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Background: Glioma is characterized by a high recurrence rate, while the results of the traditional imaging methods (including magnetic resonance imaging, MRI) to distinguish recurrence from treatment-related changes (TRCs) are poor. Prostate-specific membrane antigen (PSMA) (US10815200B2, Deutsches Krebsforschungszentrum, German Cancer Research Center) is a type II transmembrane glycoprotein overexpressed in glioma vascular endothelium, and it is a promising target for imaging and therapy. Objective: The study aimed to assess the performance of PSMA positron emission tomography/magnetic resonance (PET/MR) for diagnosing recurrence and predicting prognosis in glioma patients. Materials and Methods: Patients suspected of glioma recurrence who underwent 18F-PSMA-1007 PET/MR were prospectively enrolled. Eight metabolic parameters and fifteen texture features of the lesion were extracted from PSMA PET/MR. The ability of PSMA PET/MR to diagnose glioma recurrence was investigated and compared with conventional MRI. The diagnostic agreement was assessed using Cohen κ scores and the predictive parameters of PSMA PET/MR were obtained. Kaplan-Meier method and Cox proportional hazard model were used to analyze recurrence-free survival (RFS) and overall survival (OS). Finally, the expression of PSMA was analyzed by immunohistochemistry (IHC Results: Nineteen patients with a mean age of 48.11±15.72 were assessed. The maximum tumor-to-parotid ratio (TPRmax) and texture features extracted from PET and T1-weighted contrast enhancement (T1-CE) MR showed differences between recurrence and TRCs (all P Conclusion: This primitive study shows multiparameter PSMA PET/MR to be useful in identifying glioma (especially GBM) recurrence by providing excellent tumor background comparison, tumor heterogeneity, recurrence prediction and prognosis information, although it did not improve the diagnostic performance compared to conventional MRI. Further and larger studies are required to define its potential clinical application in this setting.

Purpose Prostate-specific membrane antigen (PSMA) positron emission tomography/magnetic resonance (PET/MR) is a novel imaging technology in neuro-oncology. This study aimed to investigate whether PET/MR-derived parameters could provide clinical characteristics and tumor heterogeneity in post-treatment glioma. The ability of PSMA PET/MR to distinguishing recurrence from treatment-related changes (TRCs) was evaluated. Methods Twenty-four glioma patients (fourteen males and ten females) suspected of recurrence who underwent PSMA PET/MR were included in this study. The results of PET/MR were evaluated qualitatively and quantitatively, including the visual intensity, classical metabolic and metric parameters, and primary tumor texture features. Results Classical metabolic parameters of PET including tumor-to-brain ratio (TBR max and mean), standardized uptake value (SUVmax and SUVpeak) showed differences in Karnofsky score (KPS) and metric parameters (area of lesion derived from MR) in 1p19q deletion status (P < 0.05). For the texture features, the shape-based, first-order and high-order primary tumor texture features of MR suggested the power to differentiate tumor grade and gene status (All P < 0.05). The sensitivity, specificity, and positive and negative predictive values of PSMA PET/MR in identifying recurrence were 64.29% (9/14), 80% (8/10), 81.82% (9/11), and 61.54% (8/13), respectively. Conclusion This work highlights the role of postoperative PSMA PET/MR in tumor-targeted imaging and differentiating recurrence in glioma, especially glioblastoma. PSMA PET/MR-derived parameters especially textural features provide additional value for characterizing glioma patient status and tumor heterogeneity. Our results indicate the significance of the hybrid PSMA PET/MR system in providing non-invasive glioma biological features, guiding precise surgical resection, and stratifying patients with PSMA targeted therapy.

