tbuckley/cabot-search huggingface dataset:
STEM-03. NOVEL METASTATIC BRAIN TUMOR TARGETS ISOLATED THROUGH PHAGE DISPLAY BIOPANNING AGAINST BRAIN METASTASIS-INITIATING CELLS
Authors: Jongmyung Kim, Shideng Bao, Jeremy N. Rich, James Liu
Journal: Neuro-Oncology (2018)

Despite treatment advances for primary cancers that may result in brain metastases, the treatment for brain metastases has lagged behind, partly due to the unique environment created by the central nervous system. Recent work has highlighted that metastatic brain tumors demonstrate significant genotypic deviation from their parental tumors, which highlights the need to focus on metastatic brain tumors for the development of more effective targeted therapeutics. The epithelial-mesenchymal transition suggests the existence of brain metastasis-initiating cells (BMICs), which may possess stem cell-like phenotypes that play a pivotal role in metastasis. To properly isolate this subpopulation of tumor cells, we compared patient derived metastatic brain tumor cells against brain metastasis cell lines. We found that both types of cells demonstrated similar morphology when grown in standard serum media conditions, but when grown in serum-free media, both demonstrated a tumor sphere morphology. Gene expression analysis showed increased expression of stem cell markers CD133 and EYA1 when grown in serum-free media. To isolate therapeutic targets specific to BMICs, we performed in vitro and in vivo phage display biopanning against BMICs. Analysis of the recovered peptides derived several potential targets. Among them were angiomotin (AMOT) and bromodomain testis-specific factor (BRDT). Gene expression analysis confirmed significant upregulation of these gene in metastatic brain tumors cells when compared to non-tumor neural cells and primary lung cancer cell lines. Tissue microarray analysis of eleven matched brain metastasis and primary lung cancer patient tissue from Moffitt Cancer Center demonstrated an increased expression in brain metastasis over primary lung tissue. Analysis through NIH GEO database demonstrated decreased survival with increased gene expression. Our results show that we can use phage display biopanning to isolate novel targets that may be specific to metastatic brain tumors by isolating the proper growth conditions that support the BMIC phenotype.
INNV-08. THE UTILIZATION OF INTRAOPERATIVE CONFOCAL LASER ENDOMICROSCOPY DURING THE FLUORESCENCE GUIDED SURGERY FOR BRAIN TUMORS
Authors: Evgenii Belykh, Claudio Cavallo, Xiaochun Zhao, Eric Miller, Arpan A Patel, Nikolay L Martirosyan, Vadim A Byvaltsev, Robert F Spetzler, Jennifer Eschbacher, Peter Nakaji, Mark Preul
Journal: Neuro-Oncology (2018)

Confocal laser endomicroscopy (CLE) allows intraoperative “optical biopsy” at a cellular level without tissue processing. We report the evolution of this technology and present analysis of recent use of the updated CLE tool on patients during fluorescein sodium (FNa) guided brain tumor surgeries. Our clinical experience with CLE includes 237 patients with gliomas, meningiomas and other CNS pathologies examined ex vivo and in vivo using a Generation1 CLE and 48 patients using a Generation2 CLE (19 HGG, 3 LGG, 11 pituitary adenomas, 2 craniopharyngiomas, 2 metastases, 2 schwannomas, 4 meningiomas, 2 treatment effects, 1 focal cortical dysplasia, 2 hemangioblastomas) examined ex vivo. Acriflavine (AF) and acridine orange (AO) were used ex vivo on selected tissue samples. In vivo CLE during FNa-guided surgery produced 77.7 ± 46.2 (average) images/optical biopsy location. A first diagnostic image was identified within seconds of CLE application. In vivo CLE specificity/sensitivity (FNa) was equal or better than frozen section (94%/91% gliomas, 93%/97% meningiomas respectively). Generation2 CLE showed improved image resolution and system operation for detectable tumor signal with Z-stack 3D imaging compared to Generation1. FNa 2 mg/kg administered during induction of anesthesia was sufficient for wide field tumor fluorescence visualization using the operative microscope Yellow560 mode. However, additional injection of FNa (2–5 mg/kg) before optical biopsy was necessary to provide sufficient CLE image contrast for immediate ex vivo CLE imaging in most of the cases. CLE imaging after rapid ex vivo application of AF and AO revealed more intense and specific contrasted intracellular structural patterns, such as nuclei. Overall, CLE rapidly provided information on tissue architecture and atypical cellular features and has potential to improve the surgery-pathology workflow. Additional injection of FNa during fluorescence-guidance surgery may be necessary for CLE optical biopsy, which may interfere with the operative microscope wide field fluorescence visualization, and require further investigation.
HOUT-34. ADVERSE EVENTS IN BRAIN TUMOR SURGERY: INCIDENCE, TYPE AND IMPACT ON CURRENT QUALITY METRICS
Authors: Stephanie Schipmann, Tobias Brix, Julian Varghese, Nils Warneke, Michael Schwake, Benjamin Brokinkel, Christian Ewelt, Martin Dugas, Walter Stummer
Journal: Neuro-Oncology (2018)

