bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to brain tissue using drug-embedded biodegradable nanofibers.
Authors: Liu Shih-Jung , Tseng Yuan-Yun 
Published: May 2019

e13501 Background: Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor cell resistance to chemotherapy. Methods: We developed bilayered poly[(d,l)-lactide- co-glycolide] nanofibrous membranes that enable the sequential and sustained release of carmustine [or bis-chloroethylnitrosourea (BCNU)], irinotecan, cisplatin, and combretastatin by employing an electrospinning technique. An elution method and a high-performance liquid chromatographic assay were employed to characterize the in vitro release behaviors of pharmaceuticals from the nanofibers. Results: The experimental results showed that the drug-eluting nanofibers exhibited a sequential drug release behavior, with the release of high concentrations of BCNU, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then placed into the cerebral cavity of rats after operative craniectomy was performed, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. A histological examination revealed the progressive atrophy of brain tissues without inflammatory reactions. Conclusions: Biodegradable drug-eluting nanofibers can be manufactured for the long-term sequential delivery of various chemotherapeutic and antiangiogenic agents in the cerebral cavity, which can potentially enhance the therapeutic efficacy of glioblastoma multiforme treatment and prevent toxic effects resulting from systemic administration.
Comparison of two dose calculation methods of intra-arterial carboplatin in the treatment of recurrent glioblastoma multiforme.
Authors: Boilard Brigitte , Hinse Alexandra , Beaulieu Karianne , Marcotte Florence , Fortin David , Lacasse Marie-Constance , joly-Mischlich Thomas , Ferland Gabrielle 
Published: May 2019

e13503 Background: Glioblastoma is a deadly brain cancer, and as part of the natural evolution, its relapses will mostly occur 32 to 36 weeks after the initial diagnosis. The standard of care for recurrent glioblastomas is not well defined and multiple options exist. Intra-arterial chemotherapy as one option is currently practiced at the Centre hospitalier universitaire de Sherbrooke, the only center doing this procedure in Canada. The aim of this study is to evaluate the impact of using the area under the curve (AUC) or body surface area (BSA) dosing formula to guide intra-arterial carboplatin administration. It was designed to explore the relation of two dose calculation methods on efficacy and toxicity, determined by progression-free survival (PFS) and hematologic toxicity, respectively. Methods: A retrospective observational study was conducted, which includes adult in-patients who received intra-arterial carboplatin for recurrent glioblastoma from June 1st, 2000 to December 31st, 2017. It examined the associations of the method used to calculate the doses, in mg or mg/mL x min-1, with clinical outcomes. Results: One hundred ninety patients were included in the analysis. For the primary endpoint, an exposure greater than 6 of AUC was found potentially harmful in terms of efficacy compared to AUC under 6 (HR 0.529, p = 0.0044). In terms of toxicity, a higher AUC is highlighted to correlate with a slightly higher incidence of thrombocytopenia and neutropenia (OR 1.051 p = 0.0271; OR 1.072 p = 0.049). No significant association between toxicity and dose calculated with BSA could be established. Conclusions: AUC greater than 6 is detrimental in terms of effectiveness according to progression free survival. Moreover, AUC could be used to predict neutropenia and thrombocytopenia. However no significant predictions were found using BSA method. We recommend the use of AUC method in intra-arterial carboplatin instead of BSA method since the latter was not statistically related to toxicity. A prospective trial comparing the two dosage methods would be needed.
Targeting the androgen receptor as a novel therapeutic strategy for high-grade gliomas by suppressing glioma cancer stem cells.
Authors: Zhao Nan , Ahmed Shaheen , Wang Fei , Dominick DiMaio J , Lin Chi , Zhang Chi 
Published: May 2019

