tbuckley/cabot-search huggingface dataset:
Abstract 281: Hepatic Liver Receptor Homolog-1, a Key Regulator of Lipid Storage and Phospholipid Diversity
Authors: Diego A Miranda, William C Krause, Amaury Cazenave, Hazel A Escusa, Diyala S Shihadih, Andreas Stahl, Markus R Wenk, David L Silver, Holly A Ingraham
Journal: Circulation Research (2017)

Cardiovascular disease and malignancy are the most common cause of death in Non-alcoholic Steatohepatitis (NASH) patients. Aside from lifestyle modification, there is currently no treatment for NASH. Activation of Liver Receptor Homolog-1 (Lrh-1), known to bind phospholipid ligands, has been shown to effectively reduce liver triglyceride (TG) in DIO mice, raising Lrh-1 as a possible target for treating NASH. Despite this finding, hepatic TGs are equivalent in controls and liver-specific Lrh-1 knockout (LKO or Lrh1 AlbCre ) mice, regardless of diet. Given this discrepancy, we sought to characterize Lrh-1’s role in hepatic lipid metabolism by acutely deleting Lrh-1 in the adult liver, thus eliminating potential compensatory developmental effects associated with LKO. To acutely eliminate Lrh-1 in hepatocytes, 6-week old Lrh-1 fl/f l male mice were infected with AVV8-TBG-eGFP (Control) or AAV8-TBG-Cre (LKO AAVCre ) via retro-orbital injection and fed chow or high fat diet. LKO AAVCre mice developed hepatic steatosis after six weeks on standard chow or high fat diet. Furthermore, LKO AAVCre hepatocytes exhibited large lipid droplets, which were visible as early as 2 wks post-infection, thus suggesting that lipid handling is significantly altered in LKO AAVCre hepatocytes, independent of fatty acid transport or oxidation. LKO AAVCre exhibited lower Pcsk9 expression, which correlated with decreased fasting plasma LDL-C. Consistent with other studies showing that perturbations in phospholipid pools affect lipid storage, lipidomic analyses revealed a significant reduction in phospholipid species containing arachidonic acid (AA), thus reducing the overall diversity of key membrane phospholipids. RNA-Seq analyses from LKO AAVCre livers confirmed that factors promoting lipid droplet size ( Cidec , Plin4 ) were greatly increased while key enzymes in biosynthesis of unsaturated fatty acids were reduced ( Fads1, Fads2 and Elovl5 ). In addition, expression of human LRH-1 in LKO AAVCre decreased hepatic TG and improved glucose tolerance in DIO mice, in a ligand dependent manner. Collectively our data establish a novel role for Lrh-1 as a key regulator of lipid storage, thereby providing the first in vivo evidence as to why phospholipid serve as Lrh-1 ligands.
Fra-2–expressing macrophages promote lung fibrosis
Authors: Alvaro C Ucero, Latifa Bakiri, Ben Roediger, Masakatsu Suzuki, Maria Jimenez, Pratyusha Mandal, Paola Braghetta, Paolo Bonaldo, Luis Paz-Ares, Coral Fustero-Torre, Pilar Ximenez-Embun, Ana Isabel Hernandez, Diego Megias, Erwin F Wagner
Journal: Journal of Clinical Investigation (2019)

Idiopathic Pulmonary Fibrosis (IPF) is a deadly disease with limited therapies. Tissue fibrosis is associated with Type 2 immune response, although the causal contribution of immune cells is not defined. The AP-1 transcription factor Fra-2 is upregulated in IPF lung sections and Fra-2 transgenic mice (Fra-2tg) exhibit spontaneous lung fibrosis. Here we show that Bleomycin-induced lung fibrosis is attenuated upon myeloid-inactivation of Fra-2 and aggravated in Fra-2tg bone marrow chimeras. Type VI collagen (ColVI), a Fra-2 transcriptional target, is up-regulated in three lung fibrosis models, and macrophages promote myofibroblast activation in vitro in a ColVI- and Fra-2-dependent manner. Fra-2 or ColVI inactivation does not affect macrophage recruitment and alternative activation, suggesting that Fra-2/ColVI specifically controls the paracrine pro-fibrotic activity of macrophages. Importantly, ColVI knock-out mice (KO) and ColVI-KO bone marrow chimeras are protected from Bleomycin-induced lung fibrosis. Therapeutic administration of a Fra-2/AP-1 inhibitor reduces ColVI expression and ameliorates fibrosis in Fra-2tg mice and in the Bleomycin model. Finally, Fra-2 and ColVI positively correlate in IPF patient samples and co-localize in lung macrophages. Therefore, the Fra-2/ColVI pro-fibrotic axis is a promising biomarker and therapeutic target for lung fibrosis, and possibly other fibrotic diseases.
Preconception health in England: a proposal for annual reporting with core metrics
Authors: Judith Stephenson, Christina Vogel, Jennifer Hall, Jayne Hutchinson, Sue Mann, Helen Duncan, Kathryn Woods-Townsend, Simon de Lusignan, Lucilla Poston, Janet Cade, Keith Godfrey, Mark Hanson, Geraldine Barrett, Mary Barker, Gabriella Conti, Geordan Shannon, Tim Colbourn
Journal: The Lancet (2019)
Real-world bevacizumab utilization and outcomes in first-line ovarian cancer.
Authors: Matthew J. Monberg, Jennifer P Hall, Rebecca Moon, Olivia Higson, Kimmie McLaurin, Tapashi Dalvi
Journal: Journal of Clinical Oncology (2019)