OBJECT: The aim of the study was to determine pre-operative factors associated with adverse events occurring within 30 days after neurosurgical tumor treatment. All adult patients that were hospitalized due to a benign or malignant brain tumor in our department between 2013 and 2017 were retrospectively assessed for quality indicators and adverse events. Administrative data were obtained, the age-adjusted Charlson Comorbidity Index (CCI) was calculated and logistic regression analyses were performed to determine risk factors for adverse events. Detailed analyses of all readmissions and reoperations were performed. Overall, 2511 cases were enrolled. The most common diagnosis was glioma (42%). The 30-days unplanned readmission rate was 5.7%. The main reason for readmission was tumor progression. Every 10thpatient had an unplanned reoperation. The incidence of surgical revisions due to infections was 2.3%. Taking together all monitored adverse events, male patients had a higher risk for any of these complications (OR: 1.236, 95%CI: 1.025–1.490, p=0.027). Age, sex and histological diagnosis were predictors of experiencing any complication. The CCI was significantly higher in patients that were readmitted within 30 days (p= 0.045) and correlated with a higher 30-days mortality rate (p< 0.001), a higher nosocomial infection rate (p< 0.001), a higher SSI rate (p= 0.027) and a longer length of stay (p< 0.001) in univariate analysis. We found that most predictors of adverse events and outcome rates are based on preoperative underlying medical conditions of the patient and are not modifiable by the surgeon. Comparing our results to the literature, we conclude that differences in readmission and reoperation rates are strongly influenced by standards in surgical decision making and that comparison of outcome rates between different health-care providers on an international basis is challenging. Each health-care system has to develop own metrics for risk adjustment and assessment of outcome variables, that require regular reassessment.
RTHP-29. A FEASIBILITY STUDY OF RADIATION THERAPY DOSE ESCALATION GUIDED BY SPECTROSCOPIC MRI IN PATIENTS WITH GLIOBLASTOMA
Authors: Eric Mellon, Saumya Gurbani, Brent Weinberg, Lawrence Kleinberg, Eduard Schreibmann, Peter Barker, Andrew Maudsley, Hui-Kuo Shu, Hyunsuk Shim
Journal: Neuro-Oncology (2018)

The standard of care for glioblastoma is neurosurgical resection followed by radiation therapy (RT) and temozolomide (TMZ) chemotherapy. Previous RT with TMZ dose escalation attempts with RT doses up to 75 Gy targeted gadolinium contrast enhancing portions of tumor. These studies generated no significant benefits in recurrence or survival, but this may be because areas of gadolinium contrast enhancement only partially correlate with areas of future recurrence. Proton spectroscopic MRI (sMRI) measures endogenous metabolite levels without intravenous contrast agent. Elevated choline to N-acetylaspartate ratios (Cho/NAA) measured with whole brain sMRI mapping have significantly correlated with histological disease and, intriguingly, sMRI metabolic abnormalities predate disease recurrence. To enable RT dose escalation by sMRI in a multi-institutional clinical study setting, we specifically designed a cloud software platform to incorporate sMRI into the RT planning workflow. In order to test the sMRI workflow across institutions, a sMRI-guided dose escalation feasibility study is underway at three university hospitals (Emory, Johns Hopkins, and U. Miami). Eligible patients with glioblastoma after biopsy or surgical resection undergo MRI and sMRI within 14 days of start of therapy with TMZ and dose painted RT. Elevated Cho/NAA and residual contrast-enhancing lesions are targeted for boosted radiation to 75 Gy while the remaining tissue received standard-of-care therapy to 60 or 51 Gy in 30 fractions. Patients also receive a second sMRI scan during the third week of therapy to assess for early tumor response. Preliminary results are encouraging. In the first of three years of planned accrual, 11 patients (Emory 5, Miami 4, Hopkins 2) of a planned 30 have been treated within this trial with no observed serious adverse events. As this is a technical feasibility study with no control group, we plan for a future randomized cooperative group study with sMRI dose escalation versus standard of care.
Hospital suspends chemotherapy because of nurse shortage
Authors: Jacqui Wise
Journal: BMJ (2018)

The decision by a NHS trust to stop providing chemotherapy at one of its hospitals because it has too few specialist cancer nurses to staff the unit has reignited the debate about nursing shortages.

