Tailoring silk fibroin fibrous architecture by a high-yield electrospinning method for fast wound healing possibilities.

In this study, a novel array electrospinning collector was devised to generate two distinct regenerated silk fibroin (SF) fibrous membranes: ordered and disordered. Leveraging electrostatic forces during the electrospinning process allowed precise control over the orientation of SF fiber, resulting in the creation of membranes comprising both aligned and randomly arranged fiber layers. This innovative approach resulted in the development of large-area membranes featuring exceptional stability due to their alternating patterned structure, achievable through expansion using the collector, and improving the aligned fiber membrane mechanical properties. The study delved into exploring the potential of these membranes in augmenting wound healing efficiency. Conducting in vitro toxicity assays with adipose tissue-derived mesenchymal stem cells (AD-MSCs) and normal human dermal fibroblasts (NHDFs) confirmed the biocompatibility of the SF membranes. We use dual perspectives on exploring the effects of different conditioned mediums produced by cells and structural cues of materials on NHDFs migration. The nanofibers providing the microenvironment can directly guide NHDFs migration and also affect the AD-MSCs and NHDFs paracrine effects, which can improve the chemotaxis of NHDFs migration. The ordered membrane, in particular, exhibited pronounced effectiveness in guiding directional cell migration. This research underscores the revelation that customizable microenvironments facilitated by SF membranes optimize the paracrine products of mesenchymal stem cells and offer valuable physical cues, presenting novel prospects for enhancing wound healing efficiency.

Leptomeningeal spread in high-grade gliomas: Is surgery or adjuvant therapy after leptomeningeal spread associated with survival benefit?

PURPOSE: This study aimed to identify prognostic factors associated with survival in patients with high-grade glioma (HGG) after leptomeningeal spread (LMS) and to clarify the behavior and treatment response. METHODS: This retrospective study included 114 patients with HGGs diagnosed with LMS from August 1, 2014, to July 30, 2021, at our institution. Clinical, radiological, pathological, and outcome data were collected. Univariable and multivariable Cox regression were used for overall survival (OS) and post-LMS survival (PLS) analysis. RESULTS: The median OS was 17.0 months and the median PLS was 6.0 months. Gross total resection (GTR) after LMS diagnosis and pathology grade III were statistically significantly associated with longer OS in all patients. GTR after LMS diagnosis and nodular LMS were independent favorable prognostic factors on PLS. Non-adjuvant therapy after LMS diagnosis was associated with shorter OS and PLS. In glioblastoma (GBM) subgroup analysis, GTR after LMS diagnosis and secondary LMS were independent favorable prognostic factors on OS. Karnofsky Performance Status (KPS) of ≥80 at LMS diagnosis, chemotherapy after LMS and intrathecal methotrexate (MTX) treatment were statistically significantly associated with longer PLS. MRI type II was a predictor of shorter PLS. CONCLUSION: The treatment of patients with glioma after LMS diagnosis is very challenging and limited. Safe GTR of tumor and subsequent adjuvant therapy after LMS remains a powerful weapon to improve survival for HGG patients with LMS. Chemotherapy and Intrathecal MTX treatment are feasible treatments after LMS. The extent of tumor dissemination may affect the survival after LMS.

C-reactive protein levels, the prognostic nutritional index, and the lactate dehydrogenase-to-lymphocyte ratio are important prognostic factors in primary central nervous system lymphoma: a single-center study of 223 patients.

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive type of extranodal non-Hodgkin lymphoma (NHL), and the prognosis is poor. Currently, the most used prognostic models are the Memorial Sloan-Kettering Cancer Center (MSKCC) and International Extranodal Lymphoma Study Group (IELSG) scores; however, their predictive effects are changing with increasing incidence and changing treatment regimens. A growing body of evidence has demonstrated that inflammatory and nutritional markers are factors that can determine tumor prognosis. Therefore, the aim of this study was to identify and validate novel prognostic factors for PCNSL. Clinical information was collected from 223 patients with PCNSL. Patients younger than 18 years of age were excluded. Progression-free survival (PFS) and overall survival (OS) were used as endpoints, and receiver operating characteristic (ROC) curve analyses were conducted to determine the cutoff values for the inflammatory indicators. Correlations between variables and PFS or OS were assessed using univariate and multivariate analyses, and positive indicators were selected for survival analysis. A prognostic nutritional index (PNI) < 49.38 was associated with worse PFS (p = 0.003), and outcomes significantly differed between patients with a PNI ≥ 49.38 and < 49.38 (p < 0.001). Age < 60 years (p < 0.001) and C-reactive protein (CRP) levels < 3.14 (p = 0.001) were associated with better OS. In elderly patients (≥ 60 years), a lactate dehydrogenase-to-lymphocyte ratio (LLR) < 95.69 (p = 0.021) was associated with better OS, and the outcome significantly differed between patients with an LLR ≥ 95.69 and LLR < 95.69 (p = 0.015). The PNI and CRP levels are prognostic factors for PCNSL, and CRP was the first time shown to be a prognosis factor of PCNSL. In elderly patients with PCNSL, the LLR can predict prognosis.

