bluuebunny/crossref_metadata_2025_split huggingface dataset:
THER-14. INFLUENCE OF CLINICAL PARAMETERS ON THE EFFICACY OF IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH NON-SMALL CELL LUNG CANCER BRAIN METASTASES (NSCLCBM)
Authors: Lauko Adam , Thapa Bicky , Muhsen Baha’eddin , Borghei-Razavi Hamid , Wei Wei , Chao Samuel , Stevens Glen , Peereboom David , Yu Jennifer , Murphy Erin , Angelov Lilyana , Mohammadi Alireza , Suh John , Barnett Gene , Pennell Nathan , Ahluwalia Manmeet 
Published: August 2019

Abstract
INTRODUCTION: Non-small cell lung cancer brain metastases (NSCLCBM) patients have a dismal prognosis. Immune checkpoint inhibitors (ICI) have resulted in improved outcomes in a subset of patients, although limited information exists on the impact of ICI in patients with NSCLCBM. METHODS: We reviewed 121 NSCLCBM (2012–2018) patients treated at our tertiary care center. All patients received at least 2 cycles of ICI therapy after diagnosis of NSCLCBM. Overall survival (OS) and progression-free survival (PFS) were calculated from the start of ICI therapy to date of death, progression or last follow up. Kaplan-Meier curves were used to estimate survival and were analyzed using the Wilcoxon test. RESULTS: Median age was 62 years (39–81) and median KPS was 90. Eighty-six patient received Nivolumab, 7 Atezolizumab, 25 Pembrolizumab, and 3 patients received multiple ICI over the course of their treatment for NSCLCBM. One hundred and twelve patients underwent stereotactic radiosurgery. Nine patients were treated with ICI alone and 25 patients underwent surgical resection. Median OS for the entire cohort was 558 (303–1159) days and median PFS was 220 (114–512) days. Twenty-four patients received oral steroids within the first 28 days of ICI (median prednisone equivalent dose of 27 mg). Patients on upfront steroid therapy had a median PFS of 148 days vs 301 days in patients not on upfront steroids (p-value .0095). Complete blood count at the start of ICI was available for 87 patients and neutrophil to lymphocyte ratios (NLR) were calculated. Patients with NLR at the start of ICI above 5 (n=33) had a median overall survival of 337 days compared to 558 days when NLR was below 5 (p-value .038). CONCLUSION: Use of steroids at initiation or within first 28 days of ICI therapy and NLR of greater than 5 are associated with worse outcomes in NSCLCBM treated with ICI.
MLTI-01. IMMUNOLOGICAL REPROGRAMMING IN THE CNS TUMOR MICROENVIRONMENT AND THERAPEUTIC EFFICACY OF RADIOTHERAPY WITH STAT3 BLOCKADE
Authors: Ott Martina , Hashimoto Yuuri , Marisetty Anantha , Wei Jun , Zamler Daniel , Leu Jia-Shiun , Kong Ling-Yuan , Zhou Shouhao , Fuller Gregory , de Groot John , Priebe Waldemar , Sulman Erik , Heimberger Amy 
Published: August 2019

Abstract
BACKGROUND: Patients with central nervous system (CNS) tumors are typically treated with radiation therapy, but this is not curative and results in the upregulation of p-STAT3 that drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of the STAT3 pathway that is currently in clinical trials (WP1066) and whole-brain radiation therapy (WBRT) in murine models of CNS malignancy. METHODS: C57BL/6 mice underwent intracerebral implantation of either B16 melanoma or GL261 glioma cells, WBRT, and treatment with WP1066 a blood-brain barrier penetrant inhibitor of the STAT3 pathway or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune incompetent backgrounds, immune monitoring, and nanostring gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the CNS tumor microenvironment. RESULTS: The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy. Immunological memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. Therapeutic efficacy was completely lost in immune incompetent mice. Extensive functional immune monitoring and nanostring profiling followed by bioinformatic processing revealed that the most robust immunological responses were located in the CNS tumor microenvironment rather than the periphery. An unbiased analysis of the immune-cell heat maps of the combination therapy relative to monotherapy were notable for upregulation of T-cell functional genes, dendritic cell function, MHC expression, and antigen presentation in the CNS tumor. These data highly suggest that antigen presentation and T-cell effector function are requirements within the tumor microenvironment of the CNS for full antitumor immune-mediated activities. CONCLUSION: This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against established tumors in the CNS by inducing dendritic cell maturation and activation in the CNS tumor.
MLTI-02. A PHASE I TRIAL OF SORAFENIB WITH WHOLE BRAIN RADIOTHERAPY (WBRT) IN BREAST CANCER PATIENTS WITH BRAIN METASTASES AND A CORRELATIVE FLT-PET BRAIN IMAGING STUDY IN PATIENTS RECEIVING WBRT +/- SORAFENIB
Authors: Morikawa Aki , Grkovski Milan , Patil Sujata , Jhaveri Komal , Tang Kendrick , Humm John , Holodny Andrei , Beal Kathryn , Schoder Heiko , Seidman Andrew 
Published: August 2019

