bluuebunny/crossref_metadata_2025_split huggingface dataset:
THER-07. DEVELOPMENT OF A NEW MOLECULAR PREDICTOR FOR RISK OF BRAIN METASTASES AND EFFICACY OF TARGETED THERAPY IN MELANOMA
Authors: Colman Howard , Boucher Ken , Stehn Chris , Kircher David , Holmen Sheri 
Published: August 2019

Abstract
Despite therapeutic advances in the treatment of melanoma, development of brain metastases (BM) continues to be a major manifestation of treatment failure. The ability to identify those patients who are at highest risk of developing brain metastases is limited with current methods. Development of sensitive and specific biomarkers to predict which stage II-III melanoma patients are at highest risk of BM would enable initiation of prospective clinical trials focused on both intensive surveillance and therapeutic prevention. To accomplish this goal, we embarked on an effort to optimize a combined molecular/clinical/pathologic predictor of BM risk. We firstanalyzed multiple gene expression datasets including TCGA (n = 437) and an independent series from Australia (n = 183) and identified a list of 60 consensus genes that is robustly predictive of development of melanoma BM (p &lt; 0.05; FDR 5%). Next, we performed a similar analysis of association of miRNAs and melanoma BM risk which identified a set of miRNAs with significant predictive power. An optimized combined set of mRNA and miRNA markers was a better predictor of BM risk than either mRNA or miRNA list alone when applied to the TCGA data set. The combined predictor was most sensitive in separating patients with no metastases from those with either BM or systemic metastases. Current efforts are focused on optimizing miRNA and mRNA separation of patients specifically with BM from those with other mets, and with integrating the expression classifier with other clinical and pathologic predictive factors including: age, stage, thickness, location, histology, ulceration, gender. The sensitivity and specificity of the resulting clinical/molecular predictor will be validated in an independent retrospective cohort, and subsequently implemented in a prospective BM screening trial to determine real-world utility of this approach in preparation for prospective BM adjuvant/chemoprevention trials utilizing both immunotherapy and targeted therapy approaches.
THER-12. PRECLINICAL EVALUATION OF NERATINIB PLUS T-DM1 IN ORTHOTOPIC PDX MODELS OF HER2-POSITIVE BREAST CANCER BRAIN METASTASES
Authors: Ni Jing , Wang Yanzhi , Diala Irmina , Kabraji Sheheryar , Freedman Rachel , Lin Nancy , Zhao Jean 
Published: August 2019

Abstract
Breast cancer brain metastases (BCBM) are a major cause of morbidity and mortality, despite multimodal management including surgery, radiotherapy, and systemic therapies. There is an urgent need to develop novel, efficacious alternatives. Neratinib is an orally bioavailable, irreversible pan-HER tyrosine kinase inhibitor that is FDA-approved in the extended adjuvant treatment setting for HER2-positive, early breast cancer (NCT00878709). Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate with reported single-agent activity against HER2-positive BCBM. Here, we used HER2-positive orthotopic patient derived xenograft (PDX) models of BCBM to test if combining neratinib with T-DM1 could improve tumor response. PDX cells are labelled with luciferase to allow tumor growth measurement in vivo. We found that neratinib is able to reduce phosphorylated HER2 in an orthotopic PDX tumor derived from HER2-positive BCBM, indicating that neratinib can cross the BBB and inhibit HER2 activation in BCBM PDX tissues. However, in both HER2-positive DF-BM354 and DF-BM355 PDX models, single agent neratinib did not block orthotopic tumor growth compared to vehicle control as monitored by bioluminescence measurements. In contrast, combined treatment of neratinib with T-DM1 significantly reduced tumor growth compared to single agent treatment with neratinib or T-DM1 at earlier time points in both models. At later time points, the combined treatment is comparable to T-DM1 alone in DF-BM354 model, but significantly prolong the survival of mice bearing DF-BM355 tumors. These data warrant further testing of neratinib alone and in combination with T-DM1 in additional BCBM PDX models to better understand drivers of resistance and susceptibility to HER2-inhibitors in HER2-positive BCBMs. Furthermore, they support the launch of a prospective clinical trial (NCT01494662) to test the efficacy and tolerability of T-DM1 in combination with neratinib in patients with progressive HER2-positive BCBM.
THER-16. EFFICACY OF UPFRONT IMMUNE CHECKPOINT INHIBITORS IN LUNG CANCER BRAIN METASTASIS
Authors: Barnett Addison , Lauko Adam , Ali Assad , Li Hong , Sagar Soumya , Chao Samuel , Pennell Nathan , Peereboom David , Stevens Glen , Angelov Lilyana , Yu Jennifer , Murphy Erin , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet 
Published: August 2019

