bluuebunny/crossref_metadata_2025_split huggingface dataset:
BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION
Authors: Ferraro Gino , Arvanitis Costas , Askoxylakis Vasileios , Guo Yutong , Datta Meenal , Bernabeu Miguel , Fukumura Dai , McDannold Nathan , Jain Rakesh 
Published: August 2019

Abstract
Blood-brain/blood-tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in HER2-positive breast cancer brain metastases at cellular resolution: the non-targeted chemotherapeutic doxorubicin and the antibody-drug conjugate ado- trastuzumab emtansine (T-DM1). Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy we demonstrate multifold increases in the extravasation of both agents (7-fold and 2-fold for doxorubicin and T-DM1, respectively) and we provide evidence of increased drug penetration (&gt;100μm vs. &lt; 20μm and 42±7μm vs. 12±4μm for doxorubicin and T-DM1, respectively) after application of FUS as compared to control (non-FUS). Integration of experimental data with physiologically based pharmacokinetic (PBPK) modeling of drug transport reveals that FUS in combination with microbubbles alleviates vascular barriers and enhances interstitial convective transport via increase in hydraulic conductivity. Combination of experimental data and PBPK modeling suggests that FUS in combination with microbubbles increases the endothelial cell transmembrane transport and uptake. PBPK modelling indicates selective increase in transvascular transport of the non- targeted small chemotherapeutic doxorubicin through small vessel-wall pores size with a narrow range (Diameter: 10-50nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of novel therapeutic strategies against brain metastases.
BSCI-10. NEUROLOGICAL DYSFUNCTION CAUSED BY BRAIN TUMOR-GENERATED SOLID STRESS IS REVERSED BY LITHIUM
Authors: Seano Giorgio , Nia Hadi , Emblem Kyrre , Datta Meenal , Ren Jun , Kloepper Jonas , Krishnan Shanmugarajan , Ghosh Mitrajit , Pinho Marco , Askoxylakis Vasileios , Ferraro Gino , Riedemann Lars , Gerstner Elizabeth , Batchelor Tracy , Wen Patrick , Lin Nancy , Grodzinsky Alan , Fukumura Dai , Huang Peigen , Baish James , Padera Timothy , Munn Lance , Jain Rakesh 
Published: August 2019

Abstract
The compression of brain tissue by a tumor mass is believed to be a major cause of the clinical symptoms seen in patients. However, the biological consequences of these physical stresses on the brain tissue are unknown. Using clinical imaging and preclinical studies, we discovered that a subgroup of primary and metastatic brain tumors, classified as nodular based on the growth pattern, exert compressive solid stress on the surrounding brain tissue, leading to a decrease in local vascular perfusion, as well as neuronal death and impaired function. We demonstrated a causal link between solid stress and neurological dysfunction, by applying and removing cerebral compression, mimicking the mechanics of tumor growth and surgical resection respectively. Finally, we showed that treatment with lithium reduced solid stress-induced neuronal death and improved motor coordination in mice. Our results indicate that brain tumor-generated solid stress impairs neurological function in patients and show lithium as a potential therapeutic intervention to counter these effects.
BSCI-16. HEMODYNAMIC SHEAR STRESS SELECTS A SUBPOPULATION OF LUNG ADENOCARCINOMA CELLS WITH HIGHER METASTATIC CAPACITY
Authors: Alvarado-Estrada Keila N , Marenco-Hillembrand Lina , Mampre David , Quinones-Hinojosa Alfredo , Sarabia-Estrada Rachel , Zhang Yu Shrike , Maharjan Sushila , Chaichana Kaisorn 
Published: August 2019

