tbuckley/cabot-search huggingface dataset:
Blood-based biomarkers in metastatic colorectal cancer patients treated with FOLFIRI plus regorafenib or placebo: Results from LCCC1029.
Authors: Yingmiao Liu, Kirsten Burdett, Mark D. Starr, J. Chris Brady, Ace Joseph Hatch, Anastasia Ivanova, Dominic T. Moore, Kelli Hammond, Michael Sangmin Lee, Bert O'Neil, Federico Innocenti, Kouros Owzar, Hanna Kelly Sanoff, Andrew B. Nixon
Journal: Journal of Clinical Oncology (2019)

587 Background: The LCCC1029 trial demonstrated that addition of the multitargeted kinase inhibitor regorafenib (Rego) to FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts) modestly prolonged progression-free survival (PFS). In this preplanned analysis, circulating angiogenic and inflammatory proteins were explored as potential prognostic and predictive biomarkers of Rego benefit. Methods: Plasma samples from 149 mCRC pts (107 in Rego + FOLFIRI and 42 in placebo + FOLFIRI) were evaluated for 20 markers at baseline (n = 149) and cycle 1 day 21 (C1D21, n = 81). Predictive and prognostic values of each marker at baseline were analyzed for both PFS and overall survival (OS) using Cox proportional hazard models. On-treatment changes were quantified as fold change [log 2 (C1D21/baseline)] and differences between arms were evaluated using the Mann-Whitney test. Results: The primary objective of this study was to determine whether any marker was predictive of benefit with Rego for PFS. Although no treatment by marker interactions were significant after adjusting for multiple testing, the top three markers of interest were OPN (unadjusted p-values of 0.02), VCAM-1 (0.02), and PDGF-AA (0.04). VCAM-1 was also predictive for OS benefit in pts treated with Rego (unadjusted p = 0.01). Baseline levels of multiple markers (including HGF, IL-6, PlGF, VEGF-R1, OPN) were prognostic for both PFS and OS. Higher levels of these markers were associated with worse survival. Biomarker changes in response to treatment were explored and compared between arms. Fold change of three markers (PlGF, VEGF-A, VCAM-1) were significantly different between arms (p &lt; 0.0001), all being markedly up-regulated in the Rego arm compared to the placebo after treatment. Conclusions: In this hypothesis generating report, VCAM-1, OPN, and PDGF-AA were the top biomarkers when analyzing the potential predictive association with PFS, where a lower hazard was observed for pts receiving Rego. Candidate prognostic markers were identified, including PlGF and VEGF-R1, key factors in VEGF biology. Biomarker changes observed here may offer insights into potential combinatorial strategies with Rego for future studies.
Abstract P6-18-33: GI toxicities in metastatic breast cancer: A comprehensive literature review
Authors: T Disher, M Siddiqui, D Mitra, C Cameron, L Zhan, S Iyer
Journal: Cancer Research (2019)

Abstract Background Treatments for advanced or metastatic breast cancer (aBC/mBC) are associated with gastrointestinal (GI) toxicities. The objective of this study was to assess the association between GI toxicities in mBC/aBC and health-related quality of life (HRQoL) and economic burden. Methods We conducted a comprehensive literature search of the Cochrane Central Register of Controlled Trials (2017), NHS Economic Evaluation Database (2016), Embase (1988 – 2017 week 34), and Ovid MEDLINE (1946 to August 2017). Eligible studies evaluated an intervention/comparator treatment in adult patients (age ≥18 years) with aBC/mBC and reported a direct connection between GI toxicities (ie, diarrhea, constipation, nausea, vomiting) and HRQoL and economic evidence. All studies published from January 2000 to August 2017 were assessed for eligibility. Editorials, case reports, conference abstracts, and studies of early, locally advanced, or inflammatory BC were excluded. Abstract and title screening, and full-text screening were conducted by single reviewers. Data were extracted by a single reviewer and verified by a second. Results were synthesized narratively. Results Database searches identified 3,428 articles; an additional 16 articles were identified through other sources. Ninety-four studies underwent full-text review, of which 27 reported a direct connection between GI toxicities and HRQoL (n = 