LTBP1 plays a potential bridge between depressive disorder and glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant tumor in human brain. Diagnosis and treatment of GBM may lead to psychological disorders such as depressive and anxiety disorders. There was no research focusing on the correlation between depressive/anxiety disorder and the outcome of GBM. Thus, the aim of this study was to investigate the possibility of depressive/anxiety disorder correlated with the outcome of GBM patients, as well as the overlapped mechanism bridge which could link depressive/anxiety disorders and GBM. METHODS: Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) were used to investigate the psychological condition of GBM patients in our department. To further explore the potential mechanism, bioinformatic methods were used to screen out genes that could be indicators of outcome in GBM, followed by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and protein-protein interaction (PPI) analysis. Further, cellular experiments were conducted to evaluate the proliferation, migration capacity of primary GBM cells from the patients. RESULTS: It was revealed that patients with higher PHQ-9 and GAD-7 scores had significantly worse prognosis than their lower-scored counterparts. Bioinformatic mining revealed that LTBP1 could be a potential genetic mechanism in both depressive/anxiety disorder and GBM. Primary GBM cells with different expression level of LTBP1 should significantly different proliferation and migration capacity. GO, KEGG analysis confirmed that extracellular matrix (ECM) was the most enriched function of LTBP1. PPI network showed the interaction of proteins altered by LTBP1. Hub genes COL1A2, COL5A1 and COL10A1, as well as mesenchymal marker CD44 and Vimentin were statistically higher expressed in LTBP1 high group; while proneural marker E-cadherin was significantly higher expressed in low LTBP1 group. CONCLUSION: There is closely correlation between depressive/anxiety disorders and GBM. LTBP1 could be a potential bridge linking the two diseases through the regulation of ECM.

Correction to: LTBP1 plays a potential bridge between depressive disorder and glioblastoma.

An amendment to this paper has been published and can be accessed via the original article.

Aging-related tumor associated fibroblasts changes could worsen the prognosis of GBM patients.

Background: Glioblastoma multiforme (GBM) is the most malignant tumor in human brain, with highly heterogeneity among different patients. Age could function as an incidence and prognosis risk factor for many tumors. Method: A series of bioinformatic experiments were conducted to evaluate the differences of incidence, differential expressed genes, enriched pathways with the data from Surveillance, Epidemiology, and End Results (SEER) program, the cancer genome atlas (TCGA) and Chinese glioma genome atlas (CGGA) project. Results: We discovered in our present study that distinct difference of incidence and prognosis of different aged GBM patients. By a series of bioinformatic method, we found that the tumor associated fibroblasts (TAFs) was the most crucial tumor microenvironment (TME) component that led to this phenomenon. Epithelial-mesenchymal transition (EMT) could be the mechanism by which TAFs regulate the progression of GBM. Conclusion: We have proposed a close correlation between age and GBM incidence and prognosis, and propose the underlying mechanism behind this correlation by mining different databases, which laid the foundation for future research.

Phosphorylation of connexin 43 induced by traumatic brain injury promotes exosome release.