Abstract
Patients with primary cancers often develop delayed brain metastases. One of the most common cancer types and sources of brain metastasis is lung cancer. For metastasis from lung cancer the 3-year survival is &lt; 5%. Cancer cells in circulation are responsible for metastatic spread. The mechanical microenvironment plays an important role in cancer cells behavior. When cancer cells reach the bloodstream they are exposed to hemodynamic shear stress. It has been shown that most of the circulating tumor cells die once they reach the bloodstream, but the biology of the survival cells is poorly understood. We designed a microfluidics system that simulated the mechanical stress in the human circulating system such as turbulence, change in pressure (0.4-15dyn/cm2) and flow rate (1.06–106.1mm/s). Lung adenocarcinoma cells (A549) were put into circulation and collected after 72 hours. It was found that, 1.4±0.3% of the cells survived, and viability was evaluated by LDH and calcein. CD133, SOX2, and NANOG were downregulated and EMT genes were upregulated in the circulating cancer cells (CCCs) compared with cells in static-suspension or 2D. After re-seeding in 2D, CCCs overexpressed CD133. Female athymic nude rats (6-8weeks,n=16) received intracardiac injections of CCCs or 2D cells (GFP-LUC lentivirus traduced). Bioluminescence imaging was performed every week; the survival in of the CCCs group was lower than the 2D group. One-way ANOVA test was used to analyze survival and gene expression. Survival data was plotted on a Kaplan-Meier curve and compared using the Mantel-Cox logrank test, p=&lt; 0.05. We have isolated a cellular subpopulation of lung adenocarcinoma with high resistance to hemodynamic shear stress that shows a higher metastatic capacity and genetic plasticity compared with cells growing in suspension or 2D. Targeting these cells would potentially allow us to develop personalized treatments to help to stop metastatic spread and improve actual therapeutical strategies.
BSCI-17. YOUNG AGE PROMOTES BREAST CANCER METASTASIS TO THE BRAIN
Authors: Wu Alex , Gossa Selam , Chung Monika , Dolan Emma , Yang Howard , Isanogle Kristine , Robinson Christina , Difilippantonio Simone , Gril Brunilde , Lee Maxwell , McGavern Dorian , Wakefield Lalage , Steeg Patricia 
Published: August 2019

Abstract
Younger women (&lt; 40 years old) diagnosed with breast cancer often have a poorer outcome and a higher risk of developing brain metastases compared to women diagnosed at an older age. Multi-variate analyses have shown that even after accounting for differences in primary tumor characteristics, young age is still an independent predictor of poorer outcome. We therefore hypothesize that rather than intrinsic tumor properties, age-related changes to microenvironmental factors can affect breast cancer metastasis. To test this hypothesis, human and mouse breast cancer cells were injected into young (&lt; 6 month) and old (&gt; 13 month) mice and metastatic tumor burden was quantified. Young mice injected with brain-seeking breast cancer cells (MDA-MB-231BR, 4T1-BR, and 99LN-BrM) developed significantly more brain metastases compared to their older counterparts. In contrast, age had no effect on lung metastatic tumor burden in five breast cancer models. The effect of age is organ-specific, and the young brain is more permissive for breast cancer metastasis. To gain mechanistic insight, the transcriptome of young and old mouse brains were analyzed by RNAseq, the metastatic microenvironment was analyzed by laser capture microdissection and mass spectrometry, immune populations have been identified by flow cytometry, and functional immune contributions analyzed by immunodepleting antibodies. Multiple brain immune subsets were altered with age. In vivo depletion experiments showed no significant contribution of CD4+ T-cells and GR1+ myeloid cells to baseline brain metastatic colonization. A subpopulation of microglia in aged metastatic brains had a high side-scatter profile, which is consistent with published reports that aged microglia are in a “pro-inflammatory” state. Depletion of microglia reduced baseline brain metastatic colonization by 50% and experiments are underway to determine their contribution to an age effect.
BSCI-25. THE ROLE OF THE IFNγ PATHWAY IN BREAST CANCER BRAIN METASTASIS FORMATION
Authors: Pedrosa Route , Schrijver Benjamin , Marques Rute B , Leenen Pieter J M , Dik Wim A , Kros Johan M , Mustafa Dana A M 
Published: August 2019

