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BACKGROUND Basal ganglia germ cell tumors (BGGCTs) are rare intracranial germ cell tumors (iGCTs) that often presents with cognitive impairment. OBJECTIVE To assess structural brain plasticity in the presence of unilateral basal ganglia germ cell tumors (BGGCTs), and the correlation between gray matter volume (GMV) changes and cognitive tests. MATERIALS AND METHODS We applied voxel-based morphometry (VBM) to structural magnetic resonance imaging (MRI) scans to compare a sample of 41 patients with BGGCTs in the left (n = 22) or right (n = 19) and a sample of 16 patients as control group using a two-sample t-test, correcting for family-wise-errors. A battery of cognitive tests was administered to all BGGCTs patients prior to MRI. We used Pearson correlation analysis to assess the correlation between cognitive test scores and GMV changes. RESULTS In patients with left BGGCTs, whole-brain VBM analysis revealed a large cluster of voxels reflecting an increase in GMV in the left parahippocampal region (k = 529 voxels, T = 4.18, p

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 (

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.

To explore the characteristics of growth disturbance in patients with intracranial germinoma with different origins.Clinical data of 151 patients with single-origin germinomas were studied retrospectively. Z-score of height (ZSOH) at both diagnosis and the last follow-up was calculated using the WHO AnthroPlus software. Linear regression was used to analyse the correlation between the absolute change in ZSOH (|ZSOHThe mean ZSOH decreased significantly in every origin subgroup at the last follow-up. In patients with sellar germinoma (n = 62), the mean ZSOH values at both diagnosis and the last follow-up were significantly lower than those in patients with pineal (n = 30) (p0.001) or basal ganglia germinomas (n = 59) (p0.001), respectively. In patients with basal ganglia germinoma, the mean absolute change in ZSOH decreased significantly compared to that in the patients with sellar (p = 0.006) or pineal germinomas (p = 0.04). Linear analysis revealed that sex (male vs female; p = 0.003) and age at diagnosis (≤10 years vs10 years; p = 0.026) had negative correlations, while radiation dose at the hypothalamic-pituitary axis (HPA) (≤40 Gy vs40 Gy; p = 0.085) had a marginally positive correlation, with absolute change in ZSOH.Patients with germinoma experienced growth retardation after treatments. The growth disturbance was consistent and more severe in patients with germinoma of sellar origin, while the greatest aggravation was observed in patients with germinoma of basal ganglia origin. Decreasing radiation dose to the HPA may minimize the negative impact of radiotherapy on growth.

Background As molecular advances have deepened the knowledge on low-grade glioma (LGG), we investigated the effect of higher radiation dose on the survival of IDH-wildtype (IDHwt) LGG. Methods In the current study, 52 IDHwt LGG patients who received radiotherapy were enrolled from the Chinese Glioma Genome Atlas dataset. Radiation doses > 54 Gy were defined as high-dose, whereas doses ≤ 54 Gy were defined as low-dose. We performed univariate and multivariate survival analyses to examine the prognostic role of high-dose radiotherapy. Results In total, the radiation dose ranged from 48.6 Gy to 61.2 Gy, with a median of 55.8 Gy, and 31 patients were grouped into high-dose radiation. Univariate survival analysis indicated that high-dose radiotherapy (p = 0.015), tumors located in the frontal lobe (p = 0.009), and pathology of astrocytoma (p = 0.037) were significantly prognostic factors for overall survival. In multivariate survival analysis, high-dose radiotherapy (p = 0.028) and tumors located in the frontal lobe (p = 0.016) were independently associated with better overall survival. Conclusions In conclusion, high-dose radiotherapy independently improved the survival of IDHwt LGG. This can guide treatments for glioma with known molecular characteristics.

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.

Wenyi Lv,1 Jin Feng,1 Li Chen,1 Shuai Liu,1,2 Xiaoguang Qiu1,2 1Department of Radiation Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, People’s Republic of China; 2Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, People’s Republic of ChinaCorrespondence: Xiaoguang Qiu; Shuai LiuBeijing Neurosurgical Institute, Capital Medical University, No. 119, South 4th Ring West Road, Fengtai District, Beijing 100070, People’s Republic of ChinaTel/Fax +86 1059975266; +86 1059975580Email qiuxiaoguang@bjtth.org; s.liu@bjtth.orgPurpose: Basal ganglia intracranial germ cell tumors (iGCTs) can specifically destroy the basal ganglia network, leading to several cognitive, learning, behavioral, and social impairments. This study aimed to investigate the behavior and social disorders of patients with basal ganglia iGCTs.Patients and Methods: We recruited 30 newly diagnosed iGCTs patients (and their parents) for the current study. The Child Behavior Checklist/6– 18 was used to evaluate emotional and behavioral problems. The Conner’s Parent Rating Scales was used to assess symptoms of hyperactivity/impulsivity and conduct problems. The health-related quality of life (HRQoL) was assessed using the Pediatric Quality of Life Inventory 4.0 Generic Core Scale. Performance status was assessed using the Lansky play-performance scale and Karnofsky performance scale. The effects of basal ganglia lesions on these scores were examined.Results: Patients with basal ganglia iGCTs (n = 10) had more behavioral problems (attention problems, aggressive behavior, learning problems, hyperactivity index), social function impairment, anxiety/depression, and poorer HRQoL compared to patients with non-basal ganglia iGCTs (n = 20). There was no significant difference in the Lansky play-performance/Karnofsky performance scale scores.Conclusion: This study demonstrates the effects of basal ganglia lesions on behavioral and emotional outcomes, social functions, and HRQoL of patients with iGCTs. The results may help to understand the function of basal ganglia and provide evidence for the benefit of early psychological intervention to improve the treatment for this rare disease.Keywords: intracranial germ cell tumors, pediatrics, The Child Behaviour Checklist, The Conner’s Parent Rating Scales, health-related quality of life

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.

