bluuebunny/crossref_metadata_2025 huggingface dataset:
STEM-06. THE ROLE OF IFITMs IN MAINTAINING GLIOMA STEM CELLS
Authors: Nita Erisa , Nekulova Marta , Brennan Paul M , Ball Kathryn
Published: December 2020

Glioblastoma, one of the most lethal and heterogeneous primary brain tumours, contains cellular hierarchies with both quiescent and self-renewing glioblastoma stem cells (GSCs). GSCs contribute to a lack of progress in patient survival as they appear to have an innate resistance to both chemotherapy and radiotherapy. The aim of this study is to elucidate how constitutive expression of interferons (IFNs) and their downstream signalling pathways maintain GSCs thereby supporting treatment resistance and tumour reoccurrence. To understand the mechanism of action of a subset of IFN regulated genes, originally characterized as a signature for radiation and chemotherapy resistance (IRDS), a panel of patient derived GSCs was generated and manipulated using CRISPR/Cas9 gene-editing. Phenotypic changes in growth, viability and drug resistance were characterised and linked to molecular level events using transcriptomic and proteomic techniques. Using this approach, in conjunction with patient tissue analysis, signalling under basal as well as IFN-activated conditions was studied in the context of GSC status. Immunohistopathology of a glioma tissue micro-array identified an increased expression of IFN induced transmembrane receptors (IFITMs), which co-localised with Nestin, around the blood vessels suggesting that IFITM positive cells were in the stem cell niche. Further analysis showed the presence of IFITM1 and IFITM3 in GSCs and established that loss of IFITMs function impacted on growth rate and cell cycle progression as well as treatment sensitivity. By using wild-type and gene-edited GSC to focus on the relationship between IFITM1 and IFITM3, we have compelling phenotypic and molecular evidence that IFN-induced changes in the localisation of IFITMs impact on the ability of stem cells to ‘escape’ normal growth control mechanisms. Taking into consideration the constitutive expression of interferons in the tumour microenvironment, our study provides evidence that IFITMs regulate GSC self-renewal and are involved in maintaining a quiescent population which can escape chemotherapy.
STEM-07. IDENTIFICATION OF A NOVEL CSC SIGNALING AXIS CONTAINING JAM-A/SERPINB3/TGF-BETA
Authors: Lauko Adam , Turaga Soumya , Volovetz Josephine , Bayik Defne , Naik Ulhas , Lathia Justin
Published: December 2020

Despite therapeutic interventions including surgery, radiation, and chemotherapy, multiple clones of treatment resistant cells repopulate the tumor, resulting in recurrence and a high rate of mortality in glioblastoma. Effective targeting of these cancer stem cells (CSCs) has been limited by our incomplete understanding of the intracellular signaling mechanisms maintaining the CSC state. Our laboratory previously identified junctional adhesion molecule-A (JAM-A) on CSCs and, through functional studies, demonstrated that JAM-A is both necessary and sufficient for self-renewal and tumor growth. We determined that JAM-A signals via Akt in GBM CSCs to sustain pluripotency transcription factor activity; however, the intermediate signaling network is yet to be fully elucidated. Therefore, our goal was to delineate the pathway downstream of JAM-A. To achieve this, we immunoprecipitated JAM-A from GBM CSCs and performed mass spectrometry leading to the identification of the serine/cysteine protease inhibitor SerpinB3. While SerpinB3 has a functional role in lung adenocarcinoma, breast, pancreas, as well as in hepatocellular carcinoma, there is limited information in GBM or CSCs, and its relationship to JAM-A is yet to be elucidated. Using in vitro CSC functional assays, we observed that SerpinB3 is necessary for the maintenance of CSCs. Additionally, in an intracranial implantation model of GBM the knockdown of SerpinB3 extended the survival of mice. Knockdown of SerpinB3 in multiple GBM CSCs models also led to decreased expression of TGF-β, a known regulator of the CSC state. We also observed that SerpinB3 stabilizes JAM-A expression and further studies are investigating the mechanism of this stabilization, identifying the specific interaction sites of JAM-A and Serpin B3, and determining how TGF-β alters the association through positive and negative feedback mechanisms. Taken together, these data highlight the role of SerpinB3 in GBM CSCs and provides a novel target to inhibit the JAM-A-mediated CSC maintenance as a next-generation GBM therapy.
STEM-08. PLATELETS DRIVES GLIOBLASTOMA ONCOGENESIS BY ENHANCING THE GLIOMA STEM CELL PHENOTYPE
Authors: Sloan Anthony , Lee-Poturalski Christine , Elder Theresa , Harris Peggy , Kerstetter-Fogle Amber , Cioffi Gino , Raghavan Alankrita , Willis John , Rich Jeremy , Barnholtz-Sloan Jill S , Jankowsky Eckhard , Sloan Andrew E
Published: December 2020

