tbuckley/cabot-search huggingface dataset:
Health behaviors and survivorship needs of short- versus long-term melanoma survivors.
Authors: Susan M. Swetter, Arianna Aldridge Gerry, Kelly Bugos, Ralph Steven Greco, Katherine L. McGurk, Oxana Palesh
Journal: Journal of Clinical Oncology (2013)

9061 Background: Little is known about melanoma survivors and their long-term symptoms, sun protection practices and support needs from health professionals. Methods: Melanoma survivors previously treated at Stanford Cancer Center completed a quality improvement survey to explore the value of a melanoma survivorship clinic, as part of the Stanford Cancer Survivorship Program. The survey period ranged from July 2012 to September 2012, and 17% of the 893 invited survivors responded. We compared responses of melanoma survivors diagnosed between 2006-2011 (short-term) and 1995-2005 (long-term). Results: 153 cancer survivors (41% short- and 59% long-term) completed the survey. On average, they were 62 years of age (SD=15.1), 94% Caucasian, 47% female, and 68% underwent local excision alone. Long- vs. short-term survivors were less likely to receive routine skin screening every 3-6 months (38% vs. 83%, p&lt;0.001) or follow-up for their melanoma in the last 6 months (54% vs. 76% p=0.045). Sun protection practices were similar between groups; however, long-term survivors decreased their use of tanning beds (33% vs. 18%, p=0.03) and time seeking a tan relative to short-term survivors (72% vs. 48%, p=0.002). Overall, survivors rated anxiety as the most prevalent symptom (33%), followed by numbness of the scar site (31%), forgetfulness (26%), sleep problems and depression (23%), pain and fatigue (17%). Sixty-eight percent of all survivors reported their symptoms were not addressed by their health provider, and of those stating their provider addressed their symptoms (32%), the survivor initiated the conversation 71% of the time. In general, survivors desired education about the long-term effects of melanoma (41%), family risk of skin cancer (28%), and protecting their skin from further damage (20%). Twenty percent of all survivors requested treatment for the long term effects of melanoma, and 12% wanted emotional support. Conclusions: Melanoma survivors experience continuing symptoms long after treatment, namely anxiety, and express a need for information about long-term melanoma effects, psychosocial support, and prevention of further skin cancer. Clinicians should routinely assess survivorship needs to improve quality of life.
Abstract IA25: Third-generation inhibitors of mTOR
Authors: Kevan M. Shokat
Journal: Cancer Research (2017)

Abstract Precision medicines exert selective pressure on tumor cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA–AKT–mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in “N-of-1” cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials. Here we seek to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumors with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first- and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants. Citation Format: Kevan M. Shokat. Third-generation inhibitors of mTOR. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA25.
Update on safety and efficacy in the REP 401 protocol: REP 2139-Mg or REP 2165-Mg used in combination with tenofovir disoproxil fumarate and pegylated Interferon alpha-2a in treatment naïve caucasian patients with chronic HBeAg negative HBV infection
Authors: M. Bazinet, V. Pantea, G. Placinta, I. Moscalu, V. Cebotarescu, L. Cojuhari, P. Jimbei, L. Iarovoi, V. Smesnoi, T. Musteata, A. Jucov, A. Krawczyk, A. Vaillant
Journal: Journal of Hepatology (2017)
Extracorporeal Ultrafiltration for Fluid Overload in Heart Failure
Authors: Maria Rosa Costanzo, Claudio Ronco, William T. Abraham, Piergiuseppe Agostoni, Jonathan Barasch, Gregg C. Fonarow, Stephen S. Gottlieb, Brian E. Jaski, Amir Kazory, Allison P. Levin, Howard R. Levin, Giancarlo Marenzi, Wilfried Mullens, Dan Negoianu, Margaret M. Redfield, W.H. Wilson Tang, Jeffrey M. Testani, Adriaan A. Voors
Journal: Journal of the American College of Cardiology (2017)