Abstract
INTRODUCTION: Immune checkpoint inhibitors (ICI) have resulted in improved outcomes in a subset of patients with lung cancer. However, data describing the efficacy of ICI in lung cancer brain metastasis (LCBM) is limited. We analyzed overall survival (OS) in patients with LCBM treated with upfront ICI, defined as having received ICI within 90 days of LCBM diagnosis, compared to non-ICI therapies. METHODS: We reviewed 665 patients with LCBM who were diagnosed between 2000 and 2018 at a major tertiary care institution. Of those patients, 240 received ICI, 164 of which received ICI after 90 days and 76 received ICI within 90 days. Propensity score (PS) was calculated using a logistic regression model including age, KPS, number of baseline brain lesions, and presence of extra-cranial metastasis (ECM) at the time of BM diagnosis. OS from BM diagnosis between PS matched cohorts were compared using Kaplan-Meier, the Log-Rank test, and Cox proportional hazards model. RESULTS: Prior to PS matching, median survival between ICI and non-ICI cohorts was not significantly different (10.9 months for both, p=0.81), although more ICI patients had ECM (57.1% vs 40.9%, p=0.006). Following PS matching, the ICI (n=76) and non-ICI (n=76) cohorts had a median age (62.4 vs 62.3 years), KPS (80 for both), lesion number (2 for both), and ECM (56.6% for both). Of matched patients, 94% received SRS, 52% received WBRT, and 29% underwent surgical resection. Compared to non-ICI, the ICI cohort has a 2-year OS hazard ratio, HR=0.87 (95% CI=0.58–1.31, p=0.51). Median and 1-year survival were not significantly different between ICI and non-ICI cohorts (median: 10.9 vs 9.1 months; 1-yr: 43.0% vs 42.4%). CONCLUSION: Patients with BM from primary lung cancer who received ICI within 90 days of their BM diagnosis did not have improvement in OS compared to patients who received non-ICI therapies.
MLTI-04. EVOLUTION OF TREATMENT PARADIGMS FOR PATIENTS WITH ≥1 BRAIN METASTASES FROM PRIMARY NON-SMALL-CELL LUNG CANCER – A SYSTEMATIC REVIEW
Authors: Brar Karanbir , Ellenbogen Yosef , Warsi Nebras , Badhiwala Jetan , Mansouri Alireza 
Published: August 2019

Abstract
BACKGROUND: Brain metastases (BM) are common in non-small cell lung cancer (NSCLC), with approximately 10% of patients presenting with BM at the time of diagnosis. The aim of this systematic review was to critically evaluate the evolution of management paradigms for BM from NSCLC. METHODS: We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, and CENTRAL for randomized controlled trials (RCTs) published until October 2018. Comparative RCTs based on ≥ 50 patients were selected. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS). RESULTS: Among 3188 abstracts, 14 RCTs (2494 patients) met inclusion criteria. Median sample size was 97 (range 59–538). Most trials were open-label, parallel, superiority trials. All included patients aged ≥18 with histologically proven NSCLC and ≥1 BM proven on CT/MRI. The majority of trials (11/14) excluded patients with non-favorable performance status (ECOG, KPS, or WHO scales), prior SRS or WBRT, and/or leptomeningeal metastases. Interventions assessed included WBRT (11/14), SRS (3/14), targeted therapies (e.g. EGFR inhibitors, 5/14), and various chemotherapeutic regimens (12/14). Most trials (12/13) reported no significant difference in OS between interventions. 4/10 trials reported a difference in PFS, two of which only included patients with EGFR-mutant NSCLC; these showed a significant increase in PFS in patients managed with EGFR inhibitors. The other two trials reported longer PFS with sodium glycididazole + WBRT vs. WBRT alone (p=0.038) and temozolomide + SRS vs. SRS alone (p=0.003). The incidence of adverse events was consistent across most treatment groups. CONCLUSIONS: Most trials showed no significant improvement in OS; however, improvement in PFS was seen in several trials, most notably in EGFR-positive patients treated with EGFR inhibitors. Given the long-standing merit of radiation-based therapies for BM management, these data support the need for an in-depth meta-analysis assessing the comparative efficacy of current management paradigms for specific patient populations.
MLTI-05. IDENTIFYING BRAIN METASTATIC CASES FROM FREE TEXT CLINICAL NARRATIVES WITH REFINEMENT OF SEMANTIC HETEROGENEITY USING MACHINE LEARNING
Authors: Wells Michael , Robin Adam , Poisson Laila , Noushmehr Houtan , Snyder James 
Published: August 2019