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 Patients with low-grade gliomas (LGGs) harboring O6-methylguanine-DNA methyltransferase promoter nonmethylation (MGMT-non-pM) have a particularly short survival and are great resistance to chemotherapy. The objective of this study was to assess the efficacy of high-dose radiotherapy (RT) for LGGs with MGMT-non-pM. Methods 268 patients with newly diagnosed adult supratentorial LGGs from the multicenter Chinese Glioma Cooperative Group (CGCG) received postoperative RT during 2005–2018. MGMT promoter methylation analysis was conducted by pyrosequencing in all patients. Univariate and multivariate analysis were performed using the Cox regression to determine the prognostic factors for overall survival (OS) and progression-free survival (PFS). RT dose–response on MGMT status defined subtypes was analyzed. Results On univariate analysis, the following were statistically significant favorable factors for both PFS and OS: oligodendrogliomas(p = 0.002 and p = 0.005), high-dose RT (> 54 Gy) (p = 0.021 and p = 0.029) and 1p/19q codeletion (p p = 0.001). On multivariate analysis, RT dose (> 54 Gy vs. ≤ 54 Gy) and IDH mutation were independently prognostic markers for OS (HR, 0.47; 95%CI, 0.22–0.98; p = 0.045; and HR, 0.44; 95%CI, 0.21–0.96; p = 0.038, respectively) and PFS (HR, 0.48; 95%CI, 0.26–0.90; p = 0.022; and HR, 0.51; 95%CI, 0.26–0.98; p = 0.044, respectively). High-dose RT was associated with longer OS (HR, 0.56; 95%CI, 0.32–0.96; p = 0.036) and PFS (HR, 0.58; 95%CI, 0.35–0.96; p = 0.033) than low-dose RT in MGMT-non-pM subtype. In contrast, no significant difference in either OS (p = 0.240) or PFS (p = 0.395) was observed with high-dose RT in the MGMT-pM subtype. Conclusions High-dose RT (> 54 Gy) is an independently protective factor for LGGs and is associated with improved survival in patients with MGMT-non-pM.

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.

Background Central nervous system germ cell tumors (CNS GCTs) represent a class of rare tumors that exhibit region-specific prevalence in some Asian areas (15.3%), higher than that in North America (3.6%), and age-specific prevalence in children and adolescents. According to the 2016 World Health Organization (WHO) classification, CNS GCTs can be categorized into germinomas and non-germinomatous GCTs (NGGCTs). Owing to the compression of the interventricular foramen by enlarged GCTs in the pineal gland, the resultant obstructive hydrocephalus may result in high intracranial pressure (HIP) at an alarming pace, which urgently requires a ventriculoperitoneal shunt for the relief of severe HIP. Although CNS GCT cells tend to migrate through the cerebrospinal fluid (CSF) starting from the subependymal lining, metastasis along the ventriculoperitoneal shunt tube is extremely rare. Case presentation In this study, we reported two cases of iGCTs with intraperitoneal metastasis. Both patients underwent ventriculoperitoneal shunt placement to alleviate HIP, and both received standard radiotherapy and chemotherapy, but they still developed abdominal metastasis, and all the abdominal masses were pathologically confirmed to be iGCTs. Conclusions We performed a literature study and found that from 1979 to 2020, a total of 18 cases of iGCTs were metastasized outside the nervous system. We also found a shift of the median of 13.5 months and that the most common primary site was the pineal region (83.3%); moreover, nearly half of the patients (44%) died within 1 year of metastasis, indicating a poor prognosis after celiac metastasis.

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.

Background Primary right brachium pontis germinoma with hypertrophic olivary degeneration (HOD) is extremely rare. A preoperative diagnosis is challenging due to the absence of characterized clinical and neuroimaging features, and biopsy should be considered. Case presentation A 20-year-old male patient presented with a case of primary intracranial germinoma originating from right brachium pontis with HOD manifesting as ocular myoclonus, nystagmus in both eyes, ataxic gait and incoordination of the limbs. Magnetic resonance imaging (MRI) revealed an irregular patchy lesion with hyperintensity on T2-weighted images (T2WI) and T2 fluid-attenuated inversion recovery (FLAIR) without enhancement by gadolinium (Gd). Furthermore, a focal hyperintense nodule on T2WI in the left inferior olive nucleus (ION) of the medulla oblongata was considered hypertrophic olivary degeneration (HOD) based on the patient’s symptoms and neuroimaging findings. Due to suspected demyelinating disease and low-grade glioma (LGG), a biopsy was planned. The pathological diagnosis was germinoma. Subsequently, he received chemoradiation therapy, resulting in the improvement of neurological deficits and the disappearance of the lesion on MRI. Conclusion A case of “Primary right brachium pontis germinoma with HOD” is reported for the first time. A preoperative diagnosis is challenging due to the fact of absence of clinical signs and symptoms and neuroimaging characteristics. However, patients can have favourable prognoses with appropriate evaluation and treatment.

