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Accurate molecular stratification of glioma patients is key to an optimal design of therapeutic strategy to maximize patient survival. Here we leveraged multi-omics analysis of glioma and detailed clinical follow-up to build a refined classification system for glioma patients using support vector machines. The model input included the number of non-synonymous mutations in cancer driver genes, the number of non-synonymous mutations in cancer related genes, the transcriptomic grouping information, the immune infiltrations predicted by RNA-seq dataset, the site of tumor occurrence, as well as other well-known markers including IDH mutation status and 1p19q co-deletion status. We validated key model predictions using TCGA and CGGA datasets. Our refined classification system outperforms current state-of-the-art framework used in clinic. Taken together, we propose a refined molecular classification for glioma combining multi-omics profiling and machine learning approaches.

BACKGROUND Thalamic glioma is a rare tumor, which is poorly understood in adults. The genetic variation of this tumor is still unknown. In this study, we investigated the mutation landscape of thalamic glioma and compared the clinical outcomes between different mutation situations in thalamic glioma. METHODS Next-generation sequencing targeting 425 cancer-relevant genes was performed with 34 thalamic glioma tissue samples. Gene mutations and copy number variations were investigated for prognostic effect with overall survival data. RESULTS Several diagnostic and prognostic biomarkers appeared in our thalamic glioma cohort, including TP53 (56%), EGFR (41%), TERT (35%), M CL1 (26%), PDGFRA (26%), PTEN (26%), CDK4/6 (24%), POLE (24%), PIK3CA (24%), NF1 (21%), ATR (21%), ATRX (18%), BRAF (15%), and ROS1 (12%). Among all genetic aberrations with a more than 10% occurrence rate, two mutations (TERT and PTEN) were associated with poor overall survival and one copy number variation (CDK4/6) was associated with favorable overall survival (univariate P < 0.1). Among these genes, CDK4/6 copy number variations (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.035–0.704; P = 0.016) remained significant survival associated in multivariate analyses. Copy number variations of CDK4/6 was seldom reported as a prognostic biomarker for glioma, especially for thalamic glioma in public databases. Besides, several gene mutations (BRIP1, MRE11A, MAP2K1, ROS1, MUTYH, JARID2, CTCF, and EGFR) were found positively associated with CDK4/6 copy number variations. Gene enrichment analysis demonstrated that those genes were related to astrocyte differentiation. CONCLUSIONS In our study, CDK4/6 copy number variation was determined as a favorable overall survival biomarker for thalamic glioma, and CDK4/6 copy number variation associated mutant genes were related to astrocyte differentiation, which could be the potential therapeutic targets for thalamic glioma.

PURPOSE Brain metastases (BMs) represent the most common adult intracranial malignancy. The prognosis of BMs is subject to many factors, i.e., the number, size and locations of the metastatic sites, tumor origins, pathologic types, gene mutation status, metastatic sites, and KPS etc. This study aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in brain metastases. METHODS A total of 480 patients diagnosed with brain metastases from a wide range of tumor origins, i.e., NSCLC, SCLC, breast cancer, melanoma, prostate, kidney, gastrointestinal cancer, cervical carcinoma, ovarian cancer, choriocarcinoma of uterus were retrospectively analyzed. Pre-radiotherapy NLR, PLR, and LMR were calculated as total neutrophil/lymphocyte, platelet/Lymphocyte, lymphocyte/monocyte, respectively. Survival rates were estimated using the Kaplan-Meier survival analysis. Cox regression models were used to identify independent prognostic factors. RESULTS The median overall survival (OS) was 14.4 months [95%CI: 13.4-15.5]. The median overall survival after radiotherapy was significantly different between patients with NLR< 4 and those with NLR≥4 (OS 16.3 mo. vs. 12.2 mo., P< 0.0001). No significant difference was observed between PLR vs. OS, and LMR vs. OS (PLR< 180: HR=1.221, P=0.240; LMR< 4: HR=0.753, P=0.141). The Cox regression model for the continuous metric values revealed that the NLR increased every 1.0 was associated with additional 5.9% of fatal risk (HR: 1.059; 95%CI = 1.033–1.087, P< 0.0001). NLR was validated as an independent prognostic factor for risk of death after adjusting for sex, age, and KPS. CONCLUSIONS We revealed pre-treatment NLR is an independent prognostic factor in patients with brain metastases for poor OS, independent of different tumor origins. The NLR warrants further studies using sub-group analysis and validation in external cohorts. Future studies in this parameter have a potential to facilitate more precise risk-stratifications to guide personalized treatment for BM.

