tbuckley/cabot-search huggingface dataset:
CDA status as predictive marker of aplasia duration and clinical outcome in AML patients receiving cytarabine based chemotherapy.
Authors: Cedric Mercier, Raphaelle Fanciullino, Julien Colle, Geoffroy Venton, Vadim Ivanov, Gerard Sebahoun, Joseph Ciccolini, Regis Costello
Journal: Journal of Clinical Oncology (2015)

7075 Background: Cytarabine is mainstays for treating hematological malignancies. As most nucleosidic analogs, cytarabine is metabolized in the liver by an exclusive enzymatic pathway driven by cytidine deaminase (CDA). CDA is highly polymorphic and dysregulations have been repeatedly associated with poor clinical outcome in patients treated with gemcitabine. Methods: We have used a test to determine, on a phenotype basis, CDA status in patients. This test was used in a subset of 42 adult patients (18F, 24M, mean age 60 years), all treated with a cytarabine-containing regimen. Response and treatment-related toxicities were monitored following current standards (CTC). This was a retrospective and prospective observational single-center study. All patients requiring a first induction chemotherapy for AML (AML de novo or secondary to myelodysplastic syndrome) and consolidation phase. The objective was to determine the relationship between the CDA status and clinical outcome. Results: In patients, mean CDA activity was 2.85 U/mg (min: 1, max: 14.8 U/mg). Ten out of 41 patients (i.e., 24%) showed low CDA activities and were considered as poor metabolizer (PM). Conversely, 4 patients (i.e., 9.75%) displayed particularly elevated (i.e., > 6U/mg) CDA activities and were considered as ultra-rapid metabolizer (UM). During first induction chemotherapy, the duration of aplasia was 30 days vs 22 days in low CDA activities group and normal or elevated CDA activities respectively (p < 0.05). During consolidation chemotherapy, the duration of aplasia was 21 days vs 9 days in low CDA activities group and normal or elevated CDA activities respectively (p < 0.001). Of note, PM patients all showed severe toxicities, including three toxic-deaths. Conversely, UM patients showed little efficacy. Conclusions: Overall this study strongly suggests that CDA status could be a relevant marker for predicting clinical outcome in patients treated with cytarabine. CDA status is significantly related with duration of aplasia, it could be further used as a covariate to tailor drug dosage so as to ensure an optimal efficacy/toxicity balance in patients with hematological malignancies.
SAT-354-Aramchol, SCD1 inhibitor, improves liver glucose homeostasis in NASH
Authors: José M. Mato, Laura delaCruz-Villar, David Fernandez-Ramos, Fernando Lopitz, Mikel Azkargorta, Félix Elortza, Marta Iruarrizaga-Lejarreta, Cristina Alonso, Lucía Barbier-Torres, Shelly C Lu, Liat Hayardeny, Tali Gorfine, Arun J. Sanyal
Journal: Journal of Hepatology (2019)
Abstract P5-07-03: Small molecule inhibition of smoothened in triple negative breast cancer-associated fibroblasts depletes cancer stem cells and sensitizes to cytotoxic chemotherapy in mice and humans
Authors: A Swarbrick, A Cazet, M Hui, S O'Toole, E Lim, M Martin
Journal: Cancer Research (2019)

Abstract The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), we use single cell genomics to show that Hh ligand produced by neoplastic cells reprograms cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and deposition of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells and the acquisition of a stem-like, drug-resistant phenotype. Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonedigib and docetaxel chemotherapy, with one patient experiencing a complete radiological response. Responders also exhibited high baseline FGFR activation and ECM deposition, suggesting a mechanism of action consistent with findings from the animal models. These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and drug resistance and an exciting new therapeutic target in TNBC. Citation Format: Swarbrick A, Cazet A, Hui M, O'Toole S, Lim E, Martin M. Small molecule inhibition of smoothened in triple negative breast cancer-associated fibroblasts depletes cancer stem cells and sensitizes to cytotoxic chemotherapy in mice and humans [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-03.
