the first progression. Clinical characteristics, biomarkers (IDH1/2 mutation, MGMT promoter methylation, LOH1p/19q, TP53 mutation, EGFR amplification, Ki-67 expression) and clinical interventions (extent of resection, chemoradiotherapy, operation after progression) were analyzed in accordance with SAP. The 1-year SAP was 14.2% (median SAP: 5.1 months). Significant prognostic factors of improved SAP were tumor grade, MGMT promoter methylation and Ki-67 expression in univariate analysis (p< 0.05). Further multivariate analysis showed that MGMT promoter methylation and Ki-67 expression were independently prognostic markers for SAP (p< 0.05). In our data, HGGs could be divided into low, intermediate and high risk groups for SAP by MGMT promoter methylation and Ki-67 expression. However, analysis of 308 patients with GBM from The Cancer Genome Atlas (TCGA) found that MGMT promoter methylation is the only prognostic marker for SAP in multivariate analysis (p< 0.05). Consequently, MGMT promoter methylation is independently prognostic marker for SAP in patients with HGGs. MGMT promoter methylation, combined with Ki-67 expression, might establish a risk model for SAP and this stratification may aid in treatment strategy selection and clinical prognosis evaluation in HGGs.

Whether craniospinal irradiation (CSI) could be replaced by limited-field radiation in non-metastatic bifocal germinoma remains controversial. We addressed the issue based on the data from our series and the literature.Data from 49 patients diagnosed with non-metastatic bifocal germinoma at our hospital during the last 10 years were collected. The Pediatric Quality of Life Inventory 4.0 was used to evaluate health-related quality of life (HRQOL). Additionally, 81 patients identified from the literature were also analyzed independently.In our cohort, 34 patients had tumors in the sellar/suprasellar (S/SS) plus pineal gland (PG) regions and 15 in the S/SS plus basal ganglia/thalamus (BG/T) regions. The median follow-up period was 52 months (range, 10 to 134 months). Our survival analysis showed that patients treated with CSI (n=12) or whole-brain radiotherapy (WBRT; n=34) had comparable disease-free survival (DFS; p=0.540), but better DFS than those treated with focal radiotherapy (FR; n=3, p=0.016). All 81 patients from the literature had tumors in the S/SS+PG regions. Relapses were documented in 4/45 patients treated with FR, 2/17 treated with whole-ventricle irradiation, 0/4 treated with WBRT, and 1/15 treated with CSI. Survival analysis did not reveal DFS differences between the types of radiation field (p=0.785). HRQOL analysis (n=44) in our cohort found that, compared with S/SS+PG germinoma, patients with BG/T involvement had significantly lower scores in social and school domains. However, HRQOL difference between patients treated with CSI and those not treated with CSI was not significant.In patients with non-metastatic bifocal germinoma, it is rational that CSI could be replaced by limited-field radiation. HRQOL in patients with BG/T involvement was poorer.

The Chinese Glioma Cooperative Group (CGCG) Guideline Panel for adult diffuse gliomas provided recommendations for diagnostic and therapeutic procedures. The Panel covered all fields of expertise in neuro-oncology, i.e. neurosurgeons, neurologists, neuropathologists, neuroradiologists, radiation and medical oncologists and clinical trial experts. The task made clearer and more transparent choices about outcomes considered most relevant through searching the references considered most relevant and evaluating their value. The scientific evidence of papers collected from the literature was evaluated and graded based on the Oxford Centre for Evidence-based Medicine Levels of Evidence and recommendations were given accordingly. The recommendations will provide a framework and assurance for the strategy of diagnostic and therapeutic measures to reduce complications from unnecessary treatment and cost. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China.

As a crucial oncogene, B cell lymphoma-2 (BCL-2) could promote cancer cell survival by inhibiting apoptosis via suppressing activation of proapoptotic proteins, such as BAX and BAK. There is a functional rs2279115 genetic polymorphism locating in BCL-2 promoter and deregulating BCL-2 expression. However, it is still largely undefined how BCL-2 rs2279115 promoter noncoding genetic variant is involved in glioma development. We examined the association between BCL-2 rs2279115 and glioma risk using a case-control approach. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression adjusted by age and sex. Our results demonstrated that BCL-2 rs2279115 was significantly associated with glioma risk. The odd of individuals harboring A allele (CA + AA genotype) was 0.50 (95% CI = 0.39-0.64, p = 1.0 × 10