Traumatic brain injury (TBI) caused by the external force leads to the neuronal dysfunction and even death. TBI has been reported to significantly increase the phosphorylation of glial gap junction protein connexin 43 (Cx43), which in turn propagates damages into surrounding brain tissues. However, the neuroprotective and anti-apoptosis effects of glia-derived exosomes have also been implicated in recent studies. Therefore, we detected whether TBI-induced phosphorylation of Cx43 would promote exosome release in rat brain. To generate TBI model, adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury. Phosphorylated Cx43 protein levels and exosome activities were quantified using Western blot analysis following TBI. Long-term potentiation (LTP) was also tested in rat hippocampal slices. TBI significantly increased the phosphorylated Cx43 and exosome markers expression in rat ipsilateral hippocampus, but not cortex. Blocking the activity of Cx43 or ERK, but not JNK, significantly suppressed TBI-induced exosome release in hippocampus. Furthermore, TBI significantly inhibited the induction of LTP in hippocampal slices, which could be partially but significantly restored by pretreatment with exosomes. The results imply that TBI-activated Cx43 could mediate a nociceptive effect by propagating the brain damages, as well as a neuroprotective effect by promoting exosome release. NEW & NOTEWORTHY We have demonstrated in rat traumatic brain injury (TBI) models that both phosphorylated connexin 43 (p-Cx43) expression and exosome release were elevated in the hippocampus following TBI. The promoted exosome release depends on the phosphorylation of Cx43 and requires ERK signaling activation. Exosome treatment could partially restore the attenuated long-term potentiation. Our results provide new insight for future therapeutic direction on the functional recovery of TBI by promoting p-Cx43-dependent exosome release but limiting the gap junction-mediated bystander effect.

Peritumoral edema shown by MRI predicts poor clinical outcome in glioblastoma.

BACKGROUND: Magnetic resonance imaging (MRI) plays an irreplaceable role in the preoperative diagnosis of glioma, and its imaging features are the base of making treatment decisions in patients with glioma, but it is still controversial whether peritumoral edema shown by MRI from preoperative routine scans are associated with patient survival. The aim of this study was to assess the prognostic value of preoperative MRI features in patients with glioblastoma. METHODS: A retrospective review of 87 patients with newly diagnosed supratentorial glioblastoma was performed using medical records and MRI data from routine scans. The Kaplan-Meier method and COX proportional hazard model were applied to evaluate the prognostic impact on overall survival of pretreatment MRI features (including peritumoral edema, edema shape, necrosis, cyst, enhancement, tumor crosses midline, edema crosses midline, and tumor size). RESULTS: In addition to patient age, Karnofsky performance status (KPS) and postoperative chemoradiotherapy, peritumoral edema extent and necrosis on preoperative MRI were independent prognostic indicator for poor survival. Furthermore, patients with two unfavorable conditions (major edema and necrosis) had a shorter overall survival compared with the remainder. CONCLUSIONS: Our data confirm that peritumoral edema extent and necrosis are helpful for predicting poor clinical outcome in glioblastoma. These features were easy to determine from routine MRI scans postoperatively and therefore could provide a certain instructive significance for clinical activities.

Comparison of the clinical efficacy of temozolomide (TMZ) versus nimustine (ACNU)-based chemotherapy in newly diagnosed glioblastoma.

Although temozolomide (TMZ) replaced nitrosoureas as the standard initial chemotherapy for glioblastoma (GBM), no studies have compared TMZ with nimustine (ACNU), a nitrosourea agent widely used in central Europe and most Asian regions. One hundred thirty-five patients with GBM who underwent extensive tumor resection in our institution received both radiation and chemotherapy as initial treatment, 34 received TMZ and 101 ACNU-based (ACNU plus teniposide or cisplatin) chemotherapy. Efficacy analysis included overall survival (OS) and progression-free survival (PFS). The following prognostic factors were taken into account: age, performance status, extent of resection, and O(6)-methylguanine-DNA-methyltransferase (MGMT) gene status. The median OS was superior in the TMZ versus the ACNU group (p = 0.011), although MGMT gene silencing, which is associated with a striking survival benefit from alkylating agents, was more frequent in the ACNU group. In multivariate Cox analysis adjusting for the common prognostic factors, TMZ chemotherapy independently predicted a favorable outcome (p = 0.002 for OS, hazard ratio [HR], 0.45; p = 0.011 for PFS, HR, 0.56). Given that >40 % of patients in ACNU group did not receive the intensive chemotherapy cycles because of severe hematological and nonhematological toxicity, we performed a further subanalysis for patients who received at least 4 cycles of chemotherapy. Although a modest improvement in survival occurred in this ACNU subgroup, the efficacy was still inferior to that in the TMZ cohort. Our data suggest that the survival benefit of TMZ therapy is superior to that of an ACNU-based regimen in patients with extensive tumor resection, also shows greater tolerability.

CNS Germ Cell Tumors: Molecular Advances, Significance in Risk Stratification and Future Directions.

