bluuebunny/crossref_metadata_2025 huggingface dataset:
CMET-13. THE COMPOSITION OF NEWLY-DIAGNOSED BRAIN METASTASES VARIES WIDELY BY PATIENT DEMOGRAPHICS
Authors: Kavouridis Vasileios , Torre Matthew , Harary Maya , Smith Timothy , Iorgulescu Bryan
Published: November 2019

INTRODUCTION

Metastases comprise a significant subset of all intracranial neoplasms, but their national composition remains unclear and challenging to track in national cancer registries.

METHODS

The patient demographics and histologic distribution of newly-diagnosed brain metastasis (BM) patients aged >18yo without a prior history of cancer (2010–2015) were evaluated using the National Cancer Database, which comprises >70% of all newly-diagnosed cancers in the U.S.

RESULTS

91,686 adults presented with a newly-diagnosed BM between 2010–2015. The most common sites of brain metastases overall were lung (82% of metastatic cases), breast (4.1%), melanoma (3.2%), kidney (2.9%), and colorectal (1.8%). The overall 1-year and 5-year OS rates for all metastatic tumors were 27.0% (95%CI=26.7–27.3]) and 5.3% (95%CI=5.1–5.5), respectively. The distribution of primary sites for newly diagnosed intracranial metastases varied by sex, age, and race. Compared to males, more females had BMs from breast (8.4% versus 0.8%) and fewer had BMs from kidney (1.9% versus 3.8%), melanoma (1.9% versus 4.5%), and esophagus (0.3% versus 2.0%). In young adults, particularly those 20-29yo, BMs were more likely from melanoma, genitourinary (in males), and soft tissue than adults in middle and advanced age. Lung carcinomas comprised fewer BMs in Hispanics (66%) compared to Whites (82%), Blacks (83%), and Asian/Pacific Islanders (85%). BMs from kidney and genitourinary primaries were higher in Hispanics (7.3% and 2.4% of BMs, respectively) than in Whites (2.8% and 0.3%, respectively), Blacks (1.8% and 0.1%, respectively), and Asian/Pacific Islanders (2.6% and 0.2%, respectively). Melanoma was more frequent in Whites (3.8% of BMs) and Hispanics (2.5%) compared to Blacks (0.3%) and Asian/Pacific Islanders (0.6%).

CONCLUSION

Our results illustrate the national distribution of newly-diagnosed BMs and investigates how the distribution varies by patient demographics.
CMET-15. SARCOPENIA INDEPENDENTLY AND STRONGLY PREDICTS SURVIVAL IN PATIENTS UNDERGOING SPINE SURGERY FOR METASTATIC TUMORS
Authors: Zakaria Hesham , Saadeh Yamaan , Lau Darryl , Pennington Zachary , Ahmed Ali , Chandra Ankush , Macki Mohamed , Lee Ian , Chou Dean , Park Paul , Sciubba Daniel , Chang Victor
Published: November 2019

INTRODUCTION

Predicting survival and surgical morbidity in patients with spinal metastases would help guide clinical decision making and stratify treatments between surgical intervention and palliative care. This multi-center retrospective cohort study evaluates whether the frailty/sarcopenia paradigm, as measured by psoas size, is predictive of survival in patients undergoing surgery for spinal metastasis.

METHODS

271 patients from four institutes who had undergone surgery for spinal metastasis were identified. Morphometric measurements were taken of the psoas muscle at the L4 vertebral level < 200d from surgery. Mortality hazard ratios were calculated using multivariate analysis, with variables included from past medical history, type and extent of tumor spread, type and intensity of surgery, and postoperative chemotherapy or radiation.

RESULTS

Psoas size was predictive of overall mortality; patients in the smallest tertile had shorter overall survival compared to the middle (OR 0.52, p< 0.001) and largest tertile (OR 0.45, p< 0.001). Psoas size predicted overall mortality more strongly than Tokuhashi score (OR 0.91, p= 0.010), Tomita score (OR 1.07, p= 0.04), and KPS (OR 0.99, p= 0.58). Psoas size was also predictive of 90-day survival; patients in the smallest tertile had shorter 90-day survival compared to the middle (OR 0.24, p= 0.003) and largest tertile (OR 0.16, p= 0.001). Psoas size predicted 90-day mortality more strongly than Tokuhashi score (OR 0.73, p= 0.002), Tomita score (OR 1.00, p= 0.92), and KPS (OR 0.98, p= 0.39).

CONCLUSION

In patients undergoing surgery for spine metastases, psoas size as a surrogate for frailty/sarcopenia predicts 90-day and overall mortality, independent of demographical, functional, oncological, and surgical characteristics. The sarcopenia/frailty paradigm is a stronger predictor of survival at these time points than the Tokuhashi score, Tomita score, and KPS. Psoas size can be used in clinical decision-making to select which patients with metastatic spine tumors are appropriate surgical candidates.
CMET-19. QUESTIONING THE PARADIGM: DO CSF CYTOLOGY AND MRI SCANNING IDENTIFY THE SAME DISEASE IN PATIENTS WITH NEOPLASTIC MENINGITIS (NM) – DATA FROM AN INTERNATIONAL NM REGISTRY AND A META-ANALYSIS
Authors: Messner Christopher , Groves Morris , Hofer Silvia , Roberge David , Aregawi Dawit , Jeyapalan Suriya , Rudà Roberta , Glantz Michael
Published: November 2019

INTRODUCTION

CSF cytology and neuraxis MRI scanning are complementary examinations for diagnosing NM. Positive cytology is the current gold standard despite relatively low sensitivity. Although MRI is an accepted alternative diagnostic tool for both treatment and clinical trial inclusion, its sensitivity and specificity are poorly understood.