5578 Background: Bevacizumab (B) is approved in combination with carboplatin and paclitaxel, followed by B monotherapy, for the treatment of advanced ovarian cancer (OC) following surgery. We sought to describe B utilization and outcomes of B in first-line (1L) OC within the US and EU. Methods: This cross-sectional study included patients who were actively receiving treatment for OC. Data were collected at a single time point from 2496 patient forms between December 2017 and March 2018 from 340 oncologists/ gynecologists across the US, France, Germany, Italy, Spain, and the UK. Patients were platinum sensitive if progression was noted &gt; 6 months after frontline platinum therapy and resistant if the interval was 0-6 months. This analysis included patients who received 1L chemotherapy (chemo) with no maintenance or 1L chemo with bevacizumab maintenance. Results: B was used in combination with chemo at 1L and as 1L maintenance monotherapy in 11% total study patients. Those receiving 1L + B were more likely to have Stage IV disease, have good performance status (PS) at diagnosis, and receive BRCA testing than patients receiving chemo only. Treatment response, platinum sensitivity, and activities of daily living are shown in the Table. Results did not vary by BRCA status. Conclusions: This study highlights differences in patient characteristics and outcomes between patients receiving/ who received 1L chemo only and those receiving/ who received B, however, this study was not designed to formally compare 1L treatment options. [Table: see text]
Biomarker-directed precision oncology of pembrolizumab-based combination therapy for non-small cell lung cancer: Phase II KEYNOTE-495/KeyImPaCT study.
Authors: Martin Gutierrez, Matthew David Hellmann, Matthew A. Gubens, Charu Aggarwal, Daniel Shao Weng Tan, Enriqueta Felip, Joanne Wing Yan Chiu, Jong Seok Lee, James Chih-Hsin Yang, Edward B. Garon, Andrea Basso, Hua Ma, Lawrence Fong, Alex Snyder, Jianda Yuan, Roy S. Herbst
Journal: Journal of Clinical Oncology (2019)

TPS9117 Background: Pembrolizumab-based combination immunotherapy aims to improve clinical outcomes over pembrolizumab monotherapy. A biomarker-based therapeutic approach may be associated with improved response to different combination therapies of immune checkpoint inhibitors and may improve overall outcomes in NSCLC. The randomized, multicenter, open-label, phase 2 KEYNOTE-495 trial ( NCT03516981 ) will evaluate the clinical usefulness of biomarker-informed, pembrolizumab-based combination therapy in patients with treatment-naive, advanced NSCLC. Methods: This is a group-sequential, adaptive randomization trial. Patients will have histologically or cytologically confirmed treatment-naive, advanced NSCLC, documented absence of EGFR and B-Raf mutations and ALK and ROS1 gene rearrangements, measurable disease per RECIST v1.1, and ECOG PS 0-1. Tumor tissue from patients will be initially screened for 2 validated, independent, next-generation biomarkers: T cellinflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on results of biomarker screening, patients will be assigned to 1 of 4 groups: TMB low GEP low , TMB high GEP low , TMB low GEP high , and TMB high GEP high . Within each group, patients will be randomly assigned to receive pembrolizumab 200 mg Q3W intravenously (IV) combined with either MK-4280 200 mg Q3W (antiLAG-3) IV or lenvatinib 20 mg orally once daily, with the randomization assignment adaptively modified based on interim efficacy analyses. Response will be assessed by imaging every 9 weeks for the first year and every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. Treatment arms may be terminated during the interim analysis due to safety, prespecified futility criteria, or both. Primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 8 countries. Clinical trial information: NCT03516981.
A circulating tumor cell specific RNA assay for assessment of androgen receptor signaling inhibitor sensitivity in metastatic castration-resistant prostate cancer.
Authors: Pai-Chi Teng, Yu Jen Jan, Junhee Yoon, Pin-Jung Chen, Jie-Fu Chen, Nu Yao, Shirley Cheng, Amber Lozano, Michael Freeman, Sungyong You, Hsian-Rong Tseng, Edwin M. Posadas
Journal: Journal of Clinical Oncology (2019)

