bluuebunny/crossref_metadata_2025_split huggingface dataset:
STEM-14. GLIOBLASTOMA STEM CELL TARGETING CHIMERIC ANTIGEN RECEPTOR T CELLS MODIFIED USING PHAGE DISPLAY ISOLATED PEPTIDES
Authors: Potez Marine , Snedal Sebastian , Kim Jongmyung , Thorner Konrad , Ramello Maria Cecilia , Abate-Daga Daniel , Liu James 
Published: December 2020

Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor with high mortality rates and resistance to conventional therapy. Their resistance to conventional therapy has been attributed to the presence of cancer stem cells (CSCs), a sub-population of tumor cells capable of self-renewal and tumor initiation. Developing novel strategies to specifically target GSCs may allow more effective therapeutic strategies. Using in vivo phage display biopanning, we have identified several peptides with the potential to selectively target and bind GSCs. We wished to leverage the GSC targeting properties of the peptides to augment therapeutic delivery vehicles for the development of novel targeting strategies. We used a combination of GSC targeting peptides to modify the antigen-binding domain of chimeric antigen receptors, by arranging the peptides in tandem at the N-terminus of the CAR molecule. These tandem peptides were tested for binding to GSCs in vitro and in vivo. The functionality of the CAR-T cells was evaluated by measuring cytokine release in the supernatant after overnight co-culture through ELISA. Apoptosis was evaluated by flow cytometry with Annexin V staining. Two different GSC-targeting peptide CAR-T cells demonstrated specific targeting GSCs. Following co-culture with GSCs, GSC targeting CAR-T cells were activated with release of Interferon gamma and subsequently induced GSCs specific apoptosis. These results demonstrate the use of phage display biopanning to isolate GSC targeting peptides which may be used to develop novel GBM specific cytotoxic therapies.
STEM-18. DEVELOPMENT OF A NOVEL GENE THERAPY APPROACH TARGETING GLIOBLASTOMA FOLLOWING AI-DIRECTED IDENTIFICATION OF A MASTER REGULATORY GENE NETWORK
Authors: Le Son , Ma Bo , Zolotukhin Sergei , Falk Darin , Tran David 
Published: December 2020

Abstract

BACKGROUND
Profound heterogeneity has severely hampered therapeutic advancements in glioblastoma (GBM). Remarkably, GBM exhibits broad clinical and histopathologic overlaps suggesting the presence of a common regulatory state. The GBM state embodies restructuring of the master regulatory gene network (MRGN) forced by founding mutations and perpetuated in subclones of GBM stem-like cells (GSC). Successful targeting and altering of the MRGN promise to circumvent the heterogeneity.

METHODS
To decipher the common MRGN in GSC, we applied a robust AI suite, NETZEN, that integrates deep neural networks with gene network-based ranking to the reference GBM network generated using TCGA’s entire GBM RNAseq dataset and a dataset containing &gt; 30 diverse GSC and paired GBM differentiated cell lines, 6 normal astrocyte and 3 normal neuronal precursor cell lines. To develop a gene therapy against the MRGN, we performed a screen of a rAAV capsid library using GBM patient-derived orthotopic xenografts (PDX) to identify capsid variants with specific tropism for GBM cells to deliver shRNA-based cassettes.

RESULTS
We discovered a putative MRGN in GSC, anchored by developmentally restricted master regulators (MR). To confirm its critical role, we deconstructed it using shRNA in a panel of PDX and uniformly observed attenuated tumor growth and mortality compared to controls (p &lt; 0.05 in all lines). More notably, when normal astrocytes were forced to reconstruct the MRGN, transformation into GSC-like cells occurred, as measured by single-cell analysis, sphere formation in vitro, and most importantly, development of lethal infiltrating brain tumors in 15/15 mice. Finally, selected novel AAV capsids with 10-40-fold higher specificity for GBM cells were utilized in a shRNA-based AAV platform to target key MR in the validated MRGN.

