Survival Analysis of Patients Undergoing Intraoperative Contrast-enhanced Ultrasound in the Surgical Treatment of Malignant Glioma

Objective:Complete resection of malignant gliomas is often challenging.Our previous study indicated that intraoperative contrast-enhanced ultrasound(ICEUS)could aid in the detection of residual tumor remnants and the total removal of brain lesions.This study aimed to investigate the survival rates of patients undergoing resection with or without the use of ICEUS and to assess the impact of ICEUS on the prognosis of patients with malignant glioma.Methods:A total of 64 patients diagnosed with malignant glioma(WHO grade HI and IV)who underwent surgery between 2012 and 2018 were included.Among them,29 patients received ICEUS.The effects of ICEUS on overall survival(OS)and progression-free survival(PFS)of patients were evaluated.A quantitative analysis was performed to compare ICEUS parameters between gliomas and the surrounding tissues.Results:The ICEUS group showed better survival rates both in OS and PFS than the control group.The univariate analysis revealed that age,pathology and ICEUS were significant prognostic factors for PFS,with only age being a significant prognostic factor for OS.In multivariate analysis,age and ICEUS were significant prognostic factors for both OS and PFS.The quantitative analysis showed that the intensity and transit time of microbubbles reaching the tumors were significantly different from those of microbubbles reaching the surrounding tissue.Conclusion:ICEUS facilitates the identification of residual tumors.Age and ICEUS are prognostic factors for malignant glioma surgery,and use of ICEUS offers a better prognosis for patients with malignant glioma.

Dendritic cell-based immunotherapy for malignant glioma

The immunotherapy for malignant glioma faces unique difficult, due to some anatomical and immunological characteristics including the existence of blood brain barrier, the absence of lymphatic tissues and dendritic cells （DCs） in the central nervous system （CNS） parenchyma, and the presence of an immunosuppressive microenvironment. Therefore, immunothera-peutic approaches will not be beneficial unless the compromised immune status in malignant glioma patients is overcome. DC-based immunotherapy, vaccinating cancer patients with DCs pulsed with various tumor antigens, is one of the most promising immunotherapeutic approaches for treatment of malignantglioma because it seems able to overcome, at least partially, the immunosuppressive state associated with primary malignancies. The preparation of DCs, choice of antigen, and route and schedule of administration are improving and optimizing with rapid development of molecular biology and gene engineering technology. DC vaccination in humans, after a number of pre-clinical models and clinical trials, would increase the clinical benefits for malignant glioma immunotherapy.

Bevacizumab rescue therapy extends the survival in patients with recurrent malignant glioma

Objective： We retrospectively studied the efficacy of bevacizumab as salvage therapy for recurrent malignant glioma with a focus on the overall survival （OS）. Methods： Patients who received a therapy other than surgery for recurrent malignant glioma were included. Efficacy was evaluated using MRI. Neurological function was evaluated using the Response Assessment in Neuro-Oncology （RANO）. The survival rate was calculated using the Kaplan-Meier method. Results： Fifty-one patients with recurrent glioma （31 grade Ⅲ, 20 grade Ⅳ） were included. Among them, 22 subjects （43.1%） received bevacizumab. The median OS was 10.2 months （range, 1 to 27 months）. Patients receiving bevacizumab had comparable OS （a median of 9.9 vs. 10.0 months） and similar 6-month survival rate （43% vs. 34%） to those who did not receive bevacizumab. A subgroup analysis failed to notice any significant difference in grade Ⅲ glioma patients receiving bevacizumab vs. those who did not. The median survival was significantly longer at 8.9 months （range, 4 to 13 months） in grade Ⅳ glioma patients receiving bevacizumab than in those who did not （5.6 months, range, 2 to 7 months, P=0.042）. The 6-month survival rate was higher （83 %） in those who received bevacizumab than in those who did not （47 %, P=0.046）. No grade 3/4 adverse events were observed in any patient. Conclusions： Bevacizumab, as a rescue therapy, provides a survival benefit for recurrent grade IV glioma.

Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia - induced cell death

Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresults of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing.Here,wereport a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hy-poxia,which contrasts with their proapoptotic effects under normoxia.Under hypoxic conditions,both agents re-

THE USE OF ANTIHUMAN GLIOMA MONOCLONAL ANTIBODIES FOR TARGETING CHEMOTHERAPY OF BRAIN GLIOMAS(POTENT SUPPRESSION OF MALIGNANT GLIOMA GROWTH WITH IMMUNOCONJUGATES IN VIVO)

Athymic nude mice bearing subcutaneous and intracerebral human glioma xenografts were used to assess the therapeutic efficacy of monoclonal anti-body-adriamycin immunoconjugates against malignant gliomas in vivo. Immunoconjugates showed a significantly stronger antitumor effect with a T/C (treated/ control tumor volume) of 30% as compared with free drug (T/C of 84%). The targeting treatment with immunoconjugates significantly prolonged 54% of median survival time of nude mice. Side effects of immunoconjugates on the normal bone marrow and small intestines were much slighter than those of the free drug. The results of this study indicate that the use of monoclonal antibodies as carriers of anti-tumor agents may have many therapeutic advantages and potential for the treatment of brain gliomas.

Local immunotherapy with interleukin - 2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma.

OBJECTIVE:Local delivery of carmustine(BCNU)from biodegradablepolymers prolongs survival against experi-mental brain tumors.Moreover,paracrine administration of interleukin-2(IL-2)has been shown to elicit apotent antitumor immune response and to improve survival in animal brain tumor models.We report the use of anovel polymeric microsphere delivery vehicle to release IL-2.We demonstrate both in vitro release of cytokinefrom the microspheres and histological evidence of the inflammatory response elicited by IL-2 released from themicrospheres in the rat brain.Thees microspheres are used to deliver IL-2,and biodegradable polymer wafers

Temozolomide chemotherapy based on MGMT protein expression for patients with malignant gliomas:a report of 40 cases

Objective This study is to evaluate the efficacy and toxicity of temozolomide (TMZ) chemotherapy based on O 6 -methylguanine-DNA methyltransferase (MGMT) protein expression in patients with malignant gliomas. Methods A total of 40 patients with pathologically confirmed malignant gliomas were enrolled. All patients had pretreated with radiotherapy and had assessable lesions.

Altered expression of EphA2 and EphrinA1 associated with prognosis of malignant glioma patients

Objective Malignant gliomas display over-expression of the receptor tyrosine kinase EphA2. However,expression levels of the EphA2 ligand,EphrinA1,have not been fully elucidated. This study aims to determine the expression of EphA2 / EphrinA1 in detail,and further detect the predictive

3D Microfluidic System for Evaluating Inhibitory Effect of Chinese Herbal Medicine Oldenlandia diffusa on Human Malignant Glioma Invasion Combined with Network Pharmacology Analysis

Objective:To investigate the anti-invasion efficacy of the ethanol extract of Oldenlandia diffusa Will.(EEOD) on a three-dimensional(3D) human malignant glioma(MG) cell invasion and perfusion model based on microfluidic chip culture and the possible mechanism of action of Oldenlandia diffusa Will.(OD).Methods:The comprehensive pharmacodynamic analysis method in this study was based on microfluidic chip 3D cell perfusion culture technology,and the action mechanism of Chinese medicine(CM) on human MG cells was investigated through network pharmacology analysis.First,the components of EEOD were analyzed by ultraperformance liquid chromatography with quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF/MS).Then,cell viability and apoptosis were assessed to determine the optimum concentration of EEOD for invasion experiments,and two-dimensional(2D) migration and invasion abilities of U87 and U251 MG cells were evaluated using scratch wound and Transwell assays.The possible mechanism underlying the effects of EEOD on glioma was analyzed through a network pharmacology approach.Results:Thirty-five compounds of EEOD were detected by UPLC-Q-TOF/MS.EEOD suppressed the viability of MG cells,promoted their apoptosis,and inhibited their migratory and invasive potentials(all P<0.05).Network pharmacology analysis showed that OD inhibited the invasion of MG cells by directly regulating MAPK and Wnt pathways through MAPK,EGFR,MYC,GSK3B,and other targets.The anti-invasion effect of OD was also found to be related to the indirect regulation of microtubule cytoskeleton organization.Conclusion:EEOD could inhibit the invasion of human MG cells,and the anti-invasion mechanism of OD might be regulating MAPK and Wnt signaling pathways and microtubule cytoskeleton organization.

