bluuebunny/crossref_metadata_2025_split huggingface dataset:
RTID-09. A RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF ENZASTAURIN ADDED TO TEMOZOLOMIDE DURING AND FOLLOWING RADIATION THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS WHO POSSESS THE NOVEL BIOMARKER, DGM1
Authors: Butowski Nicholas , Mao Ying , Wu Wilson , Luo Wen , Ge Lan , Pertschuk Daniel , Dewitt Theresa , Han Isabel , Heineman Thomas 
Published: December 2020

Abstract

BACKGROUND
Limited progress has been made in improving therapeutic outcomes for glioblastoma (GBM) patients. Enzastaurin (enza) is an oral PKC-β inhibitor that suppresses signaling through the PKC and PI3K/AKT pathways. Although enza did not significantly improve survival in a prior Phase 1/2 study, we have identified a novel genomic biomarker, DGM1, that may predict a response to enza in GBM.

PRIMARY OBJECTIVE
To assess whether enza added to temozolomide and radiation therapy (RT) improves overall survival (OS) in newly diagnosed GBM patients who possess the DGM1 biomarker.

POPULATION
Adults with newly diagnosed GBM regardless of DGM1 status who have undergone surgical resection and are candidates for chemoradiation. Approximately 318 patients will be enrolled. DGM1 status will be determined prior to analysis.

DESIGN
This is a randomized, double-blinded, placebo-controlled study. Patients will be stratified by MGMT and IDH1 status and by geographic region. Treatment will be divided into 3 phases. In the Concurrent Phase (6 weeks), patients will receive RT plus temozolomide and either enzastaurin or placebo. Patients will then enter the Single-Agent Phase and receive either enza or placebo (21-35 days). Then, patients will enter the Adjuvant Phase and receive temozolomide with either enza or placebo (6-12 cycles) followed by enza or placebo alone (to 24 cycles total).

ANALYSIS
The primary efficacy endpoint of OS will be analyzed using stratified log-rank test for all DGM1-positive randomized patients. The study has approximately 90% power to detect a HR of 0.63 assuming 196 OS events based on a 2.5% one-sided false positive error rate. Statistical significance would be achieved with an estimated observed HR &lt; 0.76. Safety evaluation will include all patients receiving at least one dose of enza or placebo. If OS in DGM1-positive patients is statistically significant, OS in the overall population will be assessed.
STEM-01. TARGETING BRAIN METASTASIS-INITIATING CELLS: A PREVENTATIVE APPROACH
Authors: Kieliszek Agata , Venugopal Chitra , Bassey-Archibong Blessing , Lam Fred , Singh Sheila , Aghaei Nikoo 
Published: December 2020

Abstract

BACKGROUND
The incidence of brain metastases (BM) is tenfold higher than primary brain tumors. BM commonly originate from primary lung, breast, and melanoma tumors with a 90% mortality rate within one year of diagnosis. Current standard of care for BM includes surgical resection with concurrent chemoradiation, but does not extend median survival past 16 months, posing a large unmet need to identify novel therapies against BM.

METHODS
From a large in-house biobank of patient-derived BM cell lines, the Singh Lab has generated murine orthotopic patient-derived xenograft (PDX) models of lung, breast, and melanoma BM that recapitulate the stages of BM progression as seen in humans. Using these three PDX models, we identified a population of “pre-metastatic” brain metastasis-initiating cells (BMICs) that are newly arrived in the brain but have yet to form detectable tumors. Pre-metastatic BMICs are not detectable in human patients but are important therapeutic targets with the potential to prevent BM in at-risk patients.

RESULTS
RNA sequencing of pre-metastatic BMICs from all three PDX primary tumor models with subsequent Connectivity Map analysis identified novel compounds that have the potential of killing all three types of BMICs. In particular, we identified two compounds that have selective killing of BMICs in vitro from all three primary tumor cohorts while sparing non-cancerous cells. We further characterized their ability to inhibit the self-renewal and proliferative properties of BMICs. Ongoing in vivo work will investigate the compounds’ preclinical utilities in preventing BM.