CONCLUSIONS
The GBM state is established by a developmental subnetwork permitting a first-of-its-kind, heterogeneity-agnostic AAV-based treatment approach. This AI-directed R&D program can be expanded to target other cancers.
STEM-22. TARGETING KIF11 TO RADIOSENSITIZE GLIOBLASTOMA
Authors: Zalenski Abigail , Venere Monica 
Published: December 2020

Abstract
Glioblastoma (GBM) is the most common primary brain tumor, and is incredibly lethal, with less than 10% of patients surviving more than 5 years after diagnosis. These tumors are routinely treated with radiotherapy, although we and others have shown that there is a subpopulation of GBM cells, called cancer stem-like cells (CSCs), that are radio-resistant, and do not respond to this standard therapy. We aim to overcome the radio-resistance of GBM CSCs by using radiotherapy in combination with a KIF11 inhibitor. We previously reported that the mitotic kinesin KIF11, required for bipolar spindle formation during mitosis, is elevated in GBM and portends poor prognosis. We also demonstrated that invasiveness and self-renewal of CSCs could be targeted with ispinesib, a small molecule inhibitor to KIF11. Furthermore, survival of mice bearing orthotopic glioblastoma was prolonged with KIF11 inhibition, although tumor burden increased with cessation of treatment. To combat tumor recurrence after treatment cessation, we proposed to use a KIF11 inhibitor with radiotherapy. KIF11 inhibitors will arrest cells in G2/M, where they are most sensitive to radiotherapy. By enriching CSCs in G2/M, we hypothesized that we would overcome CSC radio-resistance to decrease CSC viability and improve survival. We first tested the efficacy of combining a KIF11 inhibitor and irradiation in vitro. We found that using combination therapy to treat CSCs significantly decreased CSC survival over vehicle or either treatment used as a monotherapy. We then investigated the effects of combination therapy in vivo. Using a KIF11 inhibitor combined with irradiation increased survival of mice bearing orthotopic glioblastoma. Our results suggest that targeting KIF11 in combination with radiotherapy is a promising technique to overcome the radio-resistance of CSCs, and holds potential to significantly improve treatment outcomes and extend survival of patients with GBM.
STEM-25. DIFFERENTIAL REGULATION OF GLIOMA STEM-CELL MARKER NESTIN AND CD24 IN IDH-MUTANT GLIOMA
Authors: Tiburcio Patricia , Locke Mary , Bhaskara Srivydia , Chandrasekharan Mahesh , Huang Eric 
Published: December 2020

Abstract
Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, resulting in predominantly arginine to histidine substitution at codon 132. Because IDH1R132H requires a wild-type allele to produce (D)-2-hydroxyglutarate for epigenetic reprogramming, glioma cells with loss of the remaining wild-type allele (hence IDH1R132H-hemizygous) exhibit an IDH1-wild-type-like glioma phenotype and aggressive tumor growth. Although previous studies reported that transgenic IDH1R132H induced the expression of nestin—a glioma stem-cell marker, the underlying mechanism remains unclear. Furthermore, this finding seems at odds with the better outcome of IDH-mutant glioma owing to a negative association of nestin with overall survival. To gain a comprehensive understanding of glioma stem-cell marker gene regulation in IDH-mutant glioma, we compared gene expression between IDH1R132H-heterozygous and IDH1R132H-hemizygous glioma cells under adherent and spheroid growth conditions and found that glioma stem-cell marker genes, including CD44, NES, and PROM1, are generally downregulated in the spheroid growth of IDH1R132H-heterozygous cells. This result was validated in patient samples of IDH-mutant glioma compared with those of IDH-wildtype glioma, even though modest NES upregulation was observed in the adherent growth of IDH1R132H-hemizygous glioma cells. In contrast, CD24 is specifically upregulated in the spheroid growth of IDH1R132H-heterozygous cells and patient samples of IDH-mutant glioma and is apparently associated with better survival. Mechanistically, CD24 and NES expression responds differentially to alteration of (D)-2-hydroxyglutarate levels. CD24 upregulation is associated with histone and DNA demethylation as opposed to hypermethylation in those downregulated glioma stem-cell marker genes. Therefore, the better outcome of IDH-mutant glioma is orchestrated exquisitely through epigenetic reprogramming that directs bidirectional expression of glioma stem-cell marker genes.
SURG-03. COMBINATION LASER INTERSTITIAL THERMAL THERAPY PLUS SRS INCREASES TIME TO PROGRESSION FOR RECURRENT SRS-TREATED BRAIN METASTASES
Authors: Grabowski Matthew , Sankey Eric , Srinivasan Ethan , Otvos Balint , Scott Alex , Olufawo Michael , Kim Albert , Leuthardt Eric , Barnett Gene , Mohammadi Alireza , Fecci Peter 
Published: December 2020