11) and economic burden (n = 19). Some studies reported both HRQoL and economic data. Patients identified treatment-related adverse events (AEs), such as GI events, as an important aspect of treatment that can affect therapy choice, discontinuation, and switching. Generally, patients with mBC had lower HRQoL than other BC groups, and increasing toxicity was associated with a greater degree of HRQoL impairment. When patients were asked to rank which AEs they most wanted to avoid, only pain ranked higher than nausea and vomiting. In a willingness to pay study, women with mBC were willing to pay $3,894 (2014 USD) per year to avoid severe diarrhea and $3,211 to avoid severe nausea. Gastrointestinal events were among the costliest class of AEs, with mean costs as high as $4,809 (2016 USD) per episode; costs increased by 24% if events were persistent or recurrent. Conclusions Gastrointestinal toxicities are common in patients with aBC/mBC and have significant consequences for HRQoL and system-level economic outcomes. Frequency and implications of GI effects of treatment regimens should be considered carefully during patient counseling,, prescribing and coverage decisions in metastatic breast cancer. Citation Format: Disher T, Siddiqui M, Mitra D, Cameron C, Zhan L, Iyer S. GI toxicities in metastatic breast cancer: A comprehensive literature review [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 P6-18-33.
Abstract B22: Exposure of AZD4547 FGFR-TKI to a lung squamous carcinoma cell line induces resistance by small cell lung cancer-like transformation associated with ASCL1
Authors: Yosuke Amano, Takahiro Ando, Keita Maemura, Toshio Sakatini, Mitsuhiro Sunohara, Kosuke Watanabe, Hidenori Kage
Journal: Clinical Cancer Research (2018)

Abstract Molecular targeted medicine has progressed in non-small cell lung cancer in recent years, and acquired resistance to molecular targeted therapy has become a major problem. Several mechanisms of acquired resistance have been described, such as secondary mutation of targeted genes, bypass pathway activation, and phenotypic transformation, including epithelial-mesenchymal transition and small cell lung cancer transformation. However, detailed mechanisms and the strategy to overcome the resistance have yet to be clarified thoroughly. In this study, we established a squamous lung cancer cell line with acquired resistance to FGFR tyrosine kinase inhibitor in vitro and identified achaete-scute family bHLH transcription factor 1 (ASCL1) overexpression as a mechanism of the resistance to tyrosine kinase inhibitor treatment. We identified LK-2 as a squamous cell lung cancer cell line that is highly sensitive to FGFR tyrosine kinase inhibitor AZD4547, which is currently evaluated in clinical trial in squamous cell lung cancer, and established its resistant clone in vitro by exposing gradually increasing concentration of AZD4547. The resistant clone was morphologically more round-shaped and expressed ASCL1 significantly higher than the original LK-2 in a microarray analysis, but did not have additional mutations in putative genes responsible for resistance in RNA-sequencing. ASCL1 inhibition with shRNA lentivirus did not restore the sensitivity to AZD4547, but significantly suppressed the growth of the resistant clone compared to the original LK-2. Cyclin A1 (CCNA1) expression was also increased in the resistant clone and was regulated by ASCL1. CCNA1 inhibition also suppressed the growth of the resistant clone. These results suggest that ASCL1 was one of the key molecules for the acquired resistance to tyrosine kinase inhibitor therapy, and considering the evidence that ASCL1 is a master regulator of small cell lung cancer-like phenotype, it may be related to small cell lung cancer transformation as a mechanism of the resistance. ASCL1 and its downstream molecule CCNA1 may be candidates to overcome the resistance to tyrosine kinase inhibitor therapy. Citation Format: Yosuke Amano, Takahiro Ando, Keita Maemura, Toshio Sakatini, Mitsuhiro Sunohara, Kosuke Watanabe, Hidenori Kage. Exposure of AZD4547 FGFR-TKI to a lung squamous carcinoma cell line induces resistance by small cell lung cancer-like transformation associated with ASCL1 [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B22.
