bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-03. THERAPEUTIC VALUE OF SURGICAL RESECTION OF BRAIN METASTASES: A RETROSPECTIVE ANALYSIS OF 147 CASES
Authors: Mou Yonggao , Duan Hao , He Zhenqiang , Guo Chengcheng , Jiang Xiaobing 
Published: November 2019

Abstract

OBJECTIVE
Brain metastases are the most common malignant tumors of the central nervous system. In patients with brain metastases with surgical indications, total surgical resection is the most effective treatment for prolonging patient survival and relieving neurological symptoms. In this study, the clinical data of 147 patients in a single group underwent microsurgery of brain metastases were retrospectively analyzed to investigate the therapeutic value of microsurgery in patients with brain metastases.

METHODS
From January 2000 to December 2017, patients who underwent microsurgical removal of brain metastases from the Department of Neurosurgery in Sun Yat-sen University Cancer Center were retrospectively analyzed. The clinical and pathological features and prognosis of the patients were collected and analyzed. The characteristics of brain metastases were analyzed through surgical recording and videos.

RESULTS
A total of 147 patients were enrolled, including 86 males and 61 females. The average age was 54.4 years, of which 125 were younger than 65 years old. 137 people with KPS ≥ 70. 95.9% (141 patients) had an RPA grade of I-II, of which 51 (34.7%) were RPA class I and 90 (61.2%) were RPA class II. 90.5% (133 patients) were single brain metastases. 71.5% (105 cases) of patients with metastases are located in the cerebral area. The distribution of primary lesions suggested that the lung cancer was the most, reaching 62.6%; followed by breast source (10.9%). The surgical video analysis suggest that most brain metastatic lesions have obvious supplying vessels, relatively clear boundaries with a pseudo-capsule structure. The 5-year OS of all patients reached 15% with a median survival of 42.3 months.

CONCLUSION
The brain metastases have clear blood supplying vessels and relatively clear boundaries that favors gross total resection. Surgical treatment is associated with better prognosis in patients with brain metastases.
SURG-06. FOLLOWING INTRAOPERATIVE TUMOR-FREE PRINCIPLES IS AN EFFECTIVE APPROACH TO IMPROVE SURVIVAL OF PATIENTS WITH GLIOBLASTOMA
Authors: Mou Yonggao , Fuad Al-Nahari , Duan Hao , He Zhenqiang , Zhang Guanhua , Zhang Xiangheng , Sai Ke , Ke Chao , Zhang Ji , Jiang Xiaobing , Lin Fuhua , Chen Zhenghe , Chen Yinsheng 
Published: November 2019

Abstract
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.
SURG-09. CHANGING PARADIGMS IN THE MANAGEMENT OF CEREBRAL METASTASES
Authors: Telemi Edvin , Snyder James , Lee Ian , Robin Adam 
Published: November 2019

Abstract

INTRODUCTION
Paradigms in the management of cerebral metastases (CM) are evolving, in part due to the expanded use of laser interstitial thermal therapy or LITT in lesion ablation, with treatment of CM comprising up to 34% of all LITT cases. Currently, CM are treated with LITT largely in the setting of disease progression after initial therapy with focused radiation with no standard for performing biopsy prior to LITT. In this study we aim to assess the significance of the pathology of the lesion at the time of LITT on survival.

METHODS
We conducted a retrospective review of our institution’s LITT/brain tumor database and identified patients who underwent LITT with concurrent biopsy. For deceased patients, we identified cause of death if secondary to neurologic causes defined as death either due to direct intracranial disease progression leading to rapid neurologic decline or due to progressive neurologic decline without significant extracranial disease burden.

RESULTS
We identified 16 progressive CM lesions in 15 adults treated with LITT with concurrent biopsy, predominantly with non-small cell lung cancer. The mean age at LITT was 62, median follow-up was 8.5 months and thirteen of fifteen patients had previous focused radiation therapy. Eleven of sixteen lesions demonstrated radiation necrosis(RN) without tumor and 5 with tumor progression(TP). The mean survival in patients with RN was 548 days compared with 285 days in patients with TP (p=0.15). Of the 9 deceased, 2 of 5 patients with RN and 3 of 4 patients with TP died of neurologic causes.