Glioblastoma (GBM) is recognized as one of the deadliest forms of cancer, despite aggressive therapy consisting of maximal surgical resection followed by concurrent radiation and chemotherapy, the median survival remains ~15 months. Glioma stem cells (GSCs) possess potent tumor-initiating properties and comprise a cellular hierarchy that is responsible for treatment resistance and progression. Specifically targeting GSCs has been considered a promising therapeutic approach, however no clear method has been identified. Histologically, it is known that GSCs are found in perivascular and pseudsopalisading regions of GBM. Similarly, platelet aggregates are often found in pseudsopalisading necrotic regions, suggesting a potential interaction between platelets and GSCs due to their spatial locations. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Our work aimed to understand the crosstalk between GSCs and platelets within GBM solid tumors that work to enhance disease progression and treatment resistance. Our clinical studies suggest elevated platelet counts positively correlate with tumor growth and negatively correlate to overall patient survival. We found platelets and GSC co-localization in GBM solid tissue; platelet exposure to GSCs results in increased proliferation of GSCs specifically, by increasing the self-renewing capacity of GSCs in a dose dependent manner, and resulted in an increased “Stem-like” transcriptional pattern. Consequently, inhibiting the GSC-platelet interaction results in a decrease in GSC renewal and stemness. These results introduce a novel interaction between GSCs and platelets and elucidate a novel therapeutic approach specifically targeting GSCs by disrupting the GSC-platelet interaction.
STEM-09. INTRINSIC INTERFERON SIGNALING REGULATES THE CELL DEATH OF GLIOBLASTOMA STEM CELLS
Authors: Khan Khan Sabbi , Martinez-Ledesma Emmanuel , Mittal Sandeep , Gandy Kaitlin , Alfaro-Munoz Kristin , Majd Nazanin , Balasubramaniyan Veerakumar , de Groot John
Published: December 2020

Glioblastoma (GBM) is the most common, highly aggressive, and lethal primary brain tumor in adults. Interferon (IFN)-mediated signal transducer and activator of transcription 1 (STAT1) signaling contributes to various aspects of stemness, cell death, cytokine signaling in immune and non-immune cells. However, the role of IFN/STAT1 signaling in stemness, cell death and treatment resistance in GBM is unclear. This study aimed to investigate the cancer cell-intrinsic IFN/STAT1 signaling and its role in cell proliferation, stemness, and apoptosis. By using the metagene scores for type I and type II IFN-responsive genes, we evaluated basal IFN/STAT1 signaling in The Cancer Genome Atlas (TCGA) and in patient-derived cohorts of stem-like cells (GSCs) RNA expression datasets. In-silico analyses were further validated for the constitutive IFN signaling in a subset of GSCs using qPCR, WB and ELISA assays. We employed pharmacological activators and/or inhibitors of IFN/STAT1 signaling in GSCs to study its role in stemness and cell death. We found differential cell-intrinsic type I and type II IFN-signaling markers in GSCs and GBM tumors. High IFN-signaling is associated with mesenchymal phenotype and poor survival outcomes. Acute and chronic GSC exposure to recombinant IFNs reversibly activated both type I and II IFN-signaling in GSCs. IFN-β exposure induced apoptosis in intrinsically high IFN/STAT1-signaling GSCs, but not in the low IFN/STAT1-signaling GSCs. In summary, our findings demonstrate that GBM exhibit differential cell-intrinsic IFN-signaling, and basal IFN/STAT1 is a key factor for IFN-β-mediated cell death in GSCs. However, further mechanistic investigation of intrinsic IFN signaling in GBM, particularly in the stem cell compartment is needed.
STEM-17. NOT ALL GBM STEM CELLS ARE EQUAL: IMPLICATIONS FOR RESEARCH AND THERAPY
Authors: Galdieri Luciano , Jash Arijita , Malkova Olga , Mao Diane , Campian Jian , Brennan Cameron , Oh Stephen , Kim Albert , Chheda Milan
Published: December 2020

Glioblastoma (GBM) kills almost all patients within 2 years. A subpopulation of cells, GBM stem cells (GSCs), contributes to treatment resistance and recurrence. A major therapeutic goal is to kill GSCs, but no targeted therapy yet exists. Since their discovery, GSCs have been isolated using single surface markers, such as CD15, CD44, CD133, and a-6 integrin. It remains unknown how these single surface marker-defined GSC populations compare to each other in terms of signal transduction and function and whether expression of different combinations of these markers is associated with distinct phenotypes. Using mass cytometry and fresh operating room specimens, we found that 15 distinct GSC subpopulations exist in vivo and they differ in their MEK/ERK, WNT, and AKT pathway activation status. In culture, some subpopulations were lost and previously undetectable ones materialized. GSCs highly expressing all four surface markers had the greatest self-renewal capacity and in vivo tumorigenicity as well as the strongest WNT pathway activation. This work highlights the signaling and phenotypic diversity in GSC subpopulations, together suggesting that not all GSCs are equivalent. These observations should be considered when studying GSCs in the laboratory, with implications for the development of treatments that target GSCs and prevent tumor recurrence in patients.
STEM-19. THE ISOLATION AND IDENTIFICATION OF GLIOMA STEM CELLS AND MESENCHYMAL STEM CELLS FROM HUMAN GLIOMA SPECIMENS
Authors: Yu Yan-jiao , Jing Wang , Chen Zhong-ping
Published: December 2020

INTRODUCTION

Glioma is the primary malignancy with the highest incidence in central nervous system. Studies have shown that glioma stem cell (GSC) is the important origin for recurrence and closely associated with tumor microenvironment. Glioma-associated human mesenchymal stem cells (GA-hMSCs), as an important part of the tumor microenvironment, might promote proliferation and invasion of GSC. We try to isolate GSCs and GA-hMSCs through glioma primary culture, and investigate the relationship between GSC and GA-hMSCs, as well as their roles in the recurrences of glioma.

MATERIALS AND METHODS

Five surgical specimens from patients with human high-grade glioma were collected for primary culture. The surgical specimens were cut up and digested with Dispase II (collagenase), terminated by adding plenty of DNase II. Cell suspension was collected and resuspended in conditional medium for MSC or GSC. After being cultured for several passages, GSCs were identified by immunofluorescence, and GA-hMSCs were identified by flow cytometry and in vitro differentiation assays.

