bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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 > 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 < 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

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

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

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 (< 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 (>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

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

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

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< 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

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< 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

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

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.
SURG-29. CLINICAL FACTORS ASSOCIATED WITH RECURRENCE IN ATYPICAL MENINGIOMA: RETROSPECTIVE ANALYSIS OF 99 PATIENTS IN TWO INSTITUTES
Authors: Sung Kyung Soo , Song Young Jin , Zoon Kim Young
Published: December 2020

OBJECTIVE

The objectives of this study were to examine the local control (LC) rate of atypical meningioma after surgical resection with or without adjuvant treatment, to identify risk factors for the recurrence of atypical meningioma, and to compare our results to known factors from the literature.

METHODS

Clinical and radiological records of patients with atypical meningiomas diagnosed at two institutes from January 2000 to December 2018 were reviewed retrospectively. Histopathological features were also reviewed using formalin-fixed paraffin embedded samples from pathological archives.

RESULTS

Of the 99 atypical meningiomas eligible for analysis, 36 (36.4%) recurred during the follow-up period (mean 83.3 months, range 12–232 months). The rate of 3-year LC and 5-year LC was 80.8% and 74.7% respectively. The mean time-to-recurrence was 49.4 months (range 12–150 months). Multivariate analysis using Cox proportional-hazard regression model showed that the extent of resection (Hazard ratio [HR] 4.761, p=0.013), Ki67 index (HR 8.541, p=0.004), mitotic index (HR 3.275, p=0.044), tumor size (HR 3.228, p=0.041), and radiotherapy (HR 3.816, p=0.029) were independently associated with 3-year LC. These factors was also statistically associated with recurrence-free survival. In terms of radiotherapy after surgical resection, the recurrence was not prevented by immediate radiotherapy because of the strong effect of proliferative index on recurrence. Three cases of malignant transformation to WHO grade III meningioma were histopathologically confirmed after repeated surgery. Two out of these three patients succumbed to malignant transformation. The mean Ki67 proliferative index increased for recurrent cases in 18 patients (58.1%) from 7.55% (range 4-16) to 11.81% (range 5-24).

CONCLUSION

The present study suggests that the extent of resection, proliferative index (according to Ki67 expression) and mitotic index, tumor size, and radiotherapy are associated with recurrence of atypical meningiomas. However, our results should be further validated through prospective and randomized clinical trials.
SURG-34. MULTIDISCIPLINARY MANAGEMENT OF A PATIENT WITH OPTIC PATHWAY-HYPOTHALAMIC LANGERHANS CELL HISTIOCYTOSIS: A CASE REPORT
Authors: Emmanuel Custodio John , Ferraris Kevin Paul , Navarro Joseph Erroll , Seng Kenny , Alcazaren Jose Carlos , Dantes Ma Angelle
Published: December 2020

Langerhans cell histiocytosis (LCH) of the Central Nervous System (CNS) is rare. Isolated involvement of the hypothalamic region is much more extremely rare with only 0.04 to 0.6% of the cases. We report a case of a 33 year-old female who presented with a one-year history of amenorrhea and a five-month history of intermittent headache, memory lapse, and somnolence. The patient was of normal body mass index with normal visual acuity and intact visual fields. Laboratory examinations revealed panhypopituitarism with central diabetes insipidus. Cranial magnetic resonance imaging showed a large lobulated mass measuring 1.9 x 2.2 x 2 cm in the suprasellar region which extended to the pituitary infundibulum, hypothalamus and retrochiasmatic region, with surrounding edema. The patient underwent right orbitozygomatic craniotomy and subtotal excision of the mass through subfrontal and transsylvian approaches. Histopathological examination of langerhans cells were observed with positive immunohistochemical stain for CD1a and S100 protein antigen markers establishing a diagnosis of CNS LCH. Thoracoabdominal computed tomography scan and bone scan were done postoperatively and showed no evidence of extracranial lesions. The patient had been receiving prednisone and vinblastine based chemotherapy regimen. She remains to be asymptomatic and on close surveillance. To date, there is no standardized treatment strategy for CNS LCH in the adult population. An accurate histopathologic diagnosis and a specialized multidisciplinary team approach especially involving Oncology, Neurosurgery, Ophthalmology and Endocrinology are critical to optimally tailor possible effective treatment options for patients with this similar disease. Long-term follow-up is crucial due to the increased risk of local recurrence and multisystemic involvement.
SURG-37. SYSTEMATIC REVIEW OF GAMMA-KNIFE RADIOSURGERY AND MICROSURGICAL RESECTION FOR BRAINSTEM CAVERNOUS MALFORMATIONS
Authors: Kondajji Aditya , Nguyen Thien , Sheppard John , Kulinich Daniel , Unterberger Ansley , Evans Audree , Patel Kunal , Yang Isaac
Published: December 2020

BACKGROUND

Although microsurgical resection (MR) remains the gold-standard for the treatment of symptomatic cavernous malformations, some authors have proposed the use of radiosurgical Gamma-Knife Surgery (GKS) for lesions that are deep or eloquent, such as those located in the brainstem.