CONCLUSIONS
Although statistically not significant due to the small sample size, this preliminary analysis suggests that clinically significant differences in survival and cause of death may exist between patients with RN and TP. Further evaluation with implications for treatment, prognosis and the expectant management of the patient with CM is warranted.
SURG-11. PATTERNS OF RECURRENCES OF OLFACTORY NEUROBLASTOMA AFTER SURGICAL RESECTION
Authors: Hee Chang Jong , Hyung Moon Ju , Hyun Kim Eui , Sung Lee Kyu , Suh Chang-Ok 
Published: November 2019

Abstract

INTRODUCTION
Patterns of failure in patients with olfactory neuroblastoma (ONB) according to two surgical approaches, craniofacial resection (CFR) and endoscopic surgery (ENDO), have yet to be analyzed.

METHODS
We retrospectively reviewed 30 patients with surgically treated ONB between January 1995 and October 2018. Sixteen (53.3%) patients underwent CFR (9 CFR alone, 7 ENDO-assisted CFR) and 14 (46.7%) underwent ENDO. Twenty-one (70.0%) patients underwent post-operative radiotherapy (RT).

RESULTS
At a median follow-up of 53.8 months (range 10.4–195.3), the 5-year progression-free survival (PFS) and 10-year overall survival were 37.3% and 57.5%, respectively. Patients with adjuvant RT had a 5-year PFS of 46.7%, whereas those treated with surgery alone had a 5-year PFS of 19.4% (p = 0.01). Locoregional failure (LRF) occurred in ten patients (median 59.6 months after initial diagnosis; range 12.7–59.7). Neck node metastasis occurred in 23.3% (7 of 30). Five patients with ENDO showed LRF and underwent proper subsequent treatments with either surgery or adjuvant RT. Approximately 31.3% patients (five patients) in the CFR group experienced distant metastasis in the intracranial dura region (median 116.4 months after initial diagnosis; range 2.6–142.4). Three of four patients who developed LRF after CFR developed dura-based metastasis.

CONCLUSIONS
Both dura-based and neck node metastasis in the delayed phase were distinct patterns of failure in ONB. Patterns of recurrence differed based on surgical approach; dura-based metastases were common after CFR. LRF was the distinct failure pattern in ENDO, but could be successfully salvaged. Treatment outcome was improved considerably with RT following surgical resection.
SURG-16. SUPRATOTAL VERSUS GROSS TOTAL RESECTION OF GLIOBLASTOMA: A SYSTEMATIC REVIEW
Authors: Jackson Christina , Choi John , Price Carrie , Bettegowda Chetan , Lim Michael , Gallia Gary , Weingart Jon , Brem Henry , Mukherjee Debraj 
Published: November 2019

Abstract

INTRODUCTION
Due to the infiltrative nature of glioblastoma(GBM) outside of the contrast enhancing region in the peritumoral zone, there is increasing movement to perform supratotal resections (SpTR) by extending the edge of resection beyond the contrast enhancing portion of the tumor. However, there is currently no consensus on the potential survival benefit of SpTR in GBM as compared to gross total resection (GTR).

METHODS
Therefore, we performed a systematic review using PRISMA guidelines and performed a comprehensive literature search on Pubmed, EMBASE, The Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov, from inception to August 16, 2018, to identify articles comparing overall survival (OS) after SpTR versus GTR. Furthermore, we assessed study quality using the Oxford Centre for Evidence-Based Medicine guidelines.

RESULTS
We identified 8902 unique citations, of which 11 articles and 2 abstracts met study inclusion criteria. 925 patients underwent SpTR out of a total of 2137 patients. 9 of the 13 studies demonstrated improved survival with SpTR compared to GTR (median improvement in OS of 10.5 months), with no significant difference in post-operative complication rate. Conversely, one abstract found worsened outcomes with SpTR compared to GTR (median decrease in OS of 4 months). However, overall study quality was poor, with 12 of the 13 studies of level IV evidence and one study of level IIIb evidence. We were unable to perform a meta-analysis due to significant clinical and methodological heterogeneity amongst the studies (e.g. differences in adjuvant therapy and lack of standardization of definition of supratotal resection).

