tbuckley/cabot-search huggingface dataset:
Association of the Lung Immune Prognostic Index with outcome in patients with metastatic urothelial cancer treated with immune checkpoint inhibitor.
Authors: Parent Pauline, Edouard Auclin, Laura Mezquita, Nieves M. Chanza, Clement Dumont, Alejo Rodriguez-Vida, Rebeca Lozano, Beatriz Vera, Raffaele Ratta, Giulia Baciarello, Emeline Colomba, Alina Fuerea, Benjamin Besse, Yohann Loriot, Pernelle Lavaud
Journal: Journal of Clinical Oncology (2020)

545 Background: Prognostic factors for survival in metastatic urothelial carcinoma (mUC) have been reported in patients (pts) treated with chemotherapy (Bellmunt and al, JCO 2010). However, no biomarkers have been clearly identified in the setting of immune-checkpoint inhibitors (ICI). The Lung immune prognostic index (LIPI) was associated with clinical outcomes for ICI in lung cancer (Mezquita et al, Jama Oncol 2018) and other tumor types (Varga et al, TAT 2019). In this multicenter retrospective study, we correlated LIPI with outcomes in pts with mUC treated with ICI. Methods: Pts with mUC enrolled from May 2013 to July 2018 in 7 high volume centers were analysed. LIPI score includes: LDH &gt; upper limit of normal and neutrophil/[leukocytes minus neutrophils] ratio (dNLR) &gt; 3. The following LIPI subgroups were defined: good prognosis (0), intermediate prognosis (1) and poor prognosis (2 factors). Median (m) progression-free survival (PFS) and median overall survival (OS) were calculated using Kaplan-Meier method, log rank test was used for statistical comparison. Cox model was used for multivariate analysis. Results: To date, 152 mUC pts have been enrolled and preliminary analysis have been performed in 135 pts. Median age was 67 years, 111 (82%) pts were male, 106 pts (79%) had ECOG PS 0-1, 31 pts (23%) had liver metastasis. Median follow-up was 21.1 months (mo) (95% CI; 16.3-24.5), mPFS was 3.6 mo (95% CI; 2.6-6.0) and mOS was 13.8 mo (95% CI; 11.5-23.2). LIPI classified the population in good (56%), intermediate (35%) and poor (9%) prognosis group. In multivariate analysis, estimated mPFS in good, intermediate and poor prognosis were 5.8 mo (95% CI; 2.6-6.0), 3.6 mo (95% CI; 3.3-16.2) and 1.2 mo (95% CI;0.1-NR), respectively (p = 0.001). Estimated mOS in good, intermediate and poor prognosis were 17.3 mo (95% CI; 13.0-36.8), 16.9 mo (95% CI; 6.9-NR) and 5.4 mo (95% CI;2.5-NR), respectively (p = 0.19). OS data will be validated on larger cohort. Conclusions: The LIPI score is associated with clinical outcome to ICI and may be a useful tool for identifying patients who may not benefit from ICI. Validation in independent prospective cohort is ongoing.