RESULTS

Cell cultures were observed with an inverted phase-contrast microscope after 24 hours. Adherent GA-hMSCs were collected and the supernatant was discarded with non-adherent cells. GSC was cultured as neurospheres. The single-cell suspension was prepared from spheres of GSC to identify their surface expression profile by immunofluorescence assays after several passages. The results confirmed that GSCs positively expressed CD133, Nestin and SOX2, but did not express GFAP and Tublin III. GA-hMSCs positively expressed CD105, CD73, CD90 and negatively expressed CD45 and CD34. GA-hMSCs could differentiate into adipocytes, chondrocytes and osteocytes.

CONCLUSION

We isolated and identified GSCs and GA-hMSCs from glioma primary culture. Our future work will focus on the relationship between the two types of cells and their roles in the process of tumor recurrence based on the successful isolation of GSC and GA-hMSCs. Keywords: Glioma; Mesenchymal stem cells; Glioma stem cells; Recurrence
STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM
Authors: Skirboll Stephen , Lucki Natasha , Villa Genaro , Vergani Naja , Bollong Michael , Beyer Brittney , Lee Jae Wook , Anglin Justin , Spangenberg Stephan , Chin Emily , Sharma Amandeep , Johnson Kevin , Sander Phillipp , Gordon Perry , Wurdak Heiko , Schultz Peter , Mischel Paul , Lairson Luke
Published: December 2020

INTRODUCTION

Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner.

METHODS

A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation.

RESULTS

We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation.

CONCLUSIONS

Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.
STEM-27. miR-10b-5p MODULATES 5hmC EXPRESSION AND THE STEM-LIKE PHENOTYPE IN GBM
Authors: Khela Harmon , Sudhir Sweta , Lugo-Fagundo Maria , Lal Bachchu , Lopez-Bertoni Hernando , Laterra John
Published: December 2020

Epigenetic alterations such as DNA methylation and dysregulation of non-coding RNAs (e.g. miRNAs) are found in all types of cancer and are thought to play important roles in tumorigenesis. GBM is characterized by small subsets of cells, referred to as glioma stem cells (GSCs), that display stem-like properties implicated in tumor initiation, therapeutic resistance, and recurrence. DNA methylation patterns are altered in GBM and GSCs and are thought to play critical roles in tumor initiation and propagation. DNA methylation is a reversible process catalyzed, in part, by the ten-eleven translocation (TET) family of enzymes. These enzymes function as deoxygenases that catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Multiple studies found negative correlations between 5hmC levels and glioma grade and loss of 5hmC correlates with poor prognosis of GBM patients. However, the mechanisms leading to the loss of 5hmC in glioma and the role this phenomenon plays in gliomagenesis remains poorly understood. We found that Sox2 expression decreases TET2 expression and its product 5hmC in GSCs and identified miR-10b-5p as a molecular intermediary of this process. We show that miR-10b-5p expression is high in GBM compared to non-tumor in clinical specimens and high levels of this miRNA correlate with poor patient outcome. Expression of transgenic miR-10b-5p enhanced sphere formation capacity of GSCs and the expression of stem cell markers and drivers. Additionally, using a combination of molecular and biochemical endpoints, we show that miR-10b-5p modifies 5hmC levels by regulating TET2 in GSCs. Finally, we show that repression of miR-10b-5p increases 5hmC levels and inhibits tumor propagation in GBM xenograft models. Taken together, these results present a new molecular mechanism that controls 5hmC and the tumor propagating capacity of GSCs and suggests that miR-10b-5p inhibition and other strategies for enhancing TET2 function can be developed to treat GBM.
SURG-02. SURVIVAL PREDICTION AFTER NEUROSURGICAL RESECTION OF BRAIN METASTASES: A MACHINE LEARNING APPROACH
Authors: Hulsbergen Alexander , Lo Yu Tung , Kavouridis Vasileios , Phillips John , Smith Timothy , Verhoeff Joost , Yu Kun-Hsing , Broekman Marike , Arnaout Omar
Published: December 2020

INTRODUCTION

Survival prediction in brain metastases (BMs) remains challenging. Current prognostic models have been created and validated almost completely with data from patients receiving radiotherapy only, leaving uncertainty about surgical patients. Therefore, the aim of this study was to build and validate a model predicting 6-month survival after BM resection using different machine learning (ML) algorithms.

METHODS

An institutional database of 1062 patients who underwent resection for BM was split into a 80:20 training and testing set. Seven different ML algorithms were trained and assessed for performance. Moreover, an ensemble model was created incorporating random forest, adaptive boosting, gradient boosting, and logistic regression algorithms. Five-fold cross validation was used for hyperparameter tuning. Model performance was assessed using area under the receiver-operating curve (AUC) and calibration and was compared against the diagnosis-specific graded prognostic assessment (ds-GPA); the most established prognostic model in BMs.

RESULTS

The ensemble model showed superior performance with an AUC of 0.81 in the hold-out test set, a calibration slope of 1.14, and a calibration intercept of -0.08, outperforming the ds-GPA (AUC 0.68). Patients were stratified into high-, medium- and low-risk groups for death at 6 months; these strata strongly predicted both 6-months and longitudinal overall survival (p < 0.001).