Abstract
INTRODUCTION: Brain metastatic disease (BM) is ripe for discovery using computational tools like machine learning (ML) due to disease complexity and multidimensional critical data (imaging, genomics, primary disease, drug exposures)1. Leveraging real-world-evidence’ (RWE) from routine health data to inform clinical management is hindered by fragmented unstructured data and semantic heterogeneity2. Clinical data in EHR and institutional registries are typically free text narratives absent common data elements (CDE). Curating existing data into CDE with machine learning (ML) may inform contemporary approaches (RWE, N-of-1 trials, and precision medicine) that are dependent on large high-quality datasets. Harvesting existing institutional registries may expand demographic representation, confirm benchmarks of established treatments, and provide test environment for prospective ML applications. METHOD: An R-based deep convoluted neural network (DNN) using keras and an API for Tensorflow python was trained on physician narratives of 2000 BM cases and 8000 other CNS conditions labeled by diagnosis spanning 17 years3,4. The ML model was tested with 405 non-labeled narratives to: A) Identify BM from other CNS conditions (i.e. glioma, meningioma, non-tumor). B) Evaluate word embedding using GLoVe5 to standardize abbreviations and misspellings by assigning terms to CDE by training the model to plot “mets”, “metastases” and “spine” with the 20 most similar contextual words. RESULTS: DNN architecture achieved 97% accuracy in distinguishing BM (n=178) for others (n=227). “Mets” and “metastasis” have a connected contextual network suggesting shared meaning, whereas spine did not share a network. CONCLUSIONS: ML can identify BM cases in free-text registries which can serve as a quality control measure and aid data aggregation. Standardizing shorthand terminology to CDE with DNN trained in word embedding can possibly address semantic heterogeneity and facilitate data automation. Solutions are needed to compile and automate quality BM data across institutions to achieve the volume and complexity required for contemporary analysis using ML.
MLTI-06. BEVACIZUMAB VERSUS SURGICAL INTERVENTION FOR RADIATION NECROSIS IN PREVIOUSLY IRRADIATED BRAIN METASTASES
Authors: Hong Christopher , Sujijantarat Nanthiya , Chiang Veronica 
Published: August 2019

Abstract
INTRODUCTION: Both medical management with bevacizumab and surgical management via craniotomy or more recently with laser interstitial thermal ablation (LITT) have been shown to be efficacious in the management of radiation necrosis (RN) after radiosurgery for brain metastases (BM). Indications for how to choose medical versus surgical management however remains unclear. METHODS: Single-institution chart review was performed of all patients with biopsy or radiographically confirmed RN after radiosurgery for BM between 2011 and 2017. Progression-free survival (PFS) and overall survival (OS) were compared between those treated using bevacizumab versus surgical intervention. RESULTS: 15 patients underwent craniotomy, 18 patients underwent LITT, and 18 patients were treated with bevacizumab. Those treated with bevacizumab had significantly higher number of regrowing lesions (n &gt;1) at time of intervention (50.0%) versus those treated with surgery (15.2%) (p&lt; 0.05). Likewise, pre-treatment KPS was lower in the bevacizumab cohort (median: 60) vs the surgery cohort (median: 90) (p&lt; 0.05). Patients treated with bevacizumab demonstrated significantly decreased PFS (%PFS at 1-year 16.7% vs 86.7% and 87.8% for craniotomy and LITT, respectively; %PFS at 2-years 0% vs 86.7% and 73.2% for craniotomy and LITT, respectively, p &lt; 0.05). Similar results were observed for OS (%OS at 1-year for bevacizumab 33.3% vs 93.3% and 73.8% for craniotomy and LITT, respectively; %OS at 2-years for bevacizumab 11.1% vs 64.6% and 63.2% for craniotomy and LITT, respectively, p&lt; 0.05). CONCLUSIONS: Preliminary analysis shows that bevacizumab therapy in our institution is being chosen for patients with lower KPS and multiple regrowing lesions while surgical intervention is being chosen for patients with good KPS and single, symptomatic regrowing lesions. While the comparative outcomes after bevacizumab appear to be significantly worse than surgical management, it remains unknown if the difference is more related to its true efficacy or the significant discrepancy between the comparison groups.
MLTI-11. IMPLANTABLE POLYMERIC BCNU AS AN ADJUNCT TO SURGERY FOR METASTATIC INTRACRANIAL DISEASE
Authors: Ryken Timothy , Evans Linton 
Published: August 2019