The optimal target volume in localized basal ganglia (BG) germinoma is still undetermined. Thus, based on the relapse pattern and health-related quality of life (HRQOL), we evaluated three target volumes.The clinical data of 161 patients with localized BG germinoma were included in this retrospective study. Relapse status and relapse sites after treatment were explored. HRQOL was evaluated using the Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) (≤15 years) and Short Form-36 (SF-36) (15 years) questionnaires based on the patients' age at last follow-up.After a median follow-up duration of 83 months (range, 20-214 months), 19 patients experienced relapse, including 15, 4, and 0 patients in the focal radiotherapy (FR) (n = 35), whole-brain radiotherapy (WBRT) plus boost (n = 109), and craniospinal irradiation (CSI) plus boost (n = 17) groups, respectively. The 5-year disease-free survival rates were 74.3%, 97.2%, and 100%, respectively (p 0.001). Among the 15 patients who relapsed after FR, 14 had positive radiological findings, including seven (50.0%) with lesions in the periventricular area and seven (50.0%) with frontal lobe lesions. Relapse in both these areas were significantly reduced by WBRT or CSI. HRQOL data were available for 69 patients, who generally scored low. Among 38 patients evaluated by SF-36, those receiving CSI had significantly lower mental component scores than those receiving WBRT (p = 0.027) or FR (p = 0.011).Considering both disease control and HRQOL, WBRT is the optimal target volume in our series. The relapse pattern identified in patients receiving FR is informative for further treatment volume optimization.

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.

Glioblastoma (GBM) is an extremely challenging malignancy to treat. Although temozolomide (TMZ) is a standard treatment regimen, many patients with GBM develop chemoresistance. The aim of this study was to identify a DNA repair-related gene signature to better stratify patients treated with TMZ.We selected 89 cases of primary GBM (pGBM) from the Chinese Glioma Genome Atlas RNA-seq dataset as the training cohort, whereas The Cancer Genome Atlas RNA-seq and Gene Set Enrichment (GSE) 16011 mRNA array sets were used as validation cohorts. Regression analysis and linear risk score assessment were performed to build a DNA repair-related signature. We used Kaplan-Meier analysis to evaluate the predictive value of the signature for overall survival (OS) in the different groups. Multivariate Cox regression analysis was used to determine whether the 5-gene signature could independently predict OS.Using our 5-gene signature panel of APEX1, APRT, PARP2, PMS2L2, and POLR2L, we divided patients with pGBM into high- and low-risk groups. Patients with a low-risk score were predicted to have favorable survival and greater benefit from TMZ therapy compared with patients from the high-risk group (P0.05). Moreover, receiver operating characteristic curves showed that the multigene signature was the most sensitive and specific model for survival prediction (P0.05).Among patients with pGBM, classification based on a risk score determined using a 5-gene panel indicated different OS and reaction to TMZ. The findings in this study demonstrate that this unique 5-gene signature could be a novel model to predict OS and provide accurate therapy for patients with pGBM.

// Fan Yang 1, * , Pei Yang 1, * , Chuanbao Zhang 1, * , Yongzhi Wang 2 , Wei Zhang 2 , Huimin Hu 1 , Zhiliang Wang 1 , Xiaoguang Qiu 3 and Tao Jiang 1, 2, 4, 5 1 Department of Molecular Pathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 3 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 4 China National Clinical Research Center for Neurological Diseases, Beijing, China 5 Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China * These authors have contributed equally to this work Correspondence to: Tao Jiang, email: taojiang1964@163.com Keywords: glioblastoma, prognosis, recursive partitioning analysis, molecular marker, MGMT Received: July 18, 2016 Accepted: December 16, 2016 Published: April 21, 2017 ABSTRACT Glioblastoma accounts for more than half of diffuse gliomas. The prognosis of patients with glioblastoma remains poor despite comprehensive and intensive treatments. Furthermore, the clinical significance of molecular parameters and routinely available clinical variables for the prognosis prediction of glioblastomas remains limited. The authors describe a novel model may help in prognosis prediction and clinical management of glioblastoma patients. We performed a recursive partitioning analysis to generate three independent prognostic classes of 103 glioblastomas patients from TCGA dataset. Class I (MGMT promoter methylated, age 59, KPS ≥70), class III (MGMT promoter unmethylation, age 54-58, KPS ≥70; MGMT promoter unmethylation, KPS