Abstract A06: Inhibition of CD99 activity by clofarabine as a novel therapeutic for Ewing sarcoma involves a novel molecular mechanism that is different than cytarabine
Authors: Haydar Çelik, Marika Sciandra, Maria Cristina Manara, Jeffrey Torestky, Katia Scotlandi, Aykut Üren
Journal: Cancer Research (2018)

Abstract Ewing sarcoma (ES) is an aggressive bone and soft tissue malignancy of unknown primary origin. ES cells express high levels of CD99, a cell surface protein routinely used as a marker antigen in the histologic diagnosis of ES. A substantial body of evidence makes CD99 an attractive therapeutic target for patients with ES. We identified two structurally similar FDA-approved nucleoside (purine) analogues, clofarabine and cladribine, as specific CD99 inhibitors in a Biacore screening experiment. In validation experiments, both drugs exhibited selective cytotoxicity toward ES cells in a panel of 14 ES vs. 28 non-ES cell lines. A membrane-impermeable derivative of clofarabine, clofarabine-5′-triphosphate, showed a similar cytotoxicity on ES cell lines, suggesting inhibition of CD99 activity on cell surface as a likely mechanism by which the drug exerts its cytotoxic action without any effect on DNA metabolism. Clofrabine also inhibited the growth of three different ES xenografts in vivo. We performed a phosphokinase array to identify the mechanism behind how clofarabine may regulate cellular functions through inhibiting CD99. Mitogen- and stress-activated kinases 1 and 2 (MSK1/2) were the most significantly activated proteins by both CD99 antibody and clofarabine. Four of the 7 proteins with increased phosphorylation were related to MSK1/2, which were MSK1/2 itself, its substrates CREB and c-Jun, and its upstream kinase ERK1/2, thus representing the most likely intracellular pathway responsible for cell death due to CD99 inhibition. Clofarabine induced a significant increase in phosphorylation levels of MSK1/2 in cohort of ES xenografts, supporting its use as a potential pharmacodynamic marker of CD99 inhibition. We compared the activity of clofarabine with cytarabine, a structurally similar pyrimidine analog that has been identified as an inhibitor of EWS/FLI1 transcriptional activity but failed in clinical trials on ES patients. Cytarabine did not activate MSK1/2 phosphorylation in ES cells, suggesting that clofarabine may function through alternative mechanisms on ES cells that are different than cytarabine. Overall, our findings suggest that clofarabine directly binds to CD99 and inhibits its oncogenic activity through a novel mechanism in ES, and therefore it is a good candidate for early-phase clinical trials in children with ES. Citation Format: Haydar Çelik, Marika Sciandra, Maria Cristina Manara, Jeffrey Torestky, Katia Scotlandi, Aykut Üren. Inhibition of CD99 activity by clofarabine as a novel therapeutic for Ewing sarcoma involves a novel molecular mechanism that is different than cytarabine [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A06.