Phosphoproteomic Analysis of Neonatal Regenerative Myocardium Revealed Important Roles of Checkpoint Kinase 1 via Activating Mammalian Target of Rapamycin C1/Ribosomal Protein S6 Kinase b-1 Pathway
Authors: Yi Fan, Yiwei Cheng, Yafei Li, Bingrui Chen, Zimu Wang, Tianwen Wei, Hao Zhang, Yueshuai Guo, Qiming Wang, Yongyue Wei, Feng Chen, Jiahao Sha, Xuejiang Guo, Liansheng Wang
Journal: Circulation (2020)

In mammals, regenerative therapy after myocardial infarction is hampered by the limited regenerative capacity of adult heart, whereas a transient regenerative capacity is maintained in the neonatal heart. Systemic phosphorylation signaling analysis on ischemic neonatal myocardium might be helpful to identify key pathways involved in heart regeneration. Our aim was to define the kinase-substrate network in ischemic neonatal myocardium and to identify key pathways involved in heart regeneration after ischemic insult.Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium, and kinase-substrate network analysis revealed 11 kinases with enriched substrates and upregulated phosphorylation levels, including checkpoint kinase 1 (CHK1) kinase. The effect of CHK1 on cardiac regeneration was tested on Institute of Cancer Research CD1 neonatal and adult mice that underwent apical resection or myocardial infarction.In vitro, CHK1 overexpression promoted whereas CHK1 knockdown blunted cardiomyocyte proliferation. In vivo, inhibition of CHK1 hindered myocardial regeneration on resection border zone in neonatal mice. In adult myocardial infarction mice, CHK1 overexpression on infarct border zone upregulated mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway, promoted cardiomyocyte proliferation, and improved cardiac function. Inhibiting mammalian target of rapamycin activity by rapamycin blunted the neonatal cardiomyocyte proliferation induced by CHK1 overexpression in vitro.Our study indicates that phosphoproteome of neonatal regenerative myocardium could help identify important signaling pathways involved in myocardial regeneration. CHK1 is found to be a key signaling responsible for neonatal regeneration. Myocardial overexpression of CHK1 could improve cardiac regeneration in adult hearts by activating the mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway. Thus, CHK1 might serve as a potential novel target in myocardial repair after myocardial infarction.
Decreased Length of Stay In Asthmatic Patients Using A Multidisciplinary Bronchodilator Titration Guideline
Authors: Ariela Agress, Deena Miller, William Cuddy, Peter Eldridge, Georgia Christakis, Candice Williams, Dana Lorber, Kristina Schrull-Valiente, Karen Brandstaedter, Simon Li, Yehudit Pollack
Journal: Journal of Allergy and Clinical Immunology (2020)
23P Expression Of Beta-Iii Tubulin, Foxo 3 Protein and Deoxythymidine Kinase in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy
Authors: L.W.C. Chow, W.T.Y. Loo, A.Y.S. Yip, E.Y.Y. Ong, W. Ng
Journal: Annals of Oncology (2012)
Durvalumab as neoadjuvant therapy for muscle-invasive bladder cancer: Preliminary results from the Bladder Cancer Signal Seeking Trial (BLASST)-2.
Authors: Xiao X. Wei, Bradley Alexander McGregor, Richard J. Lee, Xin Gao, Kerry L. Kilbridge, Mark A. Preston, Matthew Mossanen, Matthew D. Ingham, Graeme S. Steele, Alyssa Klein, Eliezer Mendel Van Allen, Mariano Severgnini, Marios Giannakis, Guru Sonpavde
Journal: Journal of Clinical Oncology (2020)

507 Background: There is no established neoadjuvant therapy (NAT) for patients (pt) with muscle invasive bladder cancer (MIBC) ineligible for cisplatin-based chemotherapy preceding radical cystectomy. Encouraging prospective data indicate PD-1/PD-L1 inhibitors, including pembrolizumab and atezolizumab, are safe and active as NAT for MIBC. Durvalumab (D), a PD-L1 inhibitor, is FDA approved for treating locally advanced or metastatic urothelial carcinoma following platinum-based chemotherapy. The safety and activity of D as NAT in MIBC have not been reported. Methods: We are conducting a single-center sequential multicohort trial (NCT03773666) of D alone (Cohort 1, N=10) and D plus the CD73 inhibitor oleclumab (Cohort 2, N=10) in cT2-T4aN0M0 MIBC pts who are RC candidates and are ineligible for or declined cisplatin-based chemotherapy. The primary endpoint is feasibility, defined as ≥7 of 10 pts receiving at least 1 dose of D followed by radical cystectomy without dose limiting toxicity (DLT) up to 12 wks post-RC. In Cohort 1, D is administered at 750mg IV Q2W for 3 cycles followed by RC 2-4 weeks after the last dose. Baseline and RC tissue and baseline and on-study blood are collected for correlative studies, including immunohistochemistry, genomics, transcriptomics, and metabolomics. Results: Cohort 1 has completed enrollment; ten pts were enrolled between Feb 2019 to Sept 2019. Median age was 67 (Range: 53-85) and 8 (80%) were men. All 10 pts completed 3 durvalumab doses. Eight pts completed planned RC with at least 12wk follow-up post-op to date. No DLTs were observed. One Grade 3 treatment-related adverse event (trAE) was reported (anemia), with no Grade 4 or higher trAE. Pathologic response (&lt;pT2N0) was seen in 2 of 8 (25%) pts with pathologic complete response (pT0) in 1 (12.5%) pts. Updated safety and efficacy data from Cohort 1 will be presented. Conclusions: D appears to be feasible as NAT in MIBC with preliminary evidence for antitumor activity. Toxicities are consistent with data from other PD-1/PD-L1 inhibitor trials. Future cohorts will examine D-containing combination NAT strategies. Analysis of tissue and blood-based predictive biomarkers are ongoing. Clinical trial information: NCT03773666.
