tbuckley/cabot-search huggingface dataset:
Effects of a 12-week exercise programme on cardiovascular risk and body composition in men receiving androgen deprivation therapy for prostate cancer.
Authors: Yvonne Rumble, Matthew Thompson, Amy Groome, Sam Olden, Ivor Cradock, Simon Chowdhury
Journal: Journal of Clinical Oncology (2018)

e17088 Background: Androgen Deprivation Therapy (ADT) is the main stay of systemic therapy for prostate cancer. However, ADT also predisposes individuals to harmful changes in body composition and cardiovascular disease (CVD) markers. This is concerning as CVD is the next most common cause of death after the cancer. The National Institute for Health and Care Excellence (NICE) have recommended cardiovascular and resistance training as a potential strategy for combating the adverse physical side effects. We aim to investigate the effectiveness of exercise training and nutritional guidance on CVD markers. Methods: 20 males, aged 64.1 ± 7.6 years, newly diagnosed with prostate cancer and undergoing ADT, completed a 12-week programme with CP+R. This involved twice-weekly resistance sessions reaching overload, twice-weekly cardiovascular training within a prescribed heart rate zone, on-going step-count monitoring and nutritional guidance. All patients underwent pre and post programme systolic blood pressure (SBP), diastolic blood pressure (DBP), lean mass (LM) and fat mass (FM) measures. Results: SBP and DBP decreased by 7.1 mmHg and 4.8 mmHg respectively (p < 0.05) during the 12-week programme, from 135/81 mmHg to 128/76 mmHg. FM decreased by 1.9 kg (p < 0.05), whilst there was no significant reduction in LM, which increased by 0.9 kg (p = 0.16). Conclusions: Reductions in SBP, DBP and FM were achieved through a structured CP+R programme whilst receiving ADT for prostate cancer. These juxtapose expected changes whilst undergoing ADT and may provide a blueprint application of the current NICE guidelines. Given the success of ADT as a therapy in extending duration of life, further research into the optimal application of lifestyle interventions to improve quality of life and manage CVD risk is of growing importance. Data Table: Mean±SD Measures Pre Post Difference SBP (mmHg) 135.3 (±19.82) 128.2 (±12.00) -7.1 DBP (mmHg) 81.0 (± 7.24) 76.2 (±8.77) -4.8 FM (kg) 24.6 (±8.65) 22.7 (±8.11) -1.9 LM (kg) 60.9 (±10.51) 61.8 (±10.44) +0.9
A comprehensive study comparing smokers and non-smokers with lung cancer in an urban minority population.
Authors: Poras Patel, Yu Yu Thar, Vadim Zarubin, Daniel Castro, Savitha Nagaraj, Aung Lin, Elizabeth Guevara
Journal: Journal of Clinical Oncology (2017)

e18087 Background: Cigarette smoking is strongly associated with lung cancer; however, very few studies have been conducted in the urban minority population comparing various parameters between smokers and non-smokers with lung cancer. We investigated epidemiological profiles, histological subtypes, staging at diagnosis, survival after diagnosis and the quality of life. Methods: This retrospective study included urban minority population diagnosed with primary lung cancer at the Brooklyn Hospital Center between 2005-2016. The study population was divided into two groups based on smoking history and various parameters listed below were compared. The health care quality of life (HcQOL) was assessed using parameters of weight loss, cough/hemoptysis, shortness of breath, pain, opioid use and functional capacity. Results: Of the total 576 patients, 432 met inclusion criteria, who were divided into Group A (GA) - Smokers (n = 341 (78.9%)) and Group B (GB) - Non-Smokers (n = 91 (21.1%)). Majority of our study population were African American (GA 71.8%, GB 65.9%) followed by Hispanics. The prevalence of lung cancer was higher in females (GA 56%, GB 52.7%). Patients diagnosed with lung cancer before age 60 were 48.4% in GA versus 5.5% in GB. SCLC pathology was 20% in GA &amp; 0% in GB; NSCLC pathology was 80% in GA &amp; 100% in GB. At the time of diagnosis, 27% in GA had metastatic stage-4 (0% in GB), and 71.4% in GB had stage-1 (27% in GA) NSCLC. Less than 1 year survival was 15.5% in GA and 2.4% in GB; &gt; 3 years survival was 32.3% in GA and 95.2% in GB. HcQOL measure of weight loss of &gt; 10 pounds, hemoptysis, shortness of breath at rest, uncontrolled pain, opioid dependence and functional capacity &lt; 1 block was 67.6%, 17%, 61.9%, 54.1%, 75.1% and 92.2% respectively in GA and 29.1%, 3.5%, 23.2%, 18.5%, 49.4% and 24.3% respectively in GB. A 6-minute walk test was abnormal in 77% of GA and 39.1% of GB. Conclusions: In comparison to non-smokers, smokers were diagnosed with lung cancer at a younger age, had advanced stages of cancer at the time of diagnosis, higher mortality and increased opioid dependence. Smokers had significantly poor HcQOL, which was supported by abnormal six-minute walk test results. Females had overall increased incidence of lung cancer.
A phase 1b/2 study of amcasertib, a first-in-class cancer stemness kinase inhibitor, in advanced adenoid cystic carcinoma.
Authors: Gregory Michael Cote, William Jeffery Edenfield, Scott Andrew Laurie, Nicole Grace Chau, Carlos Becerra, Alexander I. Spira, Youzhi Li, Wei Li, Matthew Hitron, Chiang Li
Journal: Journal of Clinical Oncology (2017)