OBJECTIVE

Here were analyze the literature regarding patient outcomes following MR or GKS for brain stem cavernous malformations.

METHODS

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic literature review. A database search of PubMed, Scopus, Embase, and Web of Science was conducted in September 2019. This review included studies evaluating the outcomes of MR or GKS for cavernous malformations located in the brainstem.

RESULTS

Gross total resection was achieved in the majority of patients and effectively eliminated the risk of recurrent hemorrhage from the operative lesion in studies following the outcomes of MR. GKS reduces the annual hemorrhage rate for patients, although it does not eliminate the cavernous malformation. Both treatment modalities were effective in reducing prior symptomatology. Unlike resection, GKS only reduces the risk of future hemorrhage and does prevent it.

CONCLUSIONS

Both MR and GKS can improve or stabilize symptoms in patients. However, the therapeutic benefit of GKS may take months to years to take full-effect, resulting in a potential for subsequent hemorrhagic events. MR remains the best treatment option due to its ability to eliminate future bleeding events entirely and should be performed whenever gross total resection is possible.
SURG-41. BLOOD-BRAIN BARRIER DISRUPTION WITH HIGH-FREQUENCY ELECTROPORATION IN VIVO: A PRELIMINARY INVESTIGATION DEMONSTRATING THE EFFECTS OF VARIED PULSE WIDTHS AND INTRA-PHASE DELAYS
Authors: Lorenzo Melvin , Thomas Sean , Verbridge Scott , Robertson John , Rossmeisl John , Davalos Rafael
Published: December 2020

OBJECTIVE

Treatment of CNS disorders suffer from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). High-frequency electroporation (HFE) employs a series of high voltage pulsed electric fields to disrupt the BBB and/or ablate tumor tissue while sparring proteinaceous structures. Pulsing parameters pulse width and intra-phase delay can be modulated to reduce excitation of muscle and nervous tissues, though this is inherently accompanied by an increase in thresholds for ablation in non-CNS tissues. Here, we investigate the effects of pulse width and intra-phase delay on intracranial tissue for BBB disruption (BBBD) in an in vivo healthy rodent model.

METHODS

18 male Fisher rats underwent craniectomy procedure and two blunt tipped monopolar electrodes were advanced into the brain for HFE therapy. 200 bursts of HFE were delivered at a voltage-to-distance ratio 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye).

RESULTS

Gross pathological sections and contrast enhanced T1W scans demonstrated BBBD for 2-2-2 µs (n = 4, 36.6 ± 9.4 mm3, 36.7 ± 13.0 mm3), 2-5-2 µs (n = 4, 74.1 ± 7.7 mm3, 74.7 ± 9.8 mm3), 5-2-5 µs (n = 4, 53.9 ± 8.1 mm3, 59.2 ± 10.8 mm3), 5-5-5 µs (n = 4, 81.2 ± 7.9 mm3, 84.1 ± 8.7 mm3), and 10-1-10 µs (n = 2, 61.0 ± 2.8 mm3, 60.0 ± 4.2 mm3) HFE. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced with minimal muscle contractions and minimal cell death attributed to HFE. Numerical modeling indicated the threshold for HFE-mediated BBBD as low magnitude electric fields (< 201 V/cm). These data suggest HFE-mediated BBBD is only modestly affected by changes in pulse width and intra-phase delay.
TAMI-05. THE IRRADIATED BRAIN MICROENVIRONMENT SUPPORTS GLIOMA STEMNESS AND SURVIVAL VIA ASTROCYTE-DERIVED TRANSGLUTAMINASE 2
Authors: Berg Tracy , Marques Carolina , Pantazopoulou Vasiliki , Johansson Elinn , von Stedingk Kristoffer , Lindgren David , Pietras Elin , Bergström Tobias , Swartling Fredrik , Governa Valeria , Bengzon Johan , Belting Mattias , Axelson Håkan , Squatrito Massimo , Pietras Alexander
Published: December 2020