Abstract

INTRODUCTION
Laser interstitial thermal therapy (LITT) has evolved as an effective treatment for brain metastases (BM) failing stereotactic radiosurgery (SRS), and an alternative to open resection/repeat SRS. We sought to evaluate the efficacy of LITT+SRS in recurrent SRS-treated BM, and compare outcomes to LITT alone vs. repeat SRS.

METHODS
A multicenter, retrospective study was performed of patients with biopsy-proven BM recurrence after SRS. Patients were stratified by planned LITT+SRS vs. LITT alone vs. repeat SRS. Index lesion progression was determined by RANO criteria.

RESULTS
Forty-five patients fit inclusion, with a median follow-up of 7.3 months (range:1.1-30.5), age of 60 (range:37-86), KPS of 80 (range:60-100), and contrasted tumor volume (CTV) of 6.1cc (range:1.4-19.4). Histologies included NSCLC (44%), breast (24%), SCLC, melanoma, colon, and oroesophageal (&lt; 10% each). Sixty-three percent of patients underwent LITT alone, 18% had repeat SRS, while 27% had LITT+SRS (post-LITT SRS). Median time to index lesion progression was greatest in the LITT+SRS group compared to LITT alone or repeat SRS (&gt;23, 7.5, and 3.6 months, respectively [p=0.018]), as was overall survival (23.7, 5.9, and 7.0 months, respectively [p=0.023]). Age, sex, primary histology, CTV, and treatment strategy were univariate predictors of tumor progression; patients not treated with LITT+SRS were more likely to have index lesion progression (p=0.016). When controlling for histology and CTV in a multivariate model, patients not treated with LITT+SRS were significantly more likely to have progression (p=0.001). All LITT+SRS patients who experienced subsequent radiographic progression were diagnosed with recurrent tumor, while radiation necrosis incidence in the repeat SRS arm was 25%.

CONCLUSION
LITT+SRS appears superior to LITT alone or repeat SRS for treatment of biopsy-proven BM recurrence after SRS when controlling for other variables known to be predictive of progression. Prospective trials should be designed to validate the utility of combination LITT+SRS after SRS failure.
SURG-04. SALVAGE RESECTION OF RECURRENT PREVIOUSLY-IRRADIATED BRAIN METASTASES: CLINICAL AND RADIOGRAPHIC OUTCOMES
Authors: Wilcox Jessica , Newman William , Reiner Anne , Brown Samantha , Young Robert , Chen Justin , Beal Kathryn , Brennan Cameron , Panageas Katherine , Tabar Viviane , Moss Nelson 
Published: December 2020

Abstract

BACKGROUND
The management of brain metastasis (BrM) recurrence after stereotactic body radiotherapy (SBRT) poses a clinical challenge. The efficacy of salvage resection is undefined, and the role of adjuvant resection cavity reirradiation is unclear given the compounded risk of radiation injury.

METHODS
Retrospective analysis of previously-irradiated BrM that underwent resection between March 2003 and February 2020 at Memorial Sloan Kettering Cancer Center was performed. Only cases with histopathologic evidence of viable malignancy were included, and specimens were classified by the gross proportion of viable tumor versus treatment effect. Clinical and radiographic parameters were collected. Post-operative recurrence and radiation necrosis were based on RANO-BM criteria and distinguished by histopathologic, radiographic and clinical characteristics. Equivocal cases were adjudicated by a blinded neuroradiologist.