METHODS

We conducted an exhaustive, PRISMA-compliant systematic review of the literature from January 1990 to September 2016 comparing MRI to CSF cytology (the gold standard) for the diagnosis of NM. Relevant studies were assigned a level of evidence using AAN criteria. Pre-specified data was extracted, and summary statistics were calculated using the inverse variance method and random effects model. Survival of patients diagnosed with various combinations of CSF cytology and MRI was also extracted and summary statistics were calculated.

RESULTS

Thirteen studies (2 class-I, 5 class-II, 5 class-III, 1 class-IV, 1646 solid and hematologic tumor patients) provided data sufficient to calculate the diagnostic characteristics of MRI. Sensitivity and specificity were low (63.4% [56.5–71.2] and 40.1% [30.2–53.1] respectively). False positive and false negative rates were high (59.9% [46.9–69.8] and 36.6% [28.8–43.5] respectively). Various sensitivity analyses (recent studies, class I/II studies, only class I studies, specific tumor histologies) yielded very similar results. Overall survival in patients with MRI (+)/CSF (+), MRI (+)/CSF (-), and MRI (-)/CSF (+) disease (3 studies, 347 patients) were 50.8 [39.8–64.8], 115.4 [70.4–189.4] and 228.7 [130.5–400.7] days respectively (p < 0.001).

CONCLUSIONS

MRI scanning can diagnose leptomeningeal metastases, but is a very poor surrogate for CSF cytology. Patients with NM diagnosed by various combinations CSF cytology and MRI positivity have dramatically different survivals, suggesting that these categories define subsets of patients with NM with different natural histories. This finding has important implications for patient care and clinical trial design and interpretation. Novel diagnostic strategies for NM should be subjected to similar analysis.
CMET-22. CAPMATINIB (INC280) IN METΔEX14-MUTATED ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC): EFFICACY DATA FROM THE PHASE 2 GEOMETRY MONO-1 STUDY
Authors: Heist Rebecca S , Seto Takashi , Han Ji-Youn , Reguart Noemi , Garon Edward B , Groen Harry J M , Tan Daniel S W , Hida Toyoaki , de Jonge Maja , V Orlov Sergey , Smit Egbert F , Souquet Pierre-Jean , Vansteenkiste Johan , Le Mouhaer Sylvie , Robeva Anna , Waldron-Lynch Maeve , Giovannini Monica , Wolf Juergen
Published: November 2019

BACKGROUND

Capmatinib is a highly potent, selective MET-inhibitor known to cross the BBB, and intracranial activity with capmatinib has been previously reported. Updated results for overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and brain metastases (BM) activity from the GEOMETRY mono-1 study are presented here.

METHODS

GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in METΔex14-mutated or MET-amplified NSCLC patients. Patients (≥18 years) with ECOG PS 0–1, ALK-/EGFR-wt, and stage IIIB/IV NSCLC were eligible. Patients with asymptomatic BM were allowed. METΔex14-mutated patients were assigned to Cohorts 4 (1–2 prior lines of treatment) and 5b (treatment-naive) and received capmatinib 400mg BID. Endpoints by BIRC: ORR (primary, RECIST v1.1), DOR, and PFS. Ad hoc BIRC neuro-radiologic assessments of all Cohort 4 and 5b patients with baseline BM were performed.

RESULTS

As of April 15, 2019, 97 patients (Cohort 4: 69 patients; Cohort 5b: 28 patients) were evaluable for efficacy. BIRC assessments: ORR (95%CI): 40.6% (28.9–53.1) in Cohort 4; 67.9% (47.6–84.1) in Cohort 5b. Median DOR (95%CI): 9.7 (5.55–12.98) and 11.1 (5.55-NE) months and median PFS (95%CI): 5.4 (4.17–6.97) and 9.7 (5.52–13.86) months for Cohorts 4 and 5b, respectively. Of 13 evaluable patients with BM at baseline, 7 (54%) had intracranial response by BIRC, including 4 patients with complete resolution of brain lesions, and 12/13 had intracranial disease control. Responses in the brain were as fast as systemic responses. Most common treatment-related AEs (≥15%, all grades) across all cohorts (N=334): peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%); most AEs were grade 1/2.

CONCLUSION

These data confirm capmatinib to be a promising new treatment option for patients with METΔex14-mutated advanced NSCLC regardless of line of therapy, with deep and durable responses including in patients with brain metastases, and a manageable toxicity profile.
CMET-23. IMPACT OF SYSTEMIC THERAPY IN MELANOMA BRAIN METASTASIS
Authors: Sagar Soumya , Lauko Adam , Barnett Addison , (Auston) Wei Wei , Chao Samuel , Peereboom David , Stevens Glen , Angelov Lilyana , Yu Jennifer , Murphy Erin , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet
Published: November 2019

BACKGROUND

Melanoma is the third most common malignancy that results in brain metastasis and is associated with a median overall survival (OS) of approximately 9 months. In recent years, management of melanoma brain metastases (MBM) by surgery and radiation [stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT)] has been bolstered by targeted therapy and immune checkpoint inhibitors (ICI).

METHODS

351 patients, treated for MBM at our tertiary care center from 2000–2018, were grouped into: received chemotherapy, ICI, or targeted therapy. 34% of patients treated with ICI had received other systemic therapies as well as part of their management. OS was calculated from the date of diagnosis of the brain metastases. The Kaplan Meier analysis was utilized to determine median OS and difference in OS was determined by utilizing the Cox proportional hazard model.