CONCLUSION
Identification of novel small molecules that target BMICs could prevent the formation of BM completely and dramatically improve the prognosis of at-risk cancer patients.
STEM-11. INTERROGATING INTRATUMORAL TRANSCRIPTOMIC HETEROGENEITY AND PLASTICITY AS RESISTANCE MECHANISMS IN GLIOBLASTOMA
Authors: A Yabo Yahaya , Arns Thais , Oudin Anais , Grzyb Kamil , Poovathingal Suresh , Michelucci Alessandro , Skupin Alexander , Niclou Simone P , Golebiewska Anna 
Published: December 2020

Abstract
Intratumoral heterogeneity is one of the major barriers in the treatment of many tumor types. In glioblastoma (GBM) – the most aggressive brain tumor - survival of patients following standard therapy has stagnated to an average of 14 months, largely due to the inherent heterogeneity and phenotypic plasticity. Patient-derived orthotopic xenografts (PDOX) are important tools for preclinical cancer studies. We have shown that they recapitulate histological and molecular features of patient tumors, thus producing more clinically relevant study outcomes when compared to other preclinical models. To understand the impact of treatment on intratumoral heterogeneity and interactions of tumor cells with the microenvironment, we applied single-cell RNA-seq in GBM PDOX models generated from naive and treatment exposed patient tumors. Here we show that PDOX models recapitulate all the major cell types and transcriptional programs reported in GBM patient samples. We demonstrate that GBM tumor cells occur in distinct phenotypic states dictated by microenvironmental cues and treatment-induced pressure. Non-neoplastic cells present within xenografts undergo transcriptomic adaptation similar to the GBM microenvironment in patients. Analysis of treated PDOXs and longitudinal PDOX models derived from patients prior and after treatment allows us to investigate short-term and stable long-term transcriptomic adaptations. We aim to reveal key molecular regulators enhancing tumor cell plasticity and resistance, that could be targeted in combinatory treatments. Our GBM PDOX models provide a platform for high-quality pre-clinical research and an improved clinical relevance in the development and testing of novel therapeutics.
STEM-16. IGF1/N-CADHERIN/b-CATENIN/CLUSTERIN SIGNALING AXIS MEDIATES ADAPTIVE RADIORESISTANCE IN GLIOBLASTOMA
Authors: Osuka Satoru , Zhu Dan , Zhang Zhaobin , Sampetrean Oltea , Olson Jeffrey , Saya Hideyuki , Van Meir Erwin 
Published: December 2020

Abstract
Glioblastoma (GBM) is composed of heterogeneous tumor cell populations including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately less radiation sensitive than the tumor bulk and are believed to drive GBM formation and recurrence after repeated irradiation. However, it is unclear how GSCs adapt to escape the toxicity of repeated irradiation used in clinical practice. To identify important mediators of adaptive radioresistance, we generated radioresistant human and mouse GSCs by exposing them to repeat cycles of irradiation. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by increased cell-cell adhesion, slower proliferation, an elevation of stemness properties and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs lost their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of b-catenin at the cell surface, which suppressed Wnt/ b-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. Restoration of wild type N-cadherin, but not mutant N-cad lacking b-catenin binding region, led to induce radioresistance in N-cadherin knockout GSCs, indicating the importance of the binding between N-cadherin and b-catenin. We also demonstrated that N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin (PPP), a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation. Moreover, the elevation of N-cad and Clusterin are related to prognosis of GBM in the TCGA dataset. In conclusion, our data indicate that IGF1R inhibitor can block the N-cadherin-mediated resistance pathway. Our study deepens our understanding of adaptive radioresistance during repeated irradiation in GBM, and validates the IGF1/N-cadherin/b-catenin/Clusterin signaling axis as a novel target for radio-sensitization, which has direct therapeutic applicability.
STEM-26. SMALL MOLECULE DRUG CBL0137 INHIBITS THE FACT COMPLEX AND SENSITIZES GLIOBLASTOMA CANCER STEM CELLS TO RADIOTHERAPY
Authors: Tallman Miranda , Zalenski Abigail , Deighen Amanda , Schrock Morgan , Mortach Sherry , Grubb Treg , Kastury Preetham , Huntoon Kristin , Summers Matthew , Venere Monica 
Published: December 2020