Economic Burden Associated With Extended-Release vs Immediate-Release Drug Formulations Among Medicare Part D and Medicaid Beneficiaries
Authors: Andrew Sumarsono, Nathan Sumarsono, Sandeep R. Das, Muthiah Vaduganathan, Deepak Agrawal, Ambarish Pandey
Journal: JAMA Network Open (2020)

The United States spends more money on medications than any other country. Most extended-release drugs have not consistently shown therapeutic or adherence superiority, and switching these medications to less expensive, generic, immediate-release formulations may offer an opportunity to reduce health care spending.To evaluate Medicare Part D and Medicaid spending on extended-release drug formulations and the potential savings associated with switching to generic immediate-release formulations.This cross-sectional study used the 2012 to 2017 Medicare Part D Drug Event and Medicaid Spending and Utilization data sets to analyze 20 extended-release drugs with 37 Medicare formulations and 36 Medicaid formulations. Only cardiovascular, diabetes, neurologic, and psychiatric extended-release drugs saving at most 1 additional daily dose compared with their immediate-release counterparts were included. Extended-release drugs with therapeutic superiority were excluded. Analyses were conducted from January to December 2019.Estimated Medicare Part D and Medicaid savings from switching extended-release to immediate-release drug formulations between 2012 and 2017.Of the 6252 drugs screened for eligibility from the 2017 Medicaid Drug Utilization database and the 2017 Medicare Part D database, 67 drugs with extended-release formulations that were identified in the Medicare data set (20 distinct drugs with 37 formulations [19 brand, 18 generic]) were included in the analysis. In 2017, Medicare Part D spent $2.2 billion and Medicaid spent $952 million (a combined $3.1 billion) on 20 extended-release drugs. Between 2012 and 2017, Medicare Part D and Medicaid spent $12 billion and $5.9 billion, respectively, on extended-release formulations. Switching from brand-name to generic extended-release formulations was estimated to be associated with a $247 million reduction in Medicare spending and $299 million reduction in Medicaid spending in 2017, whereas switching all brand-name and generic extended-release formulations to immediate-release formulations in both Medicare and Medicaid was estimated to reduce spending by $2.6 billion ($1.8 billion for Medicare and $836 million for Medicaid) in 2017. During the study period, the estimated spending reduction associated with switching all patients receiving extended-release formulations (brand name extended-release and generic extended-release) to generic immediate-release formulations was $13.7 billion ($8.5 billion from Medicare and $5.2 billion from Medicaid).The findings suggest that switching from extended-release drug formulations to therapeutically equivalent immediate-release formulations when available represents a potential option to reduce Medicare and Medicaid spending.
NIVOREN GETUG-AFU 26 translational study: Association of PD-1, AXL, and PBRM-1 with outcomes in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) treated with nivolumab (N).