CONCLUSIONS
Our systematic review indicates that SpTR may be associated with improved OS compared to GTR for GBM. However, this is limited by poor study quality and significant clinical and methodological heterogeneity amongst the studies. There is need for prospective clinical trials to further establish standardized guidelines for SpTR in GBM.
ACTR-61. A RANDOMIZED PHASE 2 TRIAL OF CEDIRANIB IN COMBINATION WITH OLAPARIB VERSUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Arrillaga-Romany Isabel , Sahebjam Solmaz , Picconi David , Campian Jian , Giglio Pierre , Drappatz Jan , Aiken Robert , Villano John , Lee Eudocia , Welch Mary , Ellingson Benjamin , Ney Douglas , Becker Kevin , Muzikansky Alona , Das Biswajit , Swisher Elizabeth , Nixon Andrew , Karlovich Chris , Mickey Williams P , Percy Ivy S , Batchelor Tracy , Gerstner Elizabeth 
Published: November 2019

Abstract

BACKGROUND
Like most proliferating tumors, GBM relies heavily on accurate DNA repair for maintenance of genome stability. Dysfunction in repair of both single and double strand DNA breaks by PARP inhibition and impairment of homologous recombination, respectively, would be synthetically lethal. In this study we combined the PARP inhibitor olaparib with cediranib, a pan VEGF receptor inhibitor. Cediranib may mediate disruption in the homologous recombination pathway through its antiangiogenic properties.

METHODS
Through the Experimental Therapeutics Clinical Trials Network, we performed an open-label randomized phase II study of bevacizumab (BEV)- naive adult patients with first or second recurrence of glioblastoma after radiation and temozolomide. Patients were randomized 1:1 to receive either olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily or BEV 10 mg/kg IV every 2 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included safety and overall survival. Exploratory objectives included blood, tissue and imaging-based biomarkers of response to treatment.

RESULTS
Seventy patients were enrolled. Median age was 60.5 years (range: 19–79), 39% females, median KPS was 90 (range: 60–100). Baseline characteristics were well balanced. With a data cut-off of 5/2/2019, PFS6 was 14% [95% CI 4–30%] in the cediranib/olaparib arm vs 30.9% [95% CI 12.7–51.2%] in the BEV arm. Median OS was 247 days in the cediranib/olaparib arm vs 201 days in the BEV arm, HR 0.816, 95% CI (0.431, 1.546). Related grade 3, 4 or 5 toxicity was experienced in 29% vs 12% of patients for the cediranib/olaparib vs BEV arm.

CONCLUSION
Treatment with cediranib/olaparib failed to increase PFS and OS in patients with recurrent GBM. Blood, tissue and imaging correlates will be presented to help understand why this treatment combination was unsuccessful.
TMIC-03. UPREGULATION OF THE NLRC4 INFLAMMASOME CONTRIBUTES TO POOR PROGNOSIS IN GLIOMA PATIENTS
Authors: Lim Jaejoon , Park Youngjoon , Kim Minjun , Ahn Juwon , Kwack KyuBum , Cho Kyunggi 
Published: November 2019

Abstract
Inflammation in tumor microenvironments is implicated in the pathogenesis of tumor development. In particular, inflammasomes, which modulate innate immune functions, are linked to tumor growth and anticancer responses. However, the role of the NLRC4 inflammasome in gliomas remains unclear. Here, we investigated whether the upregulation of the NLRC4 inflammasome is associated with the clinical prognosis of gliomas. We analyzed the protein expression and localization of NLRC4 in glioma tissues from 11 patients by immunohistochemistry. We examined the interaction between the expression of NLRC4 and clinical prognosis via a Kaplan-Meier survival analysis. The level of NLRC4 protein was increased in brain tissues, specifically, in astrocytes, from glioma patients. NLRC4 expression was associated with a poor prognosis in glioma patients, and the upregulation of NLRC4 in astrocytomas was associated with poor survival. Furthermore, hierarchical clustering of data from the Cancer Genome Atlas dataset showed that NLRC4 was highly expressed in gliomas relative to that in a normal healthy group. Our results suggest that the upregulation of the NLRC4 inflammasome contributes to a poor prognosis for gliomas and presents a potential therapeutic target and diagnostic marker.
TMIC-19. H+ EXTRUSION PROTEIN NA/H EXCHANGER IN METABOLIC POLARIZATION OF GLIOMA-ASSOCIATED MICROGLIA/MACROPHAGES AND TUMOR IMMUNITY
Authors: Nabiul Hasan Md , Guan Xiudong , Ahuja Avani , Castro Maria , Kohanbash Gary , Sun Dandan 
Published: November 2019