Abstract
Glioblastoma (GBM) is a malignant brain tumor with nearly universal recurrence. GBM cancer stem cells (CSCs), a subpopulation of radio- and chemo-resistant cancer cells capable of self-renewal, contribute to the high rate of recurrence. The anti-cancer agent, CBL0137, inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy using both in vitro and in vivo models. Treatment of CBL0137 combined with radiotherapy led to increased DNA damage in GBM patient specimens and failure to resolve the damage led to decreased cell viability. Using clonogenic assays, we confirmed that CBL0137 radiosensitized the CSCs. To validate that combination therapy impacted CSCs, we used an in vivo subcutaneous model and showed a decrease in the frequency of cancer stem cells present in tumors as well as decreased tumor volume. Using an orthotopic model of GBM, we confirmed that treatment with CBL0137 followed by radiotherapy led to significantly increased survival compared to either treatment alone. Radiotherapy remains a critical component of patient care for GBM, even though there exists a resistant subpopulation. Radio-sensitizing agents, including CBL0137, pose an exciting treatment paradigm to increase the efficacy of irradiation, especially by inclusively targeting CSCs.
SURG-06. MANAGEMENT OF HYDROCEPHALUS IN ADULT PATIENTS WITH BRAIN METASTASES
Authors: Vaynerman A , Coombs L , Nickols H , LaRocca R , Sinicrope K , Ishihara D , Spalding A , Sun D 
Published: December 2020

Abstract

BACKGROUND
Traditionally patients presenting with hydrocephalus in the setting of brain metastases were associated with poor outcomes. However, in the area of improved systemic therapies, the prognosis of brain metastases has improved, warranting investigation into the management of concomitant hydrocephalus.

METHODS
We conducted a retrospective review of 12 consecutive patients with brain metastases presenting with hydrocephalus treated with either endoscopic third ventriculostomy (ETV) or ventriculoperitoneal shunt (VPS) from June 2013 to December 2018. We then compared our outcomes to 77 historical controls from the literature to test the hypothesis that management of hydrocephalus in patients who respond to systemic therapy is associated with improved outcomes.

RESULTS
The medial overall survival in our cohort was 182 days compared with 91 days in the reported previous studies, with an odds ratio of 0.5 (95% CI 0.24-1.04). In the 5 patients who underwent ETV, the median survival was 182 days versus 77 days reported in the literature, an odds ratio of 0.42 (95% CI 1.28-1.40). Patients with one brain metastasis did not reach median survival with 4 of 5 patients alive at last follow up, while only 3 of 7 patients with at least two metastases were alive at follow up with a median survival of 182 days. Patients who had immunotherapy were associated with improved survival, while leptomeningeal carcinomatosis still was associated with a negative outcome.

CONCLUSIONS
Patients with brain metastases and hydrocephalus who underwent neurosurgical CSF diversion had improved survival compared with historical controls, particularly in patients with one metastasis or who received immunotherapy. This study supports initial interdisciplinary evaluation of patients with brain metastases by medical and radiation oncology together with neurosurgery to facilitate immediate systemic therapy after relief of hydrocephalus.
SURG-16. PREDICTORS OF LOCAL CONTROL FOLLOWING LASER INTERSTITIAL THERMAL THERAPY FOR GLIAL TUMORS
Authors: Haider Sameah , Pawloski Jacob , Fadel Hassan , Zakaria Hesham , Chaudhry Farhan , Bartlett Seamus , Bazydlo Michael , Kalkanis Steven , Lee Ian 
Published: December 2020

Abstract

INTRODUCTION
Laser Interstitial thermal therapy (LITT) is a minimal-access procedure for intracranial tumors that are either refractory to standard treatment paradigms or difficult to access via conventional open surgery.

OBJECTIVE
To evaluate predictors of local disease control following LITT in patients with primary and secondary brain tumors.

METHODS
Single-center retrospective cohort study of all consecutive LITT ablations between 2014 and 2019. Demographic and procedural characteristics analyzed with respect to local disease control at 6 months. Chi-square tests for categorical variables, T-tests/Wilcoxon Rank-Sum tests for continuous variables for parametric and non-parametric data, respectively. Poisson regression models were used to approximate relative risk (RR) with 95% confidence intervals.