The highest-grade gliomas invariably recur as incurable tumors following standard of care comprising surgery, radiotherapy, and chemotherapy. The majority of the recurrent tumors form within the area of the brain receiving high-dose irradiation during treatment of the primary tumor, indicating that the recurrent tumor forms in an irradiated microenvironment. The tumor microenvironment has been demonstrated to influence the therapeutic response and stemness characteristics of tumor cells, but the influence of radiation on the microenvironment and its subsequent consequences for tumor cells are incompletely understood. Here, we used genetically engineered glioma mouse models and human glioma samples to characterize the impact of standard of care radiotherapy on the brain tumor microenvironment. We found that tumor-associated astrocytes subjected to radiation in vitro could enhance tumor cell stemness and survival of co-cultured glioma cells. More aggressive gliomas formed in vivo when mouse brains were irradiated prior to tumor cell implantation, suggesting that the irradiated brain microenvironment supports tumor growth. We isolated the effect of irradiated astrocytes to extracellular matrix secreted by these cells, and specifically found that astrocyte-derived transglutaminase 2 (TGM2) is a stromal promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in glioma mouse models. Recombinant TGM2 enhanced, and TGM2 inhibitors blocked, glioma cell stemness. In human GBM tissue, TGM2 levels were increased in recurrent vs. primary tumors. In summary, in addition to supporting TGM2 as a potential therapeutic target in glioma, our data indicate that radiotherapy results in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.
TAMI-07. THE IMMUNE MICROENVIRONMENT IN LOWER GRADE GLIOMAS
Authors: Kumar Anupam , Chen Katharine , Petritsch Claudia , Nicolaides Theodore , Santi-Vicini Mariarita , Perry Arie , Bollen Andrew , Solomon David , Molinaro Annette M , Phillips Joanna
Published: December 2020

The determinants of the tumor-associated immune response in brain tumors are poorly understood. Using tumor samples from two molecularly distinct subtypes of lower grade glioma, MAPK-driven glioma with biallelic inactivation of CDKN2A (n=30) and IDH-mutant, 1p/19q-intact astrocytoma (n=29), we demonstrate qualitative and quantitative differences in the tumor-associated immune response and we investigate the molecular mechanisms involved. Histologically the MAPK-driven gliomas were comprised of pleomorphic xanthoastrocytoma (PXA) (n=11) and anaplastic PXA (n=19). Seven patients had paired samples from two sequential surgeries. Immune cell populations and their activity were determined by quantitative multiplex immunostaining and Digital Spatial Profiling and gene expression was analyzed by Nanostring. Functional studies were performed using established cell lines and two new patient-derived lines from MAPK-driven LGGs. MAPK-driven tumors exhibited an increased number of CD8+ T cells and tumor-associated microglial/macrophage (TAMs), including CD163+ TAMs, as compared to IDH-mutant astrocytoma. In contrast, IDH-mutant tumors had increased FOXP3+ immunosuppressive T regulatory cells. Transcriptional and protein level analyses in MAPK-driven tumors suggested an active cytotoxic T cell response with robust expression of granzyme B, present on 27% of CD8+ T cells, increased MHC class I expression, and altered cytokine profiles. Interestingly, MAPK-driven tumors also had increased expression of immunosuppressive molecules, including CXCR4, PD-L1, and VEGFA. Expression differences for cell surface and secreted proteins were confirmed in patient-derived tumor lines and functional relationships between altered chemokine expression and immune cell infiltration was investigated. Our data provide novel insights into the immune contexture of MAPK driven LGGs and suggest MAPK driven gliomas with biallelic inactivation of CDKN2A may be particularly vulnerable to immunotherapeutic modulation
TAMI-10. CIRCULATING ANGIOGENIC CELLS (CACS) IN GLIOBLASTOMA: TOWARDS DEFINING CRUCIAL FUNCTIONAL DIFFERENCES IN CAC-INDUCED NEOPLASTIC VERSUS REACTIVE NEOVASCULARIZATION
Authors: Huizer Karin , Sacchetti Andrea , Swagemakers Sigrid , van der Spek Peter , Mustafa Dana , Kros Johan M
Published: December 2020