CONCLUSIONS

We developed and internally validated an ensemble ML model that accurately predicts 6-month survival after neurosurgical resection for BM, outperforms the most established model in the literature, and allows for meaningful risk stratification. Future efforts should focus on external validation of our model.
SURG-05. IDEAL TREATMENT REGIMEN FOR PATIENTS WITH ≥1 BRAIN METASTASIS FROM PRIMARY NON-SMALL-CELL LUNG CANCER – A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS
Authors: Brar Karanbir , Ellenbogen Yosef , Sadeghirad Behnam , Deng Jiawen , Hou Winston , Wang Xiaoqin , Taslimi Shervin , Mansouri Alireza
Published: December 2020

BACKGROUND

Brain metastases (BM) are common in non-small cell lung cancer (NSCLC). The aim of this study was to assess the comparative effectiveness of treatments for BM from NSCLC.

METHODS

We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published until October 2018. We also searched the Chinese databases Wanfang Data, Wanfang Med Online, China National Knowledge Infrastructure, and Chongqing VIP Information for RCTs published until September 2019. Trials including > 10 patients were selected. The primary outcomes were overall survival (OS) and intracranial progression-free survival (PFS). We used a frequentist random-effects model for network meta-analysis and assessed the certainty of evidence using the GRADE approach.

RESULTS

Among 8798 abstracts, 106 RCTs (9452 patients) met inclusion criteria. Median sample size was 67 (range 25-554). All trials included adult patients with histologically proven NSCLC and >1 BM proven on CT/MRI. Of trials that reported performance status (e.g. ECOG or KPS, n=67), 63/67 excluded patients with non-favorable performance status. Interventions assessed included surgery, WBRT, SRS, targeted therapies (i.e. EGFR/ALK inhibitors), and chemotherapy. Compared to WBRT alone, several interventions demonstrated a statistically significant increase in median OS, including non-targeted chemotherapy + surgery (MD: 415.3 days, 95% CI: 31.3-799.4), WBRT + EGFRi (MD: 200.2 days, 95% CI:146.3-254.1), and EGFRi alone (MD: 169.7 days, 95% CI: 49.7-289.7). Among all interventions, only WBRT + EGFRi showed a significant improvement in median PFS (MD: 108.0 days, 95%CI: 48.5-167.5).

CONCLUSIONS

Our preliminary analyses indicate an OS and PFS benefit on the addition of EGFR inhibitors to WBRT for the treatment of BMs from NSCLC. Further analyses of hazard ratios for OS/PFS are underway, and subgroup analyses are planned. These data support the growing role of targeted therapies in the treatment of BMs, particularly in susceptible mutant tumours.
SURG-10. PROGNOSTIC IMPORTANCE OF THE EXTENT OF RESECTION IN IDH-WILD TYPE GRADE II ASTROCYTOMAS ACCORDING TO PTERT MUTATION
Authors: Pellerino Alessia , Bruno Francesco , Silvani Antonio , Ius Tamara , Bello Lorenzo , Minniti Giuseppe , Pace Andrea , Lombardi Giuseppe , Soffietti Riccardo , Rudà Roberta
Published: December 2020

BACKGROUND

IDH-wild type diffuse astrocytomas with pTERT mutation have been suggested by cIMPACT-NOW update 3 to share a poor prognosis with glioblastoma (GBM). In a previous series of the Italian Association of Neuro-Oncology, we reported that IDH-wild type grade II astrocytomas benefit from gross total resection. However, the impact of surgery in the pTERT-mutated subgroup has not been addressed so far. Here, we present our preliminary data about the impact of the extent surgery according to pTERT status.

MATERIAL AND METHODS

We re-analysed a national database of 122 patients with grade II IDH-wild type astrocytoma. P-TERT mutation was evaluated by gene sequencing. Kaplan-Meier curves were used for the analysis of progression-free and overall survival (PFS and OS).

RESULTS

Median follow-up was 33.0 months. P-TERT status was available in 40 cases and the mutation was found in 27 cases (67.5%). Patients with pTERT mutation had a significantly shorter PFS (9.4 vs 147.7 months, P < 0.001) and OS (NR vs 36.6 months, P = 0.012). Furthermore, the OS of patients with pTERT mutation, who underwent gross total resection, was significantly longer than in patients with subtotal / partial resection (37.0 vs 32.0 months, P = 0.018). Thus far, the OS of patients without pTERT mutation was not reached with either subtotal / partial or gross total resection.

CONCLUSIONS

IDH-wild type astrocytomas may be stratified into classes with different outcome based on the pTERT mutation. As far as we know, this is the first study that specifically investigated the importance of a gross total resection according to pTERT status in IDH-wild type grade II astrocytomas.
SURG-13. LASER INTERSTITIAL THERMAL THERAPY FOR RECURRENT GLIOBLASTOMA: A REVIEW OF SURVIVAL OUTCOMES COMPARED TO A MATCHED SURGICAL COHORT
Authors: Fadel Hassan , Haider Sameah , Pawloski Jacob , Zakaria Hesham , Chaudhry Farhan , Bartlett Seamus , Bazydlo Michael , Kalkanis Steven , Lee Ian
Published: December 2020

INTRODUCTION

Glioblastoma (GBM) is uniformly associated with a poor prognosis and inevitable recurrence. Management of recurrent GBM remains unclear, with repeat surgery often employed with varying degrees of success. We evaluated the efficacy of Laser Interstitial Thermal Therapy (LITT) for recurrent GBM when compared to a carefully matched cohort of patients treated with repeat surgical resection.

