tbuckley/cabot-search huggingface dataset:
Phase II open-label, multi-centre study of bemcentinib (BGB324), a first-in-class selective AXL inhibitor, in combination with pembrolizumab in patients with advanced NSCLC.
Authors: James Lorens, Carlos Eduardo Arce-Lara, Edurne Arriola, Paal Brunsvig, Enric Carcereny Costa, Manuel Domine, Konstantin H. Dragnev, Enriqueta Felip, Rosario Garcia Campelo, Matthew Krebs, Santiago Ponce Aix, James F. Spicer, Jose Manuel Trigo Perez, Nuria Vinolas, Robert J Holt, Anthony Brown, Michael Jon Chisamore
Journal: Journal of Clinical Oncology (2018)

3078 Background: Bemcentinib (BGB324) is a first-in-class, oral, potent and highly selective inhibitor of the AXL tyrosine kinase currently in phase II clinical development across several cancer types. AXL over-expression has been observed in pts failing PD-1 therapy in several cancers whereas AXL inhibition via bemcentinib has shown synergistic effect with checkpoint blockade in pre-clinical models of NSCLC. Methods: In this single-arm, two-stage Phase 2 study, pts with documented Stage IV lung adenocarcinoma progressed on a single line of platinum-based chemotherapy chemotherapy and – if applicable – at least one line of licensed therapy for EGFR mutations or ALK re-arrangements received 200 mg/d bemcentinib po and 200 mg/q3wk pembrolizumab iv. Patients were required to consent to a fresh pre-treatment biopsy. Tumour assessments were done 9-weekly. The primary endpoint was objective response. Predefined secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Tumour biopsies were analysed for PD-L1 and AXL, and infiltrating immune cells. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) in patients pre-dose and at C2D1. Results: As of February 2018, 13 pts (median age 66 years) initiated therapy and 11 pts remain on treatment. Combination therapy was well tolerated with the overall serious adverse event profile being similar to that reported for pembrolizumab monotherapy. 1 of 4 pts (25%) who had reached their first scan showed a PR and another patient (25%) had SD. There were no grade 4 treatment-related events. Dose reduction from 200 to 100 mg/d of bemcentinib as a consequence of adverse events was required in 12% of patients. Conclusions: Combination treatment of bemcentinib and pembrolizumab was well tolerated. A preliminary analysis of response to combination treatment during the first stage of this study as well as biomarker correlation will be presented at the meeting. Clinical trial information: NCT03184571.
Significant up-regulation of vasodilator-stimulated phosphoprotein in human pancreatic duct adenocarcinoma.
Authors: Yifan Tu, Selvaraj Muthusamy, Ningling Kang, Nishant Poddar, Jinping Lai
Journal: Journal of Clinical Oncology (2016)

e15674 Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 5 year survival of less than 7%. Vasodilator stimulated phosphoprotein (VASP) is involved in cytoskeleton assembly and reorganization, which is frequently affected in malignant transformation. The role of VASP in the pathogenesis of PDAC has not been previously reported. Here, we investigated role of VASP in the pathogenesis of human PDAC. Methods: Tissue samples from 53 patients of PDAC (with or without PanIN and with or without benign duct), including 50 tissue arrays (20 mm2of each representative cancer tissue and adjacent pancreatic parenchyma), and 3 whole cancer sections were investigated for VASP immunohistochemistry after surgical resection. VASP immunoreactivity was blindly scored based on the density and percentage of positive cells as 1+, 2+, and 3+ . VASP low was defined as score of 1+ to 2+. VASP high was defined as score of 3+. Statistical analysis was performed using Fisher exact test and statistical significance was set at a p value less than 0.05. Results: There were 25 benign ducts, 45 PanINs, and 53 PDACs. All of the benign ducts (100%) showed low VASP expression. None (0%) showed high VASP. Thirty three of 45 PanIN (73%) showedlow VASP; Twelve (27%) were high VASP. In 53 PDACs, VASP was low in 52.8% (28/53) and high in 47.2%. Comparing to benign ducts or PanINs, VASP expression in PDAC was significantly upregulated. High VASP was expressed in 47.2% of PDACs versus 27% of PanINs (P = 0.019) versus 0% in benign ducts (P < 0.0001). VASP expression was not significantly different in PDACs with or without high risk features such as lymphovascular invasion (LVI), paraneural invasion (PNI), or local lymph node metastasis. Conclusions: VASP was significantly upregulated in PDACs comparing to surrounding benign ducts and PanINs. Hence, VASP could be used as a marker for PDAC. Probably VASP is involved in one of the pathways in pancreatic cancer pathogenesis. The current study did not show the correlation of VASP with high risk features such as LVI, PNI or local lymph node metastasis. Further research is needed to correlate VASP with cancer grade, stage, local and distant metastasis, and overall prognosis.
Clinical characteristics of patients with lymph skip metastases and prognoses of Chinese patients with pN2 non-small cell lung cancer.
Authors: Xin Li, Xiaofei Li, Xiangning Fu, Lunxu Liu, Yang Liu, Heng Zhao, Yin Li, Jian Hu, Lin Xu, Deruo Liu, Haiying Yang, Xun Zhang
Journal: Journal of Clinical Oncology (2018)