RESULTS
One-hundred fifty-five resected recurrent BrM following SBRT in 135 patients were evaluated. Seventeen received additional prior whole-brain radiation. Metastases derived from non-small-cell lung (36.8%), melanoma (27.1%), breast (21.3%), renal (3.9%), colorectal (1.9%) and other (9.0%) primary malignancies. Forty-eight (31.0%) had only microscopic malignant disease with extensive necrosis, 44 (28.4%) had mixed or unspecified tumor with treatment effect, and 63 (40.6%) were reported as purely viable tumor by histopathologic report. Thirty-nine (25.2%) post-operative cavities underwent adjuvant reirradiation within 60 days. At 6 and 12 months, local tumor recurrence occurred in 31.6% (95% CI: 24.4%-39.1%) and 40.4% (95% CI: 32.5%-48.2%), respectively, with a proportion of these lesions displaying mixed tumor plus treatment effect. Median overall survival was 13.4 months (95% CI: 10.5-17.7) from salvage resection.

CONCLUSIONS
Salvage of previously-irradiated BrM remains challenging. This represents the largest known series correlating salvage resection and histopathologically-confirmed viable recurrent BrM with long-term outcomes. Tumor recurrence risk remains high at one year. Further exploration will stratify local progression and radiation necrosis rates by features including extent of resection, degree of viable tumor and adjuvant reirradiation use.
SURG-11. NEOADJUVANT CHEMOTHERAPY FOR DIFFUSE GLIOMAS: A FEASIBLE OPTION?
Authors: Campos Paiva Aline , Araujo João Luiz Vitorino , de Aguiar Guilherme Brasileiro , Batistella Gabriel Rezende , Maldaum Marcos , veiga José Esteves 
Published: December 2020

Abstract

BACKGROUND
Diffuse gliomas are slow-growing tumors with predilection for deep and eloquent structures such as supplementary motor area and insula. They can reach huge dimensions which is a surgical challenging.

OBJECTIVE
Describe indications and limitations of neoadjuvant chemotherapy for diffuse gliomas.

METHODS
Systematic review was performed in November/2019 using Pubmed, Bireme and Cochrane databases. The following combinations were used: “Chemotherapy” AND “neoadjuvant” AND “diffuse glioma”, “Chemotherapy” AND “neoadjuvant” AND “low grade glioma”, “Chemotherapy” AND “preoperative” AND “diffuse glioma”, “Neoadjuvant” AND “Chemotherapy” AND “temozolomide” AND “diffuse glioma”.

RESULTS
After carefully analysis, 7 papers were selected. They had mixed surgical interventions and used different drugs. In general, it was observed that neoadjuvant Temozolomide for Oligodendrogliomas 1p19q codeleted with MGMT methylation had better response than other molecular groups. Tumor reduction was significant.

CONCLUSIONS
Quality of life is a main goal in neurooncology. Tumor reduction using chemotherapy is a promising therapeutic. Surgery, especially in eloquent areas, could remove more tumors with less morbidity. Recent publications are using this approach with good outcomes, however further studies with more patients and uniformization are required to stablish this approach.
SURG-12. PREDICTORS OF SURVIVAL AND UTILITY OF INTRAOPERATIVE MRI FOR RESECTION OF GRADE II ASTROCYTOMAS AND OLIGODENDROGLIOMAS: A MULTICENTER ANALYSIS
Authors: Yahanda Alexander , Patel Bhuvic , Shah Amar , Cahill Daniel , Sutherland Garnette , Honeycutt John , Jensen Randy , Rich Keith , Dowling Joshua , Limbrick David , Dacey Ralph , Kim Albert , Leuthardt Eric , Dunn Gavin , Zipfel Gregory , Leonard Jeffrey , Smyth Matthew , Shah Mitesh , Abram Steven , Evans John , Chicoine Michael 
Published: December 2020

Abstract

BACKGROUND
Few studies use large, multi-institutional patient cohorts to examine the role of intraoperative MRI (iMRI) in the resection of grade II gliomas. We assessed the impact of iMRI and other factors on overall survival (OS) and progression-free survival (PFS) for newly-diagnosed grade II astrocytomas and oligodendrogliomas.

METHODS
Retrospective analyses of a multicenter database assessed the impact of patient-, treatment-, and tumor-related factors on OS/PFS.