The Cedar Centre at King George Hospital in Ilford, east London, said that from 12 November it would not be able to offer chemotherapy, after four nurses left and two others took maternity leave.

The Royal College of Nursing and the charity Macmillan Cancer Support described the decision as “hugely concerning.”

A spokesman for Barking, Havering and Redbridge University Hospitals NHS Trust told The BMJ that plans to centralise chemotherapy services at Queen’s Hospital in nearby Romford were already under way when the staff shortages arose. He acknowledged that the trust had been forced to hasten the move when it found …
Abstract 13605: Determinants of Outcomes Following Outpatient Placement of Implantable Cardioverter Defibrillators in a Medicare Advantage Population
Authors: Yongjia Song, Teresa L Rogstad, Adam C Powell, Tristan Cordier, Stephen E Price, James W Long, Uday U Deshmukh, Jeffrey D Simmons
Journal: Circulation (2017)

Introduction: Implantable cardioverter defibrillators (ICDs) are effective in preventing sudden cardiac death; factors associated with success have not been clearly defined. Objective: To identify ...
CBMT-42. LOSS OF PROMOTER METHYLATION IN GLYCOLYTIC GENES IS ASSOCIATED WITH AGGRESSIVENESS IN IDH1-MUTANT LOWER GRADE GLIOMAS
Authors: Mioara Larion, Victor Ruiz Rodado, Tomohiro Seki, Tathiane Malta, Adrian Lita, Tyrone Dowdy, Orieta Celiku, Alejandra Cavazos Saldana, Aiguo Li, Wei Zhang, Hua Song, Dionne Davis, Sunmin Lee, Jane Neckers, Jeeva Munasinghe, Houtan Noushmehr, Christel Herold-Mende, Mark Gilbert, Murali Krishna Cherukuri
Journal: Neuro-Oncology (2018)

Identification of malignant progression is a major challenge in the field of Neuro-Oncology because of inability of traditional imaging methods to distinguish pseudo-progression from true progression. IDH1-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with malignant progression because they appear initially indolent and non-glycolytic, but eventually a subset progress towards secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood. TS603, NCH1681 and BT142 cell lines harboring IDH1 mutation were cultured in DMEM/F12+ N2 supplement, glutamine, FGF and EGF, then either harvested for metabolomics and methylation analyses or (250,000 cells) were injected into 6-week-old SCID mice brains. MRI was used to monitor tumor size; when tumors reached 100 mm3, mice were injected in the tail vain with 96 mM 1-13C pyruvate which was hyperpolarized using Oxford Hypersense hyperpolarizer and chemical shift images were acquired immediately. Metabolite quantification was done using the Agilent LC/MS 6545 QTOF mass spectrometer. DNA methylation analysis was performed using Ilumina Infinium MethylationEPIC. RESULTS AND Cell lines that demonstrate aggressive growth both in vitro and in vivo have lost methylation in the promoters of glycolytic enzymes and have increased mRNA and metabolite levels for the glycolysis pathway compared to the non-transformed model. Metabolic 13C MRI using hyperpolarized13C pyruvate confirmed that these aggressive lines have a Warburg-like phenotype (aerobic glycolysis). Moreover, the glycolytic enzyme expression of the aggressive cell line correlated with the subset of patients that are IDH1 mutated and low-G-CIMP in TCGA database. We hypothesize that specific modulation of epigenetic markers is a mechanism of malignant transformation and that monitoring lactate production may be a biomarker of transformation.
Mammary Precancerous Stem and Non-Stem Cells Evolve into Cancers of Distinct Subtypes
Authors: Wen Bu, Zhenyu Liu, Weiyu Jiang, Chandandeep Nagi, Shixia Huang, Dean P. Edwards, Eunji Jo, Qianxing Mo, Chad J. Creighton, Susan G. Hilsenbeck, Andrew D. Leavitt, Michael T. Lewis, Stephen T. C. Wong, Yi Li
Journal: Cancer Research (2018)