e13504 Background: Glioblastoma (GBM) is the most aggressive and most common type of primary brain malignancies with median overall survival being only 20.9 months. The incidence of GBM is 50% greater in men than in women, and GBM transplanted into animals grow at a slower rate in females compared with males. Gender difference in GBM indicates that sex hormones such as androgen receptor (AR) may be involved in the tumorigenesis of GBM. A newer generation of AR antagonist, Enzalutamide, is available for prostate cancer treatment in clinic and can pass the blood-brain barrier, thus a good candidate for GBM treatment. Methods: Cell proliferation assay, cell cycle analysis, and cell apoptosis assay were performed on different GBM cell lines after Enzalutamide treatment. After treating GBM cells with or without Enzalutamide in mono-layer cell culturing or tumor spheres, cancer stem cell sub-population (CD133+ cells) in different groups was compared using flow cytometry. After enriching GBM cancer stem cells by sorting CD133+ U87MG cells out, cell proliferation assay was performed on CD133+ U87MG cells. Western blotting was performed comparing marker gene expression levels including CD133 and c-Myc with total protein isolated from GBM cells treated with Enzalutamide at different time points. A syngeneic orthotopic GBM mouse model was used for in vivo study. The size of tumors in the brain was monitored weekly with and without Enzalutamide treatment by in vivo imaging system for the luciferase activities. Results: Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Enzalutamide induced apoptosis of GBM cells as well as arrested the cell cycle at G2/M phase in a cell cycle that has a potential of radio-sensitizing effect. Enzalutamide decreased the cancer stem cells population both in cultured mono-layer cells and in tumor spheres. Enzalutamide inhibited the proliferation of CD133+ U87MG cells after four days’ treatment. c-Myc is a proto-oncogene and required for maintenance of GBM cancer stem cells. Both CD133 and c-Myc expression levels decreased in GBM cell lines after Enzalutamide treatment in a time-dependent manner. Conclusions: Enzalutamide targets cancer stem cells and inhibits the proliferation of GBM.
Aberrant miRNA expression in glioma.
Authors: Pushkin Anton , Kit Oleg I. , Rostorguev Eduard Evgenevich , Porksheyan David H. , Kuznetsova Natalya S. , Kavitskiy Sergey E. 
Published: May 2019

e13506 Background: Gliomas are the most common type of primary brain tumors, with a high level of recurrence and mortality. The purpose of the study was to determine the expression profile of micro-RNA targeting components of the Hedgehog, Notch, Wnt, EGFR, TGFβ, HIF1α signaling pathways according to MirTarBase, miRDB, TargetScan. Methods: The study included 30 patients (15 women and 15 men) aged 27 to 76 years with histologically verified glial brain tumors. The RT2-qPCR method in operational biopsy specimens determined the relative expression of 12 micro-RNAs: hsa-miR-17-3p, hsa-miR-20a-3p, hsa-miR-326, hsa-miR-330-3p, hsa-miR- 107, hsa-miR-143-3p, hsa-let-7a-5p, hsa-miR-146a-5p, hsa-miR-29a-3p, hsa-miR-92a-1-5p, hsa-miR-26b-3p, hsa-miR-96-5p. Hsa-miR-7-5p and hsa-miR-126-3p were used as reference micro-RNA. Results: A statistically significant increase in the expression of hsa-miR-143-3p, hsa-miR-146a-5p and hsa-miR-92a-1-5p by 2, 2.2 and 2.9 times, respectively, was found, as well as a decrease in the expression of hsa-miR-330- 3p by 4.1 times in tumor tissue of the brain relative to normal tissue (p < 0.05). Reduced expression of micro-RNA hsa-miR-330-3p may increase the activity of the VEGFA gene, which leads to intensive vascularization of the tumor. In addition, hsa-miR-330-3p is a validated negative regulator of the E2F1 gene known as a regulator of the cell cycle and tumor suppressor proteins. The TRAF6 gene is the direct validated target of hsa-miR-146a-5p, and its overexpression is associated with the patient's chemoresistance to temozolomide. Increased hsa-miR-143-3p micro-RNA expression can reduce the activity of the EGLN1 gene that also mediates the adaptation of tumor cells to hypoxic conditions. Hsa-miR-92a-1-5p micro-RNA is a negative regulator of PTEN gene expression. Conclusions: A significant decrease in hsa-miR-330-3p expression and an increase in hsa-miR-146a-5p, hsa-miR-143-3p, and hsa-miR-92a-1-5p, which was found in gliomas, can potentially be used to develop prognostic markers and therapeutic targets for targeted therapy.
Bevacizumab-associated intracerebral hemorrhage in patients with CNS malignancy: A single-center retrospective cohort study.
Authors: Clarke Nathan , Ruff Michael 
Published: May 2019