Central Nervous System Germ Cell Tumors (CNS GCTs) represent a subtype of intracranial malignant tumors characterized by highly heterogeneous histology. Current diagnostic methods in clinical practice have notable limitations, and treatment strategies struggle to achieve personalized therapy based on patient risk stratification. Advances in molecular genetics, biology, epigenetics, and understanding of the tumor microenvironment suggest the diagnostic potential of associated molecular alterations, aiding risk subgroup identification at diagnosis. Furthermore, they suggest the existence of novel therapeutic approaches targeting chromosomal alterations, mutated genes and altered signaling pathways, methylation changes, microRNAs, and immune checkpoints. Moving forward, further research is imperative to explore the pathogenesis of CNS GCTs and unravel the intricate interactions among various molecular alterations. Additionally, these findings require validation in clinical cohorts to assess their role in the diagnosis, risk stratification, and treatment of patients.

IDH-mutant grade 4 astrocytoma: a comparison integrating the clinical, pathological, and survival features between primary and secondary patients.

OBJECTIVE: IDH-mutant grade 4 astrocytomas (AIDHmut/G4) are divided into primary de novo (pAIDHmut/G4) and secondary with a history of prior lower-grade gliomas (LGGs; sAIDHmut/G4). The mutational spectrum and DNA methylation patterns are homogeneous within de novo pAIDHmut/G4 and evolved sAIDHmut/G4, but the two groups have different diagnoses, management, and outcomes. This study sought to systematically compare the clinical, pathological, and survival characteristics between them. METHODS: Of the 871 grade 4 astrocytomas with data for IDH mutation, 698 (80.1%) were primary and 173 (19.9%) were secondary. Of the 698 primary tumors, 103 (14.8%) were pAIDHmut/G4, and of the 173 secondary tumors, 108 (62.4%) were sAIDHmut/G4. Clinical, pathological, and survival features were compared between pAIDHmut/G4 and sAIDHmut/G4. Multivariate analyses were performed to identify prognostic factors. RESULTS: Patients with sAIDHmut/G4 had significantly shorter median overall survival (OS; 11.8 vs 34.2 months, hazard ratio [HR] 2.69, 95% confidence interval [CI] 1.367-5.306, p = 0.004) and progression-free survival (PFS; 8.5 vs 24.3 months, HR 2.83, 95% CI 1.532-5.235, p = 0.001) than patients with pAIDHmut/G4. In patients with sAIDHmut/G4, resection status and chemotherapy were independent prognostic factors for OS and PFS; in patients with pAIDHmut/G4, LGG component, resection status, and O6-methylguanine DNA methyltransferase promoter methylation were independent prognostic factors. The therapeutic strategies of LGGs did not influence survival of patients with sAIDHmut/G4, but patients who had not received radiotherapy or chemotherapy when they were diagnosed with LGGs were found to benefit from radiotherapy or chemotherapy when they progressed to sAIDHmut/G4. CONCLUSIONS: The different clinical characteristics, survival, and risk factors between sAIDHmut/G4 and pAIDHmut/G4 provide a reference to guide treatment decisions in AIDHmut/G4.

Direct evidence of the left caudate's role in bilingual control: an intra-operative electrical stimulation study.

Bilinguals need control mechanisms in order to switch between languages in different communication contexts (Green, 1998, Bilingualism: Language and Cognition, 1; Price, Green, & von Studnitz, 1999, Brain, 122). There has been neural evidence showing competition to control output in L2 vs. L1 in both cortical and sub-cortical areas, when language selection is carried out (Abutalebi & Green, 2007, Journal of Neurolinguistics, 20). Here we use intra-operative direct electrical stimulation to demonstrate that the head of the left caudate is critical not only in language switching tasks but other control tasks. A bilingual Chinese-English patient was instructed to perform both language switching and switching in color-shape naming tasks during awake glioma surgery. When stimulation was applied on the left caudate, failures or difficulties in both language switching and color-shape naming were observed, with the effects greater on language switching. Stimulation to neighboring brain regions either did not affect performance or generated mild problems specific to language switching. The results provide direct evidence of the necessary role of the left caudate in language control.

Radiotherapy delays malignant transformation and prolongs survival in patients with IDH-mutant gliomas.

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

Cortical areas involved in numerical processing: an intraoperative electrostimulation study.