Abstract There are distinct cell subpopulations in normal epithelial tissue, including stem cells, progenitor cells, and more differentiated cells, all of which have been extensively studied for their susceptibility to tumorigenesis. However, normal cells usually have to progress through a precancerous lesion state before becoming a full-blown tumor. Precancerous early lesions are heterogeneous, and the cell subset that is the primary source of the eventual tumor remains largely unknown. By using mouse models that are tailored to address this question, we identified a keratin 6a-expressing precancerous stem cell (PcSC) subset and a more differentiated whey acidic protein-positive (WAP+) cell subset in mammary precancerous lesions initiated by the Wnt1 oncogene. Both cell subsets rapidly progressed to cancer upon introduction of constitutively active versions of either HRAS or BRAF. However, the resulting tumors were dramatically different in protein profiles and histopathology: keratin 6a+ precancerous cells gave rise to adenocarcinoma, whereas WAP+ cells yielded metaplastic carcinoma with severe squamous differentiation and more robust activation of MEK/ERK signaling. Therefore, both stem and non-stem cells in mammary precancerous lesions can contribute to the eventual cancers, but their differentiation status determines the resulting cancer phenotype. This work identifies a previously unknown player in cancer heterogeneity and suggests that cancer prevention should target precancerous cells broadly and not be limited to PcSC. Significance: This work uses a novel mouse mammary gland cancer model to show that tumors initiated from different precancerous mammary epithelial cells are distinct.
Antitumor activity of IMO-2055, an agonist of TLR9, in combination with erlotinib and bevacizumab in non-small cell lung cancer xenografts in mice
Authors: Daqing Wang, Ekambar Kandimalla, Dong Yu, Robert Karr, Sudhir Agrawal
Journal: Cancer Research (2008)

2078  IMO-2055 is an agonist of TLR9. It has shown potent Th1-type innate and adaptive immune responses, and antitumor activity in preclinical tumor models. In the present study, we have evaluated IMO-2055 alone and in combination with erlotinib, an inhibitor of EGFR tyrosine kinase, and bevacizumab, a monoclonal antibody against VEGF, in H358 human non-small cell lung cancer (NSCLC) xenograft model. Peritumoral injections of IMO-2055 three times a week for 7 weeks resulted in 53.6% growth inhibition on week 7 compared with PBS control group. Intra-gastric administration of erlotinib once a week or intra-peritoneal administration of bevacizumab two times a week for 7 weeks resulted in 47.6% and 46.4% tumor growth inhibition, respectively. Moreover, treatment with the combination of IMO-2055 and erlotinib or bevacizumab showed 63.0% and 76.1% tumor growth inhibition, respectively. Treatment of mice with triple combination of IMO-2055, erlotinib and bevacizumab lead to 88.8% tumor growth inhibition. Median survival (days for tumor nodules to reach 1.5 gram) of mice in IMO-2055, erlotinib, or bevacizumab treated groups was prolonged about 25, 7, or 22 days, respectively, compared with PBS control group. The combination of IMO-2055 and erlotinib or bevacizumab prolonged survival of tumor bearing mice by 36 and 40 days, respectively. The treatment with combination of all three agents resulted in complete regression of tumors in 43% of the mice, and extended median survival longer than 121 days. These results demonstrate that IMO-2055 exerts potent antitumor activity and enhances antitumor effects of erlotinib and bevacizumab in mice bearing H358 NSCLC. A clinical trial to evaluate IMO-2055 in combination with erlotinib and bevacizumab is planned.
Elimination Of Il-33 Inhibits Airways Hyperresponsiveness
Authors: C. M. Frodella, B. J. Smith, Lars T. Hellman, M. E. Poynter, A. Van Der Vliet, M. Aliyeva, N. Daphtary, M. Hristova, L. K. A. Lundblad
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
RARE-09. EFFICACY AND SAFETY OF DABRAFENIB + TRAMETINIB IN PATIENTS WITH RECURRENT/REFRACTORY BRAF V600E–MUTATED HIGH-GRADE GLIOMA (HGG)
Authors: Patrick Wen, Stein Alexander, Bang Yung-Jue, Martin van den Bent, Anas Gazzah, Sascha Dietrich, Filip de Vos, Mayra van Linde, Albert Lai, Andrew Chi, Gerald Prager, Mario Campone, Nikolas von Bubnoff, Angelica Fasolo, Jose Lopez-Martin, Bijoyesh Mookerjee, Aislyn Boran, Paul Burgess, Fatima Rangwala, Vivek Subbiah
Journal: Neuro-Oncology (2018)