RESULTS

The median survival after the diagnosis of brain metastasis was 10.4, 11.96, and 7.06 months in patients who received ICI, chemotherapy and targeted therapy respectively. A multivariate model was developed including the type of systemic therapy, presence of extracranial metastases, age, KPS and number of intracranial lesions. 114 patients underwent SRS alone, 56 underwent SRS and WBRT, 43 underwent SRS and surgical removal, 28 had surgical removal, SRS and WBRT, and 78 had no intracranial therapy. Compared to patients who received chemotherapy, patients who received immunotherapy had a hazard ratio, HR = 0.628 (confidence interval = 0.396 – 0.994, p-value = 0.047). Presence of EC metastases (HR= 1.25, p-value < .001), lower KPS (HR = .97, p-value < .0001) and multiple brain lesions (HR = 1.117, p-value < .0001) were associated with significantly worse OS.

CONCLUSIONS

Addition of ICI significantly improves the OS in MBM compared to chemotherapy. Lower performance status, multiple brain metastases, and EC metastases are associated with poor OS.
CMET-26. IN-VITRO & IN-VIVO CULTURE OF PATIENT (PT) DERIVED CSF-CTCS IN LEPTOMENINGEAL DISEASE (LMDZ) FROM MELANOMA TO IDENTIFY NOVEL TREATMENT STRATEGIES
Authors: Law Vincent , Evernden Brittany , Puskas John , Caceres Gisela , Ryzhova Elena , Smalley Inna , Tran Nam , Etame Arnold , Sahebjam Solmaz , Magliocco Anthony , Smalley Keiran , Forsyth Peter
Published: November 2019

BACKGROUND

Approx. 5% of melanoma pts develop LMDz. There are essentially no models of LMDz available for therapeutic development. Here we report, the in-vitro & in-vivo culturing of CSF-CTCs.

METHODS

CSF-CTCs were detected by the Veridex CellSearch® System. Cell-free DNA and cell-associated DNA were extracted, sequenced and profiled. Expanded ex-vivo CSF-CTCs were grown in-vitro and tested for drug sensitivity. CSF-CTCs were grown successfully in-vivo from 1 pt; labeled human Braf V600E WM164 cells were injected IT in as a control.

RESULTS

CSF-CTCs: 12 LMDz pts and 8 melanoma pts without LMDz were studied. All but 1 LMDz pts (92%) had CSF-CTCs (avg: 2148.6; range 23 - 3055 CTCs/ml). In contrast, 3/8 (37%) melanoma Brain Mets pts without LMDz had CSF-CTCs but fewer of them (avg: 0.31; range 0.13 - 0.6 CTCs/ml CSF). CSF-CTCs Profile: These had BrafV600E (83%), and GNAQ Q209P & NRAS Q61R in 1 pt each. Ex-vivoculture of CSF-CTCs and PDX model: After lengthy optimization of conditions we successfully expanded CSF-CTCs in vitro(~25% of pts), and in-vivo in immunodeficient mice from 1 pt (~10% of samples). Ceritinib, used as a FAK inhibitor, with MEKi was effective in-vitro (p=3.17e-6) and prolonged survival in-vivo in LMDz (median survival: >32 days vs control: 18 days; p=7.81e-5).

CONCLUSIONS

Though the sample size is small, this is the first report of the successful in-vitro & in-vivo culture of CSF-CTCs from pts with LMDz. Single cell analysis to determine how representative these models are and further in-vivo testing are in progress.
CMET-28. DECREASED FREQUENCY OF BRAIN METASTASES DUE TO THE USE OF PDL1-INHIBITORS IN RCC
Authors: Damante Mark , Huntoon Kristin , Pezzutti Dante , Olencki Thomas , Bradley Elder J
Published: November 2019

INTRO

Programmed cell death protein 1 (PD1)-inhibitor, nivolumab, and cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-inhibitor, ipilimumab, have been shown to be efficacious in treatment of metastatic renal cell carcinoma (RCC). Clinical trials utilizing PD1- and CTLA4-inhibitors to treat RCC have demonstrated an increase in survival, however history of brain metastases (BM) has typically excluded patients from these trials. This study evaluated the benefit of these agents in terms of overall survival from RCC diagnosis (OSRCC), from BM diagnosis (OSBM) and frequency of BM occurrence in patients with metastatic RCC.

METHODS

A retrospective single-center review between 2011–2018 identified 1149 patients treated for RCC. The study group included patients who received immunotherapy and/or non-immunotherapeutic agents during the course of their disease. Data analyzed included demographic information, systemic treatments, OS and status of BM. Two-sided Fisher’s exact test was used to evaluate frequency of BM occurrence. OSRCC and OSBM were assessed using Kaplan-Meier curves and log-rank tests.

RESULTS

Of 1149 patients, 425 (35.6%) were treated with systemic therapies during their clinical course and divided into two treatment groups: those receiving immunotherapy (n=125) and those receiving non-immunotherapeutic agents (n=300). OSRCC was improved in the immunotherapy group (80.3months 95%CI 58.7–101.9 vs 45.0 95%CI 36.4–53.6, p=0.003), with 1-, 3- and 5-year survival of 93.6%, 74.2% and 62.6%. BM were diagnosed in 113 of 425 patients. Use of immunotherapy was associated with increased OSBM (21.7months vs 8.5, p=0.001). In patients receiving systemic treatment prior to a potential BM diagnosis, BM occurred at a frequency of 8.0% in the immunotherapy group compared to 17.7% for the control (n=100 and n=266 respectively, p=0.021).

CONCLUSION

Immunotherapy not only improves OSRCC and OSBM, but also decreases the incidence of BM in patients with metastatic RCC. Prospective clinical trials are needed to further evaluate the activity of immunotherapy in treatment of RCC BM.
CMET-39. DISPARITIES IN STEREOTACTIC RADIOSURGERY USE AND OUTCOMES FOR MELANOMA BRAIN METASTASES – AN AUSTRALIAN POPULATION-BASED STUDY
Authors: Loon Ong Wee , Wada Morikatsu , Foroudi Farshad
Published: November 2019

INTRODUCTION

We aim to evaluate the use of stereotactic radiosurgery (SRS) among patients who received radiotherapy for melanoma brain metastases (MBM), and the associated outcomes.