RESULTS
232 resections (112 astrocytomas, 120 oligodendrogliomas; 135 males; mean age 36.2 ± 0.9 years) were analyzed. Oligodendrogliomas had longer OS (p&lt; 0.001) and PFS (p=0.009) than astrocytomas. Multivariate regression showed that extent of resection (EOR), including gross-total (GTR) versus near-total (NTR) resection (p=0.02, HR: 0.64, 95% CI: 0.25-.79) and GTR versus subtotal resection (STR) (p=0.006, HR: 0.23, 95% CI: 0.08-0.66), was associated with longer OS. GTR versus NTR (p=0.04, HR: 0.49, 95% CI: 0.29-.85), GTR versus STR (p=0.02, HR: .54, 95% CI: .32-.91) and iMRI use (p=0.02, HR: 0.54, 95% CI: 0.32-0.92) were associated with longer PFS. Frontal (p=0.048, HR: 2.11, 95% CI: 1.01-4.43) and occipital/parietal (p=0.003, HR: 3.59, 95% CI: 1.52-8.49) locations were associated with shorter PFS (versus temporal). Kaplan-Meier analyses showed longer OS with increasing EOR (p=0.03) and 1p/19q gene deletions (p=0.02). PFS improved with increasing EOR (p=0.01), GTR versus NTR (p=0.02), and resections above STR (p=0.04). Factors influencing adjuvant treatment (35.3% of patients) included age (p=0.002, OR: 1.04) and EOR (p=0.037, OR: 0.41 for NTR versus STR; p=0.003, OR: 0.39 for GTR versus STR), but not glioma subtype or location, as determined by logistic regression. Additional tumor resection after iMRI was performed in 105/159 (66%) iMRI cases, yielding GTR in 54.5% of these cases.

CONCLUSIONS
EOR significantly improves OS and PFS for patients with grade II astrocytomas and oligodendrogliomas. Intraoperative MRI may improve EOR and was associated with increased PFS.
SURG-23. REOPERATION IN MOLECULAR SUBTYPES OF RECURRENT GLIOBLASTOMA
Authors: Dono Antonio , Zhu Ping , Holmes Emma , Takayasu Takeshi , Blanco Angel , Hsu Sigmund , Bhattacharjee Meenakshi , Zhu Jay-Jiguang , Ballester Leomar Y , Esquenazi Yoshua , Tandon Nitin 
Published: December 2020

Abstract

BACKGROUND
Recurrent glioblastoma (rGBM) treatment is not well defined and multiple therapeutic approaches have been proposed, none of which has shown to prolong survival in randomized trials. The role of reoperation for rGBM is still unclear. While most studies demonstrate improve overall survival (OS) and post-progression survival (PPS), recent studies employing time-dependent analysis appear to undermine the OS benefit in reoperated patients. Moreover, the relevance of rGBM molecular subtypes that benefit from reoperation is an important question that may guide clinical decision-making.

METHODS
A retrospective review of rGBM demographics, clinical, molecular, and outcome characteristics was performed for all cases managed by us between 01/2005 to 10/2019 at our institution. IDH1/IDH2 status was determined by immunohistochemistry and/or next-generation sequencing (NGS). A genetic subanalysis was conducted for most rGBM IDH-wildtype (IDH-WT) by NGS. The primary outcome was PPS. Kaplan-Meier method, multivariable Cox proportional-hazards model, and accelerated failure time model were performed in survival analysis. Random survival forest was applied to identify variable importance.

RESULTS
284 rGBM patients fulfill inclusion criteria, 145 (51.1%) had reoperation at their 1st recurrence. Reoperated patients were significantly younger, had better performance status, and had a higher extent of resection at initial surgery; meanwhile, they were less likely to receive bevacizumab. Patients undergoing reoperation experienced superior PPS (11.5 vs. 7.4, months, log-rank test: p= 0.002), which kept consistent in multivariable Cox model (HR: 0.62, p= 0.001). Moreover, reoperated rGBM IDH-WT (N= 238) had 37% reduced risk of post-progression death compared to non-reoperated patients. A subanalysis of rGBM IDH-WT molecular subtypes identified that EGFR mutant, NF1 wildtype, and TP53 wildtype subgroups could benefit from reoperation (all p&lt; 0.008).