More than 1 million heart failure hospitalizations occur annually, and congestion is the predominant cause. Rehospitalizations for recurrent congestion portend poor outcomes independently of age and renal function. Persistent congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No decongestive pharmacological therapy has reduced these harmful consequences. Simplified ultrafiltration devices permit fluid removal in lower-acuity hospital settings, but with conflicting results regarding safety and efficacy. Ultrafiltration performed at fixed rates after onset of therapy-induced increased serum creatinine was not superior to standard care and resulted in more complications. In contrast, compared with diuretic agents, some data suggest that adjustment of ultrafiltration rates to patients’ vital signs and renal function may be associated with more effective decongestion and fewer heart failure events. Essential aspects of ultrafiltration remain poorly defined. Further research is urgently needed, given the burden of congestion and data suggesting sustained benefits of early and adjustable ultrafiltration.
Abstract B06: Translational control of mitochondria through mTORC1/4E-BP signaling pathway
Authors: Masahiro Morita, Julien Prudent, Heidi McBride, John Bergeron, Nahum Sonenberg
Journal: Cancer Research (2017)

Abstract mRNA translation is the most energy consuming process in the cell. Translation and energy metabolism are dysregulated in a variety of diseases including cancer. However, the mechanisms which coordinate translation and energy metabolism remain largely unknown. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates mRNA translation and other anabolic processes in response to a variety of extracellular signals and intracellular cues (e.g., growth factors, nutrients, oxygen), ultimately accelerating cellular growth and proliferation. mTORC1 is frequently hyper-activated in a series of cancer, thereby it is targeted for the cancer treatment. We previously carried out a genome-wide polysome profiling analysis using mTORC1 inhibitors, such as rapamycin and active-site mTOR inhibitors. These experiments revealed that mRNAs whose translation is regulated by mTORC1 are enriched in those encoding mitochondrial proteins. Here, by using a combination of pharmacological, genetic, biochemical and metabolomic approaches, we demonstrate that mTORC1 modulates mitochondrial functions and dynamics through translational regulation of mRNAs encoding mitochondrial proteins. Mechanistically, we indicate that the effects of mTORC1 on mitochondria are mediated by the eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). Stimulation of translation of mitochondria-related mRNAs engendered an increase in ATP production, which is required as an energy source for translation. These data support a feed-forward loop model, whereby the mTORC1/4E-BP pathway promotes translation of mitochondria-related mRNAs to increase mitochondrial ATP production to meet the high energy demand of protein synthesis in proliferating cells. This represents a novel paradigm for understanding how cellular energy homeostasis is maintained via direct coordination of energy consumption (translation) and energy production (ATP production in mitochondrion). Thereby, our findings provide a new mechanism linking aberrant mTOR signaling to conditions of abnormal cellular energy metabolism such as neoplasia. In this presentation, we will introduce our recent data and discuss the role of mTORC1/4E-BP signaling pathway on mitochondrial function, cellular metabolism and proliferation. Citation Format: Masahiro Morita, Julien Prudent, Heidi McBride, John Bergeron, Nahum Sonenberg. Translational control of mitochondria through mTORC1/4E-BP signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B06.
Characterization of neuroblastic tumors as developmental cancers with survival determined by histology, age, and location.
Authors: Karen Elizabeth Effinger, Lindsey Elizabeth Merrihew, Paul Graham Fisher
Journal: Journal of Clinical Oncology (2013)