Abstract
Immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) attributes to poor efficacy of chemotherapy and/or immunotherapy. We recently reported that SLC9A1 gene expression (Na/H exchanger 1, NHE1) in GBM tumor correlates with increased macrophage tumor infiltration and worsened patient survival. Temozolomide (TMZ) monotherapy, the standard care therapy for GBM, stimulates NHE1 protein expression in mouse syngeneic glioma models. We speculate that in response to TMZ therapy, NHE1 promotes immunosuppressive TME development via deregulation of glucose metabolism and anti-tumor function of immune cells. CD57BL/6 mice bearing GL26 glioma tumor were treated with NHE1 inhibitor HOE-642 (H, 0.3 mg/kg/day), TMZ (T, 2.5 mg/kg/day), and/or anti-PD-1 (10 mg/kg/day) monotherapy or in combination. The T+H+anti-PD-1 combination therapy increased glucose uptake (2-NBDG) and mitochondrial mass (mitotracker fluorescent intensity) of tumor infiltrating CD8+ T-cells by ~2-fold compared to the monotherapies. This suggests that NHE1 protein is involved in metabolic transformation of T-cells and affects their responses to chemo and/or immunotherapy. Furthermore, we detected that specific deletion of Nhe1 in Cx3Cr1CreErT2r+/-;Nhe1f/f mice (Nhe1 KO) alters activation of glioma-associated microglia/macrophages (GAM) and T-cells in response to TMZ therapy. TMZ monotherapy stimulated macrophage (CD11b+CD45hi) infiltration by ~2.5-fold in Cx3Cr1CreErT2-/-;Nhe1f/f (Nhe1 Con) mice bearing SB28-GFP glioma tumor with abundant proinflammatory CD16/32+ GAMs. In contrast, TMZ treated Nhe1 KO mice displayed ~3-fold reduction in tumor infiltrating GAMs with nearly abolished Ym-1+ tolerogenic macrophages, ~3-fold reduction of tumor-promoting CD4+CD25+FoxP3+ regulatory T-cells (Treg) and increased CD8+/Treg ratio by ~2-fold than the Nhe1 Con mice. Importantly, TMZ followed by anti-PD-1 therapy prolonged survival of Nhe1 KO mice but not Nhe1 Con mice. Taken together, our study suggests that NHE1 is involved in transformation of GAMs and PD-1 check point activation of T-cells. Blocking NHE1 function in combination with TMZ and anti-PD-1 may restore glucose metabolism of immune cells necessary for their anti-tumor function.
TMIC-22. IDENTIFICATION OF CANCER-ASSOCIATED FIBROBLASTS IN GLIOBLASTOMA and Defining Their Protumoral Effects
Authors: Rick Jonathan , Nguyen Alan , Chandra Ankush , Wadhwa Harsh , Shah Sumedh , Wang Lin , Lau Darryl , Safaee Michael , Ordaz Angel , Yagnik Garima , Diaz Aaron , Aghi Manish 
Published: November 2019

Abstract
While cancer-associated fibroblasts (CAFs) and their pro-tumoral effects have been demonstrated in systemic cancers, CAFs had been presumed absent in glioblastoma given the lack of normal fibroblasts in the healthy brain. Here, we show that 5–26% (mean=12%) of cells in human glioblastomas express CAF markers α-SMA or PDGFR-β, morphologically resemble fibroblasts, and transcriptomically resemble by RNA-seq CAFs from other cancers. Glioblastoma CAFs were chemotactically attracted to glioblastoma-initiating stem cells (P=0.02). While glioblastoma CAFs did not affect differentiated glioblastoma cell proliferation (P=0.4), CAFs increased glioblastoma stem cell proliferation (P=0.002) and expression of glioblastoma stem cell-associated genes (P< 0.001). To identify mediators of CAF/glioblastoma stem cell interactions, we created a resource of inferred crosstalk by mapping the expression of receptors to that of their cognate ligands/agonists, using our RNA-seq results from glioblastoma CAFs and stem cells, revealing PDGF-β/PDGFR and osteopontin/CD44 to mediate stem cell recruitment of CAFs and CAF enrichment of stem cells, as confirmed by blocking antibodies (P=0.02–0.03). CAFs also render the glioblastoma microenvironment more pro-tumoral by promoting M2 polarization of tumor-associated macrophages (P=0.01), an effect we found to arise from unique CAF production of the EDA splice variant of fibronectin binding toll-like receptor 4 (TLR4), a known EDA receptor expressed by macrophages (P=0.02). In patient glioblastomas, CAFs were enriched 3-fold in the subventricular zone (SVZ) (P=0.04) which houses the neural stem cells that generate glioblastoma stem cells. SVZs from epilepsy cases or autopsies of glioblastoma-containing brains without ventricular involvement lacked CAFs. Depleting CAFs in xenografts derived from neurosphere-containing glioblastoma stem cells slowed their growth in vivo (P< 0.001). These findings are among the first to identify and profile glioblastoma CAFs. CAF recruitment by glioblastoma stem cells and creation of a pro-tumoral microenvironment in the perivascular niche housing glioblastoma stem cells, particularly in the SVZ, makes them an intriguing therapeutic target.
ACTR-64. PHASE 2 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND CLINICAL ACTIVITY OF PI3K/mTOR INHIBITOR GDC-0084 IN GBM PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE (MGMT) PROMOTER STATUS
Authors: Wen Patrick , DeGroot John , Battiste James , Goldlust Samuel , Garner James , Simpson Jeremy , Kijlstra Jelle , Olivero Alan , Cloughesy Timothy 
Published: November 2019