e13509 Background: Gliomas are a known risk factor for the development of spontaneous intracranial hemorrhage (ICH) independent of therapies directed against them, with studies reporting an incidence of 1.9-3.8%. Bevacizumab (BEV) is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF) FDA approved for recurrent glioblastoma. ICH is commonly considered to be a potential adverse effect of BEV use in patients with glioma, with previous retrospective studies describing incidence of intracerebral hemorrhage ranging from 1.9-3.3%. Methods: We performed a single center (Mayo Clinic, Rochester, MN) retrospective chart review of all patients who received BEV therapy at our institution for a diagnosis of primary CNS malignancy. We used ICD-9 and ICD-10 codes to identify adult patients with primary CNS neoplasms that subsequently developed ICH. Results: We screened 10,507 adult patients with a diagnosis of primary CNS neoplasm treated at our center from 01/31/2008 to 12/31/2018 and found 644 patients treated with bevacizumab. Of these, 23 (3.6%) suffered an ICH within 12 weeks of a BEV infusion (median 9 days post infusion, 1-24 IQR). The dose of BEV in all hemorrhages was either 10 mg/kg every two weeks (n = 21) or 15 mg/kg every three weeks (n = 2). No patients treated with infusions at 7.5 mg/kg every three weeks (n = 79) or 5 mg/kg every two weeks (n = 17) suffered ICH events, however this did not meet significance (P = 0.06) when compared to patients on 10 mg/kg or above. The median ICH score was 1 (0-2 IQR). There was an increase in ECOG scores documented at clinical follow up following the hemorrhage compared to the pre-hemorrhage functional status (ECOG 3.28 versus 1.2, p = < 0.0001), with 13 patients (56%) having developed severe debility or death (ECOG 4 n = 3, ECOG 5 n = 10). Conclusions: In our single-center cohort of patients with a primary diagnosis of CNS neoplasms treated with BEV, ICH occurred in 3.6% of patients. Those who experienced an ICH in proximity to BEV infusion had significant morbidity and mortality with a clear decline in functional status. There was a signal of dose response as far as ICH incidence in our cohort with dosages 10 mg/kg per infusion or above.
The use of metformin to enhance radiation effects on M1 macrophage subtype polarization in bone marrow-derived macrophage in glioblastoma tumor environment.
Authors: Wang Fei , Zhao Nan , Lin Chi , Zhang Chi 
Published: May 2019

e13513 Background: Given the clinical relevance of tumor-associated macrophage (TAM) with its pro-tumor role and as a cell type compromising a large portion in glioblastoma (GBM), reversing the imbalance of TAM polarization in the tumor environment has emerged as a promising novel field for GBM treatment. Radiation therapy (RT) is the standard treatment for GBM patients after surgery, which has been shown to transiently induce M1 polarization of macrophage (M1Ø). Recent studies suggested that metformin could also promote M1Ø in tumor microenvironment. We thus postulate that metformin may enhance and sustain the M1-inducing effect of radiation in GBM. Methods: We first examined the polarization effect of metformin (0.1mM, 1mM and 2mM) on mouse bone marrow-derived macrophage (BMDM) cultured in GBM tumor environment, including media conditioned by GBM cells in monolayer culture or tumor spheres as well as in trans-well co-culturing system. We irradiated GBM cells with different doses (2 Gy, 8 Gy, and 20 Gy) after the treatment of Metformin at various time points; then we used conditioned media to treat BMDM either cultured alone or co-cultured with GBM cells in trans-well system for 24 or 48 hours. A separate set of experiment was conducted by first irradiating GBM cells and then co-culturing them with BMDM at 24 or 48 hours after radiation with metformin added at the start of co-culture. Percentage of various subtypes of BMDM was calculated after flow cytometry. Results: High concentrations of metformin (1mM and 2mM) significantly increased M1Ø and inhibited M2Ø in all culture conditions. Co-culture with irradiated GBM cells or treatment with medium conditioned by irradiated GBM cells could temporally induce M1Ø polarization in BMDM, with the effects being RT dose-dependent. Metformin at high concentrations further promoted M1Ø and suppressed M2Ø polarization in those conditions mimicking tumor microenvironment. This enhancing effect was sustained for at least 48 hours. Conclusions: Metformin at mili-molar concentrations significantly enhances the effects of radiation on M1Ø polarization in BMDM in vitro.
Effect of a novel long-acting interleukin-7 agonist, NT-I7, on survival in mouse models of glioma.
Authors: Campian Jian Li , Kapoor Vaishali , Griffith Kaylan , Mahadevan Anita , Collins Andrea , Thotala Sukrutha , Jash Arijita , Hu Tong , Lee Byung Ha , Choi Donghoon , Yang Se Hwan , Hallahan Dennis , Chheda Milan G , Thotala Dinesh 
Published: May 2019