A Phase II StudyÂ of Sequential Pembrolizumab (PEM)Â FollowedÂ By AVD for Frontline TreatmentÂ of Classical Hodgkin Lymphoma (CHL): Quantifying Response FollowingÂ PEM MonotherapyÂ with FDG-PET-Derived Metabolic Tumor Volume and Total Lesion Glycolysis
Authors: Hatice Savas, Pamela Allen, Andrew M. Evens, Barbara Pro, Gary Dillehay, Alfred Rademaker, Brett Alan Palmer, Ranjana Advani, Leo I. Gordon, Jane N. Winter
Journal: Blood (2018)
Abstract 15717: Non-sustained and Monomorphic Ventricular Tachycardia Predict Successful Antitachycardia Pacing Therapy
Authors: Anne-Floor B Quast, Tom Brouwer, Fleur Tjong, Arthur Wilde, Reinoud E Knops
Journal: Circulation (2017)

Introduction: Anti-tachycardia pacing (ATP) is a pain-free therapy modality delivered by an implantable cardioverter-defibrillator (ICD) to convert ventricular arrhythmias. Data on the success and benefit of ATP is limited. This study aims to determine incidence and predictors of successful ATP therapy, and improve patient tailored device choice. Methods: All de novo single and dual chamber ICD patients implanted in our center, between March 2011 and December 2015 were included. ICD settings were programmed according to internationally accepted standards at the time of implant. Ventricular arrhythmias terminated by ATP and not followed by a shock were considered successful ATP therapy. Cox proportional hazard analysis was performed to assess the independent effect of multiple predictors for successful ATP. Results: A total of 431 patients were included with a median follow-up of 26 months. In 67 patients (16%) ATP therapy was successful during one or more episodes. In 43 patients (10%), all ventricular ta...
Traumatic brain injury in China
Authors: Ji-Yao Jiang, Guo-Yi Gao, Jun-Feng Feng, Qing Mao, Li-Gang Chen, Xiao-Feng Yang, Jin-Fang Liu, Yu-Hai Wang, Bing-Hui Qiu, Xian-Jian Huang
Journal: The Lancet Neurology (2019)
Low Dose Oral Immunotherapy In Children With Egg and Milk Allergies: A Retrospective Case Series Study
Authors: Osamu Natsume, Yusuke Inuzuka, Mayumi Matsunaga, Yukiko Kato, Akio Hakamata, Yuko Mizoguchi, Tomohide Taguchi
Journal: Journal of Allergy and Clinical Immunology (2019)
A randomized phase II study of cabiralizumab (cabira) + nivolumab (nivo) ± chemotherapy (chemo) in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Andrea Wang-Gillam, Eileen Mary O'Reilly, Johanna C. Bendell, Zev A. Wainberg, Erkut Hasan Borazanci, Nathan Bahary, Mark H. O'Hara, Gregory Lawrence Beatty, Shubham Pant, Deirdre Jill Cohen, Stephen Leong, Muhammad Shaalan Beg, Kenneth H. Yu, T.R. Jeffry Evans, Thomas Seufferlein, Takuji Okusaka, Penny Phillips, Xuan Liu, Serena K Perna, Dung T. Le
Journal: Journal of Clinical Oncology (2019)

TPS465 Background: Treatment options for PDAC are limited; thus, new therapies that can improve outcomes and extend survival are needed. PDAC is associated with high infiltration by tumor-associated macrophages (TAMs) that inhibit antitumor T-cell activity. Blocking colony-stimulating factor 1 receptor (CSF-1R) signaling—which supports the recruitment, differentiation, and maintenance of immunosupressive macrophages in tumors—may lead to depletion of TAMs and upregulation of T-cell checkpoints. Cabira, a humanized IgG4 monoclonal antibody, binds to CSF-1R and blocks its signaling, a key determinant of TAM activation and survival. By reducing TAMs and promoting a proinflammatory microenvironment, cabira may stimulate T-cell responses, thereby sensitizing PDAC to therapy with nivo (anti‒PD-1). In a phase 1a/b study cabira + nivo was tolerable and showed evidence of on-target tumor immune modulation and durable clinical benefit in heavily pretreated patients (pts) with advanced PDAC (Wainberg et al. J Immunother Cancer. 2017 [abst O42]; Carleton et al. J Clin Oncol. 2018 [abst 3020]). Here we describe a randomized, open-label, phase 2 study evaluating the safety and efficacy of cabira + nivo ± chemo in advanced PDAC. Methods: Pts aged ≥18 y with locally advanced/metastatic PDAC that progressed on/after first-line chemo (gemcitabine [gem] or 5-fluorouracil [5-FU] based) will be enrolled. Pts with active/suspected autoimmune disease, uncontrolled/significant cardiovascular disease, or prior exposure to select immune cell–modulating antibodies are not eligible. Depending on prior chemo received, pts will be randomized to 1 of 4 arms (n≈40 each): cabira + nivo; cabira + nivo + gem/nab-paclitaxel; cabira + nivo + oxaliplatin/5-FU/leucovorin; or investigator’s choice of standard-of-care chemo. Endpoints include median progression-free survival (primary), overall survival rate, objective response rate, median duration of response, pharmacokinetics, and safety. In a completed preliminary safety cohort, 12 pts were treated with cabira + nivo + chemo and monitored for 4 wk; competitive enrollment is open, with 32 pts enrolled. (NCT03336216, NCT02526017) Clinical trial information: NCT03336216.