6036 Background: Amcasertib (BBI-503) is an oral first-in-class cancer stemness kinase inhibitor. By targeting multiple serine-threonine stemness kinases, amcasertib inhibits Nanog and other cancer stemness pathways. A phase I clinical trial of amcasertib demonstrated safety and signs of anti-cancer activity in patients (pts) with advanced solid tumors. Cancer stemness pathways have been implicated in adenoid cystic carcinoma (ACC). An RP2D expansion cohort was opened for patients with ACC. Methods: Pts with metastatic, unresectable ACC for whom systemic therapy was indicated were enrolled. Amcasertib was administered orally, once or twice daily, in continuous 28-day cycles at a starting dose of 110 mg to 300 mg total daily. Adverse events were categorized according to CTCAE v4.03 and tumor imaging was evaluated per RECIST 1.1 guidelines. Results: 14 pts with ACC were enrolled. Prior treatments included surgery and radiation in all pts (100%), while 57% (n = 8) had received prior systemic therapy (average 2 prior lines, range 1 to 4). Treatment with amcasertib was well tolerated, with grade 3 diarrhea reported in 1 patient and no related grade 4 AEs. The disease control rate (DCR, proportion with stable disease at 8-weeks, partial response, or complete response per RECIST) was 86% (n = 12) with prolonged disease control (≥ 6 months) achieved in 57% (n = 8) patients. At 12 months, 79% of pts were alive. Median overall survival (mOS) was 28.3 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with advanced ACC who received treatment with amcasertib. Long term follow-up demonstrates prolonged duration of disease control and that a majority of pts in this cohort have survived beyond 2 years. Further clinical evaluation of amcasertib in pts with ACC is warranted. Clinical trial information: NCT01781455.
Abstract 12032: Chronic Kidney Disease Augments Vein Graft Disease Through Interleukin-9-dependent Mechanisms
Authors: Lisheng Zhang, Leigh Brian, Natalie K Mattocks, Susan B Gurley, Neil J Freedman
Journal: Circulation (2015)