THU-297-Prediction of NAFLD progression according to duration of exposure to obesity and diabetes: New approach to adapt therapeutic and research strategies
Authors: Pierre Bauvin, Lassailly Guillaume, Line Carolle Ntandja Wandji, Claire Delacôte, Flavien Dautrecque, Alexandre Louvet, Caiazzo Robert, Viviane Gnemmi, Violeta Raverdi, Francois Pattou, Sylvie Deuffic-Burban, Philippe Mathurin
Journal: Journal of Hepatology (2019)
SAT-302-Predicting the severity of hepatic steatosis and fibrosis by transient elastography and MRI-based techniques in adults patients with suspected NAFLD
Authors: Stephen Harrison, Katharine Roberts, Christopher Lisanti, Ryan Schwope, Katherine Cebe, James Aden, Valérie Paradis, Pierre Bedossa, Jennifer Whitehead, Angelo Paredes
Journal: Journal of Hepatology (2019)
Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors
Authors: Jeffrey M. Conroy, Sarabjot Pabla, Mary K. Nesline, Sean T. Glenn, Antonios Papanicolau-Sengos, Blake Burgher, Jonathan Andreas, Vincent Giamo, Yirong Wang, Felicia L. Lenzo, Wiam Bshara, Maya Khalil, Grace K. Dy, Katherine G. Madden, Keisuke Shirai, Konstantin Dragnev, Laura J. Tafe, Jason Zhu, Matthew Labriola, Daniele Marin, Shannon J. McCall, Jeffrey Clarke, Daniel J. George, Tian Zhang, Matthew Zibelman, Pooja Ghatalia, Isabel Araujo-Fernandez, Luis de la Cruz-Merino, Arun Singavi, Ben George, Alexander C. MacKinnon, Jonathan Thompson, Rajbir Singh, Robin Jacob, Deepa Kasuganti, Neel Shah, Roger Day, Lorenzo Galluzzi, Mark Gardner, Carl Morrison
Journal: Journal for ImmunoTherapy of Cancer (2019)

PD-L1 immunohistochemistry (IHC) has been traditionally used for predicting clinical responses to immune checkpoint inhibitors (ICIs). However, there are at least 4 different assays and antibodies used for PD-L1 IHC, each developed with a different ICI. We set to test if next generation RNA sequencing (RNA-seq) is a robust method to determine PD-L1 mRNA expression levels and furthermore, efficacy of predicting response to ICIs as compared to routinely used, standardized IHC procedures.A total of 209 cancer patients treated on-label by FDA-approved ICIs, with evaluable responses were assessed for PD-L1 expression by RNA-seq and IHC, based on tumor proportion score (TPS) and immune cell staining (ICS). A subset of serially diluted cases was evaluated for RNA-seq assay performance across a broad range of PD-L1 expression levels.Assessment of PD-L1 mRNA levels by RNA-seq demonstrated robust linearity across high and low expression ranges. PD-L1 mRNA levels assessed by RNA-seq and IHC (TPS and ICS) were highly correlated (p < 2e-16). Sub-analyses showed sustained correlation when IHC results were classified as high or low by clinically accepted cut-offs (p < 0.01), and results did not differ by tumor type or anti-PD-L1 antibody used. Overall, a combined positive PD-L1 result (≥1% IHC TPS and high PD-L1 expression by RNA-Seq) was associated with a 2-to-5-fold higher overall response rate (ORR) compared to a double negative result. Standard assessments of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) showed that a PD-L1 positive assessment for melanoma samples by RNA-seq had the lowest sensitivity (25%) but the highest PPV (72.7%). Among the three tumor types analyzed in this study, the only non-overlapping confidence interval for predicting response was for "RNA-seq low vs high" in melanoma.Measurement of PD-L1 mRNA expression by RNA-seq is comparable to PD-L1 expression by IHC both analytically and clinically in predicting ICI response. RNA-seq has the added advantages of being amenable to standardization and avoidance of interpretation bias. PD-L1 by RNA-seq needs to be validated in future prospective ICI clinical studies across multiple histologies.