BACKGROUND Glioblastomas (GBM) is a common primary malignant brain tumor. This study performed RNA-seq with 227 glioma samples with the aim to identify the immune-related gene markers for glioma prognosis prediction. METHODS Differentially expressed genes (DEGs) were identified between glioma and healthy samples in the TCGA dataset. Differentially expressed immune-related genes (DE-IRGs) were determined by intersecting DEGs to the immune-related genes in the ImmProt database. Independent survival associated DE-IRGs were selected by univariate and multivariate cox-regression analysis in TCGA dataset and validated in the CGGA databases and our RNA-seq data. Further enrichment analysis demonstrated the hub-genes among those prognosis-associated DE-IRGs. After the expression of hub-genes were confirmed by immunohistochemistry (IHC), the hub-genes protein levels on slides were further utilized to establishing the prognosis prediction models by several machine learning methods, including least absolute shrinkage and selection operator (LASSO), generalized linear model (GLM) and linear discriminant analysis (LDA). RESULTS There were 404 DE-IRGs determined in glioma in comparison with healthy tissue samples in TCGA. After evaluated by univariate and multivariate cox-regression, 55 DE-IRGs remaining significant. Thirty-four DE-IRGs were verified to be survival associated in both CGGA and our sequencing cohort, among which, 4 hub-genes (LIF and MDK, LAMB1, and CALU) were determined by enrichment analysis. All of the 4 hub-genes were expression confirmed on the protein level by IHC staining. Based on the staining results, a survival risk score (SRS) was established by machine learning methods (GLM, LDA, and LASSO). Based on SRS, glioma patients were divided into high- and low-risk groups, the overall survivals were significantly different between those two groups, regardless of the tumor grades or pathology types. CONCLUSIONS This study identified a potential immune prognostic signature (LIF and MDK, LAMB1, and CALU) of glioma that would be helpful for OS predicting and for potential therapeutics development.

PURPOSE Intracranial germ cell tumors (GCTs) are rare pediatric central nervous system (CNS) tumors. Growth impairment induced by radiation treatments was rarely evaluated. We aimed to study the impacts of radiotherapy on height development and identify the dosimetric constraints. MATERIALS AND METHODS A total of 148 pediatric patients diagnosed with GCTs were retrospectively analyzed. Sex, age at irradiation, physical doses and biologically effective dose (BED), height, and endocrine status were obtained from patient records. The cumulative change in height was assessed using age-matched normalized height (ANH). Variables were assessed for correlations and statistical significance. RESULTS Cumulative physical doses and BEDs for the whole brain and pituitary were derived via DVHs and BEDVHs. In contrast to patients >11.5 yr, linear correlations between ANH and cumulative physical doses as well as BEDs to the whole brain and pituitary were identified in patients≤11.5 yr. Dosimetric constrains to the pituitary was 36 Gy for physical dose (AUC=0.70 [95% CI, 0.54-0.86], P< 0.05) and 63 Gy2 BED (AUC=0.69 [95% CI, 0.53-0.86], P< 0.05). Intriguingly, no significant differences in ANH were found among different CSI dose groups in patients ≤11.5 yr. (all P>0.05). Impaired hormone secretions in terms of GH and TSH were identified following cranial irradiation (both P< 0.001), particularly for those with tumors at the suprasellar region (GH: P< 0.01, TSH: P< 0.001). CONCLUSION Our study revealed the impacts of age, dosimetrics and tumor locations for growth impairment. This study will contribute to the optimization of radiation treatment planning and facilitate more individualized therapeutic strategies in pediatric patient with GCTs.