Decompressive craniectomy is widely used to treat medically refractory intracranial hypertension. There were still few studies focusing on the complications between titanium cranioplasty with non-titanium materials cranioplasty. Our systematic review and meta-analysis aimed to assess the complications following titanium cranioplasty and to make a comparison with nontitanium materials. A systematic review was used to review titanium cranioplasty characters in recent articles. A systematic literature review and meta-analysis were performed by using PubMed/MEDLINE, Scopus, the Cochrane databases and Embase for studies reporting on cranioplasty procedures that compared complication outcomes between titanium with non-titanium materials. The final 15 studies met inclusion criteria and represented 2258 cranioplasty procedures (896 titanium, 1362 nontitanium materials). Overall complications included surgical site infection, hematoma, implant exposure, seizure, cerebrospinal fluid leak, imprecise fitting. Titanium cranioplasty was associated with a significant decrease in overall complications rate (OR, 0.72; P = 0.007), hematoma rate (OR, 0.31; P = 0.0003) and imprecise fitting rate (OR, 0.35; P = 0.04). However, it also suggested that titanium cranioplasty can be greatly increased implant exposure rate (OR, 4.11; P 0.00001). Our results confirmed the advantages of titanium cranioplasty in reducing complications including hematoma, imprecise fitting, and also suggested that clinicians should pay more attention to postoperative implant exposure. With new synthetic materials emerging, it would also be interesting to study the cost-effect and functional outcomes associated with cranioplasty materials.

ImportanceHigh-grade gliomas (HGGs) constitute the most common and aggressive primary brain tumor, with 5-year survival rates of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. The add-on efficacy of interferon alfa is unclear for the treatment of HGG.ObjectivesTo compare the therapeutic efficacy and toxic effects of the combination of temozolomide and interferon alfa and temozolomide alone in patients with newly diagnosed HGG.Design, Setting, and ParticipantsThis multicenter, randomized, phase 3 clinical trial enrolled 199 patients with newly diagnosed HGG from May 1, 2012, to March 30, 2016, at 15 Chinese medical centers. Follow-up was completed July 31, 2021, and data were analyzed from September 13 to November 24, 2021. Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed HGG and had received no prior chemotherapy, radiotherapy, or immunotherapy for their HGG.InterventionsAll patients received standard radiotherapy concurrent with temozolomide. After a 4-week break, patients in the temozolomide with interferon alfa group received standard temozolomide combined with interferon alfa every 28 days. Patients in the temozolomide group received standard temozolomide.Main Outcomes and MeasuresThe primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability.ResultsA total of 199 patients with HGG were enrolled, with a median follow-up time of 66.0 (95% CI, 59.1-72.9) months. Seventy-nine patients (39.7%) were women and 120 (60.3%) were men, with ages ranging from 18 to 75 years and a median age of 46.9 (95% CI, 45.3-48.7) years. The median OS of patients in the temozolomide plus interferon alfa group (26.7 [95% CI, 21.6-31.7] months) was significantly longer than that in the standard group (18.8 [95% CI, 16.9-20.7] months; hazard ratio [HR], 0.64 [95% CI, 0.47-0.88]; P = .005). Temozolomide plus interferon alfa also significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation (24.7 [95% CI, 20.5-28.8] months) compared with temozolomide (17.4 [95% CI, 14.1-20.7] months; HR, 0.57 [95% CI, 0.37-0.87]; P = .008). Seizure and influenzalike symptoms were more common in the temozolomide plus interferon alfa group, with 2 of 100 (2.0%) and 5 of 100 (5.0%) patients with grades 1 and 2 toxic effects, respectively (P = .02). Finally, results suggested that methylation level at the IFNAR1/2 promoter was a marker of sensitivity to temozolomide plus interferon alfa.Conclusions and RelevanceCompared with the standard regimen, temozolomide plus interferon alfa treatment could prolong the survival time of patients with HGG, especially the MGMT promoter unmethylation variant, and the toxic effects remained tolerable.Trial RegistrationClinicalTrials.gov Identifier: NCT01765088

Objective To screen ideal lead compounds with potential inhibition of 3-phosphoinositi-dependent protein kinase 1 (PDK1) from ZINC15 database, which is beneficial to drug design and improvement.Methods The Discovery Studio 4.5 computer-aided virtual screening technique was used to screen potential inhibitors of PDK1. Libdock was used for virtual screening and scoring of candidate compounds, ADME module was used for physical and chemical properties and toxicity analysis, and CDOCKER module was used for molecular docking analysis. The binding affinity of ligand-PDK1 was studied through molecular docking, and the stability of ligand-PDK1 in the natural environment was analyzed through molecular dynamics simulation.Results Two natural compounds ZINC00000157721 and ZINC000034189841 were screened from ZINC15 database. These two compounds have no CYP2D6 inhibition, easy to pass the blood-brain barrier, no hepatotoxicity, high binding affinity with PDK1, higher stability in the natural environment than positive drug BX-795, and stable existence.Conclusions The results show that ZINC00000157721 and ZINC000034189841 are ideal and safe lead compounds and have a potential inhibitory effect on PDK1. These compounds are safe candidates and may provide the basis and premise for the design and optimization of specific PDK1 inhibitors.