METHODS

This is a population-based cohort of patients who received radiotherapy for MBM between 2013 and 2016, as captured in the Victorian Radiotherapy Minimum Dataset. Brain radiotherapy was classified as SRS (including multi-fraction stereotactic radiotherapy) and non-SRS. Mortality data was obtained through linkage with the Victorian Cancer Registry. The primary outcomes were: proportion of patients who had SRS for MBM, and overall survival (OS) following radiotherapy. Multivariate logistic regression was used to evaluate factors associated with SRS use, Kaplan Meier method for estimation of OS, and multivariate Cox regression for evaluation of factors associated with OS.

RESULTS

294 patients received 551 courses of radiotherapy for MBM in this study, of which 39% (116/294) patients received SRS. Patients from higher socioeconomic status were more likely to have SRS – 49% in top quintile vs. 22% in lowest quintile (P< 0.009). Patients treated in regional centres were less likely to have SRS compared to metropolitan centres (3% vs. 48%,P< 0.001). In multivariate logistic regression, treatment in regional centres was the only factor independently associated with lower likelihood of receiving SRS (OR=0.04;95%CI=0.01–0.18;P< 0.001). The median follow-up of the cohort was 3.8 months (range: 0.1–42 months). There were 227 death observed, with 12-month OS of 23%. There was significant difference in 12-month OS between patients who received SRS compared to those who did not receive SRS (43% vs. 11%; P< 0.001). In multivariate Cox regression, the use of SRS was the only factor independently associated with OS (HR=0.38;95%CI=0.28–0.51;P< 0.001).

CONCLUSION

We observed sociodemographic and institutional disparities in SRS use for MBM. The observed impact of SRS use on OS is most likely confounded by patient selections for SRS.
CMET-42. USE OF STEREOTACTIC RADIOSURGERY AND OUTCOMES FOLLOWING RADIOTHERAPY FOR BRAIN METASTASES IN PATIENTS WITH PRIMARY LUNG CANCER – AN AUSTRALIAN POPULATION-BASED STUDY
Authors: Loon Ong Wee , Wada Morikatsu , Foroudi Farshad
Published: November 2019

INTRODUCTION

We aim to evaluate the use of stereotactic radiosurgery (SRS) among lung cancer (LC) patients who received radiotherapy (RT) for brain metastases (BM), and the associated outcomes.

METHODS

This is a population-based cohort of LC patients who received RT for BM between 2013 and 2016, as captured in the Victorian Radiotherapy Minimum Dataset. Brain RT was classified as SRS (including multi-fraction stereotactic RT) and non-SRS. Mortality data was captured through data linkage with the Victorian Cancer Registry (VCR). The primary outcomes were: proportion of patients who had SRS for BM, and overall survival (OS) following brain RT. Multivariable logistic regression was used to evaluate factors associated with SRS use. Kaplan-Meier method was used to estimate OS. Multivariable Cox regression was used to evaluate factors associated with OS.

RESULTS

1,002 LC patients were included in the study. 1,395 courses of RT for BM were delivered, of which one quarter (362/1,395) were SRS. Almost all SRS were delivered in metropolitan centres (347/362), and two-third in public institutions (235/362). In multivariate logistic regressions, increasing age (OR=0.91;95%CI=0.82–0.99;P=0.04) and treatment in regional centres (OR=0.13;95%CI=0.06–0.28;P< 0.001) were independently associated with lower likelihood of SRS use. Median follow-up was 3.3 months (IQR=1.3–7.8 months). 876 deaths were observed with 12-month OS of 16%. The 12-month OS for patients who had SRS were 38% vs. 12% in patient did not have SRS (P< 0.001). In multivariable Cox regressions, the use of SRS (HR=0.44,95%CI=0.37–0.54;P< 0.001) and female (HR=0.76;95%CI=0.67–0.87;P< 0.001) were associated with improved OS, while increasing age was associated with worse OS (HR=1.02;95%CI=1.01–1.03;P< 0.001).

CONCLUSION

This is the largest Australian study reporting on SRS use for BM in LC patients. We observed geographical variations in SRS use. We believe the impact of SRS use on OS is most likely due to patient selection for SRS.
COMP-01. MODELING THE EVOLUTION OF PLOIDY IN A RESOURCE RESTRICTED ENVIRONMENT
Authors: Andor Noemi , Barnholtz-Sloan Jill , Ji Hanlee
Published: November 2019

Progression of lower-grade gliomas (LGG) to glioblastoma (GBM) is accompanied by a phenotypic switch to an invasive cell phenotype. Converging evidence from colorectal-, breast-, and lung-cancers, suggests a strong enrichment of high ploidy cells among metastatic lesions as compared to the primary. Even in normal development: trophoblast giant cells are responsible for invading the placenta during embryogenesis and these cells often have tens of copies of the genome. We formulate a mechanistic Grow-or-go model that postulates higher energy demands of high-ploidy cells as driver of invasive behavior. The unit we are modeling is a cell, that comes with a certain ploidy, proliferation-, and death-rate. Variations in ploidy emerge as a result of chromosome missegregations. For each cell we calculate the probability of cell-division as a function of energy availability in the neighborhood vs. ploidy-dependent energy demand of the cell. Underlying this comparison is the dual role of integrin signaling: integrin-mediated signals allow cells to progress from G1 to S-phase. At the same time integrins mediate cell migration. The model was implemented as a cellular automaton and 2,500 simulations were ran at variable energies and missegregation rates. In low-energy environments high-ploidy clones were enriched at the leading edge of the tumor. This was not the case in high-energy environments. We applied the model to analyze previously published exome sequencing data from 14 multi-spatial and longitudinal LGG biopsies. Using the size and ploidy of co-existing clones as summary statistics for Approximate Bayesian Computation, we infer relative chromosome missegregation rates in primary LGG. A higher missegregation rate was predictive of faster progression of LGG to GBM (multivariate Cox: HR = 7.96, P = 0.041). Future validation experiments will evaluate the potential of the model to explain differences in the prognostic power of integrin signaling and cell cycle progression between males and females.
COMP-05. A DRUG ASSOCIATION MAP OF GLIOBLASTOMA INFORMS PRECISION TARGETING OF p53-DEPENDENT METABOLIC STATES
Authors: Johansson Patrik , Almstedt Elin , Doroszko Milena , Kundu Soumi , Vinel Claire , Lane David , Nestor Marika , Marino Silvia , Krona Cecilia , Nelander Sven
Published: November 2019

Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. Because GBMs are genetically and functionally diverse, there is little systematic understanding of how hundreds of approved drugs may be active against GBM subpopulations. To identify new pharmacological subgroups of GBM, we studied comprehensively the variation in drug response across 100 well-characterised patient-derived GBM cell cultures and used statistical models to explain patient specific cellular drug response in terms of molecular markers, pathway signatures and drug mechanism-of-action. We find that the response to proteasome inhibitors, currently under clinical development for GBM, shows extreme variation across cases, which is phenocopied \emph{in vivo} and predicted by p53 pathway activity. The resistance to proteasome inhibitor response is explained by a subset of p53 functional GBM cases, which exhibit more efficient scavenging of reactive oxygen species (ROS), thereby protecting against ROS-dependent apoptosis. By interference against this protective feedback loop using secondary inhibitors, synergistic killing of GBM cells is achieved. Our results define a sizable metabolic subclass of GBM cells, with implications for precision and combination targeting.
COMP-07. MACHINE LEARNING PREDICTS PROGRESSION AND SURVIVAL IN GLIOMA USING RADIOHISTOGENOMIC FEATURES
Authors: Traylor Jeffrey , Ravikumar Visweswaran , Rao Arvind , Rao Ganesh
Published: November 2019

BACKGROUND

Random forest classifiers can predict survival and progression status with radiomic features. Here, we compare the predictions of radiomic, histomic, and genomic features on progression-free survival (PFS) and overall survival (OS) in patients with low-grade glioma (LGG).

METHODS

We identified patients from our institution and The Cancer Genome Atlas (TCGA) with LGG and analyzed histopathology, mRNA expression, and MRI sequences. Differential gene expression analysis was performed to obtain top gene expression values. Discriminative feature-oriented dictionary learning (DFDL)1 was used to extract histomic features from histopathology slides. Forty-four computer-derived texture features were extracted from segmented tumors for each MRI sequence. A random forest classifier with cross-validation was then used to evaluate binary predictions of PFS and OS using radiomic, genomic, and histomic features from institutional and TCGA data.

RESULTS

The out-of-bag (OOB) error rates for PFS and OS predictions from combined institutional and TCGA radiomic features (n = 104) was 0.22 and 0.15, respectively. Similarly, OOB error rates of PFS and OS predictions for institutional histomic features (n = 66) was 0.24 and 0.29, respectively. OOB error rates for predictions of PFS and OS from combined institutional and TCGA genomic features (n = 283) were 0.14 and 0.24, respectively. A combined model incorporating radiogenomic features from institutional and TCGA data performed slightly worse than either modality alone (PFS OOB error = 0.28, OS OOB error = 0.21), possibly due to fewer cases (n = 67).

CONCLUSION

Our findings indicate combining radiomic and genomic features can predict PFS and OS in patients with LGG. The utility of this methodology may help to predict malignant transformation in LGG. REFERENCES: Vu TH, Mousavi HS, Monga V, Rao G, Rao UA. Histopathological image classification using discriminative feature-oriented dictionary learning. IEEE transactions on medical imaging. 2015;35(3):738–51.
COMP-12. SINGLE-CELL TRANSCRIPTOME PROFILING OF GBM TISSUE ACUTE SLICE CULTURES FOR PERSONALIZED DRUG SCREENING
Authors: Zhao Wenting , Spinazzi Eleonora , Dovas Athanassios , Upadhyayula Pavan , Marie Tamara , Sisti Michael , Bruce Jeff , Canoll Peter D , Sims Peter
Published: November 2019

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor, and more effective treatment options are needed. Both inter- and intratumoral heterogeneity present major challenges to the application of targeted therapies in GBM. Therefore, precision medicine approaches to GBM would benefit significantly from the ability to predict drugs or drug combinations that target specific subpopulations of tumor cells. Model systems, such as adherent cell lines, neurospheres, patient-derived xenografts (PDXs), and patient-derived organoids, have been reported as platforms for drug screening and accessing drug responses. However, these models do not recapitulate the full heterogeneity of GBM tissue, lack key components of the tumor microenvironment or take weeks to months to establish, which limits the predictive power of drug response assays or delays clinical decision-making. To address these limitations, we are combining ex vivo slices of intact, patient-derived GBM tissue with single-cell RNA-seq (scRNA-seq) for small-scale drug screening and assessment of patient- and cell type-specific drug responses. We generated slices from both preclinical mouse glioma models and surgical specimens from GBM patients and showed that acute slices preserved both the tumor heterogeneity and tumor microenvironment observed in scRNA-seq of cells directly isolated from tumor tissue. To test drug responses, we treated tissue slices from GBM mouse models and five different patients with six drugs for 18hr. By performing scRNA-Seq and analyzing transcriptional profiles of treated and untreated control slices, we identified drug-induced transcriptional responses in specific subpopulations of tumor cells, patient-specific drug sensitivities, and drug effects conserved in both mouse and human tumors. The GBM tissue slices were generated immediately following surgical resection, and experiments were completed within 24 hours. With these features, our method is attractive for rapidly accessing cell type- and patient-specific drug responses and has potential for preclinical drug screening and guiding personalized treatment for GBM.
DDIS-05. IDENTIFICATION OF 2-FLUORO PALMITIC ACID AS A POTENTIAL THERAPEUTIC AGENT AGAINST GLIOBLASTOMA
Authors: Jiapaer Shabierjiang , Dong Yu , Kitabayashi Tomohiro , Furuta Taskuya , Sabit Hemragul , Zhang Jiakang , Zhang guangtao , Tanaka Shingo , Nakada Mitsutoshi
Published: November 2019