Background: PD-1 plays a critical part in control of immune response to malignancy. Anti-PD-1 treatment is a hopeful strategy to improve the dismal prognosis of gliomas. To characterize the role of PD-1 in diffuse gliomas, we investigated its related biological process at transcriptome level and its clinical prognostic value. Method and patients: Through Chinese Glioma Genome Atlas and TCGA datasets, we systematically reviewed a total of 994 cases with RNA-seq data and analyzed the functional annotation of PD-1 by Gene ontology (GO) analysis. Univariate and multivariate survival analysis were performed in 907 patients with survival data. Results: We found PD-1 was significantly upregulated in glioblastoma and isocitrate dehydrogenase wild type tumors. According to TCGA transcriptional classification scheme, PD-1 expression was higher in tumors of mesenchymal subtype than other subtypes, and shown good predictive value to mesenchymal subtype. GO analysis revealed that genes significantly correlated with PD-1 were involved in essential functions associated with anti-tumor immune process. Through screening transcriptomic data, we found a strong correlation between PD-1 and immune cell populations especially for T cells. In addition, we investigated the association between PD-1 and genes related to its function, and found that PD-1 was significantly correlated with genes including TGFB1, IDO1, CD40, ICOS and SATB1, and other immune checkpoint molecules including CTLA4, LAG3, TIM3 and CD276. Survival analysis suggested that higher PD-1 expression was independently associated with worse prognosis of patients with diffuse gliomas. Conclusion: Our results indicated that PD-1 was involved in key steps of anti-tumor immune process and independently predicted worse prognosis in diffuse gliomas. These findings may expend our understanding of potential anti-PD-1 treatments.

As a crucial homologous recombination repair gene, RAD52 participates in maintenance of genomic stability and prevention of tumorigenesis. Although several cancer susceptibility RAD52 single nucleotide polymorphisms (SNPs) have been identified previously, little was known on how the RAD52 SNPs are involved in glioma development in Han Chinese. Therefore, we examined the association between five RAD52 SNPs (rs1051669, rs10774474, rs11571378, rs7963551 and rs6489769) and glioma risk using a case-control design. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. We found that only the RAD52 rs7963551 SNP was significantly associated with glioma risk, with the odds of having the rs7963551 AC or CC genotype in patients was 0.49 (95 % CI 0.37-0.65, P = 9.2 × 10(-6)) or 0.39 (95 % CI 0.18-0.81, P = 0.012) compared with the AA genotype. These data are consistent with functional relevance of allelic regulation of RAD52 expression by the rs7963551 SNP and miRNA let-7 in cancer cells. Stratified analyses elucidated that statistically significant association between glioma and rs7963551 SNP only existed in either astrocytic tumors (P = 6.3 × 10(-6)) or oligoastrocytic tumors (P = 0.002). In conclusion, our results support the hypothesis that genetic variants influencing miRNA-mediated regulation of tumor suppressor genes or oncogenes may contribute glioma susceptibility.

BACKGROUND Recently, a rare subset of lower grade glioma (LoG), characterized by wild-type isocitrate dehydrogenase (IDH) and mutated TERT promoter (IDHWT-TERTpMut), has been highlighted for its dismal clinical behavior and classified as world health organization (WHO) grade IV. METHODS We examined this distinct tumor subset through genome-wide analysis of 745 gliomas and radiomic analysis of 129 LoGs. RESULTS We found that the prognosis and genetic lineage of IDHWT-TERTpMut LoGs were similar to those of glioblastoma. Importantly, a signature of 7 radiomic features from magnetic resonance imaging data differentiated IDHWT-TERTpMut LoGs from other LoGs. In addition, we found the radiomic related genes involved in many tumorigenic processes. CONCLUSIONS Overall, our findings suggest that the biological characteristics of IDHWT-TERTpMut LoGs and the radiomic signature could help in the non-invasive diagnosis of this tumor subtype.