// Xuefei Sun 1, * , Jing Liu 1, * , Yaming Wang 2 , Xueyan Bai 1 , Yuedan Chen 1 , Jun Qian 1 , Hong Zhu 1 , Fusheng Liu 3 , Xiaoguang Qiu 4 , Shengjun Sun 5 , Nan Ji 6 and Yuanbo Liu 1 1 Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 2 Department of Neurosurgery, Navy General Hospital, Beijing, China 3 Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 4 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 5 Neuroimaging Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 6 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China * These authors contributed equally to this work Correspondence to: Yuanbo Liu, email: yuanbol@ccmu.edu.cn Keywords: primary central nervous system lymphoma, rituximab, high-dose methotrexate, cytarabine, survival Received: December 21, 2016 Accepted: April 02, 2017 Published: April 13, 2017 ABSTRACT Purpose: High-dose methotrexate based chemotherapy is the standard treatment for patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The role of rituximab is controversial because of its large size, which limits its penetration of the blood-brain barrier. In this study, we investigated the efficacy and tolerability of adding rituximab to methotrexate-cytarabine-dexamethasone combination therapy (RMAD regimen). Results: The patients treated with RMAD had a complete remission rate of 66.7% after induction chemotherapy; this rate was only 33.3% in patients treated with MAD alone ( p = .011). The most common grade 1–3 adverse events were similar and included hematologic toxicity, increased aminotransferase levels, and gastrointestinal reactions. Multivariate analysis revealed that rituximab treatment was associated with longer progression-free survival (PFS, p = .005) but not overall survival (OS). Additionally, we observed that elevated serum lactate dehydrogenase was associated with shorter OS and PFS. Materials and Methods: We retrospectively analyzed 60 immunocompetent patients with newly diagnosed PCNSL at Beijing Tiantan Hospital, Capital Medical University from January 2010 to June 2016. Twenty-four patients received 3–6 courses of 3.5 g/m 2 methotrexate on day 1; 0.5–1 g/m 2 cytarabine on day 2; and 5–10 mg dexamethasone on days 1, 2 and 3. Thirty-six patients received the same combination plus rituximab 375 mg/m 2 on day 0. All patients repeated the treatment every 3 weeks. Conclusions: High-dose methotrexate based chemotherapy with rituximab yields a higher complete remission rate and does not increase serious toxicities. PFS benefits from the addition of rituximab. OS has an increasing trend in patients treated with rituximab without statistical significance.

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).

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.

Purpose To report the results of the first international pooled analysis of patients with glioblastoma treated with intraoperative radiotherapy (IORT) in addition to standard of care therapy. Methods Data from 51 patients treated at five centers in Germany, China and Peru were analyzed. All patients underwent tumor resection followed by a single application of IORT (10–40 Gy, prescribed to the applicator surface) with low-energy X-rays. Thereafter, standard adjuvant radiochemotherapy and maintenance chemotherapy were applied. Factors of interest were overall survival (OS), progression-free survival (PFS), local PFS (L-PFS; defined as appearance of new lesions ≤1 cm to the cavity border) and distant PFS (D-PFS; lesions >1 cm). The same endpoints were estimated at 1-, 2- and 3-years using the Kaplan-Meier method. Additionally, rates and severity (as per Common Terminology Criteria for Adverse Events Version 5.0) of radionecrosis (RN) were analyzed. Results The median age was 55 years (range: 16–75) and the median Karnofsky Performance Status was 80 (20–100). At a median follow-up of 18.0 months (2–42.4), the median OS, PFS, L-PFS and D-PFS were 18.0 months (95% CI: 14.7–21.3), 11.4 months (95%CI: 7.58–15.22), 16 months (95%CI: 10.21–21.8) and 30.0 months (95%CI: 18.59 – 41.41), respectively. The estimated 1-, 2- and 3-year OS, PFS, L-PFS and D-PFS were 79.5%, 38.7% and 25.6%; 46.2%, 29.4%, and 5.9%; 60.9, 37.9%, and 12.6%; and 76.7%, 65.0%, and 39.0% respectively. First progression occurred locally in only 35.3% of cases. Grade 1 RN was detected in 7.8% and grade 3 in 17.6% of the patients. No grade 4 toxicity was reported and no treatment-related deaths occurred. Conclusion Compared to historical data, this pooled analysis suggests improved efficacy and safety of IORT with low-energy X-rays for newly diagnosed glioblastoma. Prospective data is warranted to confirm these findings.

The purpose of the study was to determine the feasibility of three-dimensional (3D) constructive interference in steady state (CISS) sequences for evaluating the anterolateral ligament (ALL).Magnetic resonance imaging (MRI) of the right knee joint in 30 healthy volunteers was performed using a 3 T MRI machine. Axial T2-weighted imaging with fat saturation (T2WI-FS), coronal proton-density-weighted imaging with fat saturation (PDWI-FS), and 3D-CISS were included in the protocol. Multiplanar reconstruction (MPR) and rotating stretched curved planar reconstructions (CPRs) of the ALL at 30°, 60°, 90°, 120°, and 150° were generated from the 3D-CISS images. The visibility of the femoral part, meniscal part, tibial part, meniscal insertion, femoral footprint, and tibial footprint of the ALL on the imaging of all sequences was recorded.Based on the CPR of 3D-CISS MRI, the presence of tibial and femoral footprints of the ALL was rated superior to MPR and PDWI-FS (96.67% and 96.67%, respectively; p0.017). Rotating CPR of 3D-CISS MRI imaging was rated superior to PDWI-FS with respect to the tibial part, meniscal part, and meniscal insertion of the ALL (96.67%, 83.33%, and 83.33%, respectively; p0.05). Rotating CPR of 3D-CISS MRI was rated superior to PDWI-FS with respect to the femoral part of the ALL, but the difference was not statistically significant (p=0.095). The angle between the ALL and lateral collateral ligament (LCL) on the oblique sagittal image was 18.34±1.88°.The MRI 3D-CISS sequences significantly enhanced the ability to identify the ALL compared to the 2D MRI sequences.