Lymphadenopathy Due to Kimura’s Disease Mimicking Lymphoma on FDG PET/CT
Authors: MingMing Yu, ZhenGuang Wang, Jing Zhao, FengYu Wu
Journal: Clinical Nuclear Medicine (2019)

Kimura's disease is a clinically rare, chronic, benign lymphoproliferative disorder of unknown etiology. A 36-year-old man presented with painless axillary swelling, which was suspected as lymphoma. PET/CT was performed for staging. The images showed multiple foci of increased activity in bilateral axillary and right inguinal lymph nodes. Laboratory tests revealed an increased eosinophil ratio and eosinophil count. Pathological examination from dissected axillary lymph nodes was consistent with Kimura's disease.
A Method to Fluorescently Label the CRISPR/Cas9-gRNA RNP Complexes Enables Enrichment of Clinical-Grade Gene-Edited Primary Hematopoietic Stem Cells and iPSCs
Authors: Masoud Nasri, Perihan Mir, Benjamin Dannenmann, Diana Amend, Yun Xu, Anna Solovyeva, Sylwia Stefanczyk, Maksim Klimiankou, Cornelia Zeidler, Lothar Kanz, Karl Welte, Julia Skokowa
Journal: Blood (2018)
Assessment of Mechanisms of Acute Coronary Syndromes and Composition of Culprit Plaques in Patients With and Without Diabetes
Authors: Giovanni Ruscica, Laura Gatto, Enrico Romagnoli, Luca Di Vito, Franco Fabbiocchi, Valeria Marco, Francesco Versaci, Alessandro Di Giorgio, Nevio Taglieri, Alessio La Manna, Massimo Fineschi, Alberto Boi, Gianpaolo Niccoli, Mario Albertucci, Filippo Crea, Eloisa Arbustini, Fernando Alfonso, Francesco Prati
Journal: JACC. Cardiovascular imaging (2019)
Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib
Authors: Yllka Latifi, Federico Moccetti, Melinda Wu, Aris Xie, William Packwood, Yue Qi, Koya Ozawa, Weihui Shentu, Eran Brown, Toshiaki Shirai, Owen J. McCarty, Zaverio Ruggeri, Javid Moslehi, Junmei Chen, Brian J. Druker, Jose A. López, Jonathan R. Lindner
Journal: Blood (2019)
Abstract 20398: Improving Ideal Cardiovascular Health in a Pediatric Preventive Cardiology Clinic
Authors: Holly C Gooding, Kimberlee Gauvreau, Michael Mendelson, S S Griggs, Annette Baker, Jane Newburger, Katherine Terranova, Sarah D deFerranti
Journal: Circulation (2017)

Introduction: Achieving ideal cardiovascular health (iCVH) for children necessitates both public health and clinic-based interventions. In a pediatric population referred for dyslipidemia, we aimed to describe the change in iCVH metrics after clinic-based lifestyle counseling. We hypothesized that children referred to a preventive cardiology clinic would show improvement in iCVH factors during clinical care. Methods: We analyzed data from children ages 8-19 years seen for two consecutive visits in the Boston Children’s Hospital Preventive Cardiology clinic between 2010-2014. Height, weight, blood pressure, fasting cholesterol, and fasting glucose were measured using standard clinic and laboratory protocols; smoking, diet, and physical activity patterns were self-reported. We used the AHA definitions of ideal, intermediate, and poor iCVH with minor adaptations (Figure). Each iCVH score had a possible range of 0 (poor) to 2 (ideal); the corresponding total iCVH score could range from 0 (all poor) to 14 (all...