PURPOSE Intracranial germ cell tumours (iGCTs) originating from the basal ganglia/thalamus (BG/T) region are rare. We report the findings from a large single-centre series to explore the clinical features of this disease. PATIENTS AND METHODS Patients diagnosed as having BG/T iGCTs from January 2000 to December 2017 at our hospital were screened. Newly diagnosed patients who had histology-proven/tumour marker-elevated disease and received at least radiotherapy were eligible for analysis. RESULTS Of the 401 patients screened, 211 were eligible. The median age was 12 years (range, 5–41 years). The median duration of follow-up for surviving patients was 68 months (range, 12–189 months). In germinoma patients (n = 112), the 5-year disease-free survival (DFS) and overall survival (OS) were 94.9% and 98.2%, respectively. Multivariate analysis showed that the dose of radiotherapy could predict the DFS (hazard ratio [HR] 0.991, 95% confidence interval [CI] 0.983–0.998, p = 0.015). In non-germinomatous GCT (NGGCT) patients (n = 99), the 5-year DFS and OS were 83.8% and 88.6%, respectively. Multivariate analysis showed that irradiation field (whole-brain radiotherapy vs. local radiotherapy, HR = 0.163, 95% CI 0.031–0.897, p = 0.037; cranial spinal radiotherapy vs. local radiotherapy, HR = 0.095, 95% CI 0.009–1.031, p = 0.053) and chemotherapy cycle (>3 vs. ≤3) (HR 0.234, 95% CI 0.055–0.996, p = 0.049) were independent factors for DFS. The median Z-score for height and body mass index (BMI) in patients ≤19 years of age (n = 69) at the last follow-up were -0.45 (range, -2.67 to 3.41) and 0.59 (range, -4.73 to 3.1), respectively. CONCLUSION BG/T GCTs had unique characteristics. Radiation dose was an independent factor influencing the DFS in cases of germinoma. In NGGCTs, extended field radiation and more chemotherapy cycles yielded better disease control. Physical development after treatment was within the normal range for most patients.

To analyze the clinical characteristics and prognostic factors in patients with glioma in an academic institute in China. From October 2004 to August 2010, total 1,285 patients were diagnosed as glioma at the Glioma Center of Beijing Tiantan Hospital. Clinical and molecular pathology features and survival rates were analyzed. The median overall survival (OS) times were 78.1, 37.6 and 14.4 months for low-grade glioma (WHO grade II), anaplastic glioma (WHO grade III) and glioblastoma (WHO grade IV), respectively. In patients with low-grade glioma, age, preoperative Karnofsky performance scale (KPS), pathological type, radiotherapy, O(6)-methylguanine-DNA methyltransferase (MGMT) expression and Ki-67 expression, were significantly associated with OS in multivariate analyses; and preoperative KPS and radiotherapy were significantly associated with progression-free survival (PFS). For anaplastic gliomas, age, preoperative KPS, pathological type, extent of resection, radiotherapy, p53 expression and phosphatase and tensin homolog (PTEN) expression were associated with OS. For glioblastomas, age, preoperative KPS, pathology type, extent of resection, radiotherapy and chemotherapy were associated with OS; and age, gender, preoperative KPS, extent of resection, radiotherapy and chemotherapy were associated with PFS. This is the largest survey for glioma management in China to date. We found significant differences in age, presenting symptoms and the expression of p53, MGMT, PTEN, and Ki-67 among patients with different types of glioma. Age, preoperative KPS, tumor grades, radiotherapy, chemotherapy and Ki-67 expression were significantly associated with clinical prognosis.

As a tumor suppressor, FEN1 plays an essential role in keeping genomic instability and preventing tumorigenesis. There are two functional genetic variants (-69G>A and 4150G>T) in the FEN1 gene, which have been associated with DNA damage levels in coke-oven workers as well as risks of lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer in general populations. However, it is still unknown how these polymorphisms and their haplotypes are associated with glioma risk. Therefore, we investigated the role of these polymorphisms in glioma development using a case-control design in a Chinese population. The impact of the haplotypes constructed by these two polymorphisms on glioma risk was also examined. It was observed that the FEN1-69GG or 4150GG genotype were significantly associated to increased glioma risk compared with the -69AA or 4150TT genotype [Odds ratios (OR) = 1.87, 95 % confidence interval (CI) = 1.23-2.85, P = 0.003; or OR = 1.87, 95 % CI = 1.23-2.84, P = 0.003). The associations were more pronounced among female subjects (For -69AG or GG genotype: OR = 2.35, 95 % CI = 1.22-4.52; for 4150TG or GG genotype: OR = 2.33, 95 % CI = 1.21-4.48) and patients with grade 1 or 2 disease (For -69AG or GG genotype: OR = 2.21, 95 % CI = 1.20-4.05; for 4150TG or GG genotype: OR = 2.45, 95 % CI = 1.31-4.58). Additionally, the G(-69)G(4150) haplotype was also significantly associated with increased glioma risk compared with the A(-69)T(4150) haplotype. Our results suggest that FEN1 polymorphisms and haplotypes are associated with glioma risk.