METHODS

A retrospective single-institution database was used to identify patients who underwent LITT or surgical resection of recurrent GBM between 2014-2019. LITT patients were matched with surgical resection patients according to baseline demographics, comorbidities, tumor location, and eloquence. Subgroup analysis matching similar patients for tumor volume was also completed. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints.

RESULTS

A LITT cohort of 20 patients was matched to 50 similar patients who underwent repeat surgical resection. Baseline characteristics were similar between both cohorts apart from tumor volume, which was larger in the surgical cohort (17.5 cc vs. 4.7 cc, p< 0.01). On long-term follow-up, there was no difference in OS (HR, 0.72; 95%CI, 0.36-1.45) or PFS (HR, 0.67; 95%CI, 0.29-1.53) between the LITT and surgical cohorts when controlling for tumor volume. Subgroup analysis of 23 LITT patients matched according to tumor volume with 23 surgical patients with similar clinical characteristics also found no difference in OS (HR, 0.66; 95%CI, 0.33-1.30) or PFS (HR, 0.58; 95%CI, 0.90-1.05) between the cohorts. LITT patients had shorter length of stays (1 vs. 4 days, p< 0.001) and a higher rate of home discharge (84% vs. 67%, p=0.172) compared to the surgical cohort.

CONCLUSION

After matching for demographic, clinical, and tumor characteristics, there was no difference in outcomes between patients undergoing LITT compared to surgical resection for recurrent GBM. LITT patients had similar survival outcomes yet shorter hospital stays and more favorable dispositions, potentially mitigating post-treatment complications.
SURG-14. AWAKE CRANIOTOMY VS CRANIOTOMY UNDER GENERAL ANESTHESIA FOR GLIOBLASTOMAS: EVALUATING THE IMPACT ON OVERALL SURVIVAL AND RISK OF RECURRENCE
Authors: Moro Mario
Published: December 2020

Maximum safe resection for eloquent glioblastomas (GBMs) is the maximum tumor resection achievable without causing neurological deficits. Although challenging, it must be considered the therapeutic target for GBMs. Indeed, the extension of resection positively correlates with the overall survival and recurrences risk. Awake surgery (AS) has become paramount for achieving maximum safe resection for tumors in eloquent areas. However, there is not a unanimous consensus on the extent of resection of eloquent GBMs, especially for what concerns the so-called supratotal resection (i.e.: resection over the contrast-enhancing limits of the lesion). Recently, several studies focused their attention on the residual tumor volume as estimated from T1-contrast enhanced sequences, but few analyzed the outcomes of patients with a more extended resection. Some authors speculated that increased surgical aggressiveness, thus removing peritumoral edematous area, correlates with improved overall survival and tumor control, without increasing adverse events rates. This study aimed to assess, through quantitative volumetric analysis, the outcomes of a prospectively collected cohort of patients with primary GBM located in eloquent areas. We furtherly subdivided our population into two treatment groups: awake surgery (AS) and general anesthesia (GA) craniotomies. We analyzed the overall outcomes, especially for what concerns MRI T2-Flair signal extent of resection, related to patients’ survival and recurrences formation. Eventually, we stratified our analysis by type of treatment (awake surgery vs. general anesthesia) to rule out any significant differences in survival and postoperative GBMs behaviors. Our data confirmed extensive that T2-Flair resection (EOR≥30%) and AS could improve overall survival and reduce risk of recurrence without, at the same time, causing an increase of surgical and medical complications
SURG-15. A NOVEL RISK MODEL TO DEFINE THE RELATIVE BENEFIT OF MAXIMAL EXTENT OF RESECTION WITHIN PROGNOSTIC GROUPS IN NEWLY DIAGNOSED DIFFUSE LOW-GRADE GLIOMA
Authors: Hervey-Jumper Shawn , Molinaro Annette , Phillips Joanna , Morshed Ramin , Young Jacob , Zhang Yalan , LaFontaine Marisa , Luks Tracy , Ammanuel Simon , Kakaizada Sofia , Villanueva-Meyer Javier , Shai Anny , Warrier Gayathri , Rice Terri , Lin Yi , Crane Jason , Wrensch Margaret , Wiencke John , Bush Nancy Ann Oberheim , Taylor Jennie , Butowski Nicholas , Clarke Jennifer , Chang Susan , Chang Edward , Aghi Manish , Theodosopoulos Philip , Berger Mitchel
Published: December 2020

BACKGROUND

The overall prognostic significance of maximal surgical resection in patients with diffuse low-grade glioma has been well established. Nonetheless, prior studies omit the combined importance of molecular subclass, patient characteristics, and chemoradiation. Similar to findings recently published in newly diagnosed glioblastoma, incorporation of these interactive factors may redefine the relative benefit of cytoreductive surgery.

METHODS

We examine the interactive effects of volumetric extent of resection with molecular and clinical factors to develop a new roadmap for cytoreductive surgery. Based on a 20-year retrospective cohort of 556 patients with WHO II diffuse low-grade glioma treated with surgery at UCSF 444 had complete records for survival modeling and recursive partitioning (RPA) to investigate multivariate relationships of overall and progression free survival.