In order to identify suitable therapeutic targets for glioma anti-angiogenic therapy, the process of neovascularization mediated by circulating angiogenic cells (CACs) needs to be scrutinized. In the present study we compared the expression of neovascularization-related genes by three circulating CAC subsets (HPCs, CD34+ and KDR+ cells; internal controls: PBMCs and circulating endothelial cells) of treatment-naïve patients with glioblastoma (GBM) to those of patients undergoing reactive neovascularization (myocardial infarction (MI). CACs from umbilical cord (representing developmental neovascularization) and healthy subjects served as controls. Fluorescent activated cell sorting was used to isolate CACs, RT-PCR to determine the expression levels of a panel of 48 neovascularization-related genes, Luminex assays to measure plasma levels of 21 CAC-related circulating molecules. We found essential differences in gene expression between GBM and MI CACs. GBM CACs had a higher expression of pro-angiogenic factors (esp. KITL, CXCL12 and JAG1); growth factor and chemotactic receptors (IGF1R, TGFbR2, CXCR4 and CCR2); adhesion receptor monomers (ITGA5 and ITGA6) and matricellular factor POSTN. In addition, we found major differences in the levels of neovascularization-related plasma factors. A strong positive correlation between plasma MMP9 levels and expression of CXCR4 in the CAC subset of hematopoietic progenitor cells (HPCs) was found in GBM patients. Our findings indicate that CAC-mediated neovascularization in GBM is characterized by more efficient CAC homing to target tissue and a more potent pro-angiogenic response than in physiologic tissue repair in MI. Our findings can aid in selecting targets for therapeutic strategies acting against GBM-specific CACs.
TAMI-11. IMPACT OF oHSV ACTIVATED NOTCH SIGNALING IN TUMOR MICROENVIRONMENT, AND ITS IMPACT ON ANTI-TUMOR IMMUNITY
Authors: Otani Yoshihiro , Yoo Ji Young , Chao Samantha , Shimizu Toshihiko , Lewis Cole , Murphy Sara , Pineda Josue , Caraballo Kimberly Rivera , Hong Bangxing , Banasavadi-Siddegowda Yeshavanth Kumar , Heiss John , Yan Yuanqing , Olson Scott , Pei Guangsheng , Zhao Zhongming , Kaur Balveen
Published: December 2020

NOTCH signaling is a method of cell-cell communication where membrane bound NOTCH ligands on signal-sending cells can bind to and initiate cleavage of the NOTCH receptor, releasing NICD which can initiate signal transduction in adjacent “signal-receiving” cells. We have recently shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells. RNA sequencing of GBM cells post-infection also uncovered Gene Ontology NOTCH signaling pathway to be significantly upregulated. This activation was induced by viral miRNA-H16, which represses FIH-1 expression. FIH-1 was found to be a negative regulator of Mib1, a ubiquitin ligase, which activates NOTCH ligand-mediated activation of adjacent signal-receiving cells bearing the NOTCH receptor (Otani et al Clin. Can. Res. 2020). Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment. Treatment of brain tumors in immune competent mice with oHSV and NOTCH blocking gamma secretase inhibitor (GSI) induced an anti-tumor memory immune response. Long term survivors in mice treated with the combination also completely rejected subsequent tumor re-challenge in the other hemisphere. UMAP of flow cytometry of tumor-bearing hemispheres and functional analysis of isolated cellular fractions from treated mice showed a significant influx of MDSC cells after oHSV treatment that was rescued in mice treated with oHSV and GSI. Ongoing mechanistic studies are uncovering a significant induction of NOTCH in tumor associated macrophages that aids in recruitment of MDSC cells. Overall these studies have uncovered a significant impact of oHSV therapy on GBM tumor microenvironment and presents opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity.
TAMI-12. CANCER STEM CELL ENRICHMENT AND METABOLIC SUBSTRATE ADAPTABILITY ARE DRIVEN BY HYDROGEN SULFIDE SUPPRESSION IN GLIOBLASTOMA
Authors: Silver Daniel , Roversi Gustavo , Bithi Nazmin , Neumann Chase K , Troike Katie , Ahuja Grace , Reizes Ofer , Brown J Mark , Hine Christopher , Lathia Justin
Published: December 2020

Glioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.
TAMI-17. RELATIONSHIP BETWEEN IRON METABOLISM, IMMUNE CELL INFILTRATION AND SEX-BASED SURVIVAL DIFFERENCES IN GLIOMAS
Authors: Nesterova Darya , Lee Sang , Zacharia Brad , Proctor Elizabeth , Lathia Justin , Rubin Joshua , Berens Michael , Barnholtz-Sloan Jill S , Connor James
Published: December 2020