Wnt/β-catenin links oxidative stress to podocyte injury and proteinuria
Authors: Lili Zhou, Xiaowen Chen, Meizhi Lu, Qinyu Wu, Qian Yuan, Chengxiao Hu, Jinhua Miao, Yunfang Zhang, Hongyan Li, Fan Fan Hou, Jing Nie, Youhua Liu
Journal: Kidney International (2019)
First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA).
Authors: Yelena Yuriy Janjigian, Joanne F. Chou, Marc Simmons, Parisa Momtaz, Francisco Sanchez-Vega, Marina Shcherba, Geoffrey Yuyat Ku, Elizabeth Won, Curtis Robert Chong, Hans Gerdes, David Paul Kelsen, David H. Ilson, Kathrena Aljallad, Michal Fani Segal, Brittanie M Millang, Nikolaus Schultz, Pari M. Shah, David B. Solit, Marinela Capanu, Jaclyn Frances Hechtman
Journal: Journal of Clinical Oncology (2019)

62 Background: Trastuzumab stimulates HER2-specific T cell responses and increases tumor PD-L1 expression, and anti-PD-1 antibody can help enhance T cell-specific immunity of trastuzumab. Oxaliplatin can further enhance T-cells by activating dendritic cells. We conducted a phase II trial of pembrolizumab with chemotherapy/trastuzumab. Methods: Patients with previously untreated HER2 IHC 3+ or FISH+ tumors irrespective of PD-L1 status received intravenous P 200 mg flat dose, T 6 mg/kg (after 8 mg/kg load), O 130 mg/m2 every 3 weeks and oral C 850 mg/m2 2 weeks on/1 week off (or 5-FU continuous infusion). The primary endpoint was 6-months PFS; with target accrual of 37 patients. Secondary endpoints included safety, OS, ORR, exploratory biomarker analysis and 89Zr-trastuzumab PET. Results: 100% of the 24 evaluable pts had tumor regression (ranging from -22% to -100%). The RECIST 1.1 ORR was 83% [95%CI: 63%-95%] (17 PR , 3 CRs), median PFS 11.4 [95%CI: 6-15] months. In 31 pts evaluable for toxicity, common ( &gt; 10%) adverse events included Gr 2 fatigue (35%), Gr 2/3 nausea (35%), Gr 2 diarrhea (26%), Gr2 AST/ALT elevation (16%), Gr2 neutropenia (16%). Immune related toxicities observed in 1 pt each: Gr 2 colitis, Gr 3 interstitial nephritis, Gr 3 AST/ALT elevation; and resolved with steroids. Of 21 patients with available material, 6 (29%) expressed PD-L1. Of these 6 patients, 5 had a PR while 1 had a CR. ERBB2 amplification was evident on NGS in 56% of pre-treatment tumors from 25 tested patients, while the remaining were ERBB2- by NGS likely due to tumor heterogeneity or low tumor content. Mutations in TP53 and alterations in KRAS occurred in 68% and 16%, respectively. To identify mechanisms of acquired resistance, patients are biopsied at progression. In 6 paired sample analysis, we identified two patients with loss of ERBB2 amp at progression. Conclusions: Updated survival, correlative studies and 89Zr-trastuzumab PET imaging will be presented. These promising preliminary safety and efficacy results led to initiation of a definitive phase III Keynote 811 trial. Clinical trial information: NCT02954536.