RESULTS
A total of 76 patients underwent LITT with a median follow up of 12.3 months; pathology at time of ablation was glioblastoma multiforme (GBM, 36%), WHO grade III primary CNS (24%), low grade CNS (20%), and metastatic lesions (19%) with respective local control rates of 26%, 20%, 29%, and 26%. Pathology of GBM (RR 0.46, 0.21-1.02, p=0.055) and a 5-year increase in age at the time of ablation (RR 0.91, 0.83-0.99, p=0.028) were associated with a lower likelihood of local control at 6 months. Preoperative Karnofsky performance status (KPS) of 100 (RR 2.04, 1.13-3.69, p=0.019) was associated with a higher likelihood of local control. Extent of ablation (EOA) demonstrated a direct relationship with local control; when EOA=100% local control was 59%, with this rate dropping down to 21% when EOA=90%. Tumor location, lesion volume, gender, BMI, ethnicity, or whether there existed multiple foci of disease at the time of ablation had no strong association with local control.

CONCLUSION
Our series demonstrates that preoperative performance status and age were strong predictors of local disease control following LITT. Incomplete ablation and histology of high-grade glioma portended a higher risk of local recurrence.
SURG-20. USE OF NICO MYRIAD NOVUS DEVICE WITH LIGHT SOURCE AND REAL-TIME STEREOTACTIC NAVIGATION TO OPTIMIZE SURGICAL RESECTION OF DEEP-SEATED TUMORS
Authors: Hwang Lee , Mohammadi Alireza 
Published: December 2020

Abstract
Maximal and safe surgical resection remains a critical component of the standard of care for patients with brain tumors. Stereotactic navigation tools are often incorporated into the surgical planning and implementation. The NICO Myriad NOVUS device couples a light source with the resecting tip to allow enhanced visualization of the surgical cavity and surrounding anatomical structures. At the Cleveland Clinic, we were the first group in the U.S. to start utilizing this augmented technology to maximize the resection of particularly deep-seated brain tumors, using the xenon light and real-time stereotactic navigation of the tool tip with the BrainLAB cranial setting. The navigated tip allows us to reach the deep corners of tumors with or without a tubular retracting device by sparing large corticotomies. Furthermore, the light source within the handheld device is easier to handle and manipulate than a large microscope to illuminate the surgical cavity. In addition, this new tool allows for automated tumor and peri-tumoral tissue harvesting, annotating each sample by location intraoperatively, as well as biological preservation of the harvested tissue for post-surgical molecular analysis. We describe the techniques and advantages of using this novel technology in patients while following and preliminarily reporting their surgical outcomes. With the emergence of novel technological advances, we must adapt as neurosurgeons and develop innovative methods to optimize the surgical resection of brain tumors.
SURG-24. REPEAT CONVECTION-ENHANCED DELIVERY FOR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Bander Evan , Ramos Alexander , Wembacher-Schroeder Eva , Ivasyk Iryna , Thomson Rowena , Morgenstern Peter , Souweidane Mark 
Published: December 2020

Abstract

INTRODUCTION
While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single dose drug infusions, agents for oncologic therapy require repeated or chronic infusions to maintain therapeutic concentrations. Repeat/chronic CED infusions have rarely been described for oncologic purposes. We report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma (DIPG).

METHODS
Patients were enrolled in a phase I single center clinical trial using 124I-8H9 monoclonal antibody (124I-Omburtamab, Y-mAbs Therapeutics) administered by CED (NCT01502917). Retrospective chart review was used to assess demographic data, CED infusion data, and post-operative neurologic and surgical outcomes. MRI scans were analyzed using iPlan® Flow software (Brainlab AG, Munich, Germany) for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the Clearpoint imaging software (Clearpoint®, MRI Interventions Inc. Irvine, USA).

RESULTS
Seven patients underwent two or more sequential CED infusions. No patients experienced deficits Clinical Terminology Criteria for Adverse Events (CTCAE) grade 3 or greater. One patient had persistent grade 2 cranial nerve deficit after a second infusion. No patients experienced hemorrhage or stroke post-operatively. There was a statistically significant decrease in radial error (p= 0.005) and absolute tip error (p=0.008) for infusion two compared to the initial infusion. Sequential infusions did not result in significantly different distribution capacity between the first and second infusion (Vd:Vi ratio: 2.66 ± 0.35 versus 2.42 ± 0.75; p=0.45).