EMMPRIN/CD147 as a novel independent prognostic biomarker in melanoma.
Authors: Anne Caudron, Maxime Battistella, Jean Paul Feugeas, Cécile Pagès, Nicole Basset-Seguin, Aurelie Sadoux, Marie Pierre Podgorniak, Anne Janin, Celeste Lebbe, Samia Mourah
Journal: Journal of Clinical Oncology (2015)

e20027 Background: EMMPRIN (Extracellular Matrix MetalloPRoteinase INducer) is a member of the immunoglobulin superfamilyknown tostimulate the degradation of basement membrane components by increasing MMP synthesis. EMMPRIN has been implicated in melanoma invasion and metastasis. In this study, we investigated the prognostic value of EMMPRIN expression in a large series of cutaneous melanoma. Methods: The study evaluated 136 tumors including 27 malignant melanomas with a high Breslow index ( > 4mm), 23 melanomas with a 2-4mm Breslow index, 26 melanomas with a 1-2mm Breslow index, 32 melanomas with thickness < 1mm, and 28 in situ melanomas. In addition, 30 metastatic lymph nodes, 19 in transit metastasis, and 15 visceral metastasis were also examined. Benign cell lesions comprising 10 normal skin, 10 blue nevi, and 10 dermal nevi were used as control. EMMPRIN was assessed by immunohistochemistry (IHC) assay. The association of EMMPRIN expression with the clinicopathological characteristics and prognosis of patients was evaluated using univariate and multivariate statistical analysis. For univariate analysis, p-values were corrected for multiple comparisons (and named pc). Results: Univariate analysis showed that EMMPRIN IHC staining was significantly associated to metastatic lesions and to a reduce survival (pc < 0.05,) in melanoma with tumor thickness between 1 and 4 millimeter. Other factors associated to pronostic in the univariate analysis were Clark, Breslow and ulceration (pc < 0.05). EMMPRIN was correlated to those factors and especially to tumor thickness (r = 0.7, p < 10-8). Interestingly, multivariate variable selections retained only EMMPRIM expression and ulceration to predict metastasis or survival (p < 0.05). Therefore, EMMPRIN contributed to the aggressive behavior of melanomas and could be considered as an independent prognostic biomarker. Conclusions: EMMPRIN expression represents a particularly useful tool to predict metastasis progression risk in melanoma with tumor thickness between 1 and 4 millimeter.
Triple wild type melanoma profiling in the Caris Molecular Intelligenceregistry.
Authors: Krisztian Homicsko, Kenneth Russell, Andreas Voss, Olivier Michielin
Journal: Journal of Clinical Oncology (2015)

9054 Background: Malignant melanoma is a genetically diverse disease. The most frequent mutation is BRAF, followed by NRAS and cKIT mutations. While BRAF, NRAS and cKIT mutations represent the largest fraction of patients, there is also an important group of triple wild type patients (3xWT) in dire need for potential targeted therapies. We compared mutational and PD-L1 profiles of 3xWT tumors using the database of the Caris Molecular Intelligence. Methods: We analyzed 541 patient samples for immunohistochemistry (IHC) and next generation sequencing (NGS) data available from the Caris database. Out of the 541 samples 89 samples also had PD-L1 expression data available. Samples were grouped in 4 subtypes: BRAFmut (n = 169), NRASmut (n = 151), cKITmut(n = 25) and 3xWT (n = 197). Results: The database is skewed with an underrepresentation of BRAFmut patients and enrichment of 3xWT tumors. BRAFmut, NRASmut, cKITmutand 3xWT patient were 30%, 26%, 3.7% and 40% of the total population, respectively. BRAFmut and 3xWT subgroups have more frequent cMET expression (p = 0.002). While NRASmut tumors show lack of ERCC1 expression, cKITmut tumors lack PGP expression. All mutation subtypes present equally frequent expression of MGMT, SPARC, TOP2A, TOPO1, TS, TUBB3 and RRM1 suggestive of multiple chemoresistance pathways. TP53 mutations are recurrent (~15%) in all mutation subgroups. In 3xWT tumors a different spectrum of mutations arise with low frequency ( < 10%). Mutant KRAS, JAK3, cMET, GNA11, GNAQ, APC, KDR, BRCA1, ERBB4, represent actionable alterations in up to 40% of that subgroup. None of the 541 tumors presented mutation in Akt, BRCA2, IDH1, CSF1R, GNAS, Notch1, Smo, STK11, VHL, MLH1, MPL, MPM1 A PD-L1 subanalyzes showed an overall 75% positivity. 