Authors: Yann-Alexandre Vano, Nathalie Rioux-Leclercq, Cécile Dalban, Catherine Sautes-Fridman, Antoine Bougoüin, Nathalie Chaput, Salem Chouaib, Benoit Beuselinck, Christine Chevreau, Marine Gross-Goupil, Sylvie Negrier, Brigitte Laguerre, Delphine Borchiellini, Irelka Colina-Moreno, Wolf-Herman Fridman, Sylvie Chabaud, Florence Tantot, Janice Barros Monteiro, Bernard Escudier, Laurence Albiges
Journal: Journal of Clinical Oncology (2020)

618 Background: The NIVOREN GETUG-AFU 26 study reported safety and efficacy of N in mccRCC pts in a “real world setting”. A translationnal research program was launched to characterize immune cell populations in the tumor by immunohistochemistry (IHC) and correlate them with outcome on N. Methods: All pts treated with N in the GETUG AFU 26 NIVOREN trial who consented for translational program and with available archived paraffin- embedded (FFPE) tumor tissue samples were eligible. Tumor were centrally reviewed. Using IHC we quantified main immune populations (B-cells, CD8 T-cells, macrophages), and immune checkpoints receptors (TIM-3, LAG-3, PD-1) at the invasive margin (IM) and at the core of the tumor (CT). We also identified AXL and PBRM1/BAP1 expression. Results: Overall 324 pts were included. Pts had similar baseline characteristics (IMDC Good, Intermediate, Poor in 18%, 60% and 22%, respectively) and comparable outcomes than overall trial population (PFS/OS = 4.5 / 25.4 months). PD-1 (IM) expression was associated with better PFS whereas AXL expression by tumor cells (TC) was associated with worse PFS (table). LAG-3 expression tend to be associated with worse OS. PBRM-1 loss (15%) was associated with better OS and PFS and with a higher density of CD8 T-cells (p = 0.001) and CD163-macrophages (p = 0.01) (CT) and a higher expression of LAG-3 (CT) (p = 0.01) and PD-1 (CT) (p = 0.02). BAP-1 loss was not associated with PFS (p = 0.6) nor OS (p = 0.9) in this cohort. Conclusions: We report the largest translational analysis supporting that PD-1 and AXL expression are associated with PFS in pts with mccRCC receiving N. We further confirm that PBRM-1 loss is a strong prognostic factor in this setting.[Table: see text]
Disease Progression in Patients With Hepatitis C Virus Infection Treated With Direct-Acting Antiviral Agents
Authors: Manuel Mendizabal, Federico Piñero, Ezequiel Ridruejo, Fernando Herz Wolff, Margarita Anders, Virginia Reggiardo, Beatriz Ameigeiras, Ana Palazzo, Cristina Alonso, María Isabel Schinoni, María Grazia Videla Zuain, Federico Tanno, Sebastián Figueroa, Luisa Santos, Mirta Peralta, Alejandro Soza, Cecilia Vistarini, Raúl Adrover, Nora Fernández, Daniela Perez, Nelia Hernández, Claudio Estepo, Andres Bruno, Valeria Descalzi, Marcela Sixto, Silvia Borzi, Daniel Cocozzella, Alina Zerega, Alexandre de Araujo, Adriana Varón, Fernando Rubinstein, Hugo Cheinquer, Marcelo Silva
Journal: Clinical Gastroenterology and Hepatology (2020)
Longitudinal multiplex cytokine analysis for patients (pts) with metastatic renal cell carcinoma (mRCC) treated with ipilimumab/nivolumab (I+N).