Abstract
In previous work, we showed the prominence of the T cell response in the formation of brain metastases of primary ER-negative breast cancers. We also showed that prior co-cultured breast cancer cells with stimulated T lymphocytes bear an overexpression of Guanylate-binding protein 1 (GBP1) and possess an increased trespassing ability through an in vitro blood-brain barrier (BBB) model. In addition, we demonstrated a predilection for metastasizing to the brain of breast cancer cells that were co-cultured with activated T cells in a mouse model. In the present work, we show that activated CD8+ cytotoxic T lymphocytes, rather than CD4+ lymphocytes, are the main cause of increasing the ability of breast cancer cells to cross the BBB. While synthetic IFNγ does not change the ability of breast cancer cells to cross the BBB, this study shows that the T lymphocyte-secreted IFNγ activates the STAT1-dependent IFNγ pathway in breast cancer cells, enabling them to cross the in vitro BBB. Direct inhibition of soluble IFNγ or blocking of the IFNγ-specific receptor in breast cancer cells significantly decreases their ability to cross the BBB. The results illustrate that IFNγ signaling pathway is one of the crucial pathways in the formation of brain metastasis of ER- breast cancer. The interference with the IFNγ pathway will develop preventive strategies against the formation of brain metastases of breast cancer.
LPTO-02. INTRATHECAL (IT) TRASTUZUMAB (T) FOR THE TREATMENT OF LEPTOMENINGEAL DISEASE (LM) IN PATIENTS (PTS) WITH HUMAN EPIDERMAL RECEPTOR-2 POSITIVE (HER2+) CANCER: A MULTICENTER PHASE 1/2 STUDY
Authors: Kumthekar Priya , Lassman Andrew B , Lin Nancy , Grimm Sean , Gradishar William , Pentsova Elena , Jeyapalan Suriya , Groves Morris , Melisko Melissa , Raizer Jeffrey 
Published: August 2019

Abstract
Patients with HER2+ breast cancer have frequent LM. A multi center phase 1/2 study assessing safety and efficacy of IT T in LM patients was conducted. The primary endpoint in Phase 2 was response rate (RR). Complete response (CR) required cytologic CR (CCR) + radiographic CR (RCR) + stable clinical function. Partial response (PR) required either CCR with stable/improved imaging or RCR with stable cytology + stable/improved clinical symptoms. Pts received IT T via intraventricular Ommaya reservoir. Phase 1 dosing started at 10 mg, then increasing by 20 mg up to 80 mg. Each cycle (C) was 4 weeks with 2x treatment/week in C1, weekly in C2, and every two weeks after C2. Pts were allowed to continue on hormonal agents if systemic disease was controlled at the time of LM development. Concurrent radiation therapy was not allowed unless exceptionally needed locally for pain control. 34 pts were enrolled with 26 its in the phase 2. The median age was 51 (25–69). IT T was well tolerated with no DLTs seen throughout; determined MTD was 80 mg for phase 2. All patients treated in the Phase 2 had HER2+ breast cancer, 2 patients in the Phase 1 had non-breast histologies. Median cycles completed was 2 (1–22). Median follow up was 9.1 months (0.4- 28.9). In Phase 2, 5 pts (19.2%) had PR, 13 (50%) had SD, and 8 (30.8%) had PD. For Phase 2 pts, median PFS was 2.4 months (CI 1.0–5.5) and median OS was 12.1 months (CI 4.3–19.6) IT T was well tolerated up to a dose of 80 mg. Primary endpoint of 25% RR was not met, however 69% had clinical benefit (stable disease or better). Median OS exceeded historical controls. Future studies are warranted to evaluate IT T in HER2+ LM.
LPTO-03. 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 , Kenchappa Rajappa , Puskas John , Caceres Gisela , Ryzhova Elena , Smalley Inna , Etame Arnold , Sahebjam Solmaz , Magliocco Anthony , Smalley Keiran , Forsyth Peter 
Published: August 2019

Abstract
BACKGROUND: Approximately 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: 2148.60; 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-vivo culture 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: &gt;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.
LPTO-04. GENERATION AND CHARACTERIZATION OF PATIENT-DERIVED PRECLINICAL MODELS FROM TUMOR CELLS ISOLATED FROM CEREBROSPINAL FLUID
Authors: Offin Michael , Vojnic Morana , Liu Zebing , Lui Allan , Siau Evan , Gladstone Eric , Mattar Marissa , Khodos Inna , Drilon Alexander , Boire Adrienne , Rudin Charles , De Stanchina Elisa , Ladanyi Marc , Somwar Romel 
Published: August 2019