Chronic kidney disease (CKD, glomerular filtration rate (GFR) &lt;60 ml/min/1.73 m 2 ) is a powerful independent predictor of cardiovascular events, and CKD increases the risk of vein graft occlusion in CABG patients by 62%. Because CKD impairs clearance of small proteins, we tested the hypothesis that CKD exacerbates vein graft disease by elevating serum levels of critical cytokines that promote neointimal hyperplasia. We modeled CKD in C57BL/6 mice with 5/6ths nephrectomy and modeled vein grafting with IVC-to-carotid interposition grafting. Two wk after 5/6 th s nephrectomy, GFR was 60±10% less than in sham-operated (control) mice, as determined by FITC-inulin clearance ( p &lt;0.05); parallel mouse cohorts were used for either blood collection or vein grafting. Of 23 serum cytokines measured by a Luminex-based assay, the following were elevated in CKD (n=12) compared with control mice (n=9): IL-9 (5-fold), IL-12 (1.8-fold), MCP-1 (1.3-fold), TNF (1.3-fold), and RANTES (1.8-fold) ( p &lt; 0.0003 for each). Four wk after grafting, CKD (n=7) and control mouse (n=7) vein graft neointimas comprised predominantly smooth muscle cells (SMCs), of equivalent prevalence. However, vein graft neointimal area was 4±0.5-fold fold greater in CKD mice: 0.23±0.2 vs. 0.052±0.004 mm 2 ( p &lt;0.01). By quantitative immunofluorescence, vein grafts from CKD mice showed equivalent neointimal expression of NFκB p65 but ~2-fold greater neointimal activation of NFκB, as judged by phosphorylation of p65 on Ser536 and by expression of VCAM-1 ( p &lt;0.01). Vein graft protein levels of IL-9 and IL-9 receptor-α were 3.0±0.6- and 1.7±0.3-fold higher in CKD than control mice ( p &lt;0.01). We then treated CKD mice with IL-9-neutralizing (n=7) or isotype control IgG (n=7) for 4 wk after vein grafting. Control IgG did not affect vein graft neointimal area (0.19±0.02 mm 2 ). However, anti-IL-9 IgG treatment reduced vein graft neointimal area 4-fold (to 0.044±0.004 mm 2 , p &lt; 0.01), and reduced neointimal levels of phospho-p65, IL-9, and IL-9Rα by 40-50% ( p &lt;0.05). Of the 5 serum cytokines elevated by CKD, only IL-9 and IL-6 were reduced by anti-IL-9 IgG treatment: 26±3% and 70±20%, respectively ( p &lt;0.001). We conclude that CKD aggravates vein graft disease dramatically, in large part by elevating plasma levels of IL-9.
Long-term growth and development in 268 bevacizumab (BEV)-treated and 135 control pediatric/adolescent patients (pts): An integrated analysis.
Authors: Hermann L. Müller, Johannes H.M. Merks, Birgit Geoerger, Jacques Grill, Darren Hargrave, Julia Lynne Glade Bender, Sridharan Gururangan, Fariba Navid, Michael Johnston, Jeanette Bachir, Magalie Hilton, Sabine Fürst-Recktenwald
Journal: Journal of Clinical Oncology (2017)

10554 Background: BEV has an established safety profile in adults, but long-term data in children are limited. This analysis examined the effects of BEV on growth/development in pediatric/adolescent pts. Methods: Data (height, weight, body mass index [BMI], bone age data) were pooled (5 trials): NCT00643565 (Ph2/soft tissue sarcoma); NCT01390948 (Ph2/high-grade glioma); NCT00085111 (Ph1/refractory solid tumors); NCT00667342 (Ph2/osteosarcoma); NCT00381797 (Ph2/glioma, medulloblastoma, ependymoma). Pts (&lt;18 yrs old) received ≥1 dose of BEV + chemotherapy (CT) (n=268) or CT alone (n=135). Analyses were exploratory/descriptive. Reference growth data: WHO (&lt;2 yrs); Centres for Disease Control (≥2 yrs). Results: Across the trials, mean number of BEV administrations per pt ranged 5.6–19.9 (dose 5–15mg/kg every 2/3 weeks). Median follow-up time, months (range): BEV+CT, 37.9 (2.4–64.2); CT, 22.9 (2.8–69.2). At baseline, median height, weight, and BMI were close to that of the reference population (mean standard deviation scores [SDS] close to 0). Over 60 months, a slight decline was observed in the mean SDS for height and weight in both arms in this cohort with different tumors/treatments (Table), but remained within normal range of healthy children. Trends were similar for BMI. No delay in growth velocity or bone age in BEV-treated pts vs CT only was observed up to 3 yrs, regardless of age/gender. A subgroup analysis of pts in the growth hormone-dependent development phase was consistent with the overall results. Conclusions: In this analysis, BEV inclusion in the treatment regimen did not have a negative impact on pediatric growth/development beyond that of CT alone. [Table: see text]
Concurrent chemoradiation for non-metastatic anal carcinoma: A case series from a single institution experience.
Authors: Riccardo Lobefaro, Stefano Cavalieri, Federico Nichetti, Sara Manglaviti, Sergio Villa, Filippo G. De Braud, Marco Platania
Journal: Journal of Clinical Oncology (2018)