Authors: Tian Zhang, Yuan Wu, Anika Agarwal, Mark D. Starr, Marco Reyes-Martinez, Monika Anand, Daniella Runyambo, Michael Roger Harrison, Andrew J. Armstrong, Daniel J. George, Andrew B. Nixon
Journal: Journal of Clinical Oncology (2020)

731 Background: I+N is an established treatment for mRCC, where circulating protein biomarkers are prognostic. In a longitudinal correlative study, we characterized circulating proteins in mRCC pts treated with standard of care I+N. Methods: mRCC pts treated with I+N were prospectively enrolled at Duke Cancer Institute (NCT02978118), contributing EDTA plasma at baseline, week(wk)-4, wk-12, and disease progression. Best overall responses were characterized as disease control (DC; stable disease, partial &amp; complete responses) versus progressive disease (PD). Plasma was batch analyzed using a 46-plex MesoScale Discovery ELISA assay (IFN-g, interleukins [IL]-1b, 2, 4, 5, 6, 7, 8, 10, 12, IL-12-IL-23p40, 13, 15, 16, 17A, 21, 22, 27, 31, MIP-3a, Eotaxin, Eotaxin-3, IP-10, MCP-1&amp;4, MDC, MIP-1a &amp; 1b, TARC, TNF-a &amp; b, GM-CSF, CRP, ICAM-1, SAA, VCAM-1, FGFb, FLT-1, PlGF, Tie-2, VEGF, VEGF-, and VEGF-D). Mean and standard deviations of cytokine concentrations are reported, along with a Wilcoxon rank sum test between PD and DC groups; unadjusted p-values are nominal. Results: We enrolled 25 pts with mRCC (15 DC and 10 PD). Baseline IL-7, IL-8, IL-12-IL-23p40, ICAM-1, TNF-a, VEGF-C, and VEGF-D were lower in PD pts than DC pts (Table). MIP-1b was significantly lower for PD than DC pts at baseline (Table) and wk-4 change (PD 0.30 +/- 1.82, DC 0.83 +/- 6.49, p = 0.056). Although baseline IFN-g did not differ between groups, wk-4 IFN-g significantly increased in DC and decreased in PD pts (DC 3.5 +/- 7.1; PD -1.33 +/- 5.47, p = 0.056). Conclusions: In this pilot exploratory analysis, a subset of ILs are higher at baseline in DC than PD pts. A wk-4 increase in circulating IFN-g is associated with DC vs PD and could be linked to increased early inflammation and response to I+N. Larger prospective studies are needed to validate these findings.[Table: see text]
Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR
Authors: Jasmina Cehajic-Kapetanovic, Kanmin Xue, Cristina Martinez-Fernandez de la Camara, Anika Nanda, Alexandra Davies, Laura J. Wood, Anna Paola Salvetti, M. Dominik Fischer, James W. Aylward, Alun R. Barnard, Jasleen K. Jolly, Edmond Luo, Brandon J. Lujan, Tuyen Ong, Aniz Girach, Graeme C. M. Black, Ninel Z. Gregori, Janet L. Davis, Potyra R. Rosa, Andrew J. Lotery, Byron L. Lam, Paulo E. Stanga, Robert E. MacLaren
Journal: Nature Medicine (2020)
Abstract 16910: Complex Heart Failure Phenotypes Differ in Response to Medical Therapy and Exercise Training
Authors: Miranda Merrill, Christophe Roeder, Maggie Butler, Bethany Doran, Laura Stevens, Carsten Goerg, David Kao
Journal: Circulation (2018)

Background: Patients with heart failure (HF) are heterogeneous with multiple complex phenotypes across the ejection fraction (EF) spectrum. Phenotype-specific response to various treatments have not been well-described. Hypothesis: Clinical response to specific interventions will vary according to HF phenotype. Methods: Using latent class analysis, six cluster-based HF phenotypes across the EF spectrum were previously identified using patient data from 2130 patients enrolled in HF-ACTION (LVEF ≤ 35%) and 1767 patients enrolled from the Americas in TOPCAT (LVEF ≥ 45%) based on age, sex, race, CAD, BMI, hyperlipidemia, hypertension, diabetes mellitus, atrial fibrillation, COPD, anemia, and renal function, but not LVEF. Response to aerobic exercise training vs. usual care (HF-ACTION) and spironolactone vs. placebo (TOPCAT) were quantified by phenotype. The primary outcome was a composite of cardiovascular mortality (CVM) or HF hospitalization (HFH). Secondary outcomes included CVM, HFH, and all-cause mortality (ACM). Change in peak VO2 at 3 and 12 months were also analyzed in HF-ACTION. Results: Of the established phenotypes, the phenotype composed of elderly non-ischemic patients as well as the non-white/non-ischemic/hypertensive phenotype experienced improvement in combined CVM and HFH, ACM and exercise capacity (28% vs 38%, HR: 0.66 [0.46-0.94], 8% vs 16% HR: 0.49 [0.27-0.91], change in VO2: 1.06±3.01 vs 0.04±3.14, p&lt;0.05). Elderly patients with non-ischemic HFrEF enrolled in HF-ACTION randomized to therapeutic exercise program demonstrated significantly improved exercise capacity compared to usual care (change in VO2: 1.45±2.82 vs -0.09±2.49 and 1.25±3.18 vs 0.66±3.64 respectively, p&lt;0.05). Elderly non-ischemic patients treated with spironolactone in TOPCAT had a lower risk of the primary outcome CVM and HFH (20% vs 27%, HR: 0.67 [0.48-0.95]), driven mostly by reduced CVM (9% vs 17%, HR: 0.52 [0.32-0.84]). Conclusions: Response to varied treatments such as exercise training and spironolactone varies among complex HF phenotypes in both HFpEF and HFrEF. Additional investigation which further characterizes phenotype-specific treatments may help select specific interventions most likely to benefit specific phenotypes.