RESULTS

Regardless of molecular subtype, patients with tumor volume under 55cm3 and postoperative volume of residual under 1.9cm3 experience the longest OS (median OS: not reached). Patients with volume of residual over 1.9cm3 experience a OS similar to that of patients with large (over 55cm3) oligodendrogliomas (median OS: not reached). Patients faring worst have large (over 55cm3) astrocytic gliomas (median OS: 84.8 months). Patients not treated with chemotherapy and either ATRX wild-type tumors or ATRX-mutant tumors with small (under 1cm3) volume of residual have the longest PFS together with chemotherapy treated patients who receive either no radiation or radiation for p53-mutant tumors under 30cm3 (median PFS 119 months). Patients with the shortest PFS are under 32-years with larger volume of residual (>1cm3), who receive no chemotherapy for ATRX-mutant tumors together with patients who receive both chemoradiation for larger (>30cm3) p53 mutant tumors (median PFS 30.8 months).

CONCLUSION

This is the first study to combine extent of resection with molecular and clinical information which paves the way for rethinking surgical strategies for individual patients with newly diagnosed low-grade gliomas.
SURG-17. EFFICACY AND SAFETY OF LASER INTERSTITIAL THERMAL ABLATION IN ELDERLY BRAIN TUMOR PATIENTS
Authors: Pawloski Jacob , Haider Sameah , Fadel Hassan , Zakaria Hesham , Noh Thomas , Bazydlo Michael , Lee Ian
Published: December 2020

INTRODUCTION

Open craniotomy for tumor carries notable perioperative risks as well as associated prolonged ICU stays. Risks of surgery are increased in elderly patients. In addition, many tumors are not amenable to resection due to their deep or eloquent location. Magnetic resonance-guided laser interstitial thermal ablation (LITT) offers an alternative, minimal-access procedure.

OBJECTIVE

To examine the safety and efficacy of LITT procedures in elderly brain tumor patients.

METHODS

Data was gathered on patients over the age of 65 who underwent MRI-guided LITT for ablation of tumor at our institution between 2014-2019. These cases were analyzed retrospectively and data was collected on patient demographics, tumor characteristics, procedural details, and post-operative complications and outcomes.

RESULTS

19 patients over the age of 65 underwent LITT during the study time period and were included in the analysis. The average age was 70 years (range 65-81), with a median follow up of 7 months. Patients had an average of 3.5 pre-existing medical comorbidities with a mean pre-operative Karnofsky Performance Score (KPS) of 87 (SD = 10.4). 13 patients underwent LITT for primary CNS tumor and 6 for metastatic lesions. The average lesion volume was 3.44 cm3 with approximately one-third in eloquent areas. An average extent of ablation of 98% was achieved (90-100%). 5/19 patients experience at least one post-op complication including 2 venous thromboembolic events and 1 stroke within 30 days. The average length of stay was 2.3 days, and 13/19 patients were discharged home. No patients experienced new permanent neurological deficits and the average post-operative KPS was 83 (SD = 12.4). 9 patients experienced progression of disease after an average of 155 days, and 11 patients were deceased (average survival = 504 days).

CONCLUSION

LITT is well tolerated in appropriately selected elderly patients with short post-operative length of stay and minimal surgical morbidity.
SURG-18. THE IMPACT OF NEUROLOGIC IMPAIRMENTS ON THE RELATIVE BENEFIT OF MAXIMAL EXTENT OF RESECTION IN NEWLY DIAGNOSED IDH-WILD TYPE GLIOBLASTOMA
Authors: Hervey-Jumper Shawn , Molinaro Annette , Ore Cecilia Dalle , Brown Desmond , Zhang Yalan , Morshed Ramin , LaFontaine Marisa , Ammanuel Simon , Shai Anny , Warrier Gayathri , Rice Terri , Lin Yi , Crane Jason , Phillips Joanna , Wrensch Margaret , Wiencke John , Bush Nancy Ann Oberheim , Taylor Jennie , Butowski Nicholas , Clarke Jennifer , Chang Susan , Aghi Manish , Theodosopoulos Philip , Berger Mitchel
Published: December 2020

BACKGROUND

The prognostic importance of maximal resection of contrast enhancing and non-contrast enhancing disease has been established. Nonetheless, glioblastomas exist within the framework of complex neural circuitry serving cognition, movement, and behavior consequential leading to neurological impairments. The prognostic importance of neurological impairments on survival remains poorly understood.

METHODS

This is a retrospective, single cohort study from UCSF including 316 eligible patients diagnosed over 20 years with 9.6 years of follow-up. All patients underwent surgical resection for newly diagnosed glioblastoma for whom survival, molecular, preoperative and postoperative MRI images, and clinical data were available. All patients had chemoradiation treated IDH-wild-type glioblastoma with available preoperative and 1-month post-surgical resection neurological outcomes. We employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS).

RESULTS

Preoperative neurological impairments were present in 75.6% (n= 239) and new post resection impairments were identified in 37.3% (n=117). Univariate analysis confirmed that new postoperative cognitive impairment [HR 7.91, 95% CI 2.47-25.33] and hemiplegia [HR 3.38, 95% CI 0.83-13.67] (not hemiparesis) impact OS. Risk stratified grouping by RPA demonstrated that gross total resection of contrast enhancing tumor in patients with no new postoperative neurological impairments confers the longest OS (median OS 27.1 months 95%CI 21.5-33.7). Patients with any residual tumor volume after surgery but no new neurological deficits experience a similar survival to younger patients (under 65) with 1 or more new postoperative neurological deficits (median OS 16.6 months 95%CI 15.2-19.2). Shortest OS is identified in patients with any volume of residual tumor plus 1 or more new postoperative neurological deficits and age over 65 (median OS 11.4 months, 95%CI 9.3-13.5).