Abstract
BACKGROUND: Sorafenib has demonstrated anti-tumor efficacy in breast cancer and radiosensitizing activity preclinically. [18F] 3’deoxy-3’-fluorothymidine (FLT) is a PET tracer which correlates with cellular proliferation and may improve response assessment. METHODS: A phase I trial of whole brain radiotherapy (WBRT)+sorafenib was conducted using a 3 + 3 design. Sorafenib was given daily at the start of WBRT for 21 days (dose levels: 200mg, 400mg, and 600mg). The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment. A correlative serial FLT-PET imaging study was conducted to assess radiographic changes among pts receiving WBRT +/- sorafenib, in parallel with MRI. RESULTS:13 pts in the dose escalation were evaluable for dose-limiting toxicity (DLT). DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was 200mg. Six additional pts were treated in an expansion cohort without additional DLT. 14 pts were evaluable for response. The overall response rate was 71%: 4 complete + 6 partial responses. Median follow up was 14 months (range: 3–44). Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT+sorafenib and 5 WBRT) were enrolled in the FLT-PET study: all had baseline FLT-PET, 14 with follow up at 7–10 days post WBRT (FU1), and 9 with followup at 12 weeks post WBRT (FU2). 55 baseline lesions were observed and analyzed: 38 at FU1 and 15 at FU2. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib pts and 2/4 (50%) of WBRT only pts at FU1. CONCLUSIONS: Concurrent WBRT+sorafenib appears safe at 200mg daily dose with clinical activity. This combination should be considered for further efficacy evaluation. NCT01724606 and NCT01621906.
MLTI-10. ESTABLISHMENT OF A MULTIDISCIPLINARY BRAIN METASTASIS CLINIC TO FACILITATE PATIENT-CENTERED CARE AND COORDINATED RESEARCH
Authors: Li Jing , Lang Frederick F , Guha-Thakurta Nandita , Weinberg Jeffrey S , Rao Ganesh , Heimberger Amy , Ferguson Sherise , Prabhu Sujit , Sawaya Raymond , Yeboa Debra N , McAleer Mary Frances , Chung Caroline , Briere Tina , Davies Michael , de Groot John , Glitza Isabella , Murthy Rashmi K , Rodon Jordi , O’Brien Barbara , Dumbrava Ecaterina , Yung W K Alfred , Vining David , Schomer Donald , Wang Yan , Suki Dima , Wozny Mark , Zaebst Denise , Austin Wendy , Nguyen Alissa , Burton Elizabeth , Davis Suzanne , Tawbi Hussein 
Published: August 2019

Abstract
BACKGROUND: ~30% cancer patients develop brain metastases (BM), reflected by ~1600 BM patients treated at MD Anderson Cancer Center annually. With advances in systemic therapy and extracranial disease control, BM is a growing challenge. Multi-disciplinary BM management is critical and complex requiring coordination of multiple oncology sub-specialties. There is limited data on pragmatic clinic models to streamline and advance care. METHODS: Recognizing deficiency in BM treatment and research, a steering committee was formed at MDACC to establish an interdisciplinary BM clinic (BMC), with a multi-disciplinary BM research retreat held in 2016. The goal of BMC was to centralize patient referrals, improve patient outcomes and experience, and advance research by developing clinical trials and biomarker discovery programs. Meetings were held to address BMC format, workflow, EMR integration, data collection infrastructure, and staffing model. RESULTS: MDACC BMC clinic opened in 01/2019 with two half-day clinics staffed by neurosurgery, neuro-radiation oncology, neuro-radiology and medical/neuro oncology. A dedicated advanced practice provider screens the referrals according to a well-developed algorithm. A multidisciplinary conference is held immediately before each clinic where patient images are reviewed, cases are discussed and consensus recommendations are developed. The treatment plan and follow up appointments are arranged at the completion of the clinic visit to expedite care. ~50 patients have been seen with excellent patient satisfaction response and reduced time to treatment. ~20% patients had major change in treatment plan following multi-disciplinary evaluation. Additional efforts to develop a central BM database along with clinical and translational research programs are on-going. CONCLUSIONS: Establishment of a multi-disciplinary BMC to facilitate care and centralize research programs addresses a critical need for coordinated patient-centered BM management. This endeavor has enhanced patient experience through multi-specialty collaboration. Our program demonstrates the feasibility and effectiveness of a dedicated BMC in the treatment of this complex patient population.
MLTI-14. A SYSTEMATIC REVIEW OF TREATMENT PARADIGMS FOR PATIENTS WITH BREAST CANCER AND ONE OR MORE BRAIN METASTASES
Authors: Ellenbogen Yosef , Brar Karanbir , Warsi Nebras , Badhiwala Jetan , Mansouri Alireza 
Published: August 2019