e20524 Background: Given that the prognoses of patients with pN2 non-small cell lung cancer (NSCLC) are heterogeneous, the optimal patient management remains controversial. The real-world study was designed to evaluate prognoses of pN2 NSCLC patients with lymph skip metastases and those factors that influence skip metastases. Methods: We conducted the study based on a national collaborative prospective lung cancer database (designed by LinkDoc Technology Co, Ltd.). The study data on patient demographic/tumor bio-logical characteristics and clinical treatments in pN2 NSCLC patients with surgeries and lymphadenectomy from 2014 to 2017 were collected to compare the differences in overall survival (OS) between the Chinese patients with skip metastases and the patients without skip metastases. Results: The analysis set includes 2653 N2 NSCLC patients (33.2% skip metastases). The OS of patients with skip metastases was superior to that of patients without skip metastases (hazard ratio, HR, 0.72(0.58-0.89), p < 0.01). The one-, two-, and three-year OS rates in the patients with N2 skip metastases (90.1%, 76.2%, and 63.8%) were superior to the rates in the patients without N2 skip metastases (85.2%, 69.5%, and 56.4%). The differences in the one- and two-year OS rates were statistically significant while the differences in the three-year OS rates were not statistically significant. The Cox regression analyses presented N2 lymph skip metastases (HR = 0.62, p < 0.01) and tumor sizes ( > 5 vs < = 3cm, HR = 1.98, p < 0.01) as the impact factors of OS. The patients with squamous cell carcinoma were reported to have more possiblity than the patients with adenocarcinoma to be observed with N2 skip metastases (41.2% vs 30.5%, odd ratio = 1.79, p < 0.01). Conclusions: The OS of the patients with skip metastases was proved to be superior to that of the patients without skip metastases in the real-world study that would offer clinical guidance in practice on the choice of surgeries with appropriate patients with diverse clinical characteristics and strategies of lymphadenectomy in the Chinese N2 NSCLC patients. Clinical trial information: ChiCTR1800014729.
An Improved Inhaled Mucolytic to Treat Airway Muco-obstructive Diseases
Authors: Camille Ehre, Zachary L. Rushton, Boya Wang, Lauren N. Hothem, Cameron B. Morrison, Nicholas C. Fontana, Matthew R. Markovetz, Martial F. Delion, Takafumi Kato, Diane Villalon, William R. Thelin, Charles R. Esther, David B. Hill, Barbara R. Grubb, Alessandra Livraghi-Butrico, Scott H. Donaldson, Richard C. Boucher
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Airways obstruction with thick, adherent mucus is a pathophysiologic and clinical feature of muco-obstructive respiratory diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis (CF). Mucins, the dominant biopolymer in mucus, organize into complex polymeric networks via the formation of covalent disulfide bonds, which govern the viscoelastic properties of the mucus gel. For decades, inhaled N-acetylcysteine (NAC) has been used as a mucolytic to reduce mucin disulfide bonds with little, if any, therapeutic effects. Improvement of mucolytic therapy requires the identification of NAC deficiencies and the development of compounds that overcome them.
Trastuzumab-related subclinical cardiotoxicity in patients with early stage HER2-positive breast cancer: A retrospective single-center cohort study.
Authors: Olexiy Aseyev, Moira Rushton-Marovac, Freya L. Crawley, Christopher Johnson, Susan Faye Dent
Journal: Journal of Clinical Oncology (2017)