BACKGROUND: Numerical processing is important in our everyday lives. However, very few attempts have been made to map the numerical processing function areas during lesion surgery. OBJECTIVE: To identify and protect the cortical areas involved in numerical processing, the authors used the intraoperative brain mapping approach to study numerical processing areas in patients with parietal lobe tumors. METHODS: During resection in patients with parietal lobe tumors, local anesthesia was administered and numerical processing mapping was performed. Our mapping procedures were conducted before glioma removal and included somatosensory, language and numerical processing tasks. We focused on the numerical processing task. RESULTS: Different brain sites within the parietal lobe were detected to be specifically related to multiplication or subtraction processing. They displayed precise spatial distribution and overlapped with each other. No brain sites were found to be specifically related to numerical processing in the right hemisphere. CONCLUSIONS: To improve the quality of resection while minimizing the neurological deficits, functional boundaries of numerical processing areas should be considered during the removal of a parietal low-grade glioma. Moreover, only the left intraparietal sulcus is necessary for numerical processing, whereas the right intraparietal sulcus does not appear to be critically involved in numerical processing.

Molecular Characterization of AEBP1 at Transcriptional Level in Glioma.

BACKGROUND: Glioma is the most common malignant tumor of the brain in adult patients. The standardized treatment protocol is based on surgical therapy, supplemented with radiotherapy and chemotherapy. However, the prognosis is still unsatisfied. Chemoresistance is one of the most important reason for the poor prognosis of glioma patients. It has confirmed that glioma stem cell (GSC) is one of the reasons for chemoresistance. METHODS: In this study, three datasets (GSE23806, COSMIC, and TCGA) were used to perform the analysis to search for the key genes related to GSC, temozolomide (TMZ) resistance, and prognosis. The key gene for further research was selected by reviewing the previous studies. The selected gene investigated the relation between expression levels and clinical characteristics in both TCGA and CGGA dataset. The bioinformatics analysis was performed by Gene Ontology (GO) analysis. The survival analysis was performed by Kaplan-Meier survival analysis. RESULTS: AE binding protein 1 (AEBP1) was selected for further analysis. AEBP1 was overexpressed in GSCs and TMZ resistance cells. In both TCGA and CGGA dataset, the results showed that the expression level of AEBP1 was increased in glioblastoma (GBM) samples, IDH wild-type samples, and MGMT promoter unmethylated samples. Meanwhile, AEBP1 expression was positively related to several GSC markers. GO analysis showed that AEBP1 was related to immune response, cell adhesion, apoptotic process, inflammatory response, positive regulation of cell proliferation, angiogenesis, response to drug, and response to hypoxia. The survival analysis showed that the overexpressed level of AEBP1 was correlated with short survival time in both glioma and GBM patients. CONCLUSION: In summary, AEBP1 was related with GSC-induced TMZ resistance. Our study showed that AEBP1 might be an oncogene and a new effective therapeutic target for the treatment of glioma.

Transcriptomic Analysis of Glioma Based on IDH Status Identifies ACAA2 as a Prognostic Factor in Lower Grade Glioma.

BACKGROUND: Glioma is the most common and lethal tumor in the central nervous system (CNS). More than 70% of WHO grade II/III gliomas were found to harbor isocitrate dehydrogenase (IDH) mutations which generated targetable metabolic vulnerabilities. Focusing on the metabolic vulnerabilities, some targeted therapies, such as NAMPT, have shown significant effects in preclinical and clinical trials. METHODS: We explored the TCGA as well as CGGA database and analyzed the RNA-seq data of lower grade gliomas (LGG) with the method of weighted correlation network analysis (WGCNA). Differential expressed genes were screened, and coexpression relationships were grouped together by performing average linkage hierarchical clustering on the topological overlap. Clinical data were used to conduct Kaplan-Meier analysis. RESULTS: In this study, we identified ACAA2 as a prognostic factor in IDH mutation lower grade glioma with the method of weighted correlation network analysis (WGCNA). The difference of ACAA2 gene expressions between the IDH wild-type (IDH-WT) group and the IDH mutant (IDH-MUT) group suggested that there may be different potential targeted therapies based on the fatty acid metabolic vulnerabilities, which promoted the personalized treatment for LGG patients.

Depressive and anxiety disorders worsen the prognosis of glioblastoma.