// Pei Yang 1,2,* , Chuanbao Zhang 2,* , Jinquan Cai 9 , Gan You 1,2 , Yinyan Wang 1,2 , Xiaoguang Qiu 3 , Shouwei Li 5 , Chenxing Wu 5 , Kun Yao 6 , Wenbin Li 7 , Xiaoxia Peng 10 , Wei Zhang 1,2 and Tao Jiang 2,4,8 1 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 2 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 3 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 4 China National Clinical Research Center for Neurological Diseases, Beijing, China 5 Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 6 Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 7 Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 8 Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China 9 Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China 10 Department of Epidemiology and Biostatistics, School of Public Health and Family Medicine, Capital Medical University, Beijing, China * The first two authors contributed equally to this work Correspondence to: Wei Zhang, email: // Tao Jiang, email: // Keywords : high-grade glioma, young adult, radiation, temozolomide, survival Received : November 16, 2015 Accepted : August 22, 2016 Published : August 31, 2016 Abstract Purpose: Age is a major prognostic factor for malignant gliomas. However, few studies have investigated the management of gliomas in young adults. We determined the role of survival and treatment in young adults with advanced gliomas in a large population from the Chinese Glioma Genome Atlas (CGGA). Methods: This study included 726 adults (age ≥ 18) with histologically proven anaplastic glioma or glioblastoma multiforme (GBM). The overall and progression-free survival was determined in young (age < 50) and older groups (age ≥ 50). Results: The study included an older group (OP) of 264 patients and a younger group (YP) of 462patients. In the OP group with GBM and anaplastic glioma, patients treated with RT combined with temozolomide (TMZ) manifested significantly longer OS and PFS compared with patients assigned to RT alone (P < 0.05). In contrast, the YP group diagnosed with anaplastic glioma failed to show any survival advantage with RT plus TMZ compared with RT alone. Conclusions: We observed no survival benefit in young adults (age < 50) with anaplastic glioma when treated with TMZ combined with RT. Our findings warrant further investigation of younger patients diagnosed with anaplastic glioma treated with radiotherapy plus TMZ chemotherapy.

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: The role of postradiation systemic therapy in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) was controversial. Thus, we explored the role of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) and graded prognostic assessment (GPA) in identifying population who may benefit from postradiation systemic therapy. Methods: The clinical data of NSCLC patients with documented BM from August 2007 to April 2015 of two hospitals were studied retrospectively. Cox regression was used for multivariate analysis. Survival of patients with or without postradiation systemic therapy was compared in subgroups stratified according to RTOG-RPA or GPA. Results: Of 216 included patients, 67.1% received stereotactic radiosurgery (SRS), 24.1% received whole-brain radiation therapy (WBRT), and 8.8% received both. After radiotherapy, systemic therapy was administered in 58.3% of patients. Multivariate analysis found that postradiation systemic therapy (yes vs. no) (hazard ratio [HR] = 0.361, 95% confidence interval [CI] = 0.202- 0.648, P= 0.001), radiation technique (SRS vs. WBRT) (HR = 0.462, 95% CI = 0.238- 0.849, P= 0.022), extracranial metastasis (yes vs. no) (HR= 3.970, 95% CI = 1.757–8.970, P= 0.001), and Karnofsky performance status (

Background Risk factors and treatments for brain metastasis (BM) in patients with adenocarcinoma have not been fully profiled in previous studies because of the enrolment of patients with tumours of mixed histology. Thus, we specifically addressed the issue in patients with adenocarcinoma. Methods Clinical data for 373 patients with pathologically confirmed adenocarcinoma were studied retrospectively. Factors including age (≤60 vs. > 60), gender (male vs. female), stage at diagnosis, T status (T1–2 vs. T3–4), N status (N0–1 vs. N2–3), epidermal growth factor receptor (EGFR) mutation status (wild-type vs. mutant) and smoking status (never vs. current) were analyzed. Results In multivariate analysis, age (P = 0.006) and N status (P = 0.041) were independent risk factors for BM. In patients with BM, adding systemic therapy to local therapy improved median post-brain-metastasis survival (mPBMS) (P = 0.02). However, if stratification was conducted according to the recursive partitioning analysis (RPA) classification or graded prognostic assessment (GPA) scoring, only patients in RPA class II (P = 0.020) or with GPA score 1.5-2.5 (P = 0.032) could benefit from local plus systemic therapy. Those who received both pemetrexed and tyrosine kinase inhibitors (TKIs) as systemic therapies had a longer mPBMS than those who received TKIs alone, regardless of whether local therapy was applied. In patients with EGFR-sensitive mutations, TKIs therapy led to a longer mPBMS than conventional chemotherapy (P = 0.002). Conclusions Adenocarcinoma patients who were younger than 60 years of age and those with N2–3 disease have a significantly higher risk of BM. The addition of systemic therapy to local therapy can significantly prolong mPBMS, but the survival benefit confined in certain populations. Patients with opportunity to receive both pemetrexed and TKIs had the longest mPBMS.