10123 Background: Trastuzumab-based therapy (TT) is standard treatment for HER2-positive breast cancer (HBC). Subclinical cardiotoxicity (SCTx), defined as asymptomatic decline in left ventricular ejection fraction (LVEF) &gt; 10% to &lt; 50%, has been reported in up to 30 % of HBC patients (pts) receiving TT. Objectives included: determine prevalence of SCTx; associated risk factors (RF); and completion rates of TT in pts with HBC referred to a cardio-oncology clinic (COC). Methods: HBC patients receiving TT referred to the Ottawa Hospital COC were included. Demographics, TNM staging, performance status, stage, cardio-vascular (CV) RF (history of heart disease, hypertension, smoking, dyslipidemia, and diabetes), cardiac medications (CM) (ACE-inhibitors, beta-blockers), baseline LVEF, previous cancer therapy, baseline anthracycline exposure, previous radiation therapy (RT) (including mediastinal RT) were collected. LVEF was evaluated by ECHO or MUGA. Rate of successful completion of TT among pts with SCTx was determined. Risk ratio (RR) and logistic regression analysis was performed. Results: 240/408 BC pts referred to the COC (2008-2016) had HBC and 163/240 (68%) were referred with SCTx while on TT. 139/163 (85 %) pts with SCTx recovered after COC assessment: 77/163 (47%) pts were prescribed CMs. A significantly higher proportion of recovery was observed in pts who did not require CM (0.92 vs 0.78, p = 0.012; RR = 0.85, 95%CI:0.74-0.91). A total of 129/163 (79%) pts who experienced SCTx finished a full course of TT. Regression analysis found baseline LVEF, diabetes, and diastolic blood pressure as significant RFs for SCTx. There were no independent predictors for recovery after asymptomatic drop in LVEF while on TT. Diabetes (OR:2.97, 95%CI:1.3-6.8) and left chest wall RT (OR:2.4, 95%CI:1.1-5.6) significantly increased risk of permanent TT interruption in pts with asymptomatic drop in LVEF. Conclusions: The majority of HBC pts who experience SCTx can safely complete a full course of TT; many without use of CMs. While CV RFs were associated with increased risk of SCTx, this did not impact CV recovery after asymptomatic drops in LVEF.
LINE-1 hypomethylation is a specific aberration in human hepatocellular carcinomas and correlates with shorter overall survival and CIMP-phenotypes
Authors: S.L. Anwar, A. Vogel, U. Lehmann
Journal: Annals of Oncology (2018)