CONCLUSIONS
This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural work flow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncologic purposes.
SURG-30. SURGICAL RESECTION OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: IMPACT OF PATIENT SELECTION ON OVERALL SURVIVAL
Authors: Schellekes Nadav , Barbotti Arianna , Abramov Yael , Sitt Razi , Meco Francesco Di , Ram Zvi , Grossman Rachel 
Published: December 2020

Abstract

OBJECTIVE
A possible prolonged survival after surgical resection for primary central nervous system lymphoma (PCNSL) lesions in selected patients has been suggested, but selection criteria for surgery, especially for solitary lesions, have never been established.

METHODS
We retrospectively searched our patient database for records of adult patients (≥18 years) who were diagnosed and treated for a solitary lesion of PCNSL between 2005 and 2019. Patients were divided into groups according to whether they underwent surgical resection or needle biopsy. Statistical analyses were performed in an attempt to identify variables affecting outcome and possible survival advantage and to characterize subgroups of patients who would benefit from resection of their tumor compared to undergoing biopsy only.

RESULTS
113 patients with a solitary lesion of PCNSL were identified, 36 underwent surgical resection and 77 a diagnostic stereotaxic biopsy only. Pre-operative risk factors were found to include age &gt; 70 years ([HR] 9.61, 95% [CI] 2.42-38.11, p=0.001) and deep seated lesions (adjusted HR 3.33, 95% CI 1.13-9.84, p=0.030). Having a postoperative Karnofsky Performance Scale (KPS) under 80 (adjusted HR 3.21, 95% CI 1.05-9.77, p=0.040) or surgical-site infections (adjusted HR 4.27, 95% CI 1.18-15.47, p=0.027) were significant postoperative risk factors. In a subgroup analysis, patients with a superficial tumor who underwent surgical resection had significantly longer survival times compared with those who underwent needle biopsy (median survival 34.3 months versus 8.9 months, p=0.014). Patients under 70 years who had a superficial tumor and underwent surgical resection had significantly prolonged survival, with a median survival of 35.0 months versus 8.9 months in patients from the same group who underwent needle biopsy (p=0.007).

CONCLUSION
Specific subgroups of patients with a solitary PCNSL lesion might gain a survival benefit from surgical resection compared to undergoing only a diagnostic biopsy.
SURG-31. SURGICAL OUTCOME ANALYSES ON 244 CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA
Authors: Takami Hirokazu , Burns Terry C , Parney Ian 
Published: December 2020

Abstract

BACKGROUND
Surgical resection of the central nervous system hemangioblastoma is often challenging, with vascular-rich nature and surrounding critical structures. von Hippel-Lindau (VHL) disease cases make the management more difficult with repeated surgeries required for multiple lesions. Here we investigated the surgical outcome of CNS HGBs on a large cohort to clarify the clinical and radiological parameters pertaining to the surgical success.

METHODS
Retrospective analysis of consecutive, neurosurgically managed CNS HGB at Mayo Clinic, 1988-2018.

RESULTS
Total 244 surgeries were performed for 172 patients. Gross total resection (GTR) was achieved in 90.0%, which was lower in cases brainstem lesions (78.3%) and was associated with the tumor, especially solid-portion volume (p=0.017). Intraoperative blood loss correlated with the size of solid portions, and the transfusion was performed in 7.5%. Postoperative complication was observed in 52.2%, including new/worsening neurological deficit in 45.4%, wound complication in 9.1% and systemic complication in 4.0%. Postoperative rehabilitation was introduced in 61.7% of the patients, which was statistically associated with age, non-GTR and tumor location (brainstem and spine) on multivariate analysis (p=0.0031, 0.027 and 0.0066, respectively). Treatment-free survival was longer in VHL (vs sporadic) cases and GTR (vs non-GTR) cases, and multivariate analysis showed GTR was the only factor associated with treatment-free survival (p=0.0015).

CONCLUSIONS
Surgery for CNS HGBs was shown to be challenging, with abundant intraoperative bleeding and high risk of postoperative complications necessitating rehabilitation. GTR of the lesion is of utmost importance, which increases the chance of long treatment-free survival as well as favorable direct postoperative clinical course.