e13516 Background: Glioblastoma is one of the most devastating cancers, with a 5-year overall survival < 10%. Patients are routinely treated with radiation therapy (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia which is associated with shorter survival. Interleukin-7 (IL-7) is a cytokine that preferentially supports growth and survival of CD4+ and CD8+ lymphocytes. IL-7 levels were inappropriately low in glioblastoma patients treated with chemoradiation who developed severe treatment-related lymphopenia (TRL). NT-I7 (rhIL-7-hyFc, from NeoImmuneTech, Inc.) is a long-acting cytokine consisting of recombinant human IL-7 fused to a hybrid Fc (hyFc) region of IgD and IgG4. Similarly to murine IL-7, human IL-7 also induces proliferation of murine cell lines. Consequently, NT-I7 can be studied using comparable dosing in both mice and humans. We hypothesized that administration of NT-I7 could mitigate TRL and improve survival. Methods: We developed a murine glioma model with chemoradiation induced lymphopenia. The C57BL/6 mice were injected intracranially with mouse glioma cells (GL261) expressing luciferase. Tumor-bearing mice were treated with clinically-relevant RT (2 Gy for 5 consecutive days) and concomitant TMZ (33mg/kg daily during RT) to induce lymphopenia. NT-I7 was given subcutaneously at 10 mg/kg one day after completion of RT/TMZ. Peripheral blood samples were collected on days 1, 3, 7, 14- and 28-days post-RT/TMZ. Lymphocyte counts including CD3, CD4, CD8, and CD19 were analyzed by flow cytometry. Tumor growth was monitored by bioluminescence imaging and mouse survival was monitored daily. Results: We found that 1) NT-I7 significantly improved lymphocyte count recovery post RT/TMZ; 2) mice receiving NT-I7 lived significantly longer than controls. Presently, we are elucidating the mechanisms of survival benefit found by NT-I7 administration. Conclusions: Overall, our data suggest that NT-I7 may be a feasible solution for immune reconstitution and may synergize anti-tumor effect with standard chemoradiation in glioma. Further studies are ongoing to confirm these findings in a different glioma model and to evaluate whether NT-I7 can alter tumor micro-environment.
Intracerebral immunotherapy for brain tumors.
Authors: Carillio Guido , Santaguida Luigi , Di Paola Eugenio Donato , Lavecchia Anna Maria , Vescio Virginia , Iannello Alfonso , Molè Rosa , Serrao Maria Gabriella , Mirabelli Rosanna , Mauro Giuseppe , Molica Stefano 
Published: May 2019

e13522 Background: Immunotherapy is a promising approach for the treatment of brain tumors, but available data are still inconclusive. The main drawback is represented by transport across the blood–brain barrier of high molecular weight drugs. Convection-enhanced delivery (CED) has been designed to overcome some difficulties. We wondered whether a CED strategy based on the use of novel immune checkpoint inhibitors could be effective. Methods: Frameless biopsy by fluorescein tracer and neuronavigation-assisted system, followed by an injection of nivolumab 40mg/4mL into the brain lesion, were offered to patients with: a) high grade gliomas (HGG) inoperable or progressed during or after standard treatment (i.e. surgery and radio-chemotherapy); b) HGG at first diagnosis or after disease progression treated with radical surgery (nivolumab delivered in the surgical cavity after tumor removal); c) other brain tumors or solitary metastases judged suitable for surgical procedure. PD-L1 expression was assessed in all patients, but it was not a strict criterion for accrual. Standard therapy, usually based on chemotherapy, radiotherapy or both, was sequentially administered to patients able to tolerate such an approach. End-points were safety, response rate, disease control, predictive value of PD-L1 expression. This is a non-sponsored monocentric, real life, basket trial approved by Ethical Committee (EudraCT number: 2018-001560-33). Results: Since August 2018, 17 patients with brain tumors (16 HGG and 1 heavily pretreated medulloblastoma) and 5 patients with brain metastasis (of lung and gastrointestinal cancers) were enrolled. Median age was 63 years (range 26-83). After a median follow up of three months (range 1-6), all patients are alive and in good clinical conditions. No signs of neurologic toxicity due to intracerebral nivolumab were observed. Brain MRI performed at 4 to 12 weeks after nivolumab CED revealed findings suggesting a perivascular lymphocyte infiltration. Correlation between PD-L1 expression and treatment efficacy will be evaluated over time. Conclusions: Intracerebral nivolumab appears to be a feasible and safe option for patients with HGG and brain metastases at the dose investigated in the study. Long-term follow up could contribute to well understand the role of this strategy. Clinical trial information: 2018-001560-33.
Validation and revision of the RANO Leptomeningeal Metastasis Group scorecard for response assessment.
Authors: Le Rhun Emilie , Devos Patrick , Boulanger Thomas , Smits Marion , Brandsma Dieta , Ruda Roberta , Furtner Julia , Hempel Johann-Martin , Postma Tjeerd , Roth Patrick , Snijders Tom J. , Winkler Frank , Winklhofer Sebastian , Castellano Antonella , Hattingen Elke , Capellades Jaume , Van Den Bent Martin J. , Wen Patrick Y. , Bendszus Martin , Weller Michael 
Published: May 2019