BACKGROUND Gliomas are the malignancy with a poor prognosis. Our previous database mining study demonstrated that M1 macrophage infiltration predicted the survival of GBM patients. Here in this study, we further explored the findings. METHODS RNA-seq was performed on 90 WHO IV glioma tissue samples. The sequencing data was investigated with xCell for the cell infiltration levels, and the M1 macrophage infiltration was further analyzed for the prognostic prediction effect with overall survival (OS) data. Differentially expressed genes (DEGs) were calculated between groups and the hub genes were determined by the MCC models in Cytoscape. The survival risk score (SRS) calculating models were established by several machine learning methods, including the least absolute shrinkage and selection operator (LASSO), generalized linear model (GLM), and linear discriminant analysis (LDA). RESULTS Compared with M1 macrophages none infiltration, WHO IV gliomas with M1 macrophages infiltration was associated with poor prognosis, and this result remained significant in multivariate analyses (hazard ratio [HR], 0.219; 95% CI, 0.047–0.723; P = 0.035). Protein-to-protein (PPI) network analysis of top 200 up-regulated DEGs determined 10 hub genes (P4HB, PDIA6, LAMB1, PRKCSH, CSF1, LAMB2, LGALS1, RCN1, CALU, and TNC). Further analysis determined that the 10 hub genes were enriched in the ECM-receptor interaction signaling pathway, and six out of the ten gene expressions were confirmed by immunohistochemistry staining. Based on the 6 genes, a survival risk score (SRS) was established by machine learning methods. SRS was able to distinguish the high-risk and low-risk WHO IV gliomas with an AUC = 0.80 [95% CI: 0.74 – 0.86, P < 0.01]. CONCLUSIONS M1 macrophage infiltration was an unfavorable prognostic biomarker for WHO IV gliomas. ECM-receptor interaction signaling pathway was involved in M1 macrophage infiltration. Hub genes in the signaling pathway could be the potential therapeutic targets for WHO IV gliomas.

OBJECTIVE To evaluate the clinical factors related to the prognosis of basal ganglia germ cell tumors. METHODS A retrospective analysis of 52 cases of the basal ganglia germ cell tumors treated from January 2009 to January 2019 in the department of oncology of Guangdong Sanjiu Brain Hospital. The median age: 12 years (range: 5–32), The median course of disease: 11.7 months (range: 1–54). Thirteen cases were diagnosed by biopsy and 39 cases were diagnosed by elevated tumor markers. There were 31 patients (59.6%) diagnosed with germinomas and 21 patients (40.4%) with non-germ germ cell tumors. Univariate and multivariate survival analysis was performed. RESULTS To October 15, 2019, the median follow-up time was 30.4 months (range 2–124 months). The 5-year survival rate was 85%, and the 5-year progression-free survival rate was 84%. Multivariate analysis found whether serum AFP was greater than 100mIU / ml, (with HR: 11.441,95% CI: 2.09–47.66, P = 0.005),the degree of surgical resection(with HR 5.323 (1.19–23.812), P = 0.029), PD as the effect of radiotherapy (HR: 16.53, (1.19–23.81), P = 0.001) were independent prognostic factor affecting survival. CONCLUSION The pathological type, degree of surgical resection, and response to initial treatment can all affect survival.

PURPOSE Intracranial non-germinomatous germ cell tumors (NGGCTs) have lower overall survival than germinoma because relatively higher recurrence usually occurs after first line therapy. METHODS Between January 2003 and December 2018, 111 consecutive patients diagnosed with NGGCTs reviewed. Those who progressed after first line therapy were included in this study. Data of first line treatment, salvage treatment, clinicopathological features and survival were collected and analyzed. RESULTS Totally, thirty patients (30/111, 27.0%) relapsed in our cohort, including 19 patients with accurate relapse information detail, and 11 patients who died of disease progression during follow up but without exact time and site of relapse. The median OS from diagnosis of the disease was 49.2 months (95% CI: 14.1 to 84.3 months) and 3-year OS was 54.3%. Patients who received both CSI and chemotherapy relapsed less than those who received reduced volume of radiotherapy or only CSI or only chemotherapy (22.5% vs. 45.5%, p=0.034). Of 19 patients who had detail information of recurrence time and site, the median time from diagnosis of disease to relapse was 9.5 months (2.2 to 72.1 months). Regarding to recurrence site, most patients relapsed in primary site (10/19, 52.6%) or distant intracranial (6/19, 31.6%). The recurrence site of other 3 patients were spinal (n=1), ventricular (n=1) and peritoneal (n=1). CONCLUSION Protracted follow-up is recommended because late recurrence is not uncommon. Primary tumor site and distant intracranial are the most prevalent relapsed location. Patients who relapsed could benefited from both CSI and salvage chemotherapy.