Insulin-like growth factor binding protein 2 (IGFBP-2) is a malignancy-associated protein measurable in tumors and blood. Increased IGFBP-2 is associated with shortened survival of advanced glioma patients. Thus, we examined plasma IGFBP-2 levels in glioma patients and healthy controls to evaluate its value as a plasma biomarker for glioma. Plasma IGFBP-2 levels in 196 patients with newly diagnosed glioma and 55 healthy controls were analyzed using an IGFBP-2 ELISA kit. Blood was collected before surgery, after two-cycle adjuvant chemotherapy, and at recurrence. Plasma IGFBP-2 levels were correlated with disease-free survival DFS) using Cox regression analyses. We found that preoperative plasma IGFBP-2 levels were significantly higher in high-grade glioma patients n = 43 for grade III glioma; n = 72 for glioblastoma multiforme [GBM]) than in healthy controls n = 55; p < 0.001) and low-grade (grade II) glioma patients n 5 81; p, 0.001). No significant differences in preoperative plasma IGFBP-2 levels were observed between grade III glioma and GBM patients or between grade II glioma patients and healthy controls. After recurrence, plasma IGFBP-2 levels were significantly increased in GBM patients (n = 26; p < 0.001). Preoperative plasma IGFBP-2 levels were significantly correlated with DFS in GBM patients ( hazard ratio, 1.404; 95% confidence interval, 1.078-1.828; p = 0.012). We conclude that preoperative plasma IGFBP-2 levels are significantly higher in high-grade glioma patients than in low-grade glioma patients and healthy subjects, and are significantly correlated with recurrence and DFS in patients with GBM. Longitudinal studies with a larger study population are needed to confirm these findings. Neuro-Oncology 11, 468-476, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00199, January 22, 2009. URL http://neuro-oncology. dukejournals. org; DOI: 10.1215/15228517-2008-114)

BACKGROUND Grade II and III gliomas have variable clinical behaviors, showing the distinct molecular genetic alterations from glioblastoma (GBM), many of which eventually transform into more aggressive tumors. Since the classifications of grade II/III gliomas based on the genetic alterations have been recently emerging, it is now a trend to include molecular data into the standard diagnostic algorithm of glioma. METHODS Here we sequenced TERT promoter mutational status (TERTp-mut) in the DNA of 377 grade II/III gliomas and analyzed the clinical factors, molecular aberrations, and transcriptome profiles. RESULTS We found that TERTp-mut occurred in 145 of 377 grade II and III gliomas (38.5%), mutually exclusive with a TP53 mutation (TP53-mut; P < .001) and coincident with a 1p/19q co-deletion (P = .002). TERTp-mut was an independent predictive factor of a good prognosis in all patients (P = .048). It has been an independent factor associated with a good outcome in the IDH mutation (IDH-mut) subgroup (P = .018), but it has also been associated with a poor outcome in the IDH wild-type (IDH-wt) subgroup (P = .049). Combining TERTp-mut and IDH-mut allowed the grade II/III malignancies to be reclassified into IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt. 1p/19q co-deletion, TP53-muts, Ki-67 expression differences, and p-MET expression differences characterized IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt subtypes, respectively. CONCLUSIONS Our results showed that TERTp-mut combined with IDH-mut allowed simple classification of grade II/III gliomas for stratifying patients and clarifying diagnostic accuracy by supplementing standard histopathological criteria.

Purpose : The incidence of the primary intracranial leiomyosarcoma is extremely rare, and few cases have been previously reported worldwide to date. This report was to clarify the potential role of radiotherapy in the management of primary intracranial leiomyosarcoma. Methods and Materials : This report presented a 49-year old man with a 3-month history of a progressively headache and walk ing unsteadily. The diagnosis was confirmed with thalamic leiomyosarcoma of high-grade malignancy according to the pathologic examination after neurosurgical biopsy. The patient didn’t undergo surgical resection because of a high risk death. After biopsy, radiotherapy using 3D-CRT technique to the mass site with 55.8Gy/31f/43d was given accordingly. Results : The mass didn’t reduce much at the end of radiotherapy. The patient refused systemic chemotherapy, he was alive without signs of local relapse and brain side-effects with 6 month’s follow-up. After living eleven months and three weeks after radiotherapy, he died of local progression. Conclusions : Through literature review, the current therapeutic approaches including surgery, radiotherapy as well as chemotherapy appear to have limited effect, but could be beneficious of patients in tumor local control and improvement of the life quality.