Abstract

BACKGROUND
GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR). GDC-0084 crosses the blood-brain barrier and achieves a brain / plasma ratio of approximately 1.0. GDC-0084 was given as once daily dosing in a phase 1 study (Wen et al, J Clin Oncol 34, 2016(15) suppl.2012) in 47 patients with recurrent high-grade gliomas. The adverse events were generally consistent with the established PI3K/mTOR inhibitor class-effects. The MTD identified was 45mg once daily.

METHODS
The current study is conducted in the newly diagnosed GBM patient with unmethylated MGMT promotor status upon completion of standard adjuvant XRT/TMZ. It has a 2-part design: an open-label, dose-escalation phase to assess the safety, tolerability, MTD (Part 1, followed by an expansion cohort (Part 2) commencing once MTD is established. Dose-escalation started at 60mg, and progressed in 15mg increments, per standard 3 + 3 rules. Part 2 recruits 20 patients, who are randomized to take GDC-0084 at the identified MTD, in fed and fasted states.

RESULTS
Part 1 of the study is complete. There were no DLTs among 3 pts treated at the 60mg. Among 6 pts treated at 75mg, DLTs were identified as hyperglycaemia (symptomatic) and oral mucositis. Adverse effects seen were generally modest, manageable and consistent with the PI3K-class. PK parameters are in line with phase 1 data. Part 2 recruitment is ongoing.

CONCLUSION
GDC-0084 displays a safety profile consistent with previous data in recurrent high-grade glioma but appears better tolerated in the newly diagnosed GBM setting. An MTD of 60mg is identified.
TMIC-32. PARALLEL SINGLE CELL NUCLEOSOME OCCUPANCY AND RNA SEQUENCING ON RECURRENT GBM
Authors: Shireman Jack , Gauchat Eric , Eckart Heather , Park Cheol , Basu Anindita , Pott Sebastian , Ahmed Atique 
Published: November 2019

Abstract
Nearly all patients diagnosed with Glioblastoma (GBM) will experience a fatal recurrence of the tumor. Thought to be in part driven by immense tumor heterogeneity it is important to explore the small subpopulations of tumor cells with in depth single cell sequencing pre and post therapy in order to understand recurrence. To this end, we created an experimental in vivo pipeline that allows us profile not only gene expression changes during therapy, but also epigenetic shifts due to methylation across the genome at the single cell level from a single tumor. Single Cell NomE-Seq libraries were created and correctly identified characteristic CTCF binding regions within DNase1 hypersensitivity regions when compared back to representative encode data sets. Primary tumors analyzed by single cell RNA sequencing showed enrichment for on average 5 significant principle components (St. Dev >2 verified by Elbow Plot). Comparatively, recurrent temozolomide (TMZ) exposed tumors averaged 10 significant principle components (St. Dev >2 verified by Elbow Plot) suggesting TMZ therapy causes tumors to diversify their gene expression profiles. For direct comparison samples were merged into a continuous data set and dimensional analysis with TSNE reduction (15 dimensions used) identified 6 unique clusters, with one cluster being over-represented by cells from recurrent, TMZ exposed mice. Gene Ontology analysis on expression values contained within in this cluster demonstrated significant enrichment for ribosome biogenesis/ribosomal structure, (p=2.87e-17) and mRNA catabolic processes (p=2.47e-30). Further, comparison to a similar data set gathered using cells in vitro culture conditions demonstrates superior intraturmoral heterogeneity from cells isolated freshly from the brains of mice as opposed to tissue culture, indicating the effectiveness of our model for assaying heterogeneity. Ultimately, these data illuminate possible new mechanisms for TMZ induced ribosomal modifications underlying intraturmoral heterogeneity in GBM and provide an expandable technique for further experimentation.