Ideal lead compounds and candidate drugs with inhibitory effect on BCL2 were screened from ZINC database, which laid a foundation for drug development and compound improvement of drug treatment for diffuse large B-cell lymphoma (DLCBL). Identification of potential BCL2 inhibitors by computer-aided virtual screening. Libdock was applied to 17,931 compounds and the top 20 were selected for further analysis. Selected compounds were performed absorption, distribution, metabolism, and excretion (ADME) and toxicity prediction. The binding affinity between the selected ligands and BCL2 was confirmed by Molecular docking. The new natural compounds, ZINC00000255131 and ZINC00013298233, were found to bind closely with BCL2. Furthermore, they all scored lower in ames-induced mutagenicity, rodent carcinogenicity, non-developmental toxicity potential, and cytochrome P4502D6 tolerance. Molecular dynamics simulation shows that the combinations of ZINC00000255131 and ZINC00013298233 with BCL2 in the natural environment are more stable. Two new compounds, ZINC00000255131 and ZINC00013298233, were found to be potential inhibitors of BCL2. These compounds have been proved to be safe, which is of great significance for the development and improvement of DLCBL drugs.

Background and Aim: Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in a lower survival. Dianhydrogalactitol (VAL-083) is a novel bi-functional DNA-targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. Subjects and Methods: The study has two parts: part 1 is a dose–escalation and induction format to enroll up to ten patients in which they received VAL-083 at 20, 30, or 40 mg/m2 per day for 3 days every 21 days concurrently with standard radiation treatment and VAL-083 for up to eight additional cycles. Part 2 comprises an expansion phase to enroll up to twenty additional patients. This study was performed with approval by the Institutional Review Board of Sun Yat-sen University Cancer Center (B2016-058-01) on January 13, 2017, and registered with the ClinicalTrials.gov (NCT03050736) on February 13, 2017. Results: After completion of dose escalation, VAL-083, 30 mg/m2 per day, in combination with radiation therapy, was generally safe and well tolerated. At the cutoff date, 23 patients had been enrolled, 14 of whom had been treated in the expansion phase. Consistent with prior studies, myelosuppression was the most common adverse event. Pharmacokinetic assessment indicated that the levels of VAL-083 were as high in the cerebrospinal fluid as in plasma, 2 h postinfusion. Of the 22 patients who had reached their four precycle magnetic resonance imaging assessments, 12 were assessed with disease progression, with a median progression-free survival of 9.9 (95% confidence interval 7.3–12.0) months for all the patients studied. Conclusion: These preliminary data support VAL-083 as a potentially valuable treatment option for newly diagnosed GBM.

Background and Aim: Guidelines recommend adjuvant treatment for patients with high-grade gliomas and low-grade gliomas with high risk of progression. In clinical practice, however, treatments may not conform to these suggested guidelines. In this study, we reviewed the treatments and outcomes in patients with gliomas at Sun Yat-Sen University Cancer Center (SYSUCC), China. Materials and Methods: Medical records and radiologic images of 1215 glioma patients who underwent surgery at the center from 2000 to 2017 were retrospectively reviewed, and their clinicopathological characteristics, treatment method, and overall survival (OS) were analyzed. The study was approved by the Ethics Committee of SYSUCC on February 20, 2019 (approval No. GZR2019-219). Results: A total of 1001 patients diagnosed with glioma (initially World Health Organization 2007 criteria, then 2016 criteria) were enrolled, including 90 patients with Grade I, 307 Grade II, 239 Grade III, and 365 Grade IV gliomas. A total of 331 of 604 patients with high-grade glioma (54.8%) and 159 of 397 with low-grade glioma (40.1%) received postsurgical radiotherapy, and 285 patients with high-grade tumors (47.1%) and 80 with low-grade tumors (20.2%) received adjuvant chemotherapy. The median OS was 17.5 months for Grade IV and 43.1 months for Grade III gliomas. The median OS of patients with low-grade glioma was not reached. The 5-year survival rates of patients with Grades I, II, III, and IV gliomas were 94.7%, 73.7%, 45.7%, and 18.6%, respectively. Multivariate analysis identified onset age, preoperative seizure, tumor location, pathological subtype, resection extent, and postsurgical treatment as independent predictors of OS in patients with high-grade gliomas. Patients with high-grade glioma who received postsurgical treatment had better survival than those without adjuvant therapy (Grade III: 52.6 vs. 20.3 months, P = 0.012; Grade IV: 22.6 vs. 12.1 months, P < 0.001). Among patients with diffuse low-grade gliomas, age, performance status, preoperative seizure, Ki-67 index, tumor subtype, and resection extent were associated with clinical outcomes. Conclusion: Glioma patients are not always treated according to guidelines. Although standard care may lead to favorable prognoses, individualized treatments may be more acceptable and result in better outcomes and should thus be considered in routine clinical practice.