10046 Background: Mortality associated with peripheral neuroblastic tumors (pNT), comprising neuroblastoma (NB) and ganglioneuroblastoma (GNB), varies with some tumors spontaneously regressing and others showing poor response to therapy, indicating different biologic mechanisms. We aimed to determine how epidemiologic constructs inform the underlying biology of pNT. Methods: Using the Surveillance Epidemiology and End Results (SEER 18) population-based registry, we identified 3,540 pNT (3,003 NB and 537 GNB) in patients from 1973-2009. Differences in histology (NB vs. GNB), gender, age (&lt;18 months, 18 months-4 years, 5-14 years, or ≥15 years), race (white, black, or other), location of primary tumor (adrenal, abdominal, chest, head/neck, pelvic, or other), and stage (locoregional vs. metastatic) were evaluated with chi-squared tests using SAS 9.3. Kaplan Meier curves with log-rank tests as well as univariate and multivariate Cox proportional hazard regression methods were employed to determine the influence of these factors on survival. Results: NB occurred more frequently in infants (50%), arose in the adrenals (45%), and were metastatic at diagnosis (57%), while GNB more often affected children 18 months-4 years (48%, p &lt;0.001), occurred in the chest (31%, p &lt;0.001), and were locoregional (78%, p &lt;0.001). The 5-year overall survival (OS) rate in NB was 59% compared to 80% in GNB (p &lt;0.001). In NB, the 5-year OS rate was 81% in infants &lt;18 months and 21-39% in the older groups (p &lt;0.001); however, in GNB, the 5-year OS was 40% in subjects &gt;15 years and 81-93% in the younger groups (p &lt;0.001). In multivariate analysis of pNT, neuroblastoma, age &gt;18 months, adrenal site of primary tumor, and metastatic disease were independent poor prognostic factors. Chest (HR 0.27 [0.21-0.35]), head/neck (HR 0.34 [0.20-0.52]), and pelvic (HR 0.35 [0.24-0.52]) tumors had the most improved survival compared to adrenal primaries. Conclusions: Although pNT are often evaluated together, NB and GNB represent two significantly distinct diseases. For each, survival is strongly determined by age, primary tumor location, and stage. These differences may stem from unique developmental mechanisms underlying tumorigenesis.
Results from OAK subgroup analyses: A randomized Phase III study of atezolizumab vs docetaxel in patients (pts) with advanced NSCLC
Authors: D. Cortinovis, S.M. Gadgeel, A. Rittmeyer, F. Barlesi, M. Cobo Dols, T. Hida, P. He, M. Ballinger, D.R. Gandara, J. von Pawel
Journal: Annals of Oncology (2017)
Main drivers of outcome differ between short and long-term in severe alcoholic hepatitis: a prospective study
Authors: A. Louvet, J. Labreuche, F. Artru, A. Bouthors, B. Rolland, P. Saffers, S. Dharancy, G. Lassailly, V. Canva-Delcambre, A. Duhamel, P. Mathurin
Journal: Journal of Hepatology (2017)
Development of a high-performance, blood-based screening diagnostic to detect early-stage breast cancer.
Authors: Joseph Wagner, Karen Chapman, Maria Prendes-Garcia, Markus Lacher, Jennifer Kidd, Nadia Sheibani, Orlena Tam, Michael West
Journal: Journal of Clinical Oncology (2013)

e22083 Background: Limitations of current screening mammography, particularly in younger women, demonstrate the need for an alternative breast cancer screening strategy. A non-invasive, easily interpreted and low cost test should address this need. Methods: Gene expression microarray analysis was carried out on 128 individual tumor samples representing over 20 tumor types, 86 samples representing 31 diverse normal tissue types, 68 tumor cell lines and 97 diverse normal primary cell cultures. Genes were ranked for elevated expression in either: i) a large number and variety of tumors relative to normal tissues, or ii) in breast tumors. Elevated expression was verified for a subset of genes using qPCR in a set of independent RNA samples. Proteins coded by genes elevated in breast cancer samples were analyzed in a retrospective training set of breast cancer patient sera samples with cancer-free patient and benign pathology controls using ELISA or bead-based detection assay. Results: Based on availability of suitable reagents, 25 candidate biomarkers were assessed in patient sera samples (31-227 patient samples per biomarker) using ELISA or bead-based assays. Individually, the performance of individual markers varied (ROC AUC, 0.51 - 0.88); however, when expression levels of the best performing markers were combined, the multiplex test demonstrated high-sensitivity (&gt;80%) and specificity (&gt;90%) in identifying early-stage breast cancer patients. Conclusions: A multiplex, proteomic-based approach may provide for a high-performance, blood-based screening diagnostic for breast cancer.
Knee and hip intra-articular adipose tissues (IAATs) compared with autologous subcutaneous adipose tissue: a specific phenotype for a central player in osteoarthritis
Authors: Florent Eymard, Audrey Pigenet, Danièle Citadelle, Joan Tordjman, Louise Foucher, Cindy Rose, Charles-Henri Flouzat Lachaniette, Christine Rouault, Karine Clément, Francis Berenbaum, Xavier Chevalier, Xavier Houard
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> Compared with subcutaneous adipose tissue (SCAT), infrapatellar fat pad (IFP), the main knee intra-articular adipose tissue (IAAT), has an inflammatory phenotype in patients with osteoarthritis (OA). We phenotyped suprapatellar fat pad (SPFP) and hip acetabular fat pad (AFP), two other IAATs, to determinate the unique signature of IAATs compared with SCAT. <h3>Methods</h3> IFP, SPFP, AFP and autologous SCAT were obtained from patients with OA during total knee (n=38) or hip replacement (n=5). Fibrosis and adipocyte area were analysed by histology and vascularisation, leucocyte and mast cell infiltration were analysed by immunohistochemistry for von Willebrand factor, leucocytes and tryptase, respectively. Secretion of interleukin (IL)-6, IL-8 and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) was assessed by ELISA. The mRNA expression of adipocyte-associated genes (ATGL, LPL, PPAR-γ, FABP4 and CD36) and developmental genes (SFRP2, HoxC9 and EN1) was determined. The inflammatory response of isolated fibroblast-like synoviocytes (FLS) to autologous IFP and SPFP conditioned media was examined. <h3>Results</h3> Fibrosis, vascularisation and leucocyte and mast cell infiltration were greater in IAATs than SCAT, and levels of IL-6, IL-8 and PGE<sub>2</sub> were greater in all IAATs than SCAT. IFP and SPFP induced a similar inflammatory response to FLS. Adipocyte area was smaller in IAATs than SCAT. Adipocyte-associated and developmental genes showed a similar gene expression pattern in all IAATs, different from SCAT. <h3>Conclusions</h3> IFP but also SPFP and AFP (gathered under the term 'IAAT') may play a deleterious role in OA by affecting joint homeostasis because of their inflammatory phenotype and their close interaction with synovium in the same functional unit.
C-reactive Protein and Amyloid A as Predictors of Cardiovascular Events in Type 2 Diabetes in the CARDS Study
Authors: V. Charlton-Menys, H.M. Colhoun, D.J. Betteridge, S.S. Soedamah-Muthu, G. Hitman, A. Neil, S. Livingstone, W. Bao, D.A. DeMicco, G.M. Preston, J. Fuller, P. Durrington
Journal: Circulation (2009)
Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes
Authors: Silvia Cerboni, Nadia Jeremiah, Matteo Gentili, Ulf Gehrmann, Cécile Conrad, Marie-Claude Stolzenberg, Capucine Picard, Bénédicte Neven, Alain Fischer, Sébastian Amigorena, Frédéric Rieux-Laucat, Nicolas Manel
Journal: The Journal of Experimental Medicine (2017)