Abstract
BACKGROUND: Upwards of 50% of patients with advanced breast cancer are diagnosed with brain metastases (BM). Treatment options for these patients have been rapidly evolving due to increased understanding of the tumor pathophysiology and its genetic underpinnings. This systematic review of randomized controlled trials (RCTs) aims to clarify the evidence guiding the treatment of brain metastases from breast cancer. METHODS: MEDLINE, EMBASE, Cochrane Controlled Register of Trials, ClincialTrials.gov, and Web of Science were searched from inception to October 2018 for RCTs comparing treatments for breast cancer BM. We screened studies, extracted data, and assessed risk of bias independently and in duplicate. Outcomes assessed were overall survival (OS), progression-free survival (PFS), and adverse events (Grade 3+). RESULTS: Among 3188 abstracts, only 3 RCTs (N=412; mean sample size per group N=54.7) meeting inclusion criteria were identified. The studies were phase II or III open-label parallel superiority trials. Inclusion criteria among these trials consisted of age &gt;18 with radiologic evidence of &gt;1 BM. Exclusion criteria consisted of poor-performance functional status (ECOG &gt;2 or KPS &lt; 70). The treatment groups included whole-brain radiation therapy (WBRT) vs WBRT + Temozolomide, WBRT vs WBRT + Efaproxiral, and Afatinib vs Vinorelbine vs investigators’ choice (86% of these patients received WBRT or SRS prior to study enrolment). While two trials found no significant difference in OS, one trial found significant improvement in OS with Efaproxiral in addition to WBRT compared to WBRT alone (HR 0.52; 95%CI 0.332–0.816). No significant differences were found with PFS or rate of adverse events amongst treatment groups. CONCLUSION: Considering the high prevalence of breast cancer BM and our improved understanding of genomic/molecular features of these tumors, a greater number of RCTs dedicated at this disease are needed.
MLTI-18. PRECISION IMAGING OF METASTATIC AND PRIMARY BRAIN TUMORS AFTER RADIATION WITH 18F-FDOPA PET-MRI IS FEASIBLE AND COST EFFECT
Authors: Aboian Mariam , Ravanfar Vahid , Bahroos Emma , Tong Elizabeth , Taylor Jennie , Oberheim Bush Nancy Ann , Seo Youngho , Cha Soonmee , Pampaloni Miguel Hernandez 
Published: August 2019

Abstract
PURPOSE: Post-radiation changes in the brain can mimic tumor recurrence on MRI, requiring multiple short term follow-ups to differentiate tumor progression from radiation necrosis. We propose combining functional and anatomic imaging with FDOPA PET tracer in hybrid PET-MRI to improve detection of tumor recurrence. MATERIALS AND METHODS: Seventeen adult patients treated with radiation therapy were identified - four with metastatic disease from breast and lung cancer and thirteen with primary brain glioma (11 IDH wildtype glioblastoma and 2 astrocytoma). Patients were scanned on hybrid PET-MRI (GE Healthcare) with clinical MRI brain sequences and dynamic FDOPA uptake. Dynamic FDOPA uptake within these tumors over 45 minutes after tracer injection was analyzed and compared to ADC histogram analysis. RESULTS: For each of the patients, clinical multi sequence gadolinium enhanced MRI and dynamic PET imaging for up to 45 minutes with 18F-FDOPA amino acid tracer was obtained. The total cost savings of scanning 17 patients in groups was 51.4% ($28,321), as opposed to the cost of individual radiosynthesis performed for each study. Quantitative analysis of tracer uptake in striatum, internal carotid artery, and superior sagittal sinus were performed with appropriate accumulation and subsequent washout of tracer respectively. Successful dynamic FDOPA uptake within the tumor was seen in all patients and ratio of tumor to contralateral ROI were found to range from 1.8–4.5. While raw SUV values did not differentiate between recurrent tumor and radiation changes, T/C SUVmax ratios were elevated to 4.5 in recurrent glioblastoma, 2.5 in hypoxic treated glioblastoma, and 1.8 in non-recurrent metastatic breast cancer after gamma knife treatment. CONCLUSION: Batch imaging of patients with [18F]FDOPA PET-MRI is feasible and cost effective. Understanding radionuclide synthesis process is critical for increasing accessibility of novel PET tracers to patients and results in significant cost savings.
OTHR-03. ENHANCEMENT OF T1W-GAD MRI IS ASSOCIATED WITH POST-SRS LOCAL CONTROL OF NSCLC BRAIN METASTASES
Authors: Milchenko Mikhail , LaMontagne Pamela , Abraham Christopher , Robinson Clifford , Marcus Daniel 
Published: August 2019