e15575 Background: Squamous cell carcinoma of the anus (SCCA) is an uncommon malignancy, whose incidence is rising in recent years. Given the rarity of the disease and the presence of an effective multimodal treatment with cure rates up to 90%, limited investigation on locoregional disease case series has been conducted. Methods: We retrospectively analyzed clinical data about patients affected by non-metastatic SCCA treated at our Institution between November 2004 and January 2018. Results: A total of 67 patients were identified, of which 59 (88%) were females. Median age was 66 years (44-88). Primary tumor site was anal canal in 94% and anal margin in 5%, with a clinical stage at the diagnosis being I, II, IIIA and IIIB in 25%, 31%, 21% and 21% respectively. 66 out of 67 patients were treated with concurrent chemotherapy and radiation (CT-RT). Treatment schedules consisted in either intravenous mitomycin (37%) (one dose of 10 mg/m2 on day 1, 29) or cisplatin (55%) (one dose of 20 mg/m2 per day on days 1-5 and 29-32) plus fluorouracil (one dose of 1000 mg/m2 or 750 mg/m2, in mytomicin and cisplatin schedules respectively, per day on days 1-4 and 29-32) and radiotherapy (50.4 Gy in 28 daily fractions). 5 patients received only CT or RT. The most common grade 3-4 adverse events were neutropenia (16%), thrombocytopenia (7%) and diarrhea (6%). Response evaluation for patients treated with CT-RT was available for 64 patients: Complete response (CR) was observed in 96.8% of cases, partial response (PR) in 3.1% of cases. Local or distant relapse occurred in 7 patients (11.2%), who were all previous complete responders. Median PFS was 45.6 months (29.4-57.4). Relapse-free rates at 5 and 10 years were 85.7% and 80.7% respectively. Ten years survival rate was 90.7%. Conclusions: Our data confirm the efficacy of definitive concurrent CT-RT in non-metastatic SCCA, with acceptable toxicity. Notably, half of patients are still treated with alternative CT backbones with cisplatin, which may have a role in metastatic disease. Further studies should investigate clinical and biological characteristics of patients progressing after definitive treatment.
Dose-intensified ONC201 to exert anti-metastatic efficacy and to promote intra-tumoral recruitment of NK-cells in mice.
Authors: Jessica Wagner, Christina Leah B. Kline, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2016)

11550 Background: ONC201 is a novel, first-in-class, orally active anti-tumor agent that upregulates the cytotoxic ligand TRAIL and activates an integrated stress response, leading to upregulation of death receptor 5 in bulk tumor and cancer stem cells. ONC201 is being evaluated in multiple clinical trials, where it has demonstrated safety and a preliminary efficacy signal. In the first-in-human trial, patients were dosed every 3 weeks. We investigated dose-intensification of ONC201 to determine whether a higher dose and frequency schedule could impact efficacy with limited toxicity. Methods: HT-29-luciferase, HCT116 p53-null, and MDA-MB-231-luciferase xenografts were treated with ONC201 at doses ranging from 25 mg/kg to 100 mg/kg and frequencies ranging from twice per week to once every 1, 2, 3, or 4 weeks. Results: ONC201 exerted a dose- and schedule-dependent effect on tumor progression in vivo. ONC201 potently suppressed Akt and ERK in a dose- and frequency-dependent manner in vivo, and TRAIL serum levels were impacted by drug frequency. In mouse xenograft models we noted a potent anti-metastatic effect. In culture, ONC201 negatively impacted cancer cell migration and invasion, even in cells that are resistant to ONC201-induced apoptosis. We observed accumulation of CD3+/NK1.1+ cells within ONC201-treated tumors in athymic nude mice, and an upregulation of NK1.1+ cells in C57/BL6 mice without tumor xenografts. The accumulation of CD3+/NK1.1 cells within ONC201-treated tumors appeared more pronounced with dose intensification and is currently being investigated in syngeneic models. Conclusions: These results prompted a phase I dose intensification clinical trial at Fox Chase Cancer Center that is actively enrolling patients. We are evaluating the characteristics and function of the CD3+/NK1.1+ cells and the relationship of their intra-tumoral accumulation to the observed anti-tumor effects of ONC201. Our results present evidence of the unique and potent nature of ONC201 as an anti-tumor agent that demonstrates efficacy, reduces or prevents metastasis, and increases NK cell recruitment to tumors.
TCT-452 Hemodynamics and its Predictors During Impella-Protected PCI in High Risk Patients with Reduced Ejection Fraction
Authors: Giulio Russo, Francesco Burzotta, Domenico D'Amario, Flavio Ribichini, Anna Piccoli, Lazzaro Paraggio, Leonardo Previ, Gabriele Pesarini, Italo Porto, Antonio Maria Leone, Giampaolo Niccoli, Cristina Aurigemma, Diana Verdirosi, Carlo Trani, Filippo Crea
Journal: Journal of the American College of Cardiology (2018)
Genome-wide microRNA expression profiling in malignant pleural effusion to identify a ten-microRNA signature.
Authors: Meiling Zhang, Miaojun Zhu, Qin Hu, Chun Li, Zhenhua Zhu, Yingyong Hou, Jing Xu, Hailong Wang, Tong Zhu, Tom Tang, Ruoying Tan, Xin Zhang
Journal: Journal of Clinical Oncology (2017)