BACKGROUND

Glioblastoma (GBM) represents the most aggressive and frequent type of primary malignant brain tumors with a dismal clinical outcome. Though adjuvant temozolomide (TMZ) chemotherapy followed by surgical resection can extend patient`s post-operative survival, a considerable number of GBM cases are refractory to TMZ. Novel therapeutic agents that can overcome chemoresistance against TMZ are urgent. Drug repositioning is a process of identifying new indications for existing drugs and provides potential possibilities to discover new drugs. In this study, we explored novel anti-glioma agents which enhances the effect of TMZ with the strategy of drug repositioning.

METHODS

Drug library which contains 1300 diverse chemical compounds was screened using 2 kinds of glioma stem cell (GSC) lines to select novel therapeutic candidate. The effect of candidate drug on the proliferation of GSCs was estimated by sphere formation assay. To evaluate its efficacy against glioma cell biology, proliferation assay, matrigel invasion assay were performed. To clarify the mechanism of drug effects, we investigated target molecules by gelatin zymography and western blot.

RESULTS

Acyl CoA synthetase inhibitor named 2-fluoropalmitic acid (2-FPA) was selected as a novel candidate. 2-FPA suppressed proliferation of glioma cell lines by single administration and/or combination with TMZ. The sphere formation of GSCs was suppressed by combination therapy. Combination therapy enhanced TMZ effect. 2-FPA also suppressed invasion of glioma cell lines in a dose dependent manner. 2-FPA suppressed MMP-2 activity and phosphorylation of STAT3.

CONCLUSION

2-FPA was identified as a novel potential therapeutic agent against GBM.
DDIS-35. RelA-ACTIVITY IS ESSENTIAL FOR CANNABIDIOL-MEDIATED CYTOTOXICITY IN AN IDENTIFIED SUBSET OF GLIOBLASTOMA
Authors: Volmar Marie , Nagl Bernhard , Haug Alisha , Richter Sven , Alenezi Haithanm , Herold-Mende Christel , Lamszus Katrin , Synowitz Michael , Schick Joel , Kälin Roland , Glass Rainer
Published: November 2019

Glioblastoma (GBM) therapy could strongly profit from simplified procedures for personalized medicine. Cannabidiol (CBD) is explored for GBM-patients, but the mode of drug-action is largely unknown and stratification markers are missing. We investigated CBD-induced cytotoxicity in a panel of human primary GBM cells as well as transgenic mouse gliomas and in different orthotopic or transgenic in vivo models. We observed therapeutic efficiency of CBD in a subset of GBM, obtained genetic markers indicating CBD-sensitive GBM and found that the p53 status segregated cell-death modes. Genome wide loss of function screening, transcription factor binding studies and knockout-models indicated a central for role for NFkB (RelA) in CBD-initiated GBM-death. CBD mediated nuclear import of RelA lacking an essential post-translational modification and reduced RelA-activity. CBD altered redox levels specifically in drug-sensitive GBM and ROS-levels in unstimulated GBM predicted therapeutic response. Hence, quantifying ROS in GBM represents a simple bioassay to identify individuals potentially profiting from CBD-application in neurooncology.
DDIS-37. SMALL MOLECULE AUTOPHAGY ACTIVATORS IN GROWTH INHIBITION OF GLIOBLASTOMA
Authors: Waters Ariana , Nurmammadov Elmar , Nomura Natsuko , Babic Ivan , Kesari Santosh , Yenugonda Venkata
Published: November 2019

Glioblastoma (GBM) is one of the most lethal human tumors, and despite considerable advances in multimodality treatments consisting of surgical removal, radiation and chemotherapy, overall survival is 14 to 16 months after diagnosis. Therefore, there is a need to target non-apoptotic death pathways and inhibit pro-survival signaling mechanisms that contribute to both tumorigenesis and treatment resistance. Depending on tumor type and environment, autophagy modulation plays an important role in tumor cell survival and inhibition pathways. Increasing evidence supports that chemical modulation of autophagy inhibition and activation holds a therapeutic potential and these studies have led to the initiation of multiple clinical trials combining chemotherapeutic agents and autophagy inhibitors and activators for various cancer types. However, recent studies have also demonstrated a therapeutic potential for enhancers of autophagy in GBM. This clearly demonstrates the need for further investigation into the autophagy induced mechanism of GBM, and the development of better treatments. We have identified a new chemical entity VMY-BC-1 that showed promising effects in both serum and patient-derived glioma cell lines. Drug target engagement studies identified an autophagy induction protein, UNC-51 like kinase 1 (ULK1), as the main target of VMY-BC-1, in which VMY-BC-1 covalently bound to the protein’s active pocket and increased ULK1 phosphorylation.ULK1 is a component of the ULK1 complex (ULK1-ATG13-FIP200) that is essential for inducing autophagy, a lysosome-dependent mechanism of intracellular degradation for maintaining cellular homeostasis. Additionally, our molecule cross talks to the apoptotic and DNA damage pathways, which could potentially overcome treatment resistance.VMY-BC-1 is orally bioavailable, brain penetrant, and inhibits cell invasion and tumor growth in GBM flank models, making this small molecule an ideal candidate for further development. We hypothesize that activating ULK1-modulated autophagy will be a therapeutic strategy for GBM growth inhibition
DRES-03. PARP INHIBITOR, INHIBITION OF HOMOLOGOUS RECOMBINATION, OR DIANHYDRODULCITOL CAN OVERCOME TEMOZOLOMIDE-RESISTANCE IN GLIOMA CELLS
Authors: Ohba Shigeo , Hirose Yuichi
Published: November 2019