Glioblastoma multiforme (GBM) is one of the most malignant tumors. Depressive and anxiety disorders may co-exist with GBM. We investigated whether depression and anxiety influenced the outcomes of GBM. The Patient Health Questionnaire 9-item (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) scales were used to investigate the mental condition of GBM patients in our department, and the overall survival times of these patients were monitored. The scores on both scales were higher in GBM patients than in healthy controls. For each scale, GBM patients were divided into high- and low-score groups based on the average score. The prognosis was poorer for GBM patients in the high-score groups than for those in the low-score groups. Moreover, magnetic resonance imaging revealed that tumor necrosis was more prevalent among high-scored GBM patients. Cellular experiments were performed on primary GBM cells from patients with either high or low scores on both scales. Sphere formation, EdU and wound healing assays revealed greater proliferation and invasion capacities in GBM cells from patients with high scores on both scales. Western blotting assay revealed significantly different expression of epithelial and mesenchymal markers between the two groups. Thus, our analysis revealed a clinically important correlation between depression/anxiety and GBM prognosis.

Receptor tyrosine kinase expression in high-grade gliomas before and after chemoradiotherapy.

Glioma is the most common type of malignant brain tumor, and is characterized by invasive growth and chemoradiotherapy resistance. The following Cancer Genome Atlas mutation subtypes were identified in initial high-grade gliomas and recurrent gliomas treated by chemoradiotherapy: Isocitrate dehydrogenase 1/2 (IDH1/2) mutation, epidermal growth factor receptor variant III (EGFRvIII) mutation, tumor protein P53 mutation, PTEN mutation, O6-methylguanine-DNA methyltransferase promoter methylation and telomerase reverse transcriptase (TERT) mutation. The expression profile of 58 receptor tyrosine kinases (RTKs) were also examined. It was revealed that the proneural tumor subtype and IDH1/2 mutation are more frequent in recurrent tumors compared with initial tumors. Lower frequencies of the classical subtype, EGFRvIII mutation and TERT mutation were identified in recurrent tumors. A set of six RTK genes in which the level of expression was influenced by chemoradiotherapy was identified. Survival analysis revealed that the expression of several RTKs, including apoptosis-associated tyrosine kinase, fibroblast growth factor receptor 1 and insulin-like growth factor 1 receptor (IGF1R), was associated with patient survival. The stimulation of glioma cells by IGF1 in vitro was found to decreased the viability of the cells following treatment with temozolomide (TMZ). In addition, the expression level of IGF1R was increased in glioma cells treated with TMZ. These data suggest that altered RTK expression levels may influence the sensitivity of glioma to chemoradiotherapy.

Bioactivity and safety of chimeric switch receptor T cells in glioblastoma patients.

Experimental evidence has shown that chimeric switch receptor T (CSR-T) cells, activated by binding programmed death-ligand 1 on the tumor cell surface, lead to tumor regression in experimental animals. In this phase I clinical study, we evaluated the safety and bioactivity of CSR-T cell therapy in 14 patients with recurrent glioblastoma who were unresponsive to surgical resection and standard radiotherapy. Patients who received 108 CSR-T cells either intravenously or intracranially showed an increase in the levels of IFN-gamma and IL-6, respectively, in peripheral blood or cerbrospinal fluid (CSF). Moreover, the number of T cells present in CSF significantly increased after the treatment. Patients did not show grade 3 or 4 adverse effects. The evidence of in vivo biological activity and lack of adverse effects of treatment with CSR-T cells suggest that such treatment can be subjected to further analysis to show the efficacy of this new treatment strategy in the treatment of cancers that are not responsive to traditional therapeutic regimens.

Fractionated resection on low grade gliomas involving Broca's area and insights to brain plasticity.

BACKGROUND: Recent advances on functional mapping have enabled us to conduct surgery on gliomas within the eloquent area. The objective of the article is to discuss the feasibility of a planned fractionated strategy of resection on low-grade gliomas (LGGs) involving Broca's area. We report the first surgical series of planned fractionated resections on LGGs within Broca's area, focusing on language functional reshaping. METHODS: Four patients were treated with fractionated operations for LGGs involving Broca's area. All cases underwent conventional magnetic resonance (MR) scanning, language functional MR and diffusion tensor imaging (DTI) before operation. The resections were then performed on patients under awake anesthesia using intraoperative electrical stimulation (IES) for functional mapping. Pre- and post-operative neuro-psychological examinations were evaluated. RESULTS: Total resections were achieved in all cases as confirmed by the postoperative control MR. After transient language worsening, all patients recovered to normal 3-6 months later. Language functional MR scannings have shown language functional cortical and subcortical pathway reorganization (in the perilesion or contra-lateral hemisphere) after the operation. All patients returned to a normal socioprofessional life. CONCLUSIONS: By utilizing the dynamic interaction between brain plasticity and fractionated resections, we can totally remove the tumor involving Broca's structure without inducing permanent postoperative deficits and even improve the quality of life.