CONCLUSIONS

This study confirms that new postoperative neurological impairments impact overall survival in patients with chemoradiation treated IDH-wild-type glioblastoma.
SURG-21. A CROWDSOURCED CONSENSUS ON SUPRATOTAL RESECTION VERSUS GROSS TOTAL RESECTION FOR ANATOMICALLY DISTINCT PRIMARY GLIOBLASTOMA
Authors: Mukherjee Debraj , Rakovec Maureen , Bettegowda Chetan , Jackson Christopher , Gallia Gary , Lim Michael , Weingart Jon , Esquenazi Yoshua , Zacharia Brad , Goldschmidt Ezequiel , Ziu Mateo , Ivan Michael , Venteicher Andrew , Nduom Edjah , Mamelak Adam , Chu Ray , Yu John , Sheehan Jason , Nahed Brian , Carter Bob , Berger Mitchel , Sawaya Raymond , Khalafallah Adham
Published: December 2020

Gross total resection (GTR) of contrast-enhancing tumor is associated with significantly increased overall survival in primary glioblastoma (GBM). Even when achieved, recurrence is likely, in part due to malignant cells infiltrating outside enhanced regions. Subsequently, there has been increasing interest in performing supratotal resections (SpTRs) for GBM. Published results have varied in part due to a lack of consensus on the definition of SpTR in GBM and its appropriate use. A crowdsourcing approach was used to survey 21 academic neurosurgical oncologists representing 13 health systems nationwide. Participants’ demographics including fellowship training status, years of experience, and operative volume with various techniques was collected. Participants were presented with 11 definitions of SpTR from published, peer-reviewed studies and asked to rate the appropriateness of each definition. Subsequently, participants reviewed T1-weighed post-contrast and FLAIR MR imaging videos in the axial, coronal, and sagittal planes for 22 GBMs. Participants were asked to assess eloquence of the tumor’s location, perceived equipoise of enrolling patients in a randomized clinical trial comparing GTR to SpTR, and their own personal surgical treatment plans. Most neurosurgeons surveyed (n=18, 85.7%) agree or strongly agree that GTR plus resection of some non-contrast enhancement is an appropriate definition for SpTR. Overall, there was only moderate inter-rater agreement, measured using sample variance and the index of qualitative variation, regarding eloquence, equipoise, and personal treatment plans. Neurosurgeons who performed more than 10 SpTRs for GBMs in the past year were more likely than counterparts to recommend it as their personal treatment plan (p< 0.005). Anterior temporal and right frontal GBMs were considered the best randomization candidates. We established a consensus definition for SpTR of GBM and identified anatomically distinct locations deemed most amenable to SpTR. These results will be used to plan prospective trials further investigating the potential clinical utility of SpTR for GBMs.
SURG-32. DIFFERENCES IN SURGICAL OUTCOME BETWEEN VON HIPPEL-LINDAU DISEASE RELATED AND SPORADIC HEMANGIOBLASTOMAS IN THE CENTRAL NERVOUS SYSTEM
Authors: Nambu Shohei , Takayanagi Shunsaku , Takami Hirokazu , Kin Taichi , Tanaka Shota , Nakatomi Hirofumi , Saito Nobuhito
Published: December 2020

Central nervous system hemangioblastoma (CNS HB) is a benign but highly vascular tumor, which accounts for 1.7% of all intracranial tumors. CNS HBs predominantly arise in the cerebellum, brainstem, and spinal cord. Approximately 20% of CNS HB is related to von-Hippel-Lindau (VHL) disease and repeated surgical resections are often required in VHL patients due to the presence of multiple CNS HBs. To explore the differences of surgical effect between VHL disease related and sporadic CNS HBs, outcome analyses were performed based on the tumor locations. PATIENT AND METHODS: A total 83 cases that underwent surgical resections of CNS HBs at Tokyo University in 1996-2019 were included. Clinical information including age, sex, number of past surgical resections, pre- and post-operative modified Rankin Scale(mRS) were examined. RESULTS: Regarding the etiology, 46 VHL cases(cerebellum:30, medulla oblongata:6, spinal cord:10) and 37 sporadic cases (cerebellum: 28, medulla oblongata:4, spinal cord:5) were enrolled. The average changes in the postoperative mRS minus preoperative mRS were cerebellum -0.9/medulla oblongata -0.5/spinal cord -0.8 for VHL cases, and cerebellum -0.75/medulla oblongata -1/spinal cord -1 for sporadic cases. Fisher`s exact tests were used for between-group comparison. DISCUSSION: The study showed no statistically significant difference between cerebellar and spinal cord cases regarding the perioperative change in the patient capability. Because of multiple lesions and repeated surgeries, VHL patients have a possibility to present with worse neurology after surgery. Further analysis is needed to clarify differences in surgical outcome for VHL disease related and sporadic related CNS HBs.
SURG-38. SEIZURE OUTCOME AFTER EPILEPSY SURGERY IN CHILDREN WITH BRAIN TUMORS
Authors: Siddiqui Ayat , McGregor Amy L , Wheless James W , Fulton Stephen P , Weatherspoon Sarah E , Kilmo Paul , Boop Frederick A , Khan Raja B
Published: December 2020

INTRODUCTION

Epilepsy is a common chronic neurological complication of childhood brain tumors and seizures are refractory to medical therapy in up to 10% of patients. Referral for a diagnostic evaluation is recommended in patients with seizures refractory to ≥2 anti-epileptic drugs (AED). Utility of epilepsy surgery is not established in children with brain tumors.