Antisense MMP-9 RNA inhibits malignant glioma cell growth in vitro and in vivo

The matrix-degrading metalloproteinases （MMPs）, particularly MMP-9, play important roles in the pathogenesis and development of malignant gliomas. In the present study, the oncogenic role of MMP-9 in malignant glioma cells was investigated via antisense RNA blockade in vitro and in vivo. TJ905 malignant glioma cells were transfected with pcDNA3.0 vector expressing antisense MMP-9 RNA （pcDNA-AS-MMP9）, which significantly decreased MMP-9 expression, and cell proliferation was assessed. For in vivo studies, U251 cells, a human malignant glioma cell line, were implanted subcutaneously into 4-to 6-week-old BALB/c nude mice. The mice bearing well-established U251 gliomas were treated with intratumoral pcDNA-AS-MMP9-Lipofectamine complex （AS-MMP-9-treated group）, subcutaneous injection of endostatin （endostatin-treated group）, or both （combined therapy group）. Mice treated with pcDNA （empty vector）-Lipofectamine served as the control group. Four or eight weeks later, the volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity were assayed. We demonstrate that pcDNA-AS-MMP9 significantly decreased MMP-9 expression and inhibited glioma cell proliferation. Volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity in the antisense-MMP-9-treated and therapeutic alliance groups were significantly lower than those in the control group. The results suggest that MMP-9 not only promotes malignant glioma cell invasiveness, but also affects tumor cell proliferation. Blocking the expression of MMP-9 with antisense RNA substantially suppresses the malignant phenotype of glioma cells, and thus can be used as an effective therapeutic strategy for malignant gliomas.

Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence

Subject Code:H30With the support by the National Natural Science Foundation of China,the research group led by Prof.Zhang Can(张灿)from China Pharmaceutical University made important progress in the chemotherapy of post-operative malignant glioma,which was published in Nature Nanotechnology(2017,12(7):692—700).

Management of Malignants Gliomas: About 20 Cases Treated in the Medical Oncology Department of Fattouma Bourguiba University Hospital-Monastir

Introduction: Malignant gliomas refer to grade III or IV brain tumors defined according to the World Health Organization (WHO) classification. They are a heterogeneous group of pathologies and represent a serious health problem by their frequency, severity and treatment difficulties. The prognosis of malignant gliomas remains poor despite all the medical advances. Materials and Methods: It is a retrospective study included 20 cases of malignant glial tumors treated at the medical oncology department, Fattouma Bourguiba hospital in Monastir between 2012 and 2016, according to the STUPP protocol. Results: These were 12 men and 8 women with a median age of 43. Clinical signs were not very specific, dominated by intracranial hypertension and deficit signs. Imagery referred to the diagnosis of malignant gliomas in 1st intention. Surgery consisted of a macroscopically complete exeresis in (15%) cases, a partial exeresis in (50%), the rest of the patients had a stereotactic biopsy. Histology found GBM in 16 patients (80%), 2 cases of Grade III anaplastic astrocytoma (10%), 1 case of anaplastic oligodendroglioma (5%), and 1 case of Grade III anaplastic eppendymoma (5%). Most of our patients received concurrent radio-chemotherapy and adjuvant TMZ chemotherapy was administered in 15 patients, 7 of whom received the full 6 scheduled cures. A relapse treatment was decided in only one of the 12 patients who relapsed. 6 patients are still alive. The median survival is 11.27 months. In our series, overall survival was related to histological type (p = 0.006) and neurological status assessed at the end of RT-CT (p = 0.001). While age, general condition score, type of surgery, and post-therapeutic development did not show a statistically significant relationship, although survival rates were consistent with the criteria assessed. Conclusion: Malignant gliomas are rare tumors, bad prognosis, aggravated in Tunisia by a diagnostic delay. The creation of a multidisciplinary neuro-oncology group can help to improve management.

Diagnostic pitfalls in malignant gliomas： the analysis of misdiagnosis and current recommendations

The malignant glioma is characterized by intrinsic aggressiveness and carries a dismal prognosis. Thecurrent standard treatment regimen for patients with malignant gliomas, specifically glioblastoma, is a combined therapy comprised of surgical resection followed by adjunctive radiation and chemotherapy. Yet, even with this new multimodality treatment, glioblastoma （GBM） recurs after a median time of 7 months following diagnosis, requiring a second-line treatment. But the clinical decisions are always difficult.

Progress on molecular biomarkers and classification of malignant gliomas

Gliomas are the most common primary intracranial tumors in adults.Anaplastic gliomas(WHO gradeⅢ)and glioblastomas(WHO gradeⅣ)represent the major groups of malignant gliomas in the brain.Several diagnostic,predictive,and prognostic biomarkers for malignant gliomas have been reported over the last few decades,and these markers have made great contributions to the accuracy of diagnosis,therapeutic decision making,and prognosis of patients.However,heterogeneity in patient outcomes may still be observed,which highlights the insufficiency of a classification system based purely on histopathology.Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment.In this review,we summarize three distinctive biomarkers,three most commonly altered pathways,and three classifications based on microarray data in malignant gliomas.