To comprehensively and noninvasively risk-stratify glioma grade, isocitrate dehydrogenase (IDH) genotype, and 1p/19q codeletion status using multi-contrast Z-spectral magnetic resonance imaging (MRI). One hundred and thirteen patients with glioma were retrospectively included. Multiple contrasts contributing to Z-spectra, including direct saturation of water (DSW), semi-solid magnetization transfer contrast (MTC), amide proton transfer (APT) effect, aliphatic nuclear Overhauser effect, and the 2-ppm chemical exchange saturation transfer peak (CEST@2ppm), were fitted with five individual Lorentzian functions. Z-spectral contrasts were compared according to the three most important risk stratifications: tumor grade, IDH genotype, and 1p/19q codeletion status. We further investigated the differentiation of 1p/19q codeletion status within IDH mutant gliomas. The stratification performance of individual Z-spectral contrasts and their combination was quantified using receiver operating characteristic (ROC) analyses. DSW was significantly different within grade, IDH genotypes, and 1p/19q codeletion status. APT was significantly different with grade and IDH mutation, but not with 1p/19q subtypes. CEST@2ppm was only significantly different with 1p/19q codeletion subtypes. DSW and CEST@2ppm were the two Z-spectral contrasts able to differentiate 1p/19q codeletion subtypes within IDH mutant gliomas. For differentiating glioma grades using ROC analyses, DSW achieved the largest AUC. For differentiating IDH genotypes, DSW and APT achieved comparable AUCs. DSW was the best metric for differentiating 1p/19q codeletion status within all patients and within the IDH mutant patients. Combining all Z-spectral contrasts improved sensitivity and specificity for all risk stratifications. Multi-parametric Z-spectral MRI serves as a useful, comprehensive, and noninvasive imaging technique for glioma stratification in clinical patients. • Multiple contrasts contributing to Z-spectra were separately fitted with Lorentzian functions. • Z-spectral contrasts were compared within the three most important and common tumor risk stratifications for gliomas: tumor grade, IDH genotype, and 1p/19q codeletion status. • The stratification performance of individual Z-spectral contrasts and their combination was quantified using receiver operating characteristic analyses, which found Z-spectral MRI to be a useful and comprehensive imaging biomarker for glioma stratification.

Background: Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Studies have shown that the link between socio-economic status, morbidity and mortality from major cancers has changed significantly over the past 50 years, and therefore the socio-economic variation in cancer incidence is dynamic. Meanwhile, Socio-economic status (SES) characteristics of patients with medulloblastoma and the influence of Socio-economic status on their prognosis have been rarely discussed. Methods: Purpose of our study was aiming to understand ethnic, gender and socioeconomic disparities in medulloblastoma by using the SEER database. Propensity score matching of cases with controls by gender was conducted at the ratio of 1:1. Multivariate cox proportional hazards model was used to assess SES impact and clinically relevant variables of medulloblastoma specific death and overall survival. Independent prognostic factors determined by multivariate analysis were used to construct nomograms. Results: 2660 patients were enrolled after the matching. Study showed unemployed (MBSD, high level vs. low level, HR = 1.334) (OS, high level vs. low level, HR = 1.311) and marital status (OS, married vs unmarried/unknow., HR = 0.706) were important factors affecting the prognosis of medulloblastoma in male. Meanwhile, median household income (MBSD, Quartile 1 vs. Quartile 3, HR = 1.029) (OS, Quartile 1 vs. Quartile 2, HR = 1.809) (OS, Quartile 1 vs. Quartile 3, HR = 1.592), residence (MBSD, urban vs. rural, HR = 0.414) and insurance status (MBSD, insured vs. uninsured/unknow, HR = 0.566) (OS, insured vs. uninsured/unknow, HR = 0.573) were significant factors affecting the prognosis of medulloblastoma in female. Through the calibration plot and C-index test, our nomogram was also of predictive significance. Conclusions: The unique features of medulloblastoma have provided a scenario for the analysis of the impact of racial, ethnic, gender and socioeconomic factors. The current findings have important public health implications for achieving the goal of a healthy population. Given the known morbidity rates and the long-term psychological, financial and medical burdens that these children and their families must bear, it is critical to identify and address these gaps.