// Pei Yang 1, 2, * , Wei Zhang 1, 2, * , Yinyan Wang 1, 2 , Xiaoxia Peng 3 , Baoshi Chen 2 , Xiaoguang Qiu 4 , Guilin Li 6 , Shouwei Li 7 , Chenxing Wu 7 , Kun Yao 8 , Wenbin Li 9 , Wei Yan 10 , Jie Li 11 , Yongping You 10 , Clark C. Chen 11 , Tao Jiang 1, 2, 5 1 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 3 Department of Epidemiology and Biostatistics, School of Public Health and Family Medicine, Capital Medical University, Beijing, China 4 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 5 China National Clinical Research Center for Neurological Diseases, Beijing, China 6 Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 7 Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 8 Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 9 Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 10 Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China 11 Center for Theoretic and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego, CA, USA * These authors have contributed equally to this work Correspondence to: Tao Jiang, e-mail: taojiang1964@163.com Clark Chen, e-mail: clarkchen@ucsd.edu Yongping You, e-mail: yypl9@njmu.edu.cn Keywords: glioblastomas, IDH, MGMT, temozolomide, radiation Received: June 10, 2015 Accepted: September 13, 2015 Published: October 12, 2015 ABSTRACT Background: The relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood. Methods: We investigated the association between methMGMT and mIDH with progression free survival and overall survival in a prospectively collected molecular registry of 274 glioblastoma patients. Results: For glioblastoma patients who underwent Temozolomide and Radiation Therapy, OS and PFS was most favorable for those with tumors harboring both mIDH and methMGMT (median OS: 35.8 mo, median PFS: 27.5 mo); patients afflicted glioblastomas with either mIDH or methMGMT exhibited intermediate OS and PFS (mOS: 36 and 17.1 mo; mPFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1 (wtIDH1) glioblastomas that were MGMT promoter unmethylated (mOS: 15 mo, mPFS: 9.7 mo). For patients with wtIDH glioblastomas, TMZ+RT was associated with improved OS and PFS relative to patients treated with RT (OS: 15.4 mo v 9.6 mo, p < 0.001; PFS: 9.9 mo v 6.5 mo, p < 0.001). While TMZ+RT and RT treated mIDH patients exhibited improved overall survival relative to those with wtIDH, there were no differences between the TMZ+RT or RT group. These results suggest that mIDH1 conferred resistance to TMZ. Supporting this hypothesis, exogenous expression of mIDH1 in independent astrocytoma/glioblastoma lines resulted in a 3–10 fold increase in TMZ resistance after long-term passage. Conclusion: Our study demonstrates IDH mutation and MGMT promoter methylation status independently associate with favorable outcome in TMZ+RT treated glioblastoma patients. However, these biomarkers differentially impact clinical TMZ response.

Background: For patients with a brain metastasis (BM), systemic therapy is usually administered after the completion of radiotherapy, especially in cases of multiple BMs. However, the role of systemic therapy in patients with a limited number of BMs is not clear. Therefore, we conducted a retrospective study to explore this question. Methods: Consecutive patients with a pathologically confirmed malignancy and 1–3 intracranial lesions that had been documented within the last decade were selected from the databases of three hospitals in China. Results: A total of 250 patients were enrolled; of them, 135 received radiotherapy alone and 115 received radiotherapy plus systemic therapy. In patients receiving whole-brain radiation therapy (WBRT) as radiotherapy, 28 received WBRT alone and 35 patients received WBRT plus systemic therapy. Of the patients treated with stereotactic radiosurgery (SRS), 107 received SRS alone and 80 received SRS plus systemic therapy. Multivariate analysis revealed that systemic therapy significantly reduced the risk of mortality compared with radiotherapy alone (hazard ratio [HR] = 0.294, 95% confidence interval [CI] = 0.158- 0.548). Further, when the analysis was conducted in subgroups of WBRT (HR = 0.230, 95% CI = 0.081- 0.653) or SRS (HR = 0.305, 95% CI = 0.127–0.731), systemic therapy still showed the ability to reduce the risk of mortality in patients with BMs. Conclusion: Systemic therapy after either SRS or WBRT radiotherapy may significantly reduce the risk of mortality of patients with 1–3 BMs. Key words: Brain Metastasis; Stereotactic Radiosurgery; Systemic Therapy; Whole-brain Radiation Therapy

Background To explore risk factors and the efficacy of treatment strategies for brain metastasis (BM) in squamous cell carcinoma (SCC) of the lung. Methods The clinical data of 188 pathologically confirmed as squamous cell carcinoma or adenosquamous carcinoma patients were studied retrospectively. Factors including age (

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.