Activation of the cyclic dinucleotide sensor stimulator of interferon (IFN) genes (STING) is critical for IFN and inflammatory gene expression during innate immune responses. However, the role of STING in adaptive immunity is still unknown. In this study, we show that STING activation reduces the proliferation of T lymphocytes. This activity was independent of TBK1 and IRF3 recruitment and of type I IFN but required a distinct C-terminal domain of STING that activates NF-κB. Inhibition of cell proliferation by STING required its relocalization to the Golgi apparatus and caused mitotic errors. T lymphocytes from patients carrying constitutive active mutations in TMEM173 encoding STING showed impaired proliferation and reduced numbers of memory cells. Endogenous STING inhibited proliferation of mouse T lymphocytes. Therefore, STING, a critical innate sensor, also functions intrinsically in cells of the adaptive immune system to inhibit proliferation.
Durability of HBsAg loss with nucleotide analogs and pegylated interferon in patients infected with hepatitis B virus
Authors: H.L. Chan, A. Lok, S. Locarnini, F. Zoulim, M. Ghany, G. Dusheiko, A. Gaggar, G. Wu, G.M. Subramanian, M. Buti, P. Marcellin
Journal: Journal of Hepatology (2017)
Multiplex testing for driver mutations in squamous cell carcinomas of the lung.
Authors: Paul K. Paik, Adnan Hasanovic, Lu Wang, Natasha Rekhtman, Marc Ladanyi, Mark G. Kris
Journal: Journal of Clinical Oncology (2012)