OBJECTIVE We retrospectively analyzed the clinical features of pediatric glioblastoma patients in our center in the past 10 years. METHODS From November 2009 to December 2018, patients with glioblastoma under 18 years were admitted to Guangdong Sanjiu Brain Hospital. Clinical and pathological features were summarized, and the curative effect was evaluated. RESULTS A total of 31 pediatric patients were enrolled. The median age is 13.8 years (range 0.8–18), including 19 males and 12 females. To Sep, 2019, the median follow-up time was 18 months(Range 4–80 months). Among them, 2 were lost to follow-up, 13 died, 16 still survived, and the longest survivor survived for 80 months. The median survival time was 16.4 months, the 2-year survival rate was 38%. In the prognostic factor analysis, the median survival time of patients with surgical resection ≥90% was 18 months (95% CI 15.9–20 months), and for children with resection 90% was 11 months (95% CI 9.9–12 months), P=0.027, with significantly statistically difference. Multivariate analysis showed that tumor resection rate was an independent prognostic factor for survival. CONCLUSION The prognosis of pediatric glioblastoma is still dismal. This study demonstrates that prognosis of such patients with GTR or near GTR is better.

OBJECTIVE To evaluate the clinical factors related to the prognosis of basal ganglia germ cell tumors. METHODS A retrospective analysis of 52 cases of the basal ganglia germ cell tumors treated from January 2009 to January 2019 in the department of oncology of Guangdong Sanjiu Brain Hospital. The median age: 12 years (range: 5–32), The median course of disease: 11.7 months (range: 1–54). Thirteen cases were diagnosed by biopsy and 39 cases were diagnosed by elevated tumor markers. There were 31 patients (59.6%) diagnosed with germinomas and 21 patients (40.4%) with non-germ germ cell tumors. Univariate and multivariate survival analysis was performed. RESULTS To October 15, 2019, the median follow-up time was 30.4 months (range 2–124 months). The 5-year survival rate was 85%, and the 5-year progression-free survival rate was 84%. Multivariate analysis found whether serum AFP was greater than 100mIU / ml, (with HR: 11.441,95% CI: 2.09–47.66, P = 0.005),the degree of surgical resection(with HR 5.323 (1.19–23.812), P = 0.029), PD as the effect of radiotherapy (HR: 16.53, (1.19–23.81), P = 0.001) were independent prognostic factor affecting survival. CONCLUSION The pathological type, degree of surgical resection, and response to initial treatment can all affect survival.

OBJECTIVE To investigate the clinical values of real-world cerebrospinal fluid (CSF) examination in the diagnosis and prognosis of leptomeningeal metastases (LM) in the patients with non-small cell lung cancer (NSCLC). METHODS The clinical manifestations of patients diagnosed with NSCLC-LM in Guangdong Sanjiu Brain Hospital from 2010 until 2019 and the results from the routine, biochemical and cytologic examinations of their CSF were analyzed retrospectively. Moreover, the effects of different indicators on the prognosis of patients were determined by survival analysis. RESULTS Fifty-eight of the 80 patients underwent CSF examination, and the median values of the initial CSF pressure measured by lumbar puncture was 255mmH2O (60-350mmH2O). Tumor cells were found by the cytologic examination of CSF in 56 of the 58 cases (96.6%). The median levels of protein, glucose, chloride, lactate dehydrogenase (LDH) and carcinoembryonic antigen (CEA) in CSF were 0.4g/L (0–8.3g/L), 2.7mmol/L (0–11.9mmol/L), 120.7mmol/L (0–140.5mmol/L), 21.3U/L (0–221.5U/L) and 31.4ng/ml (0–784.2ng/ml), respectively. Sixteen patients underwent gene detection, and the results showed that there were 4 cases of wild type and 12 cases of mutation type. The survival analysis revealed that the median overall survival (mOS) after being diagnosed with LM, patients in LDH≤37U/L group and those in LDH >37U/L group were 8.0 months, 23.7 months and 4.6 months (P=0.039), respectively, which indicated that the LDH level in CSF was the independent prognostic factor for the survival. CONCLUSION Using the cytologic examination of CSF in patients with LM to detect tumor cells is conducive to the early diagnosis of LM. The high CSF pressure in patients with LM is one of the reasons for the neurologic signs and symptoms. The gene mutations found in the CSF in some patients can be used to guide the further systematic treatment. The LDH level in CSF is the independent prognostic factor affecting the survival.