CONCLUSIONS
Maximal safe re-resection improved the PPS of rGBM regardless of their IDH status. Reoperation for 1st recurrence was especially beneficial for GBM IDH-WT harboring EGFR alteration, TP53 WT, and NF1-WT.
SURG-25. EFFECT OF VENTRICULAR ENTRY DURING GLIOBLASTOMA RESECTION ON PATIENT OUTCOMES
Authors: Young Jacob , Gogos Andrew , Pereira Matheus , Morshed Ramin , Li Jing , Barkovich Matthew , Hervey-Jumper Shawn , Berger Mitchel 
Published: December 2020

Abstract

BACKGROUND
Tumor proximity to the ventricle and ventricular entry (VE) during surgery have both been associated with poorer prognoses; however, the interaction between these two factors is poorly understood.

METHODS
The UCSF tumor registry was searched for patients with newly diagnosed and recurrent supratentorial glioblastoma who underwent surgical resection with the senior author between 2013 – 2018. Tumor location with respect to the subventricular zone (SVZ), size, VE, and extent of resection were assessed using pre and postoperative imaging.

RESULTS
In the 200-patient cohort of newly diagnosed and recurrent glioblastoma, 26.5% had VE. Comparing patients with VE to those without VE, there was no difference in postoperative hydrocephalus (1.9% vs. 4.8%, p = 0.36), ventriculoperitoneal shunting (0% vs. 3.4%, p = 0.17), pseudomeningoceles (7.5% vs. 5.4%, p = 0.58), or subdural hematomas (11.3% vs. 3.4%, p = 0.07). Importantly, rates of leptomeningeal disease (7.5% in VE vs. 10.2% w/o VE, p = 0.57) and distant parenchymal recurrence (17.9% in VE vs. 23.1% w/o VE, p = 0.35) were not different between the groups. There was no effect of VE on EOR when controlling for SVZ type. Newly diagnosed patients with tumors contacting the SVZ (Type 1 or 2) had worse survival than patients with tumors that did not contact the SVZ (Type 3 or 4) (1.27 vs 1.84 years, p = 0.014, HR 1.8, CI 1.08 – 3.03), but VE was not associated with worse survival in these patients with high risk SVZ Type 1 and 2 tumors (1.15 vs 1.68 years, p = 0.151, HR 0.59, CI 0.26 – 1.34).

DISCUSSION
VE was well tolerated with complications being rare events. There was no increase in leptomeningeal spread or distant parenchymal recurrence in patients with VE. Finally, VE did not change survival for patients with tumors contacting the ventricle.
SURG-28. PRESENTATION OF A POSTERIOR FOSSA TUMOR AT A HOSPITAL IN WESTERN JAMAICA
Authors: Dixon Brandon , Holness Renn , Walker Tasha-Kay , Pencle Franz 
Published: December 2020

Abstract
The posterior cranial fossa is part of the cranial cavity, located between the foramen magnum and tentorium cerebelli that houses the cerebellum, pons and medulla oblongata. Commonly, tumors arising from this region in adults are cerebellar metastases or schwannomas of the vestibular nerve – the incidence of primary neoplasms is uncommon and more reserved for the pediatric population. A 28 year old female was in her usual state of health until last year when she started experiencing recurrent headaches with associated vomiting and intermittent loss of consciousness. A CT brain was done upon presentation to the hospital that revealed a 4th ventricle mass with obstructive hydrocephalus. A ventriculoperitoneal (VP) shunt was done thereafter to decompress the ventricular system, in anticipation for further surgical intervention for mass. Occipital craniotomy and resection of tumor was done and patient managed in a multidisciplinary manner in the intensive care unit. Post-operative course was marked by occipital pseudomeningocele with an associated CSF leak; a lumbar drain was placed in situ until complete resolution of leak. Histological analysis showed WHO Grade II Astrocytoma. Adult primary posterior fossa tumors are rare and can present with a constellation of symptoms. Although patient presented with findings in keeping with the diagnosis of an ependymoma, close clinical follow up will be required henceforth due to the refractory nature of such a low grade astrocytoma post-resection. Radiotherapy can also be considered in further management of case.