Iron plays a central role in cellular metabolism, both in normal cellular functioning and in tumorigenesis. Recent evidence has shown sex-based survival differences in glioblastoma (GBM) may be related to differential expression of metabolism genes. We previously reported the iron regulating gene, HFE, was shown to have a sex-based survival impact in both low-grade gliomas and GBM. We additionally found that females with low HFE expressing tumors have significantly higher survival than males in GBM. To evaluate the relationship between iron gene expression and sex-based survival differences in GBM, we analyzed TCGA GBM gene expression and clinical data. We first analyzed the impact of iron genes on sex-based survival. In addition to HFE, FTL, TFRC, TF, and SLC39A8 (ZIP8), also showed sex-based survival differences. We then compared correlations of HFE and other iron genes to identify whether male and female GBMs differ in iron regulation and metabolism. HFE expression is significantly positively correlated with HMOX1, SLC25A28, SLC11A2, FTH1, HAMP, and TFR2 only in females. Alternatively, HFE expression is negatively correlated with ACO2 (mitochondrial aconitase) in males and ACO1 (cytoplasmic aconitase) in females. We noted that the expression of certain iron genes was highly associated with immune cell infiltration based on sex. TFR2, LRP1, and XIST expression were negatively correlated with low immune cell infiltration in females, but not males. Alternatively, in males, SLC11A2, ACO2, FOXO1, HIF1a, and HAMP genes were negatively correlated with immune infiltration. This suggests that differences in iron regulation between males and females may be contributing to differences in immune function and subsequent survival in GBM. These data suggest that the iron signature of a tumor reflects and possibly drives the metabolic and immune landscape of the tumor microenvironment thereby directly impacting survival differences between male and female GBMs.
TAMI-21. MALIGNANT GLIOMAS REMODEL FUNCTIONAL NEURAL CIRCUITS THROUGH PARACRINE SIGNALING WHICH CONFERS A NEGATIVE PROGNOSIS
Authors: Krishna Saritha , Choudhury Abrar , Ni Lijun , Seo Kyounghee , Kakaizada Sofia , Findlay Anne , Lee Anthony , Sudharshan Rasika , Cao Caroline , Venkatesh Humsa , Vogel Hannes , Phillips Joanna , Almeida Nyle , Nagarajan Srikantan , Berger Mitchel , Raleigh David , Brang David , Monje Michelle , Hervey-Jumper Shawn
Published: December 2020

BACKGROUND

Unlike cancers affecting many solid organs, gliomas exist within the context of complex neural circuitry. It remains unknown whether glioma-neuron interactions play a role in maintaining functional circuits underlying cognition. We test the hypothesis that malignant gliomas remodel functional circuits through glioma-neuron interactions.

METHODS

Using language processing as a model for functional circuit dynamics, we enrolled 53 patients with dominant hemisphere IDH-wild-type glioblastoma. Task related circuit dynamics were measured using electrocorticography. Magnetoencephalography measures of functional connectivity identified intratumoral connectivity (HFC) and suppressed connectivity (LFC) regions. Primary patient samples and cultures from HFC and LFC-sites were assessed by single-cell RNA sequencing, pre/post-synaptic marker expression, cocultured with murine hippocampal neurons, and induced neuron organoids. Hippocampal tumor xenografts were created. Language/survival statistics were performed to correlate with functional connectivity measures.

RESULTS

Speech production evokes neuronal population spikes within the entire area of tumor-infiltrated cortex, far beyond the cortical territory normally involved in expressive language. Primary patient samples from HFC-regions are enriched for glioblastoma cells with a synaptogenic profile as characterized by pre-and post-synaptic marker expression at both tissue and cellular levels. RNA-sequencing and proteomic analyses from HFC samples revealed a neurogenic signature including thrombospondin-1 originating from glioma cells in HFC-regions and non-tumor astrocytes in LFC-regions. HFC xenografts demonstrated increased total number of synapses. Importantly, when compared with gliomas without intratumoral functional connectivity, connected gliomas have worse language task performance (r= -0.54,p=0.03) and shorter OS (medianOS-64 weeks compared with 107-weeks,p=0.04).

CONCLUSION

Glioma infiltrated regions generate task-relevant neural responses, with speech production evoking neuronal activity throughout tumor-involved cortex in the dominant hemisphere. An enriched population of synaptogenic glioma cells are organized within functionally connected intratumoral regions and this confers negative functional and survival outcomes. Together, these findings indicate that malignant gliomas can functionally remodel neural circuitry, thereby impairing neurological function and promoting tumor progression.
TAMI-26. SINGLE-CELL TRANSCRIPTOME ANALYSIS REVEALS THAT ENDOTHELIAL TRANSFORMATION DRIVES GLIOBLASTOMA CHEMORESISTANCE VIA Wnt/β-CATENIN/MRP-1
Authors: Huang Menggui , Zhang Duo , Fan Yi
Published: December 2020

Therapeutic resistance remains a persistent challenge for patients with glioblastoma (GBM). Here, we report that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)-like cells in GBM, driving tumor resistance to cytotoxic treatment. Single-cell transcriptome analysis identified an EC-derived cell population that robustly expresses mesenchymal genes and stem cell-associated markers, suggesting that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met-mediated axis that induces β-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance-associated protein-1 (MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of β-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity-based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/β-catenin-mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.