BACKGROUND Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to assess the impact of whole brain radiotherapy (WBRT), chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on survival. METHODS Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Sanjiu Brain Hospital were retrospectively reviewed. Survival was assessed by Kaplan-Meier analyses. RESULTS The median age was 54.5 (range 30–76) years. LM were diagnosed by MRI (36/74), cytology (4/74), or both (34/74). Eighteen patients (24.3%) were diagnosed at the initial presentation of lung cancer. Forty-seven (63.5%) patients harboring EGFR positive mutation while other twenty-seven patients (36.5%) were EGFR wild type. The median overall survival from diagnosis of LM was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients who received EGFR-TKIs after LM had longer survival than those who did not (10.5 vs. 4.4 months, p＜0.001). No significant differences in survival were seen between patients who were treated with WBRT and those without, whether in EGFR mutation positive patients (11.6 vs. 15.0 months, p=0.353), or in EGFR wild type ones (5.1 vs. 3.3 months, p=0.116). Similarly, intravenous chemotherapy after LM had no impact on overall survival (7.5 vs. 8.1 months, p=0.9). CONCLUSION Median overall survival was higher than historical experience in our retrospective analysis. Survival was not improved by WBRT or intravenous chemotherapy. EGFR-TKIs could prolong survival of patients with LM from NSCLC.

OBJECTIVE To analyze the genes related to the signaling pathways in pediatric gliomas and drug-related genes with whole-exome sequencing technology. METHODS The tumor tissues and matched blood samples of 17 enrolled patients were detected with whole-exome sequencing technology. There were 3 cases of diffuse midline gliomas, 2 cases of childhood glioblastomas, 3 cases of disffuse astrocytoma, 1 case of pleomorphic xanthoastrocytoma, 1 case of ganglioglioma, 6 cases of anaplastic ependymoma and 1 case of ependymoma in this study. All the enrolled patients who were no more than 14 years old received surgery in the Department of Neurosurgery, Guangdong Sanjiu Brain Hospital. The diagnosis was confirmed by pathological examination and the sample acquisition was approved by hospital ethics committee. RESULTS With the use of whole-exome sequencing technology, a total of 31 related genetic mutations were detected in 15 cases, while no genetic mutation was detected in the other 2 cases. The genes related to the signaling pathways in pediatric gliomas included ATRX, ASL1, BCOR, EP300, FGFR1, H3F3A, IGF1R, MED12, PIK3R1, PRKDC, RB1, SETD2, SMARCA4, SOX2, TGFBR2, and the drug-related genes included AKT1, BCL2, BRAF, BRCA2, CCND1, CCND2, CDK6, EGFR, FGF3, KRAS, MET, PDGFRA, PIK3CA, PTEN, TP53, TSC1. One patient only had genes related to the signaling pathways, and 14 patients had drug-related genes. CONCLUSION Applying whole-exome sequencing technology in the genetic analysis of pediatric patients with gliomas has remarkable guiding significance for revealing the mechanism of disease, searching for therapeutic targets and adopting individualized treatment, which can bring potential benefits to pediatric patients. However, more samples and further data analysis and verification are needed in future study.

OBJECTIVES The present study aimed to investigate the clinical features associating with intracranial germ cell tumors(GCTs) of poor prognosis. METHODS We retrospectively analyzed the death data cohort based on 47 patients (30 males and 17 females) who had been diagnosed with GCTs between 2005 and 2018 in our hospital. The median age at initial diagnosis was 16 years (range, 3¬60 years). Among those, 18 patients were germinoma and 29 patients were non¬seminomatous germ-cell tumors (NGGCTs). RESULTS According to Kaplan-Meier survival analysis, children aged ≤ 10 years were observed with a very short survival compared to patients aged > 10 years, indicating a 5-year survival rate of 0 and 50%, respectively (P < 0.001). To be more specific, disseminated tumors were found to be the most prominent factor for prognosis in children aged ≤ 10 years: the 1-year survival for MR positive versus MR negative of disseminated tumors were 0 and 62.5%, respectively (P < 0.05). On the other hand, the pre¬treatment serum alpha-fetoprotein (AFP) level was found to be an important surrogate for prognosis. In the subgroup of patients > 10 years, the 5-year survival for AFP > 1.5ng/ml was 25%, in comparison to 66% for AFP ≤ 1.5ng/ml (P < 0.05). Further, solid survival advantages were found in patients received stereotactic radiosurgery (SRS) compared to none. The 5¬year survival for SRS versus non-SRS patients were 62% and 29%, respectively (P < 0.05). CONCLUSION Our data highlights a number of critical factors that may facilitate the prognosis stratifications of GCTs. What’s more, neither the locations of the primary tumors nor the numbers of lesions are associated with the prognosis of GCTs. These results warrant further investigation via randomized prospective studies.