Glioblastoma is one of the most aggressive tumors in the central nervous system tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). The acquisition of resistance to TMZ and the heterogeneity of the tumor are considered to be associated with poor prognosis. TMZ is a DNA-methylating agent, delivering a methyl group to DNA (O6-guanine, N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to futile DNA mismatch repair (MMR), formation of double strand breaks and eventual cell death, when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The object of the study was to reveal the mechanisms of resistance to TMZ and to find the way to overcome the resistance in glioma. Several clones of TMZ-resistant U251 were obtained and analyzed. A clone showed high homologous recombination (HR), and inhibition of HR resensitized the clone to TMZ. MMR system was suppressed in the other clones. Inhibition of BER by PARP inhibitor resensitized them to TMZ. PARP inhibitor enhanced the TMZ-induced cytotoxicity in glioma cells with high expression of MGMT. Dianhydrodulcitol, alkylating agent, suppressed the proliferation in U251 and even U251-derived resistant clones. These effects were shown in U87MG-dereived resistant clones and MGMT-proficient cell lines. Moreover, inhibition of HR enhanced the cytotoxicity of dianhydrodulcitol. To select the appropriate treatment according to the mechanisms of resistance to TMZ can overcome the resistance in glioma cells.
DRES-06. PROSTAGLANDIN E RECEPTOR 3 MEDIATES RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA CELLS
Authors: Chen Dongjiang , Le Son , Thomas Nagheme , Tran David
Published: November 2019

OBJECTIVES

Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. However, most GBM patients eventually develop resistance to TTFields. The mechanism of TTFields resistance remains largely unexplored. Understanding how GBM cells circumvent the biophysical forces of TTFields and their downstream effects will improve therapeutic efficacy of this novel anti-cancer treatment modality.

METHODS

A panel of GBM cell lines were treated continuously with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally.

RESULTS

TTFields-induced chromosomal instability such as the formation of cytoplasmic micronuclei is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay. Using an innovative computational platform, we methodically dissected this stemness program in resistant cells. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked master regulator responsible for resistance. PTGER3 is rapidly upregulated in GBM cells upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Pharmacological inhibition of PTGER3 either using aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors resensitized cells to TTFields.

CONCLUSIONS

We have identified a novel pathway with PTGER3 at the apex that plays a critical role in TTFields resistance. This pathway is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.
DRES-12. QUANTIFYING INDIVIDUALIZED ABT-414 SENSITIVITY AND BLOOD-BRAIN BARRIER PENETRANCE FROM SERIAL IMAGING OF PATIENT-DERIVED XENOGRAFTS MODELS OF GLIOBLASTOMA
Authors: Urcuyo Javier , Christine Massey Susan , Marin Bianca-Maria , Sarkaria Jann , Swanson Kristin
Published: November 2019

INTRODUCTION

Glioblastoma (GBM) is an aggressive primary brain tumor, known for its poor prognosis. Due to its diffuse invasiveness into normal-appearing brain, localized treatments such as surgical resection and radiotherapy are typically supplemented with chemotherapy. However, to reach invading tumor cells, such antineoplastic drugs must cross the blood-brain barrier (BBB). That is, while angiogenesis induces BBB breakdown in dense tumor regions, the BBB remains rather intact for invading GBM cells. As a result, it is unclear whether BBB-impermeable drugs are delivered at a sufficient level to be effective.

METHODS

In order to study heterogeneity in BBB breakdown, experiments were conducted using both flank and intracranial patient-derived xenografts (PDXs) treated with the EGFR-targeted monoclonal antibody drug conjugate, depatuxizumab mafodotin (ABT-414). Time-series bioluminescence imaging (BLI) data was used to develop a differential equation model of tumor growth for three PDX cell lines. Data from untreated PDXs, both in flank and intracranially, were used to parameterize tumor proliferation rates. Flank PDX data were used to parameterize individual sensitivity to ABT-414, whereas intracranial PDX data were used to determine the proportion of drug exposed to the tumor.

RESULTS

Each PDX line differed in response to the study drug ABT-414. As expected, such heterogeneous responses can primarily be attributed to differences in both drug sensitivity and the proportion of drug that reached the tumor. Notably, the estimated proportion of drug that reached the tumor was highest in the PDX line with the longest survival times, despite also having higher estimates of resistance. This suggests that PDXs with greater overall BBB breakdown may respond better to this agent.

CONCLUSIONS

Although more cell lines are needed to validate our approach, parameterizing this model for PDXs gives valuable insight into the extent of BBB breakdown in patient GBMs and may aid in determining optimal therapies for individual patients.
DRES-13. DUAL KINASE INHIBITION TO COMBAT EGFR-INHIBITOR RESISTANCE IN GLIOBLASTOMA
Authors: Smithberger Erin , Shelton Abigail , Butler Madison , Flores Alex , Bash Ryan , Angus Steven , East Michael , Sciaky Noah , Dhruv Harshil , Johnson Gary , Berens Michael , Furnari Frank , Ryan Miller C
Published: November 2019