Abstract
BACKGROUND: Local control (LC) of brain metastasis (BM) is an important clinical endpoint. To date predictors of LC have been limited to patient and treatment related factors. Quantitative imaging features predictive of LC have not been well described for BMs treated by stereotactic radiosurgery (SRS). This study aimed primarily at assessing quantitative imaging predictors of LC that may be used for tailored SRS treatment of BM patients. METHODS: A cohort of non-small cell lung cancer (NSCLC) treated with SRS alone were identified. Post-operative SRS, radiosurgical boost, or prior WBRT cases were excluded. All patients underwent pre-SRS and follow-up T1-Gad MR imaging (termed here T1-SRS and T1-FWU). BM regions were outlined using T1-SRS during treatment planning. LC was assessed for each treated lesion by a Radiation Oncologist. Intensity histograms were normalized to account for inter-individual brain signal heterogeneity. For each BM, computed predictor factors were derived from established LC markers (volume), features associated with tumor shape (compactness, eccentricity), and signal intensity distribution in BM region (percentiles, standard deviation). RESULTS: A total of 106 NSCLC BMs in 82 participants (41 female) were examined. Mean follow-up time was 9±9 months (median 6.5 months). Kaplan-Meier (KM) curves for LC were split by the predictor factors, with split threshold ranging between -0.5 and 0.5 of sample standard deviation, optimized to maximize the difference between lower and upper curves. KM curves for lower volume (p=0.02), lower eccentricity (p=0.004), higher intensity standard deviation (p=0.02), and higher 95th intensity percentile (p=0.05) resulted in significantly higher LC. CONCLUSION: Volume, eccentricity, intensity standard deviation, and 95th intensity percentile were found to predict LC. Intensity standard deviation and intensity percentile as predictors of LC merit validation in larger, independent datasets or in future prospective studies.
OTHR-05. THE ABILITY TO MAKE INFORMED TREATMENT DECISIONS IS COMPROMISED IN ADULTS WITH ADVANCED STAGE CANCER
Authors: Triebel Kristen , Mulhauser Kyler , Gammon Meredith , Gerstenecker Adam , Nabors L Burt , Fiveash John 
Published: August 2019

Abstract
OBJECTIVE: To investigate medical decision-making capacity (MDC) in patients with advanced stage cancer. METHODS: Participants were 113 newly diagnosed adults with brain metastases and 41 adults with metastatic cancer without brain metastases who were recruited from an academic medical center and 40 demographically-matched healthy controls recruited from the community. We evaluated MDC using the Capacity to Consent to Treatment Instrument (CCTI) Vignette B and its four clinically relevant consent standards (expressing a treatment choice, appreciation, reasoning, and understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, and severe impairment) on the consent standards were also assigned to each participant using cutoff scores derived statistically from the performance of the control group. RESULTS: Both of the metastatic cancer groups (with and without brain metastasis) performed significantly below controls on consent standards of understanding and reasoning. The brain metastasis group performed below the non-metastatic cancer group on understanding. Capacity compromise was defined as performance ≤1.5 standard deviations (SD) below the control group mean. Using this definition, approximately 65% of the participants with brain metastases and 51% of participants with metastatic cancer without brain metastases were impaired on at least one MDC standard. CONCLUSION: Over half of participants with metastatic cancer regardless of whether they have brain disease have reduced capacity to make treatment decisions. The finding of impaired MDC in patients without brain metastases is surprising and suggests this group likely exhibits cognitive deficits that impact their ability to understand and reason about different treatment options. The reasons underlying this impairment will be investigated. This highlights the importance of routine clinical assessment of MDC in all patients with metastatic cancer when important treatment decisions are being discussed. These results also indicate a need for the development and investigation of interventions to support or improve MDC in this patient population.
OTHR-08. PREDICTION OF RISK OF CENTRAL NERVOUS SYSTEM METASTASIS FOR AJCC 8TH EDITION STAGE III MELANOMA PATIENTS
Authors: Haydu Lauren , Lo Serigne , McQuade Jennifer , Glitza Isabella , Tawbi Hussein , Carlino Matteo , Menzies Alexander , Long Georgina , Lazar Alexander , Tetzlaff Michael , Scolyer Richard , Gershenwald Jeffrey , Thompson John , Davies Michael 
Published: August 2019