Abstract
SUMMARY: One hundred and thirty cases of craniotomy for tumor utilizing BCNU implantable chemotherapy were performed by the authors between including 23 cases for metastatic intracranial disease. The series included 12 woman and 11 men with an average age of 56.9 years. The diagnoses were as follows: non-small lung carcinoma (13), breast cancer (6), small-cell lung cancer (1), colon cancer (1), unknown primary (2). Patients undergoing resection plus implantable chemotherapy following whole brain radiotherapy (5 patients) or following stereotactic radiosurgery (5 patients) were the most common. Only patient developed possible local recurrence (3%). Complications included two cerebrospinal fluid leaks with associated complications requiring reoperations (11%) both following whole brain radiotherapy and 3 patients (17%) with thromboembolic episodes (3 deep venous thromboses, one with a pulmonary embolus and sudural hematoma). In this challenging population, local implantable chemotherapy appears relatively safe and a reasonable consideration as a surgical adjunct.
MLTI-12. TIMING OF SYSTEMIC THERAPY ADMINISTRATION RELATIVE TO STEREOTACTIC RADIOSURGERY AND DEVELOPMENT OF RADIATION NECROSIS IN PATIENTS WITH BRAIN METASTASES
Authors: Hammoudeh Lubna , Cagney Daniel , Aizer Ayal 
Published: August 2019

Abstract
PURPOSE: The mainstay of oncologic therapy for patients with brain metastases involves brain-directed radiation, increasingly given via stereotactic radiosurgery (SRS), and systemic therapy for extracranial disease control. We sought to investigate the association between the timing of systemic therapy and SRS administration on development of radiation necrosis among patients with brain metastases. METHODS: We retrospectively identified 429 patients treated at Brigham and Women’s Hospital/Dana-Farber Cancer Institute with SRS for newly-diagnosed brain metastases between 2001–2015. Systemic therapy was tiered into 4 categories: chemotherapy, immunotherapy, hormonal therapy, and targeted therapy. All images were manually reviewed by two radiation oncologists specializing in brain tumors to assess the presence versus absence of radiographic necrosis. Patients with radiographic necrosis who harbored associated neurologic symptoms or were managed with steroids/bevacizumab/resection were considered to have symptomatic radiation necrosis. Data were analyzed using univariable Cox regression in SAS v9.4. The median follow-up in surviving patients was 1.79 years. RESULTS: In total, 252/429 and 361/429 patients received systemic therapy pre and/or post SRS, respectively. Patients receiving systemic therapy ≤5 days before SRS displayed higher rates of radiographic (HR 2.48, 95% CI 1.06–5.81, p=.04) and symptomatic (HR 3.74, 95% CI 1.08–12.98, p=.04) necrosis; a similar association was seen in patients receiving systemic therapy ≤5 days after SRS (HR 1.72, 95% CI 0.84–3.53, p=.14 and HR 4.42, 95% CI 1.75–11.14, p=.002, respectively). Trends towards increased necrosis risk were noted when comparing systemic therapy administration 1–5 days versus 6–10 days before/after SRS. The above 4 associations were significant when restricting the cohort to patients receiving targeted systemic therapy (HR-range 3.57–21.49, p-range 0.01–0.04). CONCLUSIONS: Our results suggest that a reasonable delay between SRS and systemic therapy administration may reduce rates of radiation necrosis, even among patients receiving targeted therapies. Validation in an independent data set would lend further support to this concept.
MLTI-13. RESPONSE ASSESSMENT OF MELANOMA BRAIN METASTASES TREATED BY STEREOTACTIC RADIOTHERAPY OR IMMUNOTHERAPY OR BOTH: A COMPARISON OF RECIST 1.1, RANO AND iRANO CRITERIA
Authors: Le Rhun Emilie , Wolpert Fabian , Fialek Maud , Devos Patrick , Andratschke Nicolaus , Reyns Nicolas , Dummer Reinhard , Mortier Laurent , Weller Michael 
Published: August 2019