5059 Background: Our objective is to develop a circulating tumor cell (CTC)-RNA assay for characterizing clinically relevant RNA signatures for the assessment of androgen receptor signaling inhibitors (ARSIs) sensitivity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: We developed NanoVelcro CTC-RNA Assay by combining Thermoresponsive(TR)-NanoVelcro CTC purification system with NanoString nCounter platform for CTC purification and RNA analysis. Based on the well-validated, tissue-based Prostate Cancer Classification System (PCS), we selected the most aggressive and ARSI-resistant subtype- the PCS1, for CTC analysis. We applied a rigorous bioinformatic process to develop a CTC-PCS1 panel that is specific to PC CTCs. We validated NanoVelcro CTC-RNA Assay and CTC-PCS1 panel with PC cell lines to demonstrate sensitivity and specificity of the PCS1 Z score (the likelihood estimate of the PCS1 subtype) for identifying PCS1 subtype and ARSI resistance. We then selected 31 blood samples from 23 PC patients receiving ARSIs to test in our assay. The PCS1 Z score of each sample was computed and compared with ARSI treatment sensitivity. Results: We established a 16-gene CTC-PCS1 panel that consists of CTC-specific RNA signatures. The validation studies using PC cell lines showed that the assay can detect the RNA transcripts with high sensitivity and scalability in the range of 1-100 cells. We also showed that the genes in CTC-PCS1 panel is highly expressed in PC cells. We further demonstrated that the CTC-PCS1 panel is highly specific in identifying PCS1-like samples, and the high PCS1 Z score is associated with ARSI resistance. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). In 8 patients who were initially sensitive to ARSI (ARSI-S) and later developed resistance (ARSI-R), we found that the PCS1 Z score increased from the time of ARSI-S to the time of ARSI-R (Pairwise T-test, P=0.016). Conclusions: Using our new methodology, we developed a first-in-class CTC-RNA assay and demonstrated the feasibility of transforming clinically-relevant tissue-based RNA profiling into CTC tests. This approach allows for detecting RNA expression relevant to clinical drug resistance in a non-invasive fashion, which can facilitate patient-specific treatment selection and early detection of drug resistance- a goal in precision oncology.
Phase I study of OKT3 x hu3F8 bispecific antibody (GD2Bi) armed T cells (GD2BATs) in GD2-positive tumors.
Authors: Maxim Yankelevich, Shakeel Modak, Roland Chu, Daniel W. Lee, Archana Thakur, Nai-Kong V. Cheung, Lawrence G. Lum
Journal: Journal of Clinical Oncology (2019)