Abstract
Among common solid tumors, melanoma has the highest risk of CNS metastasis. Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for at-risk patients. Clinical data were extracted from two institutions for AJCC 8th edition stage III melanoma patients, diagnosed from 1998–2014 who had negative baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death from stage III presentation, and at benchmark time points 1-, 2-, and 5-years post-diagnosis. The cohort (N=1,918) consisted of patients from major melanoma centers in the US (50.6%) and Australia (49.4%). The first site of distant metastasis was CNS only for 3.9%, CNS and extra-cranial sites (ECS) for 1.9%, and ECS only for 31.2% of patients (N=1918); 15.5% of patients who developed distant metastases (N=708) had CNS involvement at first diagnosis of stage IV disease. Cumulative incidence of CNS metastasis from stage III diagnosis was 3.7% (95% Confidence Interval (CI): 2.9–4.6) at 1-year; 9.6% (95% CI: 8.3–11.0) at 2-years; and 15.9% (95% CI: 14.2–17.7) at 5-years. In multivariable analyses, risk of CNS metastasis was significantly higher for males; younger patients; increasing AJCC stage group; scalp primary tumor site, acral melanoma subtype, and increased primary tumor mitotic rate. Conditional analyses showed that only high primary tumor mitotic rate (&gt;9 per mm2) was significantly associated with risk of subsequent CNS metastasis among patients who survived without CNS recurrence 1-, 2-, and 5-years after the diagnosis of stage III disease. Similar rates of CNS metastasis were observed between these two large, geographically-distinct stage III melanoma patient cohorts. These results provide a framework for developing evidence-based surveillance strategies and for evaluating the impact of contemporary adjuvant therapies on the risk of melanoma CNS metastasis.
OTHR-17. PHYLOGENETIC RESOLUTION OF TISSUE-SPECIFIC METASTOGENIC CLONES IN RENAL CELL CARCINOMA
Authors: Moss Nelson , Berman Samuel , Piscuoglio Salvatore , Ng Charlotte , Selenica Pier , Kumar Rahul , Filho Jorge Reis , Brennan Cameron 
Published: August 2019

Abstract
Genomic factors predictive of organ-specific tropism have been established in several models of cancer. However, the evolutionary dynamics at work in metastatic carcinoma have yet to be characterized in detail. We identified a cohort of clear cell renal cell carcinoma (RCC) patients who also had multiple metastasectomies, and performed deep sequencing and statistical inference of subclonal populations to infer phylogeny and essential genetic features acquired prior to systemic dissemination and site-specific colonization. Exome capture and deep sequencing were performed on tissues from 3 patients with polymetastatic RCC (including 12 metastases, multiple regions of primary tumors, and paired germline tissue) to a mean depth of 250x. Somatic point mutations were called with Mutect, and insertions and deletions with Strelka and VarScan. Validation was performed with a custom NimbleGen panel hybridized to a custom sequence library and sequenced to a mean depth of &gt;500x. Allele-specific copy number and clonal prevalence were established using ABSOLUTE, and analyzed with Pyclone across primary and metastatic lesions to determine clonal architecture. Phylogenetic reconstruction identified ancestral clones, with attendant driver mutations in RCC tumor suppressors (including VHL, SETD2, PBRM1, MTOR) and independent subclonal populations in the metastases of all 3 patients. In an index case with multiple metastases separated spatially and temporally, bone and soft tissue metastases demonstrate apparent independent ancestors. Convergent loss of known tumor suppressors was also noted in all cases, and in several cases found in conjunction with de novo mutations in known RCC driver genes acquired late in tumor development. In this demonstration of subclonal and evolutionary analysis of multiple paired multi-organ RCC metastases, we identified subclonal populations characterized by alteration of several tumor suppressors which subsequently exhibited organ-specific patterns of metastasis.