Background Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, and prognosis. Among the signatures cataloged at COSMIC, mutational signature 4 has been linked to smoking. However, the distribution of signature 4 in Chinese lung cancer patients has not been evaluated, and its clinical value has not been evaluated. Here we survey mutational signatures in Chinese lung cancer patients and explore the relationship between signature 4 and other genomic features in the patients. Methods We extracted mutational signatures from whole-exome sequencing data of Chinese non-small cell lung cancer patients. The data included 401 lung adenocarcinoma (LUAD) and 92 squamous cell carcinoma (LUSC). We then performed statistical analysis to search for genomic and clinical features that can be linked to mutation signatures. Results We found signature 4 is the most frequent mutational signature in LUSC and the second most frequent in LUAD. Fifty-six LUAD and thirty-five LUSC patients were named with high signature 4 similarities (cosine similarity >0.7). These patients have shorter survival and higher tumor mutational burden comparing to those with low signature 4 similarities. Dozens of genes with single nucleotide variation, index mutations, and copy number variations were differentially enriched in the patients with high signature 4 similarities. Among these genes, CSMD3, LRP1B, TP53, SYNE1, SLIT2, FGF4, and FGF19 are common in both LUADs and LUSCs with high signature 4 similarities, showing that these genes are tightly associated with signature 4. Conclusions The present study is the first to report a comparison in Chinese NSCLC patients with or without COSMIC mutational signature 4. These results will help find the Signature 4 related mutational process in NSCLC.

Background Skull base meningioma surgery is often difficult and complicated to perform. Therefore, this study aims to investigate the effectiveness of 3-dimensional (3D)-printed models of skull base meningioma in the representation of anatomical structures, the simulation of surgical plans, and patient education on surgical outcomes. Methods A retrospective study of 35 patients (3D group: 19 patients and non-3D group: 16 patients) with skull base meningioma was conducted. Mimics software was used to create 3D reconstructions (with the skull, blood vessels, nerves, and tumors set to different colors), and 3D solid models were printed to determine the surgical protocols and communication pathways with the patient. Results The 3D-printed model can visually display the relationship of different structures, including the skull, blood vessels, cranial nerves, and tumors. The surgeon should select the proper surgical approaches before surgery through the model and pay attention to protecting the important structures during the operation. According to the models, the surgeon should cut off the blood supply to the tumor to reduce intraoperative bleeding. For patients with skull base bone destruction, the skull base repair should be prepared in advance. Patients and their families should have a thorough understanding of the disease through the model, and there should be effective communication between doctors and patients. Conclusions The 3D-printed model of a skull base meningioma can present the structures in a detailed manner and facilitate in helping the surgeon to develop a surgical plan. At the same time, it helps patients and their families to understand the condition and the surgical plan, which is conducive to better patient education.