7505 Background: While the majority of lung adenocarcinomas (ADCL) harbor an identifiable driver mutation, targeted therapies for squamous cell lung carcinomas (SQCLC) have lagged in development due to a paucity of druggable oncogenic events. Three targets, which together occur in up to 50% of SQCLC, have been recently identified (FGFR1 amplification, DDR2 mutations, PIK3CA mutations/PTEN loss). Comprehensive molecular analysis of SQCLC tumors by The Cancer Genome Atlas is ongoing, with new therapeutic targets on the horizon. Methods: We have instituted prospective, multiplex testing of SQCLC tumors (Squamous Cell Lung Cancer Mutation Analysis Program, “SQ-MAP”). Tests include FISH for FGFR1 amplification (defined as FGFR1:CEP8 ≥ 2 in &gt;10% of cells), IHC for loss of PTEN expression, and Sequenom MassARRAY for PIK3CA mutations (and others, below). We are also incorporating targeted exon sequencing (Agilent SureSelect/Ion Torrent) of a panel of over 80 lung cancer oncogenes and tumor suppressors in preparation for future studies. All tests were performed on formalin-fixed paraffin-embedded samples and with Institutional Review Board/Biospecimen Utilization Committee approval. Results: 40 SQCLC patient specimens have been processed through SQ-MAP over 3 months. 8 samples were excluded (insufficient tissue in 4, reclassification to ADCL in 4). Data are available for 28 patients. PTEN IHC was performed on 15 samples to date. Molecular results are summarized in the table. Events were non-overlapping. Results for the ≥80 gene sequencing component will be described. Based on SQ-MAP, accrual to 2 approved clinical trials (FGFR1 inhibition; PI3K inhibition) has begun, with a third planned (DDR2 mutations). Conclusions: Actionable defects were detected in 60% (95% CI: 37-75%) of SQCLC specimens. Mutation data for ≥80 other oncogenes and tumor suppressors will be available shortly (including DDR2). SQ-MAP serves as a platform supporting both personalized care and research. [Table: see text]
Secondary sarcomas after radiation in patients with breast cancer
Authors: C. M. Mery, S. George, C. P. Raut
Journal: Journal of Clinical Oncology (2007)

10072 Background: Studies have shown that radiation (RT) predisposes patients with breast cancer (BCa) to develop a secondary sarcoma (SS). Few have analyzed recent incidence trends or have been powered to assess specific histologies. The goal of this study was to quantify the risk of developing different types of SS after RT in BCa and assess time trends using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Females with microscopically-confirmed non-metastatic BCa reported to SEER between 1973 and 2003 were included. Development of SS was analyzed with Kaplan-Meier curves and proportional hazard models, and reported as hazard ratios (HR) with 95% confidence intervals. Descriptive variables were analyzed with chi square. Results: The cohort of 482,469 BCa patients (age 60.1±13.4yrs) was divided in 2 groups: RT (37%) and no RT, based on treatment. RT patients were younger (p&lt;0.0001) and had more partial mastectomies (p&lt;0.0001). RT usage increased with time (from 23% in 1973–1977 to 48% in 2001–2003, p&lt;0.0001). 874 patients developed SS 12–343 months after BCa diagnosis. RT patients had a higher incidence of all SS (30 vs 21 cases/100,000 person-years, HR: 1.57 [1.4–1.8]), angiosarcomas (HR: 7.8 [4.9–12.2]) and malignant fibrous histiocytomas (MFH) (HR: 2.5 [1.6–3.9]). Risk was increased in sites close to the RT field (chest and ipsilateral arm) (HR: 4.17 [3.2–5.5]) but not in others (HR: 1.07 [0.91–1.3]). Risk increased with age and time period at BCa diagnosis (p&lt;0.0001). RT remained a significant predictor of SS development after adjustment for these variables (HR: 1.5 [1.3–1.7]). The hazard of developing SS after RT increased over the first several years after diagnosis of BCa, peaked at 10–14 years, and then decreased again, reaching the non-RT hazard at ∼22 years. 5-yr survival after SS diagnosis was 38%. Conclusions: Administration of RT for BCa increases the risk for development of SS, in particular angiosarcomas and MFH in sites associated with the RT field. Risk of SS has increased with time, independently of RT usage. Patients receiving RT for BCa should be followed closely for more than 20 years. No significant financial relationships to disclose.
Donor specific antibodies are associated with higher inflammatory activity, more fibrosis and higher expression of rejection associated transcripts in human liver allografts with subclinical rejection
Authors: A. Höfer, M. Verboom, M. Hallensleben, B. Hartleben, D. Jonigk, J. Schlue, F. Lehner, S. Hübscher, M.P. Manns, E. Jaeckel, R. Taubert
Journal: Journal of Hepatology (2017)
Abstract 14978: Nitrated Fatty Acids Suppress Ventricular Arrhythmias During Acute Myocardial Ischemia
Authors: Anne C Geisler, Kai Friedrichs, Alexander Schwoerer, Tanja K Rudolph, Anna Klinke, Denise Lau, Matti Adam, Florian Deuschl, Bruce Freeman, Stefan Blankenberg, Stephan Willems, Stephan Baldus, Volker Rudolph
Journal: Circulation (2011)

Background: Nitrated fatty acids (NO2-FA) are termination products of radical chain reactions and have been identified as potent anti-inflammatory signaling mediators. Previously we demonstrated th...