The process of life adjustment in patients at onset of glioma who are receiving continuous oral anticancer drug: A qualitative descriptive study

Objective: Patients with malignant gliomas have to adjust their daily lives because of the threat of impending death and declining abilities.Thus,clarifying the process of life adjustment in such patients would help them lead a normal life.To clarify the process of life adjustment in patients at the onset of glioma,who continuously receive oral anticancer drug.Methods: The study institution consisted of two designated cancer centers.Semi-structured interviews were conducted with 10 patients,and the data were analyzed using the Modified Grounded Theory Approach of Kinoshita (M-GTA).Results: As a core category representing the process of life adjustment in patients at the onset of glioma,"trials and errors for self-fulfillment even in a limited lifespan" was extracted.Patients began "seeking information about the unfamiliar life-threatening disease," and "imaging their uncertain lives after the disease and the resulting disability" while "conducting repeated trials and errors to establish coping methods according to their abilities." When facing difficulties in such trials and errors,they reported "losing self-confidence due to unexpected limitations." However,they regulated their feelings by "resigning themselves to their unchangeable reality." Contrarily,as "functional improvement enhanced their motivation to recover," they attempted to promote functional recovery and organized their daily lives in "fulfilling their desires in their limited lifespan." Conclusion: The process of life adjustment in patients with malignant gliomas involved identifying a way of living despite limited lifespan.To ensure appropriate nursing care for patients at the onset of glioma,it is important to help them establish coping methods in accordance with their abilities.

THE EFFECT OF TRANSFECTED CX43 GENE ON THE GJIC AND PROLIFERATION OF GLIOMA CELLS

Objective: To evaluate the effect of Cx43 gene on gap junction intercellular communication (GJIC) and proliferation of glioma cells. Methods: Cx43 cDNA was transfected into TJ905 human glioblastoma cells using lipofectamine. The expression of Cx43 was identified by Northern blot analyses, in situ hybridization and immunohistochemistry. MTT assay and average number of AgNORs (Argyrophlic nuclear organizer regions) were used to determine the cell proliferation. TUNEL method was used for detection of cell apoptosis, and scrape loading and dye tranfer method for examination of GJIC. Results: The Cx43 expression was greatly upregulated when Cx43 gene was transfected into TJ905 glioma cells. The cell proliferation was inhibited while the cell apoptosis was not increased and GJIC was significantly restored in the glioma cells transfected with Cx43 gene. Conclusion: Cx43 gene has an inhibitory effect on the glioma cell proliferation, but no effect on induction of cell apoptosis. The restoration of GJIC may be the major mechanism involved in its effect. Cx43 gene can be the candidate for gene therapy of gliomas.

Commentary:Evaluating potential glioma serum biomarkers,with future applications

Systemic inflammation within malignant glioma is a topic of ongoing significance.In this commentary,we highlight recent findings from Gandhi et al and discuss alternative approaches.We present a counter argument with findings that IL-6 markers are controversial.We highlight the potential benefit of looking at microRNAs and other biomarkers.Finally,we present ideas for future application involving differentiation between radiation necrosis and recurrence.The commentary is intended to serve as a catalyst for further scientific discovery.

Expert opinion on translational research for advanced glioblastoma treatment

Malignant gliomas are known to be one of the most difficult diseases to diagnose and treat because of the infiltrative growth pattern,rapid progression,and poor prognosis.Many antitumor drugs are not ideal for the treatment of gliomas due to the blood-brain barrier.Temozolomide(TMZ)is a DNA alkylating agent that can cross the blood-brain barrier.As the only first-line chemotherapeutic drug for malignant gliomas at present,TMZ is widely utilized to provide a survival benefit;however,some patients are inherently insensitive to TMZ.In addition,patients could develop acquired resistance during TMZ treatment,which limits antitumor efficacy.To clarify the mechanism underlying TMZ resistance,numerous studies have provided multilevel solutions,such as improving the effective concentration of TMZ in tumors and developing novel small molecule drugs.This review discusses the in-depth mechanisms underlying TMZ drug resistance,thus aiming to provide possibilities for the establishment of personalized therapeutic strategies against malignant gliomas and the accelerated development and transformation of new targeted drugs.