BACKGROUND: The present study explored the predictive value of systemic inflammatory indexes in diagnosing grade III gliomas of oligodendroglial origin. METHODS: A retrospective study of 154 patients with grade III gliomas was conducted. Systemic inflammatory indexes, including neutrophil-to-lymphocyte ratio (NLR), albumin-to-gamma-glutamyl transferase ratio (AGR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, prognostic nutritional index, and fibrinogen-to-albumin ratio, were reviewed. The resulting predictive model was externally validated using a demographic-matched cohort of 49 grade III glioma patients. RESULTS: In the training set, gliomas of oligodendroglial origin tended to have a lower NLR (P=0.018) and a higher AGR (P=0.036) than those with tumors of astrocytic origin. Moreover, both NLR and AGR had predictive value for oligodendroglial tumors, when compared with astrocytic tumors. The best diagnostic value was obtained using NLR + AGR (AUC =64.9%, 95% CI: 55.5–74.3%, P=0.005). In the validation set, NLR + AGR satisfactorily predicted the presence of oligodendroglial tumors (AUC =66.5%, 95% CI: 50.6–82.4%, P

The intraoperative tumor-free principles refer to the operation techniques that must be carried out to prevent the exfoliation and planting of tumor cells during the operation, so as to prevent local recurrence and distant metastasis. Following the intraoperative tumor-free principles has been valued in resection of extracranial solid tumors. However, the significance of intraoperative tumor-free principles for brain tumors is still unclear. We retrospectively analyzed 106 patients with primary glioblastoma who underwent resection following the intraoperative tumor-free principles from 2010 to 2016. By February 28, 2019, 11 (10.4%) patients were lost to follow-up. The median overall survival (OS) was 20.2 months, and the 1-, 3-, and 5-year survival rates were 71%, 30%, and 26%, respectively. For patients with complete tumor resection, the median OS was 24.8 months, and the 1-, 3-, and 5-year survival rates were 80%, 38%, and 36%, respectively. Patients who received postoperative Stupp regimen had a median OS of 74.1 months, and the 1-, 3-, and 5-year survival rates were 82%, 51%, and 51%, respectively. A total of 36 patients had complete tumor resection followed by Stupp regimen. Their 1-, 3-, and 5-year survival rates were 94%, 68%, and 68%, respectively. Median OS was not reached. The patient with the longest OS had survived for 108 months and was still alive. In summary, the OS of patients in this study was relatively longer than that reported in most previous literatures, which suggests that following the intraoperative tumor-free principles in resection of GBM can benefit patient survival.

BACKGROUND It is challenging to resect or just biopsy the lesions in the brainstem, due to the essential function of the surfaces and limited space. Neuro-navigation is not always reliable and stereotatic biopsy is infrequently inconclusive due to small or inadequate samples. We want to share our experiences in the application of fluorescein sodium in surgery on patients with brainstem lesion which is contrast enhancing in MRI. METHODS Between January 2017 and June 2021, 5 patients with brainstem lesion underwent fluorescein sodium-guided surgery in neurosurgery department of Sun Yat-sen University Cancer Center. After injection of low dose of sodium fluorescein (3 mg/kg), the lesions with strong fluorescence staining were identified as the target area for biopsy or resection. RESULTS 5 consecutive patients (aged 6–47 years) with brainstem lesions prospectively underwent fluorescein sodium-guided surgery. The lesions were located in pontine in 3 patients and in the medulla in 2 patients. Gross total resection was achieved in 2 patients, and partial resection in the other 3 patients. In all patients, a pathological diagnosis was obtained (4 gliomas and 1 metastasis from non-small cell lung carcinoma) without severe complications, including mild facial or abduct nerve palsy in 3 patients. And all the specimens with strong fluorescence staining sent for pathology were proved to be tumorous. CONCLUSION Fluorescein sodium-guided technique was helpful to locate the lesion in brainstem which was contrast-enhanced in MRI. It was effective and safe to figure out an ideal trajectory to avoid damage of the crucial structures and improve the diagnostic rate.

We aimed to develop a high-throughput deep DNA sequencing assay of cerebrospinal fluid (CSF) to identify clinically relevant oncogenic mutations that contribute to the development of glioblastoma (GBM) and serve as biomarkers to predict patients' responses to surgery. For this purpose, we recruited five patients diagnosed with highly suspicious GBM according to preoperative magnet resonance imaging. Subsequently, patients were histologically diagnosed with GBM. CSF was obtained through routine lumbar puncture, and plasma from peripheral blood was collected before surgery and 7 days after. Fresh tumor samples were collected using routine surgical procedures. Targeted deep sequencing was used to characterize the genomic landscape and identify mutational profile that differed between pre-surgical and post-surgical samples. Sequence analysis was designed to detect protein-coding exons, exon-intron boundaries, and the untranslated regions of 50 genes associated with cancers of the central nervous system. Circulating tumor DNAs (ctDNAs) were prepared from the CSF and plasma from peripheral blood. For comparison, DNA was isolated from fresh tumor tissues. Non-silent coding variants were detected in CSF and plasma ctDNAs, and the overall minor allele frequency (MAF) of the former corresponded to an earlier disease stage compared with that of plasma when the tumor burden was released (surgical removal). Gene mutation loads of GBMs significantly correlated with overall survival (OS, days) (Pearson correlation = −0.95, P = 0.01). We conclude that CSF ctDNAs better reflected the sequential mutational changes of driver genes compared with those of plasma ctDNAs. Deep sequencing of the CSF of patients with GBM may therefore serve as an alternative clinical assay to improve patients' outcomes.

Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF comparing with the corresponding tumor tissue samples (3.56±0.75 vs. 2.22±0.32, P=0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.12% ± 6.03% vs. 73.83% ± 5.95%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3F3A which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.

Background: The conventional way of patient treatment should be following guidelines. While in clinical practice, patients received treatments very often away from suggested guideline. In this report, we reviewed glioma patients received real world treatment at Sun Yat-sen University Cancer Center (SYSUCC) and results of this patient series. Methods: Total of 1215 glioma patients received surgery at SYSUCC from 2000 to 2017 were enclosed for analysis. The pathologic diagnosis of patients has followed WHO classification (initially 2007 standard, than 2016 standard). Results: A total of 1001 newly diagnosed brain glioma patients were analyzed, including 90 cases WHO grade I, 307 grade II, 239 grade III and 365 grade IV. The median age of onset was 14 (1–75), 35 (2–69), 41 (8–82) and 50 (2–86) years old, respectively, for grade I, II, III and IV glioma patients. Tumor total resection was achieved in 567 patients (57.5%). Among all patients, 331 high-grade gliomas (54.8%) and 159 low-grade glioma (40.1%) received radiotherapy, whereas 285 high-grade gliomas (47.1%) and 80 low-grade tumors (20.2%) received chemotherapy. Among high-grade gliomas, the median OS of glioblastoma, anaplastic astrocytoma and anaplastic oligodendroglial tumors were 17.7 months (15.7–19.7 months), 33.7 months (24.0–43.4 months) and 110.6 months (43.5–177.7 months), respectively, whereas the median OS of low-grade gliomas was not reach. The 5-year survival rate of grade I, II, III and IV gliomas was 94.7%, 73.7%, 45.1% and 18.6%, respectively. Multivariate analysis identified that onset age, Karnofsky performance status, tumor location, preoperative seizure, pathological subtype, resection extent and post-surgical treatment were independent predictors of OS for patients with high-grade gliomas. Patients received post-surgical radiotherapy and (or) chemotherapy had better survival than those without adjuvant treatment (grade III: 53.3 vs. 20.6 months, p =0.012; grade IV: 22.9 vs. 12.3 months, p < 0.001). For low-grade gliomas, patients’ age, Ki-67 index, tumor subtype and resection extent were associated with clinical outcomes. Conclusions: Glioma patients received treatments do not always following guidelines in clinical practice. Although standard care for patients may beneficial for prognosis, personalized treatment may more acceptable for patients and even resulting better outcome which should keep in mind in routine clinical practice.

Background The occurrence of medulloblastoma in the absence of hereditary syndromes is rare. Dextrocardia with situs inversus is also called mirror-image dextrocardia. A combination of mirror-image dextrocardia with medulloblastoma has not been reported previously. To the best of our knowledge, this is the first report of this rare combination in a family with medulloblastoma. Methods The clinical manifestation, radiographic characteristics, treatment, and outcomes of 3 medulloblastoma cases in 2 cousins and their maternal uncle was described. Tumor samples of the 2 cousins were first examined for histologic subtypes. Total RNA of their tumors was extracted from formalin-fixed and paraffin-embedded samples. Then, expression of 22 subgroup-specific genes and 3 housekeeping genes was analyzed by the NanoString nCounter Analysis System. The posttest data were normalized by NanoStringNorm package for molecular subgroup prediction. Results The proband remains tumor free and alive up to the latest follow-up. His cousin, who had combined mirror-image dextrocardia with situs inversus, died of anoxia after surgery and his uncle died of tumor 2.5 years after surgery. Medulloblastoma of the 2 cousins was classified as classic and molecular group 4 subtype. Conclusions The same classic and molecular group 4 subtype of the 2 cousins may suggest a similar genetic predisposition. Involvement of the Otx2 gene dysfunction in both group 4 subtype medulloblastoma and mirror-image dextrocardia with situs inversus points to a possible mechanism that dysfunction of a shared signaling pathway such as Otx2 might be the underlying cause of these 2 conditions in this family.