Implementation and Follow Up of an In-patient Penicillin Allergy Skin Testing Program at One Large University Hospital
Authors: Rajan Ravikumar, Sherry Zhou, Gregory Eschenauer, David Bozaan, Elizabeth Spranger, Linda Bashaw, Katie Barwig, Sheryl Penar, Matthew Enell, Kiela Samuels, Tejal Gandhi
Journal: Journal of Allergy and Clinical Immunology (2020)
Ibrutinib plus CIT for R/R mature B-NHL in children (SPARKLE trial): initial safety, pharmacokinetics, and efficacy
Authors: G. A. Amos Burke, Auke Beishuizen, Deepa Bhojwani, Birgit Burkhardt, Véronique Minard-Colin, Robin E. Norris, Edita Kabickova, F. Guclu Pinarli, Nurdan Tacyildiz, Angela Howes, Jan de Jong, Grace Liu, Kerri Nottage, Mariya Salman, Xavier Woot de Trixhe, Mitchell Cairo
Journal: Leukemia (2020)
Safety of Dual Sublingual Immunotherapy with Japanese Cedar Pollen and SQ House Dust Mite Tablets in Children, Adolescents and Adults
Authors: Yoshitaka Okamoto, Syuji Yonekura, Minoru Gotoh, Shinya Kaneko, Yuriko Maekawa, Kimihiro Okubo
Journal: Journal of Allergy and Clinical Immunology (2020)
Differences in the serum metabolome and lipidome identify potential biomarkers for seronegative rheumatoid arthritis versus psoriatic arthritis
Authors: Margarida Souto-Carneiro, Lilla Tóth, Rouven Behnisch, Konstantin Urbach, Karel D Klika, Rui A Carvalho, Hanns-Martin Lorenz
Journal: Annals of the Rheumatic Diseases (2020)

The differential diagnosis of seronegative rheumatoid arthritis (negRA) and psoriasis arthritis (PsA) is often difficult due to the similarity of symptoms and the unavailability of reliable clinical markers. Since chronic inflammation induces major changes in the serum metabolome and lipidome, we tested whether differences in serum metabolites and lipids could aid in improving the differential diagnosis of these diseases.Sera from negRA and PsA patients with established diagnosis were collected to build a biomarker-discovery cohort and a blinded validation cohort. Samples were analysed by proton nuclear magnetic resonance. Metabolite concentrations were calculated from the spectra and used to select the variables to build a multivariate diagnostic model.Univariate analysis demonstrated differences in serological concentrations of amino acids: alanine, threonine, leucine, phenylalanine and valine; organic compounds: acetate, creatine, lactate and choline; and lipid ratios L3/L1, L5/L1 and L6/L1, but yielded area under the curve (AUC) values lower than 70%, indicating poor specificity and sensitivity. A multivariate diagnostic model that included age, gender, the concentrations of alanine, succinate and creatine phosphate and the lipid ratios L2/L1, L5/L1 and L6/L1 improved the sensitivity and specificity of the diagnosis with an AUC of 84.5%. Using this biomarker model, 71% of patients from a blinded validation cohort were correctly classified.PsA and negRA have distinct serum metabolomic and lipidomic signatures that can be used as biomarkers to discriminate between them. After validation in larger multiethnic cohorts this diagnostic model may become a valuable tool for a definite diagnosis of negRA or PsA patients.