The aim of this study was to differentiate primary central nervous system lymphoma (PCNSL) from glioblastomas (GBM) using the fractal analysis of conventional MRI data. Sixty patients with PCNSL and 107 patients with GBM with MRI data available were enrolled. Fractal dimension (FD) and lacunarity values of the tumour region were calculated using fractal analysis. A predictive model combining fractal parameters and anatomical characteristics was built using logistic regression. The role of FD, lacunarity and the predictive model in differential diagnosis was evaluated using receiver-operating characteristic (ROC) curve analysis. The association between fractal parameters and anatomical characteristics of tumours was also investigated. PCNSL had lower FD values (p < 0.001) and higher lacunarity values (p < 0.001) than GBM. ROC curve analysis revealed that FD, lacunarity, and the predictive model could distinguish PCNSL from GBM (area under the curve: 0.895, 0.776, and 0.969, respectively). The following associations were observed between fractal parameters and anatomical characteristics: multiple lesions were significantly associated with higher lacunarity (p = 0.024), necrosis with higher FD (p = 0.027), corpus callosum involvement with higher lacunarity (p < 0.001) in PCNSL and subventricular zone involvement with higher FD (p < 0.001) in GBM. The findings of the study indicate that fractal analysis on conventional MRI performs well in distinguishing PCNSL from GBM. • Fractal dimension and lacunarity were capable of differentiating PCNSL from GBM. • PCNSL and GBM exhibited different anatomical characteristics. • Fractal parameters were associated with some of these anatomical characteristics.

Necrosis is a hallmark feature of glioblastoma (GBM). This study investigated the prognostic role of necrotic patterns in GBM using fractal dimension (FD) and lacunarity analyses of magnetic resonance imaging (MRI) data and evaluated the role of lacunarity in the biological processes leading to necrosis. We retrospectively reviewed clinical and MRI data of 95 patients with GBM. FD and lacunarity of the necrosis on MRI were calculated by fractal analysis and subjected to survival analysis. We also performed gene ontology analysis in 32 patients with available RNA-seq data. Univariate analysis revealed that FD 0.46 significantly correlated with poor progression-free survival (p = 0.006 and p = 0.012, respectively) and overall survival (p = 0.008 and p = 0.005, respectively). Multivariate analysis revealed that both parameters were independent factors for unfavorable progression-free survival (p = 0.001 and p = 0.015, respectively) and overall survival (p = 0.002 and p = 0.007, respectively). Gene ontology analysis revealed that genes positively correlated with lacunarity were involved in the suppression of apoptosis and necrosis-associated biological processes. We demonstrate that the fractal parameters of necrosis in GBM can predict patient survival and are associated with the biological processes of tumor necrosis.

Background Medulloblastoma (MB) has been classified into four core subgroups according to the transcriptional profile in recent years. However, some disagreement among researchers remains regarding the prognoses and most effective treatments of the different subgroups with different age distributions. Objective The objective of this study was to analyze MB prognosis in children population based on the classification of four molecular subgroups. Methods From January 2011 to January 2013, 84 consecutive MB patients aged underwent tumor removal at Beijing Tiantan Hospital. A total of 55 patients who ranged in age from 4 to 18 years underwent detailed follow-up. Molecular subgrouping was performed using RT-PCR. Results The 2-year progression-free survival (PFS) and overall survival (OS) rates for the entire cohort were 76.2 ± 5.8 and 81.8 ± 5.2%, respectively. Univariate analysis revealed that the Group 4 patients had a better survival (2-year OS, 90.6 ± 5.2%) than the SHH subgroup (P = 0.002) and Group 3 patients (P = 0.008). Only two of the 23 non-metastasized Group 4 patients relapsed, and chemotherapy did significantly affect these patients (PFS, P = 0.685). One out of five WNT patients had tumor relapse and died at last. Large cell/anaplastic (LC/A) histology and chemotherapy were independent risk factors in multivariate analysis. Conclusion In our study, the non-metastasized Group 4 patients had an excellent prognosis. The SHH subgroup and Group 3 patients had worst prognoses. LC/A histology had a dismal prognosis in our cohorts, which warrants intensive treatment.

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.