e13546 Background: The Response Assessment in Neuro-Oncology (RANO) group has proposed a scorecard to evaluate response assessed by magnetic resonance imaging (MRI) during treatment of leptomeningeal metastasis (LM). Methods: To validate the LM-RANO scorecard, cerebrospinal MRI of 22 patients with LM from solid tumors were rated by 10 neuro-oncologists and 9 neuroradiologists at baseline and during follow-up after treatment. The original scorecard and its instructions were sent to the raters. The inter-observer agreement for the evaluation of single items was assessed using the Krippendorff alpha coefficient. The agreement between numerical parameters including scores at baseline and at follow-up after treatment and total scores was determined using the intraclass coefficient of correlation (ICC). Results: Instructions of the scorecard were not clear for the majority of raters. The alpha concordance coefficients obtained for the rating of single items at baseline and at follow-up were low (Krippendorf alpha coefficient < 0.61 for all raters). The best concordances were noted for spinal nodules (0.60). The worst concordances were obtained for brain linear leptomeningeal enhancement and cranial nerve enhancement. The concordance was better among neuroradiologists than among neuro-oncologists. A poor agreement was also noted when evaluating changes between baseline and follow-up and for total scores (ICC < 0.65 for the best score for all raters). Conclusions: Assessing response of LM by MRI remains challenging. The definition of a measurable lesion and the determination of response were the most important challenges. A central review is therefore recommended for clinical trials in LM. Based on this study we propose a new scorecard that will require a similar assessment as conducted here.
Evaluation of prognostic role of inflammatory index in glioblastoma multiforme patients undergoing to concomitant radio-chemotherapy.
Authors: Fausti Valentina , Foca Flavia , Riva Nada , Bongiovanni Alberto , Gurrieri Lorena , Di Menna Giandomenico , Calpona Sebastiano , De Bonis Silvia Angela , Mercatali Laura , Spadazzi Chiara , De Vita Alessandro , Liverani Chiara , Miserocchi Giacomo , Cocchi Claudia , Dall'Agata Monia , Tosatto Luigino , Romeo Antonino , Amadori Dino , Martinelli Giovanni , Ibrahim Toni 
Published: May 2019

e13549 Background: Hematologic markers of inflammation have been shown to be prognostic in different malignancies. Also in glioblastoma multiforme (GBM) a prognostic role has been demonstrated. The purpose of this study is to evaluate retrospectively the prognostic role of these markers in patients receiving a concomitant radio-chemotherapy after surgery. Methods: Sixty-five GBM patients have been treated with concomitant radio-chemotherapy after surgery at our institute from 2008 to 2017. Information on blood counts were carried out the day before starting therapy and after the day before the last cycle of chemotherapy. Neutrophil/lymphocyte ratio (NLR) and Platelet/lymphocyte ratio (PLR) were computed as the ratio of the absolute neutrophil count and absolute platelet count by the absolute lymphocyte count respectively. Systemic Inflammatory Index (SII) was calculated as platelet count × neutrophil count/lymphocyte count. The optimal cut-point was obtained using X-tile software version 3.6.1. Results: NLR and PLR baseline value didn’t show a statistic a statistically significant prognostic role in PFS or OS. Patients with baseline SII < 480 showed both better PFS and OS (OS: 22.1 VS 11.8 mo p-values 0.0516; PFS: 10.6 VS 5.7 mo p-values 0.0351). Patients aged < 60 years showed better PFS and OS. (PFS 10.3 VS 5.5 p-values 0.0501; OS: 20.6 VS 11.2 mo p-values 0.0124). Statistical significance for SII and age was maintained for both PFS and OS in multivariate analysis as shown in Table 1. Baseline values of NLR PLR and SII have also been correlated with the best response and ORR without showing statistical significance. Conclusions: This restorative study confirms the prognostic value of inflammatory indices in patients with GBM. Correlation analysis with the methylation status of MGMT is ongoing.[Table: see text][Table: see text]