Background Pilocytic astrocytomas (PAs) are slow growing neoplasms and usually located at the cerebellum. There has been certainty regarding the truthful benefit of surgical resection for patients with PA. Gross total resection (GTR) of PAs, especially those being situated in deep regions, remains a surgical challenge. Generally, they are considered as benign and usually develop in young patients. PAs, belonging to WHO I can be cured by radical resection. The patients with PA have excellent prognosis if complete resection can be conducted. The use of fluorescein in vermis PA surgery has not been yet reported. Our data presents fluorescein facilitates surgical resection of vermis PA. Methods Five milligrams per kilogram of fluorescein sodium was intravenously injected directly before general anesthesia for the three patients with PA. The yellow 560 filter was employed for microsurgical tumor resection. Surgical outcomes were assessed concerning the extent of resection. Results Most portion of PA in the three cases was found to be highly fluorescent after intravenous fluorescein sodium injection, which markedly enhanced tumor visibility. Gross total resection in all of the patients was achieved without further neurological deficits. No adverse effects and complications resulting from fluorescein sodium were observed over the postoperative course. Conclusions Intraoperative guidance by fluorescein sodium as a new, simple, safe, and practical procedure can enhance the fidelity of tumor tissue and increase the possibility of completely resecting PAs.

BACKGROUND: Glioblastoma is a highly invasive and vascularized primary CNS tumor and the effect of anti-angiogenesis therapy on glioblastoma is not as adequate yet. Vasculogenic mimicry (VM), a vessel-like structure formed by highly invasive tumor cells, has been considered as one of reasons to failure from anti-angiogenesis therapy for GBM patients. Tenascin-c (TNC), an extracellular protein overexpressed in glioblastoma, may stimulate angiogenesis in tumor. However, whether TNC contributes to VM formation remains unclear. MATERIAL AND METHODS: Fifty tumor samples from glioblastoma patients were evaluated for VM formation and TNC expression by Immunohistochemistry staining. The results were compared with prognosis of the patients. Tenascin-c expressions were also examined for glioma cell lines, U251, A172, U373, U138 and LN308 by western blotting analysis, and the results were compared with the VM formation ability evaluated by three-dimensional culture assay. The direct effect of TNC on VM formation of glioma cell lines were investigated by exogenous tenascin-c exposure. RESULTS: Tenascin-c positive stainings were found in 54% (27/50) of GBM samples, while VM channels were determined in 34% (17/50) of GBM samples. Tenascin-c expression was significantly higher in VM positive group (15/17) than in the VM negative group (12/33; χ(2)=12.154, P

BACKGROUND: Vasculogenic mimicry(VM) has been reported in many malignant human tumors, including gliomas. In the present study, we have found four types of microcirculation vessels in human glioblastomas. Method and material: Thirty-seven human glioblastoma samples were examined for VM by CD34 and PAS dual staining,as well as immunofluorescence dual staining for CD34 and GFAP. The GFAP positive (GFAP+) cells were considered as glioma cells. Even though CD34 positive (CD34+) was endothelial cells, but both CD34 + / GFAP+ should be also considered as glioma cells. Result: CD34 and PAS dual staining revealed 4 types of microcirculation vessels in human glioblastoma samples: endothelium dependent vessels, tumor cell dependent vessels, extracellular matrix (ECM) dependent vessels, and mosaic vessels. While immunofluorescence study confirmed VM should be vessels lined with GFAP+ cells (could be CD34- or co-express CD34). Twelve samples were found VM by CD34 and PAS dual staining (32%), while 20 samples were revealed VM by immunofluorescence dual staining (57%). CONCLUSION: Our results suggest that glioblastoma cells have potential to express endothelial cell marker CD34. And immunofluorescence dual staining is a more sensitive as well accurate technique revealing VM vessels in glioblastoma.