Recent genome-wide association studies have identified several leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Our previous data demonstrated that two SNPs (rs398652 on 14q21 and rs621559 on 1p34.2) were associated with LTL and risk of esophageal squamous cell carcinoma in Chinese. However, the role of these genetic variants on glioma risk is still unknown. Therefore, we examined if these genetic variants have impact on the genetic susceptibility of glioma in Chinese. On the basis of analyzing 404 glioma patients and frequency-matched 820 controls, we found that subjects having the 1p34.2 rs621559 AG or GG genotype had an OR of 1.82 (95 % CI = 1.07–3.09, P = 0.026) or 2.12 (95 % CI = 1.26–3.56, P = 0.005) for developing glioma, respectively, compared with subjects having the rs621559 AA genotype. Similarly, the 14q21 rs398652 AG or GG genotype was associated with increased glioma risk (OR = 1.39, 95 % CI = 1.07–1.80, P = 0.012; OR = 1.52, 95 % CI = 1.04–2.20, P = 0.029) compared to AA genotype. In all, our results highlight the possible role of telomere in carcinogenesis.

A comprehensive evaluation of cytokine levels in patients with gliomas could provide important information for the progression and host responses of gliomas. We studied a panel of 120 cytokines and growth factors and investigated their prognostic values for glioma. A protein antibody array was first performed to study the prognostic significance of 120 cytokines in the plasma samples of 45 glioblastoma patients prior to craniotomy or biopsy procedure. An independent set of plasma samples from 260 patients with astrocytomas (80 grade II, 80 grade III, 100 grade IV) with complete clinicopathologic data and follow-ups were used for validation. Ten cytokines were identified by significance analysis of microarray, in which four were associated with poor prognosis (IL-15, MCP-1, GDNF, IL-1R4/ST2), and six were associated with good prognosis (IGFBP-6, MIP-1δ, ICAM-3, IL-7, MIP-3β, and sgp130) of the glioblastoma patients. Moreover, a 4-cytokine panel composed of IL-7, IL1R4/ST2, sgp130 and MCP-1 showed significant correlation with overall survival of the glioblastoma patients (HR 2.068; 95 % CI 1.357–3.153; p = 0.001). In the validation set, the cytokine panel was significantly correlated with overall survival in the 260 glioma patients (HR 3.480, 95 % CI 1.890–6.422) in multivariate Cox regression analysis. It also showed strong correlation with survival in patients with malignant gliomas (grade III: HR 2.790, 95 % CI 1.597–3.984, p = 0.002; grade IV: HR 1.753; 95 % CI 1.502–2.255, p

The increased chemosensitivity of oligodendroglial tumors has been associated with loss of heterozygosity (LOH) on chromosomes 1p and 19q. Other clinical and molecular factors have also been identified as being prognostic and predictive for treatment outcome. Seventy-seven patients with anaplastic oligodendroglioma (AO) or anaplastic oligoastrocytoma (AOA), treated in Beijing Tiantan Hospital from 2006 through 2008, were reviewed. LOH 1p, LOH 19q, IDH1 mutation, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and protein expression level of MGMT, P53, EGFR, and Ki-67 were evaluated. Age at diagnosis, LOH 1p and 19q, IDH1 mutation, P53 expression level, reoperation when progression, and adjuvant chemotherapy were statistically significant factors for overall survival (OS) in univariate analysis. Further multivariate analysis showed that age at diagnosis (P = .010), LOH 1p and 19q (P = .016), IDH1 mutation (P = .011), and reoperation after progression (P = .048) were independent predictors for longer survival in these patients. Nonrandom associations were found between LOH 1p and LOH 19q, MGMT promoter methylation and LOH 1p or 19q, IDH1 mutation and LOH 1p and 19q, IDH1 mutation and MGMT promoter methylation, whereas mutual exclusion was found between MGMT promoter methylation and MGMT expression level. The present study confirmed that age at diagnosis, LOH 1p and 19q, IDH1 mutation, and reoperation after progression were independent significant prognostic factors for patients with anaplastic oligodendroglial tumors. Inter-relationship between LOH 1p, LOH 19q, IDH1 mutation, MGMT promoter methylation, and MGMT expression level were also revealed. Future clinical trials for AO and AOA should consider the molecular alterations of patients.