2533 Background: With the proven success of anti-GD2 monoclonal antibodies in eradicating minimal residual disease in neuroblastoma (NB), exploiting antibody based anti-GD2 in T cell mediated strategies has potential to combat higher disease burden and improve patient outcome. We hypothesized that arming of ex vivo expanded and activated, autologous, blood derived T cells (ATC) with chemically heteroconjugated GD2Bi should redirect them to target NB. In vitro, ATC coated (armed) with 50 ng/10 6 cells of GD2Bi exhibited specific killing of NB and osteosarcoma (OS) cell lines. Methods: In this phase I study (NCT02173093), patients with GD2-positive tumors received 8, biweekly infusions of GD2BATs + daily low-dose IL-2 and biweekly granulocyte-macrophage colony stimulating factor (GM-CSF). The study followed the standard 3+3 design with dose levels of 40, 80, and 160 x 10 6 GD2BATs/kg/infusion. Results: Twelve patients (NB = 7, OS = 3, Desmoplastic Small Round Cell Tumor = 2) were enrolled from 11/2013 to 12/2017 and 9 completed therapy. Adequate ATCs could not be grown in one patient and two patients did not complete 8 infusions because of rapid disease progression. Infusions were given in outpatient settings. All patients developed a mild, dose-independent and manageable form of cytokine release syndrome with grades 2-3 fevers/chills, headaches and occasional hypotension for up to 48 hours after infusion. No patients developed significant pain. Maximum tolerated dose was not reached. Evidence of activity was seen in several patients including one patient with OS who had a PET response, one patient with NB who had complete bone marrow response (this patient had remained progression free for 2.5 years after completion of infusions), and another NB patient who had a minor response on MIBG scan. Four patients with NB are currently alive after additional therapies at 12, 14, 18, and 47 months post BAT infusions. Conclusions: Autologous T cells from heavily pretreated patients could be expanded ex vivo to large numbers, armed with GD2Bi, cryopreserved and thawed for safe IV administration up to total dose of 1.28x10 9 /kg. Ongoing phase II arm of the trial will focus on evaluation of clinical activity of GD2BATs in patients with NB. Clinical trial information: NCT02173093.
Tumor responses and early onset cytokine release syndrome in synovial sarcoma patients treated with a novel affinity-enhanced NY-ESO-1-targeting TCR-redirected T cell transfer.
Authors: Mikiya Ishihara, Shigehisa Kitano, Hiroyoshi Hattori, Yoshihiro Miyahara, Hidefumi Kato, Hideyuki Mishima, Noboru Yamamoto, Takeru Funakoshi, Takashi Kojima, Tetsuro Sasada, Eiichi Sato, Sachiko Okamoto, Daisuke Tomura, Hideto Chono, Ikuei Nukaya, Junichi Mineno, Hiroaki Ikeda, Takashi Watanabe, Shinichi Kageyama, Hiroshi Shiku
Journal: Journal of Clinical Oncology (2019)

2530 Background: Adoptive transfer of TCR-redirected T cells has been reported to exhibit efficacy in some of melanoma and sarcoma patients. However, there have not been well known about cytokine release syndrome (CRS) or its relations to tumor responses. This study evaluates clinical responses in association with the cell kinetics and CRSs after transfer of high-affinity NY-ESO-1 TCR-gene transduced T cells in NY-ESO-1-expressiong cancer patients (NCT02366546). Methods: We developed a novel-type affinity-enhanced NY-ESO-1-specific TCR and an originally-developed retrovirus vector that encodes siRNA to silence endogenous TCR creation. The NY-ESO-1/TCR sequence is mutated for high affinity with replacements of G50A and A51E in CDR2 region. This is a first-in-man clinical trial of the novel NY-ESO-1-specfic TCR-T cell transfer to evaluate the safety, in vivo cell kinetics and clinical responses. It was designed as a cell-dose escalation from 5 x10 8 to 5 x10 9 cells. NY-ESO-1-expressing refractory cancer patients were enrolled, with 3+3 cohort design. Cyclophosphamide (1,500mg/m 2 ) were administered prior to the TCR-T cell transfer as pre-conditioning. Results: 9 patients were treated with the NY-ESO-1/TCR-T cell transfer. The TCR-T cells expanded in peripheral blood with a dose-dependent manner, associated with rapid proliferation within 5 days after the cell transfer. 3 patients receiving 5x10 9 cells developed early-onset CRSs, with elevations of serum IL-6, IFN-γ. The CRSs developed on day1 or 2 after the cell transfer. They were well managed with tocilizumab treatment. 3 synovial sarcoma patients exhibited tumor shrinkages of partial responses, and they all had high-expression of NY-ESO-1 in the tumor samples, namely, 75% or more. Exploratory analysis revealed that multiple chemotactic cytokines including CCL2 and CCL7, and IL-3 increased in the serum from the patients with CRS. The proportions of effector-memory phenotype T cells in the infused cell-product were significantly associated with CRS development. Conclusions: The affinity-enhanced NY-ESO-1/TCR-T cell transfer exhibited early-onset CRS in association with in vivo cell proliferation and sequential tumor responses in the patients with high-NY-ESO-1-expressing synovial sarcoma. Clinical trial information: NCT02366546.
Predictors of financial toxicity among head and neck cancer patients: A prospective cohort study.
Authors: John R. de Almeida, Katrina Hueniken, Lawson Eng, Meredith Giuliani, Jolie Ringash, Aaron Richard Hansen, Geoffrey Liu, Wei Xu, Madeline Li, David Paul Goldstein
Journal: Journal of Clinical Oncology (2019)