3xWT tumors were more frequently PD-L1 negative as compared to BRAFmut(p = 0.077) Conclusions: To our knowledge,the Caris database provides one of the largest profiling of 3xWT. In contrast to BRAFmut, NRASmut and cKITmut tumors, 3xWT melanoma harbor a more complex mutational landscape. Low frequency mutations can identify targets in up to 40% of these patients. 3xWT are less frequently PD-L1 positive. Overall 3xWT patients should be tested for multiple markers in order to identify low frequency mutations
FRI-097-PBI-4050 treatment decreases sepsis-induced liver injury in mice
Authors: Jean-François Thibodeau, Brigitte Grouix, Jean-Christophe Simard, Chet Holterman, Alex Gutsol, Alexandra Blais, Alexandre Laverdure, Richard Hébert, François Leblond, Pierre Laurin, Chris Kennedy, Lyne Gagnon
Journal: Journal of Hepatology (2019)
PS-191-External validation of an algorithm combining multi-analyte blood tests (FibroTest-LCR1-LCR2) for identifying subjects at risk of hepatocellular carcinoma among patients with chronic liver disease
Authors: Valentina Peta, Marianne Ziol, Imbert-Bismut Francoise, Angela Sutton, Mona Munteanu, Frederic Charlotte, Olivier Lucidarme, Tam Pham, Olivier Scatton, Yen Ngo, An Ngo, Olivier Deckmyn, Dominique Thabut, Vlad Ratziu, Chantal Housset, Thierry Poynard, Pierre Nahon
Journal: Journal of Hepatology (2019)
Avoiding over- and undertreatment in patients with resected node-positive breast cancer with the use of gene expression signatures: are we there yet?
Authors: A. Matikas, T. Foukakis, S. Swain, J. Bergh
Journal: Annals of Oncology (2019)

Prediction of benefit from adjuvant chemotherapy following resection of early breast cancer and, as a result, proper selection of candidates remains an elusive goal since the relative magnitude of benefit is the same regardless of the presence of clinicopathologic factors. Multiple studies, including randomized trials, establish the role of certain gene expression signatures in node-negative disease since they predict the risk of breast cancer relapse being so low that adjuvant chemotherapy can be omitted. In contrast, more limited data are available in higher risk, node-positive breast cancer patients, making the exclusion of adjuvant chemotherapy potentially hazardous. 'Prospective-retrospective' studies and limited prospective data show that several signatures, namely Oncotype Dx, MammaPrint, Prosigna, EndoPredict and Breast Cancer Index, select with different levels of success node-positive patients at very low risk for distant recurrence despite not receiving chemotherapy, although the long-term follow-up is still awaited. Pending, however the publication of the results from ongoing randomized studies which enroll patients with node-positive disease, major caution is warranted. Improper use and misinterpretation of these transcriptomic profiles can lead to undertreatment and exposure of patients to unnecessary risks resulting in increased breast cancer mortality for patients with axillary node-positive disease. With this review we critically discuss the available data on gene expression signatures that are used in clinical practice and offer practical recommendations regarding the management of patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive breast cancer.