OBJECTIVE

Primary aim of this study was to determine seizure outcome after epilepsy surgery in children with childhood brain tumors.

METHODS

Institutional Review Board’s approval was obtained for this retrospective study. A diagnosis of childhood brain tumor and a referral to the epilepsy monitoring unit (EMU) were required to be included in this study. Seizure outcome was defined according to International League Against Epilepsy (ILAE) outcome scale. Pre and post-operative MRIs were reviewed.

RESULTS

Forty-two children were referred to the EMU from May 2004 to July 2019. Of the 10 patients that underwent epilepsy surgery, 7 (70%) had pre-surgery frequency of >10 seizures/month and 3(30%) of these had multiple daily seizures; the rest had 3-4 seizures/month. All were taking ≥3 AEDs. Median time from first seizure to surgery was 83.7 months (range 24.3-151.6). At a median follow-up of 67.5 months (range 4.9-133.5) after epilepsy surgery, 60% reported no seizures in the 6-months before the last follow-up. Three (30%) had ILAE class-1 outcome, 4 (40%) class-3, and 3 (30%) were class-4. One child was off AEDs and the others were on a single AED at last follow-up. No post-operative neurological or cognitive deficits were recognized. Focal cortical atrophy was present in 40% of children before and in 30% after surgery.

CONCLUSION

Epilepsy surgery improved seizure outcome in all children that had epilepsy surgery and reduced the number of AEDs needed to treat seizures. Children with brain tumors and intractable seizures should be referred for epilepsy surgery evaluation.
SURG-40. SURGICAL RESECTIONS IN BROCA’S AREA DO NOT LEAD TO BROCA’S APHASIA
Authors: Andrews John , Cahn Nathan , Speidel Benjamin , Lu Valerie , Berger Mitchel , Chang Edward
Published: December 2020

Brodmann’s areas 44/45 of the inferior frontal gyrus (IFG), are the seat of Broca’s area. The Western Aphasia Battery is a commonly used language battery that diagnoses aphasias based on fluency, comprehension, naming and repetition. Broca’s aphasia is defined as low fluency (0-4/10), retained comprehension (4-10/10), and variable deficits in repetition (0-7.9/10) and naming (0-8/10). The purpose of this study was to find anatomic areas associated with Broca’s aphasia. Patients who underwent resective brain surgery in the dominant hemisphere were evaluated with standardized language batteries pre-op, POD 2, and 1-month post-op. The resection cavities were outlined to construct 3D-volumes of interest. These were aligned using an affine transformation to MNI brain space. A voxel-based lesion-symptom mapping (VLSM) algorithm determined areas associated with Broca’s aphasia when incorporated into a resection. Post-op MRIs were reviewed blindly and percent involvement of pars orbitalis, triangularis and opercularis was recorded. 287 patients had pre-op and POD 2 language evaluations and 178 had 1 month post-op language evaluation. 82/287 patients had IFG involvement in resections. Only 5/82 IFG resections led to Broca’s aphasia. 11/16 patients with Broca’s aphasia at POD 2 had no involvement of IFG in resection. 35% of IFG resections were associated with non-specific dysnomia and 36% were normal. By one-month, 76% of patients had normal speech. 80% of patients with Broca’s aphasia at POD 2 improved to normal speech at 1-month, with 20% improved to non-specific dysnomia. The most highly correlated (P< 0.005) anatomic areas with Broca’s aphasia were juxta-sylvian pre- and post-central gyrus extending to supramarginal gyrus. While Broca’s area resections were rarely associated with Broca’s aphasia, juxta-sylvian pre- and post-central gyri extending to the supramarginal gyrus were statistically associated with Broca’s type aphasia when resected. These results have implications for planning resective brain surgery in these presumed eloquent brain areas.
SURG-43. APPLICATIONS AND RESTRICTION OF 980NM DIODE LASER FOR BRAIN TUMOR MICROSURGERY - A PIONEER CASE SERIES AND A CRITICAL REVIEW
Authors: Campos Paiva Aline , Araujo João Luiz Vitorino , Lovato Renan , Krambek Márcio , Veiga José Esteves
Published: December 2020

BACKGROUND

Quality of life is essential for oncological patients. There are several tools that help surgery become more precise with less morbidity. Diode laser can cut and coagulate through thermal effect being helpful during surgery. It is a precise and useful technology that improves outcomes in neurooncology.

OBJECTIVES

To describe a pioneer case series of oncological use of diode laser and main applications of several types of laser in neurooncology.

METHODS

Detailed description of a pioneer case series of oncological patients that undergone to neurosurgical laser assisted procedures. An interventional longitudinal prospective study was conducted. Patients that had as mainly hypothesis the diagnosis of glioma or meningioma were selected. Also it was performed an extensive literature review about lasers in neurosurgery with special focus in diode laser.

RESULTS

There was not any paper describing the use of diode laser in neurooncology. The 980nm diode laser was used in 15 patients. The device had an easy handling. Decreased intra-operative time for hemostasis, lesser blood loss requiring less blood transfusion was observed. No post-operative complications occurred.

CONCLUSIONS

Diode laser is a useful tool for brain tumor surgery especially concerning hemostasis, providing decreased blood loss with lesser intra-operative duration. Surgical site coagulation is more effective causing less damage to adjacent structures specially in gliomas near eloquent regions. We consider this technique as a suitable adjuvant therapy for brain tumor surgeries providing an excellent hemostasis and helping cutting and vaporize lesion. This device makes surgery safer and decrease oncological morbidity.