Glioblastoma (GBM) is an aggressive primary brain tumor with a poor survival rate. One of the most common molecular alterations seen in GBM is amplification and/or mutation of the Epidermal Growth Factor Receptor (EGFR), which has made it an attractive therapeutic target. However, several EGFR tyrosine kinase inhibitors have been tested clinically in GBM with minimal success. One reason for this lack of efficacy could be due to acute, adaptive resistance via alternative pathway activation. To investigate this mechanism of tumor resistance, we used RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the transcriptomes and kinomes of genetically engineered murine astrocytes with common GBM genotypes. We have previously shown that 38% of the expressed kinome varied among a panel of diverse nGEM astrocytes harboring Cdkn2a deletion (C) plus Pten deletion (CP), wild-type human EGFR (CE) or EGFRvIII (CEv3) overexpression or both EGFRvIII overexpression and Pten deletion (CEv3P). Although CE have a similar transcriptional profile to C cells at baseline, when treated with the EGFR inhibitor afatinib, CE respond more similarly to CEv3 cells. When cells containing endogenous murine EGFR (C and CP) are treated with afatinib, fewer than 0.5% of kinases showed differential expression. In cells with EGFR overexpression alone, more than 6% of kinases were differentially expressed upon afatinib treatment, including Ntrk3, Fgfr2 and 3, Lyn, Bmx, Epha2 and 5, Fn3k, a kinase involved in fructosamine processing, and Nrbp2, a kinase involved in regulation of apoptosis. This effect was blunted in cells lacking Pten in addition to having EGFRvIII (CEv3P), resulting in less than 2% of kinases being differentially expressed. The only kinase upregulated in all three EGFR-overexpressing cell types was Coq8a, which is involved in electron transport and response to DNA damage. Given this overlap in response, Coq8a could be a potential dual treatment target for GBM.
EPID-04. ASSOCIATION BETWEEN URBANICITY AND SURGICAL TREATMENT AMONG PATIENTS WITH PRIMARY GLIOBLASTOMA IN THE UNITED STATES
Authors: Cioffi Gino , Cote David , Patil Nirav , Wright James , Wright Christina , Sloan Andrew , Ostrom Quinn , Kruchko Carol , Barnholtz-Sloan Jill
Published: November 2019

BACKGROUND

Glioblastoma (GBM) is the most common malignant brain and other central nervous system (CNS) tumor and also the most fatal. Extent of surgical resection is one of the most significant factors associated with improved survival. Historically, patients living in non-metropolitan counties have limited access to optimal treatment and healthcare services. The aim of this study is to determine if there is an association between urbanicity and surgical treatment patterns among patients with primary GBM.

METHODS

Cases with histologically-confirmed, primary GBM diagnosed between 2005 and 2015 were obtained from the Central Brain Tumor Registry of the United States (CBTRUS). Site specific surgery codes for brain and CNS defined surgery were grouped as follows: gross total resection (GTR; 30,55), subtotal resection (STR; 21, 40), biopsy only (20) and none (00). Urbanicity was defined using the 2013 USDA Rural Urban Continuum (RUC) Code Definitions (metropolitan: RUC 1–3, non-metropolitan: RUC 4–9). Multivariable logistic regression models were constructed to assess the association between urbanicity and receipt of surgical treatment (GTR/STR vs. biopsy only/none) and extent of resection (GTR vs. STR), adjusted for age at diagnosis, sex, race, U.S. regional division, and primary site of tumor.

RESULTS

Residence in a metropolitan county was significantly associated with receiving surgical treatment among patients with GBM, with patients residing in non-metropolitan counties 7% less likely to receive surgical treatment (adjusted OR=0.93, 95% CI: 0.89–0.96, P value: < .0001). Among those who received surgical treatment, metropolitan status was not significantly associated with receiving GTR vs. STR (adjusted OR=0.99, 95% CI: 0.94–1.04, P value: 0.620).

CONCLUSIONS

Among U.S. patients with GBM, urbanicity is associated with receipt of surgical treatment, but among patients who receive surgery, was not associated with extent of resection. These results point to potential differences in access to healthcare for those in non-metropolitan areas that warrant further exploration.
EPID-05. PREDIAGNOSTIC SYMPTOMS AND SIGNS OF ADULT GLIOMA: THE PATIENTS’ VIEW
Authors: Peeters Marthe , Dirven Linda , Koekkoek Johan , Gortmaker Ellen , Fritz Lara , Vos Maaike , Taphoorn Martin
Published: November 2019

BACKGROUND

Little is known about the symptoms/signs glioma patients experience in the year before diagnosis, either or not resulting in health care usage. The objective of this study was to determine the incidence of symptoms/signs glioma patients experienced in the year prior to diagnosis, as well as visits to a general practitioner (GP) related to these issues.

METHODS

Glioma patients were asked to complete a 30-item study-specific questionnaire, if possible with input of a proxy, focusing on symptoms and signs they experienced in the 12 months before diagnosis. For each indicated symptom/sign, patients were asked whether they consulted the GP for this issue.

RESULTS

Between July 2016 and April 2019, 59 patients completed the questionnaires, 54 (93%) with input of a proxy. Forty (68%) patients were men, with a median age of 60 years and the median time since diagnosis was 4 months (range 1–12). The median number of symptoms/signs experienced in the year before diagnosis was 9 (range 2–19) in low-grade and 5 (range 0–24) in high-grade glioma (p=0.230). The five most frequently mentioned problems were fatigue (34, 58%), mental tiredness (30, 51%), sleeping disorder (24, 41%), headache (23, 39%) and stress (20, 34%), with no differences between low- and high grade glioma. Twenty-six (44%) patients had visited the GP with at least one issue. We found that patients who did consult their GP reported significantly more often muscle weakness (11 vs 3, p =0.003) than patients who did not, which remained significant after correction for multiple testing, which was not the case for paralysis in hand/leg (10 vs 4), focussing (11 vs 6) or a change in awareness (9 vs 4).

CONCLUSIONS

Glioma patients experience a range of problems in the year prior to diagnosis, but patients who consult the GP report significantly more often neurological problems.