FRI-267-Serial measurement of serum dextran absorption by novel competition ELISA demonstrates larazotide acetate significantly improves "leaky gut" in a Western diet murine model of metabolic liver disease
Authors: Rebecca Caffrey, Jonathon Marioneaux, Madhavi Bhat, Christopher Prior, Jay Madan, Sandeep Laumas, Arun Sanyal
Journal: Journal of Hepatology (2019)
Abstract 125: Exercise-Induced Prominent Anterior QRS Force Is a Reliable Sign of Left Anterior Descending Coronary Artery Disease
Authors: Miguel Angel Cobos, Eduardo Pozo, Juan Jose Gonzalez Ferrer
Journal: Circulation (2011)

Prominent anterior QRS force (PAF), defined as tall R waves in the right or middle precordial leads, can be the expression of left septal fascicular block. Some cases of intermittent PAF during acu...
PS-201-External validation in NAFLD cohorts of the FibroScan-based FAST score combining liver stiffness, controlled attenuation parameter and AST to identify patients with active NASH (NAS ≥ 4) and significant fibrosis (F ≥ 2)
Authors: Jerome Boursier, Ming-Hua Zheng, Vincent Wai-Sun Wong, Sophie Michalak, Yang-Yang Li, Anthony Wing-Hung Chan, Grace Lai-HungWong, Xiao-Yan Pan, Paul Cales
Journal: Journal of Hepatology (2019)
FRI-303-How to develop a differentiated FXR agonist: GS-9674 shows a reduced side effect profile in mice, monkeys amd human phase 1 studies compared to its predecessor Px-102
Authors: Eva Hambruch, David Hollenback, John Liles, Olaf Kinzel, Manfred Birkel, Gero Fink, Dorothy French, Christian Gege, Martin Hornberger, William Watkins, Claus Kremoser
Journal: Journal of Hepatology (2019)
LBP-21-Effect of NGM282, an FGF19 Analogue, on Pruritus in Patients with Primary Sclerosing Cholangitis: Analysis of a Phase, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Marlyn J. Mayo, Lei Ling, Stacie Hudgens, Kathline H. Kim, Gideon Hirschfield, Alex DePaoli, Ulrich Beuers
Journal: Journal of Hepatology (2019)
Impact of EUCAST ceftaroline breakpoint change on the susceptibility of methicillin-resistant Staphylococcus aureus isolates collected from patients with complicated skin and soft-tissue infections
Authors: E. Urbán, G.G. Stone
Journal: Clinical Microbiology and Infection (2019)

ObjectivesIn 2018, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) introduced an intermediate breakpoint for ceftaroline against Staphylococcus aureus. The objective of this study was to compare data on resistance to ceftaroline among methicillin-resistant S. aureus (MRSA) isolates using versions 7.1 (March 2017) and 8.0 (January 2018) of the EUCAST breakpoints.MethodsParticipating centers were located in Africa, Asia, Europe, Oceania and South America. Isolates were collected from patients with complicated skin and soft-tissue infections and were cultured from integumentary sources. Methicillin resistance among S. aureus was confirmed locally using the oxacillin method. The CLSI broth microdilution method was used to measure ceftaroline MICs at the central laboratory. Versions 7.1 and 8.0 of the EUCAST breakpoints were used to interpret MIC data.ResultsBetween 2015 and 2016, 9559 isolates of S. aureus were collected, of which 5566 (58.2%) isolates were MRSA. Overall, the lowest rate of MRSA was in Asia (56.5%; 705/1247) and the highest rate was in Oceania (62.7%; 299/477). Using version 7.1 of the EUCAST breakpoints, 4.5% (250/5566) of all MRSA isolates were resistant to ceftaroline and when version 8.0 of the breakpoints was applied, 4.2% (235/5566) of MRSA were in the intermediate category and 0.3% (15/5566) of all isolates were considered resistant.ConclusionsBy applying version 8.0 of the EUCAST breakpoints, the majority of MRSA isolates that were resistant are now in the intermediate category for ceftaroline. Ceftaroline resistance among MRSA now appears rare.