Abstract
BACKGROUND: CNS metastases occur in 20–50% of lung cancer patients during their disease; leptomeningeal disease (LMD) representing 5–8%, classically carries a poor prognosis with a median overall survival ranging from 1–11 months. There is a paucity of patient-derived preclinical disease models using tumor cells isolated from the CSF. Models that faithfully recapitulate the biology of CNS tumors would offer new insights into the biology of the disease as well as provide the basis for developing more effective therapy. METHODS: To create more representative preclinical models to study LMD we isolated tumor cells from CSF of 5 patients with cytologically proven LMD and implanted the cells into the subcutaneous flank of immune-compromised mice. Where possible, cell lines were also generated from PDX tissues. Models were characterized by next generation sequencing (NGS), growth rates, expression of driver oncogenes and sensitivity to small molecule inhibitors. RESULTS: To date, one PDX (LUAD-0048A) and cell line model were successfully derived from CSF samples (NSCLC patient with MET amplification) and 4 are pending. MET amplification and mRNA over-expression were confirmed by quantitative PCR in the PDX tissue and the cell line. Western blot analysis indicated that over-expressed MET was phosphorylated in both PDX tissue and cell line. These results were confirmed by immunohistochemistry. Growth of LUAD-0048A cells were unaffected by 3 MET inhibitors (crizotinib, cabozantinib, glesatinib). Similarly, MET inhibitors did not induce apoptosis in the cells. CONCLUSION: LMD represents an aggressive metastatic event in lung cancer patients. Here we were able to successfully establish a PDX from the CSF of a patient with LMD and trial targeted therapies in vivo. Translational collaborations where patients with clinical suspicion of LMD undergo CSF sampling, NGS/ctDNA analysis, and PDX modeling are crucial in improving our understanding of this metastatic compartment and investigating novel treatment paradigms.
LPTO-05. FACTORS INFLUENCING RISK OF LEPTOMENINGEAL METASTASIS IN BREAST CANCER PATIENTS RECEIVING STEREOTACTIC RADIOSURGERY FOR LIMITED BRAIN METASTASES
Authors: Zhang Michael , Chan Jason , Xu Chelsea , Anderson August , Lazar Ann , Villanueva-Meyer Javier , McDermott Mike , Melisko Michelle , Sneed Penny , Morin Olivier , Braunstein Steve 
Published: August 2019

Abstract
Leptomeningeal metastasis (LM) is a late stage manifestation of advanced breast cancer frequently managed with whole brain radiotherapy (WBRT) and/or intrathecal chemotherapy. A subset of breast cancer patients who undergo stereotactic radiosurgery (SRS) for limited brain metastases (BM) ultimately develop LM. We hypothesized that this subset of high-risk patients may be identified by patient, disease, and/or treatment parameters. Clinical records from 135 consecutive breast cancer patients from a single institution who underwent SRS for BM between February 2010 and March 2018 were retrospectively analyzed. Diagnosis of LM was determined radiographically and/or by cerebrospinal fluid analysis. Demographic data, clinical history, histopathology, BM features, systemic disease burden, and prior treatments were analyzed with Cox proportional hazards regression. In our cohort, 22 (16.3%) patients ultimately developed LM. With a median follow up of 18.9 (IQR 8.6–38.7) months after diagnosis of BM, the actuarial rate of LM at 18 months was 14.5% (95% CI, 7.0–21.4%). Median OS after diagnosis of LM was 7.3 (95% CI, 3.1–15.4) months. There was significantly increased risk of LM with ≥5 vs &lt; 5 BM at BM diagnosis (33.0% vs 7.5% [18-month actuarial risk], HR 3.5, p=0.0045), and ≥7 vs &lt; 7 cumulative number of BM treated (21.9% vs 11.1% [18-month actuarial risk], HR 2.7, p=0.023). Variables not significantly associated with the risk of LM included tumor receptor status (ER, PR, HER2, triple negative), graded prognostic assessment, KPS, extracranial metastases, total BM volume, prior WBRT, or prior surgical resection. In conclusion, patients with a larger number of brain metastases at BM diagnosis or ≥7 cumulative number of brain metastases treated appear to be at higher risk of developing LM and may benefit from stronger consideration of WBRT, intrathecal chemotherapy, and/or brain-penetrating systemic therapy.
LPTO-10. ASSESSMENT OF LEPTOMENINGEAL CARCINOMATOSIS DIAGNOSIS AND OUTCOMES FROM 2005 TO 2015 AT THE OHIO STATE UNIVERSITY
Authors: Williams Nicole , Rinehardt Hannah , Morgan Evan , Kassem Mahmoud , Palettas Marilly , Puduvalli Vinay , Giglo Pierre , Lustberg Maryam , Wesolowski Robert , Sardesai Sagar , Stover Daniel , Vandeusen Jeffrey , Bazan Jose , Ramaswamy Bhuvaneswari , Noonan Anne 
Published: August 2019