// Linbo Cai 1 , Xiaoguang Qiu 2 , Haihong Yang 3 , Mingyao Lai 1 , Changguo Shan 1 , Weiping Hong 1 , Juan Li 1 , Longhui Luo 1 , Ping Zhang 1 , Lichao Wang 1 1 Department of Oncology, Guangdong 999 Brain Hospital, Guangzhou, China 2 Department of Neurosurgery of Beijing Tiantan Hospital, Capital Medical University, Beijing, China 3 Department of Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Correspondence to: Linbo Cai, email: cai_linbo@sina.com Xiaoguang Qiu, email: qxgtiantan@sina.com Keywords: stereotactic radiosurgery, X-knife, EGFR, NSCLC, brain metastases Received: February 23, 2016 Accepted: June 09, 2016 Published: July 06, 2016 ABSTRACT Background: Stereotactic radiosurgery (SRS) is a widely used therapy for brain metastases(BMs) in Non-small cell lung cancer(NSCLC). However, its role in symptomatic patients with EGFR mutation remains unclear. We have retrospectively reviewed the clinical data of patients with symptomatic BMs whom received SRS as a salvage approach and concurrent gifitinib therapy. Methods: Seven patients with primary NSCLC, symptomatic BMs, and EGFR mutation were identified in a retrospective review of patients treated with SRS using X-knife at Guangdong 999 Brain Hospital between 1 January 2012 and 31 August 2014. The median follow-up of these patients was 16 months. Image fusion technique was used to determine cumulative doses to targeted lesions, whole brain, and critical brain structures. Toxicities and complications were identified by clinical records. Results: SRS(X-knife) was selected to be performed on seven patients (two males and five females) diagnosed with NSCLC and EGFR mutation due to the presence of encephaledema, compression of ventricles, or other complications. Neurological symptoms (such as paresis, aphasia, sensory and visual disturbances) were not present in any patients before or after SRS treatment, and the postoperative Karnofsky performance status(KPS) was improved in all patients. Median overall survival(OS) was 16 months and median progression free survival(PFS) was 10 months. Conclusions: The improvement of KPS and survival were reliable by SRS(X-knife) with concurrent gifitinib therapy in NSCLC patients with symptomatic BMs, and EGFR mutation. Given the small sample size, further prospective studies with a greater number of patients are warranted to confirm our results.

Aberrant c-Met has been implicated in the development of many cancers. The objective of this study was to identify an unfavorable prognostic marker that might guide decisions regarding clinical treatment strategies for high-grade gliomas. C-Met expression was measured using immunohistochemistry in 783 gliomas, and we further analyzed c-Met mRNA levels using the Agilent Whole Genome mRNA Microarray in 286 frozen samples. In vitro, we performed cell migration and invasion assays. Cell sensitivity to temozolomide (TMZ) chemotherapy was determined using MTT assays. Both mRNA and protein levels of c-Met were significantly associated with tumor grade progression and inversely correlated with overall and progression-free survival in high-grade gliomas (all P in vitro revealed that downregulating the expression of c-Met dramatically inhibited cell migration and invasion capacities, enhanced sensitivity to TMZ chemotherapy in H4 and U87 glioma cells. Our results suggest that c-Met may serve as a potential predictive maker for clinical decision making.

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)

Purpose Epilepsy is one of the most common manifestations in gliomas and has a severe effect on the life expectancy and quality of life of patients. The aim of our study was to assess the potential connections between clinicopathological factors and postoperative seizure. Method We retrospectively investigated a group of 147 Chinese high-grade glioma (HGG) patients with preoperative seizure to examine the correlation between postoperative seizure and clinicopathological factors and prognosis. Univariate analyses and multivariate logistic regression analyses were performed to identify factors associated with postoperative seizures. Survival function curves were calculated using the Kaplan–Meier method. Results 53 patients (36%) were completely seizure-free (Engel class I), and 94 (64%) experienced a postoperative seizure (Engel classes II, III, and IV). A Chi-squared analysis showed that anaplastic oligodendroglioma/anaplastic oligoastrocytoma (AO/AOA) ( P =0.05), epidermal growth factor receptor (EGFR) expression ( P =0.0004), O 6 -methylguanine DNA methyltransferase (MGMT) expression ( P =0.011), and phosphatase and tensin homolog (PTEN) expression ( P =0.045) were all significantly different. A logistic regression analysis showed that MGMT expression ( P =0.05), EGFR expression ( P =0.001), and AO/AOA ( P =0.038) are independent factors of postoperative seizure. Patients with lower MGMT and EGFR expression and AO/AOA showed more frequent instances of postoperative seizure. Postoperative seizure showed no statistical significance on overall survival (OS) and progression-free survival (PFS). Conclusion Our study identified clinicopathological factors related to postoperative seizure in HGGs and found two predictive biomarkers of postoperative seizure: MGMT and EGFR. These findings provided insight treatment strategies aimed at prolonging survival and improving quality of life.

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.

BACKGROUND How germline single nucleotide polymorphisms are involved in the etiology of medulloblastoma remans poorly understood. We hypothesized that CCDKN2A/B rs1063192 and rs4977756 and also the long noncoding RNA (lncRNA) CDKN2BAS rs2157719 glioma susceptibility polymorphisms identified by genome-wide association studies may contribute to medulloblastoma predisposition. METHODS To test this hypothesis, we genotyped these genetic variants among 160 medulloblastoma patients and 443 health controls in a Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS We found that only the lncRNA CDKN2BAS rs2157719 T>C genetic polymorphism was significantly associated with an increased medulloblastoma risk (C allele: OR = 1.85, 95% CI = 1.32-2.58; p = 2.7 × 10-4 ). The stratified analyses showed an elevated risk of pediatric medulloblastoma associated with CDKN2BAS rs2157719 CC or TC genotype (both p < 0.05). Moreover, the association between the CDKN2BAS rs2157719 polymorphism and medulloblastoma risk is more pronounced in males (OR = 2.22, 95% CI = 1.36-3.62; p = 0.001). CONCLUSIONS The findings of the present study provide important insights into the genetic complexities and predisposition of medulloblastoma in Chinese, especially at the lncRNA germline variation level.