Abstract
BACKGROUND: The evaluation of response for brain metastases (BM) may be challenging in the context of treatment by stereotactic radiotherapy (SRT) or immunotherapy or both. METHODS: We reviewed clinical and neuroimaging data of 62 melanoma patients with newly diagnosed BM treated by the combination of immunotherapy and SRT (n=33, group A), immunotherapy alone (n=10, group B) or SRT alone or in combination with other systemic therapies (n=19, group C). Response was assessed using RECIST 1.1, RANO or iRANO criteria. RESULTS: BRAF mutations were noted in 26 patients. 54 patients (87%) had 1–3 metastases. The median DS-GPA was 3. After a median follow-up of 30.5 months, 39 patients have experienced CNS progression, 16 (48.5%) in group A, 9 (90%) in group B, 14 (73.5%) in group C. Median PFS was 129.5 days (range 82–532) in group A, 75 days (range 35–203) in group B, 136 days (range 59–514) in group C. Forty-seven patients (76%) had died at the time of the analysis, 22 (66.5%) in group A, 7 (70%) in group B, 18 (94.5%) in group C. Median OS was 345 days (range 65–1824) in group A, 174.5 days (range 50–1361) in group B, 409 days (range 102–1244) in group C. 52 MRI scans were available for central review: pseudoprogression was documented in 9 patients (29%) in group A, 0 (0%) in group B, 5 (29.5%) in group C. Response rates were similar with all three sets of response criteria. Progressive disease was less often called when applying iRANO to assess SRT target lesions. CONCLUSIONS: Despite the retrospective nature and the small sample size, these data may indicate that the omission of SRT from first-line treatment may compromise outcome. Pseudoprogression is uncommon with immunotherapy alone; pseudoprogression rates were similar after SRT alone or in combination with immunotherapy or other systemic treatment.
OTHR-06. ANALYSIS OF GENOMIC ALTERATIONS IN 154 BRAIN METASTASES
Authors: Ostorga Antonio Dono , Hines Gabriella , Moghadamtous Soheil Zorofchian , Esquenazi Yoshua , Ballester Leomar Y 
Published: August 2019

Abstract
Brain Metastases (BM) are associated with poor prognosis. Understanding the genomic alterations (GA) that drive tumor metastasis to the brain will increase our ability to identify patients at risk for BM, and provide better opportunities to implement targeted therapies. We performed a retrospective review of genomic alterations in 154 patients with BM from various primary sites (80 Lung, 22 Breast, 16 Melanoma, 5 Kidney, 4 Colorectal, 4 Prostate, and 23 carcinomas from unknown primary (UP). All cases were analyzed by a next generation sequencing assay the detects mutations in the coding region of 327 genes and rearrangements involving 37 genes. The most commonly mutated genes were; TP53, CDKN2A/B, KRAS, MYC, RB1, NF1, PIKC3A, STK11, and PTEN. A comparison of GA in our BM cases with unmatched primary tumors from COSMIC revealed differences in the frequency of mutated genes: TP53 (Lung 85% vs 38%, Breast 63.6% vs 26.0%) CDKN2A/B (Lung 33.7% vs 7%, Melanoma 56.2% vs 18%, Kidney 40% vs 2%, UC 34.7% vs 9%), ERBB2 (Breast 36.3% vs 4%), MYC (Breast 36.36% vs 0.3%), TERT (Melanoma 62.5% vs 25%, Kidney 40% vs 2%), APC (Colon 100% vs 48%), KRAS (Colon 100% vs 31%), PTEN (Prostate 50% vs 7%), TSC1 (Kidney 40% vs 2%), STK11 (UC 26.0% vs 6%). Our results demonstrate a higher frequency of TP53 mutations (p=0.001) in metastatic lung cancer, and a higher frequency of MYC amplification (p=0.01) in metastatic breast cancer, when compared to primary tumors. The present study demonstrates significant differences in the frequency of mutations between primary tumors and BM. Such differences may play an important role in the pathogenesis of BM and may allow for targeted strategies utilizing existing therapies.
OTHR-10. THE NATIONAL DISTRIBUTION OF NEWLY-DIAGNOSED BRAIN METASTASES IN ADULTS VARIES WIDELY BY PATIENT DEMOGRAPHICS
Authors: Kavouridis Vasileios , Torre Matthew , Harary Maya , Smith Timothy , Iorgulescu Bryan 
Published: August 2019

Abstract
INTRODUCTION: Metastases are oft-cited as comprising approximately half of all adult intracranial neoplasms, and their national composition remains unclear. METHODS: The patient demographics and histologic distribution of newly-diagnosed brain metastasis (BM) patients aged &gt; 18yo without a prior history of cancer (2010–2015) were evaluated using the National Cancer Database, which comprises &gt; 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 BMs 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 BMs 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.