e18361 Background: Treatment of Head and Neck Cancer (HNC) is associated with significant costs and treatment morbidity. The impact of treatment on financial well-being has not been investigated. Methods: Patients with HNC treated at Princess Margaret Cancer Centre, Canada between 2014 and 2018 were enrolled in a longitudinal study from treatment up to 24 months of follow up. Participants completed questionnaires for demographics, out-of-pocket cost during treatment and at 3, 6, 12, 24 months, and the Financial Toxicity Index (FTI) at 12 and 24 months. The FTI is a 14 item, Likert response scale, with summary score out of 14, and higher scores indicating greater toxicity. Preliminary reliability, validity, and responsiveness for the FTI are very good and ongoing. Uni- and multi-variable analyses (UVA, MVA) were performed to identify predictors for FTI score. Results: Among 363 patients enrolled, average age was 61, 76% male, 81% Caucasian, 72% married, 84% living with others, 53% at least college educated, 57% currently unemployed and 59% had stage IV disease. Median pre-treatment household income was $85K, median lost household income was $15K over 12 months following treatment. At least some difficulty paying for food (14%), housing (17%), or medications (11%) was experienced; 13% had to borrow money and 5% had to relocate housing due to financial pressures. Predictors of greater FTI scores on MVA were younger age (p &lt; 0.001), living alone (p = 0.009), and lower baseline household income (p &lt; 0.001). In subgroup analysis of patients with available information, lost household income (p &lt; 0.001) but not out of pocket costs (p = 0.58) was associated with higher FTI score. Conclusions: Financial toxicity is not uncommon in patients with HNC. Younger age, lower baseline income, living alone, and loss of household income are associated with financial toxicity. This should be a priority population for research into improved supportive care and return to work strategies.
Health care resource utilization in patients with advanced melanoma receiving immunotherapies in the real world.
Authors: Richard Wayne Joseph, Alicia C. Shillington, Todd Lee, Cynthia Macahilig, Scott J. Diede, Vaidehi Dave, Qing Harshaw, Emilie Taymor, Frank Xiaoqing Liu
Journal: Journal of Clinical Oncology (2019)

9532 Background: Both pembrolizumab (PEMBRO) and combination ipilimumab + nivolumab (IPI+NIVO) are FDA-approved immunotherapies for advanced melanoma (AM). These two treatment regimens have different toxicity profiles which may impact health care resource utilization (HCRU). Our aim was to compare real-world risk of hospitalization and emergency department (ED) visits within 12 months of starting the two treatment regimens. Methods: A retrospective cohort study was conducted in patients ≥18 years old with AM initiating PEMBRO or IPI+NIVO between Jan 1, 2016 – Dec 30, 2017. Patients were identified from 12 US academic medical centers and affiliated satellite clinics. Data were abstracted through chart review. All-cause hospitalizations or ED visits and the rates per patient per month (PPPM) through 12 months of follow-up were calculated. Utilization was compared between PEMRBO and IPI+NIVO using multivariate logistic regression analysis. Results: 400 patients were included, 200 each PEMBRO and IPI+NIVO with mean (SD) follow-up time of 10 (3) and 10 (4) months, respectively. The PEMBRO cohort had poorer Eastern Cooperative Group (ECOG) performance status at treatment start, 71% ECOG 0 or 1 vs 88% (p &lt; .001); more diabetes, 21% vs 13% (p = .045); a trend towards more heart disease, 18% vs 12% (p = .067); were more likely to be PD-L1 expression positive, 77% vs 63% (p = .011); and less likely to harbor a BRAF mutation, 35% vs 50% (p = .003). The proportion with at least one hospitalization through 12 months was 17% PEMBRO vs 24% IPI+NIVO. Less than 2% of patients had more than one admission and none had more than two, regardless of cohort. Unadjusted mean (SD) PPPM hospitalizations were .016 (.037) for PEMBRO and .020 (.038) for IPI+NIVO. The adjusted odds ratio for any hospitalization with PEMBRO was 0.55 (95% CI .31, .97; p = .039) vs. IPI+NIVO. ED visits occurred in 18% vs 21% in PEMBRO and IPI+NIVO respectively, with no difference in covariate-adjusted analysis (p = .147). Conclusions: Patients receiving PEMBRO had a significantly lower probability of hospitalization and similar probability of ER visits compared with IPI+NIVO in the real world through 12 months.