FRI-006-Soluble CD163 and mannose receptor as markers of liver disease severity and long term prognosis in patients with primary biliary cholangitis
Authors: Lars Bossen, Paola Rebora, Francesca Bernuzzi, Chiara Aloise, Peter Jepsen, Alessio Gerussi, Holger Jon Møller, Maria Grazia Valsecchi, Marco Carbone, Henning Grønbæk, Pietro Invernizzi
Journal: Journal of Hepatology (2019)
FRI-200-Spend less get more;cost effectiveness of various models of care in hepatitis C treatment
Authors: Jeyamani Ramachandran, Billingsley Kaambwa, Kate Muller, James Haridy, Edmund Tse, Emma Tilley, Victoria Waddell, David Gordon, David Shaw, Renjy Nelson, mark boyd, Morgyn Warner, Lucy Ralton, Anton Colman, jeffery stewart, Damian Harding, Asif Chinnaratha, Richard Woodman, Dep Huynh, Alan Wigg
Journal: Journal of Hepatology (2019)
FRI-478-Survival outcomes of TACE in treatment-naive and recurrent HCC after curative resection: A propensity score-matched analysis
Authors: David Kim, Tae Seop Lim, Mi Young Jeon, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Oidov Baatarkhuu, Seung Up Kim
Journal: Journal of Hepatology (2019)
How comprehensive are lung cancer-specific PRO measures for patients with ALK+ NSCLC?
Authors: Medha Sasane, Jennifer Devlen, Nada Saleh, Olga Moshkovich, Kenneth W. Culver, Emuella Flood
Journal: Journal of Clinical Oncology (2015)

e19055 Background: ALK+ NSCLC patients tend to be younger, non-smoking and receive targeted treatments with impacts different from chemotherapy. This study describes the symptoms and impacts relevant to ALK+ NSCLC patients and assesses if lung cancer-specific patient reported outcome (PRO) measures adequately evaluate these concepts. Methods: In depth interviews conducted with ALK+ NSCLC patients were audio-recorded, transcribed and thematically analyzed to identify symptoms and impacts. Seven clinical experts were interviewed to confirm the clinical relevance of symptoms. Identified concepts were mapped against PROs. Results: A literature search identified the Lung Cancer Symptom Scale (LCSS), EORTC C30/LC13 and FACT-L as the most commonly used PROs. The LCSS focuses on symptoms while the EORTC and FACT cover symptoms and impacts. Twenty patients (mean age: 52.25 yrs (+ 11.68); 11 females) were interviewed. Common symptoms of cough (N = 12), dyspnea (N = 11), thoracic pain (N = 8) and fatigue (N = 8) were captured by all 3 PROs. Hemoptysis (N = 2) is not captured by the FACT-L. Clinician interviews confirmed that while lung symptoms are similar to NSCLC, brain metastases are more likely in ALK+ patients. Nine patients had brain metastases; 7 reported symptoms such as headaches (N = 5), cognitive difficulties (N = 4), not captured by the PROs. Other relevant impacts on daily activities (e.g., difficulties with childcare) in this younger population were also not adequately captured. The EORTC and FACT include items on emotional impacts, but neither includes the stigma reported by non-smoking patients. Commonly reported effects of crizotinib (e.g. visual disturbances (N = 13) which could interfere with driving, and edema (N = 10)) are not captured by the 3 PROs. The EORTC and FACT include items related to smoking and chemotherapy impacts that are less relevant to ALK+ patients. Conclusions: Lung-cancer specific PROs capture many key disease- and treatment-related symptoms and impacts reported by ALK+NSCLC patients. To comprehensively evaluate new ALK+NSCLC treatments, these could be supplemented with measures relevant to brain metastases and items capturing effects of targeted treatments relevant to this population.