e23123 Background: Pleural carcinosis caused by tumors of the chest (e.g., lung and breast cancer) or elsewhere in the body (e.g., ovarian carcinoma) that metastasize to the visceral and/or parietal pleura. Recurrent malignant pleural effusion due to pleural carcinosis is one of the most common findings in oncology. The aim of the study was to identify a miRNA signature associated with clinicians’ prescription of patients with MPE. Methods: We used qRT-PCR assay to evaluate a wide range miRNAs (1920 miRNAs) signature measured from pleural effusion between patients with cancer and healthy controls. From the data of our previous studies we selected a panel of 96 miRNAs related to malignant pleural effusion. Data were compared by three classification methods software for statistics and modeling. We used a first set of 77 pleural effusion samples as training group, including 27 patients affected by Lung Adenocarcinomas (LAC), 9 with other lung cancer, 17 with other tumors and 24 inflammatory patients as negative controls. Moreover, we used more 64 pleural effusion samples for double-blind predictive study. Data analysis was performed using a machine learning approach of a Support Vector Machine classifier with a Student's t-test feature selection procedure. Results: We identified a panel of ten miRNAs with optimum classification performance. The combination of these 10-miRNAs alone could discriminate MPE cases from negative controls with an AUC of 0.969 (accuracy = 93.5%; specificity = 91.7%). The selected panel of another 10-miRNAs could separate lung cancer cases from negative controls with an AUC of 0.973 (accuracy = 94.8%; specificity = 95.8%), and a small panel of 4-miRNAs could good discriminate LAC cases from negative controls with an AUC of 0.946 (accuracy 88.9%; specificity = 100%). The accuracy rate of the double-blind predictive sensitivity value was 90.9% and specificity value was 95.8% for MPE patients with lung cancer of miRNA signature. Conclusions: Our miRNAs profile may serve as a new biomarker for MPE diagnosis. Otherwise, we identified a 10-miRNAs signature for MPE patients with lung cancer and a 4-miRNAs for MPE patients with lung adenocarcinoma.
P17 Neutrophil to Lymphocyte Ratio as an Inexpensive Prognostic Marker in Metastatic Non–Small Cell Lung Cancer
Authors: E. Alanya Rodriguez, A. Figueroa Torrejon, W. Li Torres, D. Castro, N. Cuevas, B. Beltran Garate, R. Salas Rojas
Journal: Journal of Thoracic Oncology (2018)
P04.44 Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma
Authors: M Han, S Wang, J Wang, X Li, R Bjerkvig
Journal: Neuro-Oncology (2018)

Tumor cells display higher cholesterol levels compared to normal cells and emerging evidence indicates a pivotal role of cholesterol content in tumor cell proliferation and growth mediated by a dysregulation of key regulators involved in cholesterol homeostasis has been implicated in various cancers. In this study, we assessed the dependency of glioblastoma (GBM) cells to extracellular cholesterol levels for growth. Through analysis of whole-transcriptome databases, we identified the cholesterol homeostasis-related genes whose expression are dysregulated in gliomas. One of the most dramatically down-regulated genes identified encodes cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for elimination of cholesterol via conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC). Molecular and clinical data was obtained from The Cancer Genome Atlas (TCGA) database. Immunohistochemistry was applied to assess the protein level of CYP46A1 in tissue microarrays. Functionally, CYP46A1 overexpression was determined using lentiviral constructs in LN229 and a primary glioblastoma cell line (GBM#P3). Cells were characterized in vitro and implanted in vivo to generate orthotopic xenografts in order to assess their molecular status, cell survival, and self-renewal by western blotting, flow cytometry, and extreme limiting dilution assay (ELDA), respectively. Down-regulation of CYP46A1 was found in malignant glioma samples compared to normal brain tissue. Importantly, reduced CYP46A1 expression was associated with aggressive clinicopathological features and poor prognosis of GBM patients. In functional assays, restoration of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. Consistent, treatment of GBM cells with 24OHC inhibited tumour growth and induced apoptosis in a dose dependent manner. Mechanistically, 24OHC incubation reduced cellular cholesterol levels by suppressing the activation of the sterol regulatory-element binding protein 2 (SREBP2), thus downregulating downstream targets including low-density lipoprotein receptor (LDLR). Intriguingly, efavirenz (EFV), a widespread used anti-HIV medication that effectively penetrates the blood-brain barrier, has recently been reported as a potent activator of the CYP46A1 enzyme. The therapeutic potential of EFV is currently being assessed in vivo and the data will be presented. Collectively, our findings demonstrate that CYP46A1 is a critical cellular cholesterol regulator in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target in GBM.