bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSIG-26. IS INTRINSIC APOPTOSIS THE SIGNALING PATHWAY ACTIVATED BY TUMOR-TREATING FIELDS FOR GLIOBLASTOMA?
Authors: Carlson Kristen , Tuszynski Jack , Bomzon Ze’ev 
Published: November 2019

Abstract
Increasingly, tumor-treating fields (TTFields, 2 V/cm, 200 kHz) are accepted as the fourth treatment modality for glioblastoma. Evidence shows that substituting non-steroidal inflammation control (celecoxib) for dexamethasone increases overall survival from 4.8 to 11.0 months, and more recently, up to 60 months. Toward explaining TTFields mechanism of action (MoA), our numerical simulations indicate that TTFields disrupt functionality of microtubules, which in turn trigger the intrinsic apoptotic pathway independent of cell cycle checkpoints. We present the theory and empirical evidence. 1) TTFields act similarly to chemotherapeutic ‘spindle poisons’ by interfering with microtubule (MT) polymerization, increasing free tubulin by 20% in relative terms; 2) Finite element modeling shows TTFields amplify electric field strength, in accord with empirical results, a) along the MT when aligned with the cell axis, where field strength exceeds 10–16 N required to disrupt motor protein transit, and b) 15x at MT ends when orthogonal to cell axis; 3) Either through producing excess free tubulin, which may block voltage-dependent anion channels, or direct effects on the mitochondrial inner and outer membranes, TTFields inhibit expression of pro-survival protein Bcl-2; 4) Decreased Bcl-2 expression activates the intrinsic apoptotic pathway in a novel cell-cycle-checkpoint and caspase-independent manner; 5) Patients using low (< 4.1 mg/day) vs. high (>4.1 mg/day) dexamethasone doses experienced an average 8.7 vs. 3.2 months OS and up to 60 months; 6) Numerous studies in both brain and other tissues show that dexamethasone a) promotes extrinsic, immune-system apoptosis and b) inhibits intrinsic, Bcl-2/Bax mediated apoptosis; 7) Downstream effects of intrinsic apoptosis are remarkably similar to empirically-observed effects of TTFields on tumor cells. Research supported by Novocure Ltd. Dept of Neurosurgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston MA USA. carlsokw@bidmc.harvard.edu. Dept of Physics, University of Alberta, Edmonton, Canada, Novocure Ltd., Haifa, Israel.
CSIG-29. STRUCTURAL AND FUNCTIONAL STUDIES OF PID1, A NOVEL GROWTH SUPPRESSOR IN BRAIN TUMORS
Authors: Ren Xiuhai , Hirsh Emi , Mahdi Min , Ito Fumiyaki , Chen Xiaojiang , Shackleford Gregory , Erdreich-Epstein Anat 
Published: November 2019

Abstract

BACKGROUND
Brain cancers, including medulloblastomas and gliomas, are a major cause of death in children and adults. We reported that PID1 (Phosphotyrosine Interaction Domain containing 1) is a growth suppressor in medulloblastomas and gliomas (PMID: 24300787). PID1 also enhances the anti-tumor effects of chemotherapy (PMID: 28400607). We are now seeking to better understand the structure and mechanism of PID1, in order to utilize this knowledge to develop innovative PID1-based therapies.

METHODS
PID1 mutants were expressed in E. coli as MBP fusion proteins, purified and used for MALS analysis. Additional epitope tagged PID1 constructs (HA, V5, tGFP, eGFP) were generated, expressed in mammalian cells and analyzed by western blots, immunoprecipitation, and functional assays.

RESULTS
We carried out screening and testing of multiple mutants of purified PID1 and characterized them. Experiments in cell culture supported presence of similar findings in mammalian cells. Colony assays in glioma and medulloblastoma cell lines identified a region in PID1 that confers the most robust growth-inhibitory effect. Experiments are underway to further refine the boundaries and characteristics of this growth-inhibitory region.

CONCLUSIONS
This project, which is focused on better understanding of the structure and function of PID1, is uncovering novel aspects of its molecular function. Insights gained from this work will guide studies to develop innovative PID1-based therapies for gliomas and medulloblastomas.
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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.