Abstract
BACKGROUND: Leptomeningeal carcinomatosis (LMC) is a complication of solid tumor malignancies where tumors metastasize to the leptomeninges. LMC complicates 4–15% of malignancies with incidence increasing as survival of patients with advanced cancer improves. Diagnostic methods include magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology. We assessed detection methods, incidence, and outcomes of LMC at The Ohio State University Comprehensive Cancer Center from 2005–2015. METHODS: This was a single-institution retrospective study of 160 patients with confirmed diagnosis of LMC. Patients with hematologic and central nervous system malignancies were excluded. Descriptive statistics were used to summarize demographic and clinical characteristics. Overall survival (OS) was defined as time from LMC diagnosis to death or last known follow-up, and was generated using Kaplan-Meier methods. RESULTS: Median age of LMC diagnosis was 55.8 years (range: 48, 62.5). 69 (43%) patients had primary breast cancer, 41 (26%) had lung cancer, and 17 (11%) had melanoma. 73 patients (46%) presented with stage IV disease at initial diagnosis of the primary cancer, 41 (26%) with stage III disease, and 26 (16%) with stage II disease. Median time from diagnosis of primary cancer to diagnosis of LMC was 2 years (range: 0, 31.2). 158 (99%) patients had metastases at the time of LMC diagnosis, predominantly in bone (36%) or brain (36%). Median OS was 1.9 months (CI: 1.3, 2.5). 160 (100%) patients had an MRI of the brain or spine and 155 (97%) had MRI findings consistent with LMC. 75 (47%) patients underwent lumbar puncture, and 39 (52%) had CSF cytology positive for malignancy. CONCLUSIONS: Despite treatment, prognosis remains poor and confirmation of diagnosis can be challenging. This study highlights the need for novel therapeutics and improved diagnostic techniques for patients with LMC.
TRLS-02. A PILOT STUDY OF EVALUATING EARLY TREATMENT RESPONSE OF BRAIN METASTASES AFTER STEREOTACTIC RADIOSURGERY USING DYNAMIC SUSCEPTIBILITY-WEIGHTED PERFUSION MAGNETIC RESONANCE IMAGING
Authors: Huang Jiayi , Rao Yuan , Milchenko Mikhail , LaMontagne Pamela , Abraham Christopher , Robinson Clifford , Wan Leping , Shimony Joshua , Rich Keith , Benzinger Tammie 
Published: August 2019

Abstract
PURPOSE: To determine if dynamic susceptibility-weighted perfusion magnetic resonance imaging (DSC-PMR) can be used to predict local recurrence (LR) of brain metastases after stereotactic radiosurgery (SRS). METHODS: This is a prospective observational study of adult brain metastasis patients treated with single-fraction SRS, who were imaged with DSC-PMRs before SRS and after 1 week. DSC-PMRs were performed with tracer method in which injection of gadolinium was followed by repeated T2*-weighted gradient echo-planar image acquisition. Regions of interests (ROIs) were generated based on the T1-enhancing tumors irradiated. Relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) parameter maps were calculated by dividing the top 5% of CBV or CBF values within a ROI by the contralateral normal thalamus. LR was determined according to the RECIST 1.1 criteria. Cox regression was conducted to identify factors associated with time to LR. LR rates were estimated with the Kaplan-Meier method and compared using log-rank test. RESULTS: Twenty-three patients were enrolled from 2013 through 2016, with 24 evaluable lesions from 17 patients. After a median follow-up of 12.8 months (range: 3.0–53.7), 5 lesions (21%) developed LR after a median of 3.4 months (range: 2.3–5.7). On univariable analysis, higher rCBV at week 1 (HR 1.06, 95% CI 1.01–1.11, p=0.02), lower SRS dose (HR 0.43, 95% CI 0.20–0.91, p=0.03), and larger tumor volume (HR 1.52, 95% CI 1.05–2.20, p=0.03) were significantly associated with LR, but not histology, rCBV at baseline, change of rCBV at week 1 from baseline, or any rCBF parameters. Higher rCBV at week 1 (above the median) was associated with significantly higher risk of LR than lower rCBV (44% vs 0% at 1 year, respectively, p=0.02). CONCLUSIONS: DSC-PMR and specifically rCBV at week 1 may be a promising imaging biomarker to predict treatment response of brain metastasis after SRS and warrant further investigation.