Current treatment outcomes for patients with recurrent HGG are poor, with median progression-free survival (PFS) and overall survival (OS) of 2.5 and 7.5 months, respectively. Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) resulted in an intracranial overall response rate (ORR) of 58% in BRAF V600–mutated melanoma brain metastases. Dabrafenib + trametinib was evaluated as treatment for patients with BRAF V600E–mutated HGG. In this phase 2, open-label trial (NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including HGG, received continuous dabrafenib (150 mg BID) + trametinib (2 mg QD) until unacceptable toxicity, disease progression, or death. For the HGG cohort, eligible patients had histologically confirmed recurrent or progressive WHO grade 3 or 4 glioma and had prior treatment with radiotherapy and first-line chemotherapy or concurrent chemoradiation therapy. The primary endpoint was investigator-assessed ORR by RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. Thirty-seven patients with HGG had enrolled at data cutoff (3 January 2018). Median age was 42 years, 31 of 37 patients were evaluable for response. Investigator-assessed confirmed ORR was 26% (8/31; 95% CI, 12%-45%), including 1 complete response (CR). Six of 8 responses were ongoing at data cutoff. Five of 8 responding patients had a DOR of ≥ 12 months. Median PFS was 1.9 months (95% CI, 1.7–18.5). Median OS was 11.7 months (95% CI, 6.4-not reached). Adverse events (AEs) in patients with HGG included fatigue (35%), headache (30%), and rash (24%). Grade 3/4 AEs included neutropenia (8%) and fatigue (5%). Biomarker analyses are ongoing and will be presented. CONCLUSIONS: Dabrafenib + trametinib demonstrated promising efficacy in patients with BRAF V600E-mutated recurrent/refractory HGG, as 1 patient had a CR, and most responders had a prolonged DOR.
Unloading the Left Ventricle Before Reperfusion in Patients With Anterior ST-Segment–Elevation Myocardial Infarction
Authors: Navin K. Kapur, Mohamad A. Alkhouli, Tony J. DeMartini, Haroon Faraz, Zachary H. George, Mark J. Goodwin, Jaime A. Hernandez-Montfort, Vijay S. Iyer, Noam Josephy, Sanjog Kalra, Amir Kaki, Richard H. Karas, Carey D. Kimmelstiel, Gerald C. Koenig, Evan Lau, Kapildeo Lotun, Ryan D. Madder, Salvatore F. Mannino, Perwaiz M. Meraj, Jason A. Moreland, Jeffrey W. Moses, Raymond L. Kim, Theodore L. Schreiber, James E. Udelson, Christian Witzke, David H.W. Wohns, William W. O’Neill
Journal: Circulation (2019)

In ST-segment-elevation myocardial infarction (STEMI), infarct size correlates directly with heart failure and mortality. Preclinical testing has shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) before reperfusion reduces infarct size and that 30 minutes of unloading activates a cardioprotective program that limits reperfusion injury. The DTU-STEMI pilot trial (Door-To-Unload in STEMI Pilot Trial) represents the first exploratory study testing whether LV unloading and delayed reperfusion in patients with STEMI without cardiogenic shock is safe and feasible.In a multicenter, prospective, randomized exploratory safety and feasibility trial, we assigned 50 patients with anterior STEMI to LV unloading by using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events at 30 days. Efficacy parameters included the assessment of infarct size by using cardiac magnetic resonance imaging.All patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective mean door-to-balloon times of 72 versus 97 minutes. Major adverse cardiovascular and cerebrovascular event rates were not statistically different between the U-IR versus U-DR groups (8% versus 12%, respectively, P=0.99). In comparison with the U-IR group, delaying reperfusion in the U-DR group did not affect 30-day mean infarct size measured as a percentage of LV mass (15±12% versus 13±11%, U-IR versus U-DR, P=0.53).We report that LV unloading using the Impella CP device with a 30-minute delay before reperfusion is feasible within a relatively short time period in anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety signals that would preclude proceeding to a larger pivotal study of LV unloading before reperfusion. An appropriately powered pivotal trial comparing LV unloading before reperfusion to the current standard of care is required.URL: https://www.clinicaltrials.gov . Unique identifier: NCT03000270.
Mineralocorticoid Receptor Antagonism Treatment for All Patients With ST-Segment Myocardial Infarction?—Reply
Authors: Khagendra Dahal, Kalgi Modi
Journal: JAMA Internal Medicine (2018)

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