Background: Reactivation of interspersed repetitive sequences due to loss of methylation is associated with genome instability, one of the hallmarks in cancer. LINE-1 hypomethylation represents global methylation loss and has potential diagnostic and prognostic biomarkers in tumors. However, the correlation of LINE-1 hypomethylation with clinicopathological determinants and CpG island methylator phenotype (CIMP) in patients with liver tumors is not yet well defined. Methods: We performed quantitative DNA methylation analysis in LINE-1, RASSF1A, and CCND2 genes using pyrosequencing in human hepatocellular carcinomas (HCC, n = 40), hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5), and respective peritumoral liver tissues as well as healthy liver tissues (n = 5). Results: We found loss of LINE-1 DNA methylation only in HCCs and significantly correlated with poor survival (log rank test, p = 0.007). Inverse correlation was found between LINE-1 with RASSF1A DNA methylation levels (r2 = -0.47, p = 0.002). LINE-1 hypomethylation correlated with concurrent RASSF1/CCND2 hypermethylation (Fisher's exact test, p = 0.02). LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation were not found in benign hepatocellular tumors (HCA and FNH) representing specific aberrations only in malignant liver transformation. Conclusions: LINE-1 hypomethylation might serve as a future predictive biomarker to identify HCC patients with unfavorable overall survival and CIMP-phenotypes. Legal entity responsible for the study: Medizinische Hochschule Hannover, Germany. Funding: DFG Deutsche Forschunggemeinschaft. Disclosure: All authors have declared no conflicts of interest.
Abstract 11769: Impact of Exercise to the Heterogeneity of Regional Left Ventricular Mechanics
Authors: Rayji S Tsutsui, Kenya Kusunose, James D Thomas, Zoran B Popovic
Journal: Circulation (2014)

Background: The segmental heterogeneity of strain and strain rate in speckle tracking echocardiography are pitfalls in the assessment of left ventricular (LV) mechanics in subjects without LV wall motion abnormality. We aimed to assess the segmental heterogeneity of strain and strain rate at rest and during exercise in healthy subjects. Methods: Twenty-three healthy young volunteers (38 ± 10 years, 13 female) underwent supine bicycle stress testing. Segmental circumferential (Scirc), radial (Srad) and longitudinal (Slong) end-systolic strains and corresponding peak systolic strain rates (SRcirc, SRrad, SRlong) were obtained by STE (EchoPac, GE Medical) for each of 16 LV segments at rest and during exercise. Global values of strain and strain rate components were obtained by averaging segmental values. Results: At rest, all three end-systolic strains showed significant segmental heterogeneity (p &lt; 0.01 for all comparisons). In contrast, peak systolic SRcirc and SRrad had uniform values throughout segments, while SRlong had modest segmental heterogeneity (p = 0.02). During exercise, heart rate (67 ± 10 to 136 ± 19 bpm), systolic blood pressure (124 ± 13 to 170 ± 21mmHg), and biplane ejection fraction (58 ± 4 to 72 ± 5 %), increased significantly (p &lt; 0.001 for all comparisons). At peak exercise, there was a small, but significant increase in global Slong (-19.9 to -23.9%, p &lt; 0.001) and Scirc (-19.6 to -24.2%, p &lt; 0.001) without the change in Srad (46.8 to 41.1%, p &gt; 0.05). On the other hand, all global systolic strain rates almost doubled during exercise; SRcirc from -1.26 to -2.49 s -1 , p &lt; 0.0001; SRrad from 1.82 to 3.26 s -1 , p &lt; 0.0001; SRlong from -1.56 to -2.93 s -1 , p &lt; 0.0001. Importantly, segmental heterogeneity following exercise was not present for all strain and strain rate components (p &gt; 0.05 for all comparisons). Conclusions: Segmental heterogeneity was less pronounced in peak systolic strain rates than in end-systolic strains at rest. Exercise abolished segmental heterogeneity for all strain and strain rate components. Overall, peak systolic strain rate is least affected by segmental heterogeneity and may be more useful in the assessment of LV mechanics than end-systolic strain.
EORTC-ESSO 1409 GITCG: A prospective colorectal liver metastasis database with an integrated quality assurance program (CLIMB).
Authors: Carmela Aves Caballero, Lucia Carrion Alvarez, Henrik Nilsson, Theo Ruers, Perrine Senellart, Michel Rivoire, Stefan Stattner, Florian Primavesi, Roberto Troisi, Thomas Gruenberger, Jan Heil, Andreas Schnitzbauer, Nuh N. Rahbari, Rutger-Jan Swijnenburg, Hassan Zakria Malik, Mladjan Protic, Anouk Neven, Murielle E. Mauer, Graeme John Poston, Serge Evrard
Journal: Journal of Clinical Oncology (2018)

3558 Background: The European Organization for Research & Treatment of Cancer & European Society of Surgical Oncology joined forces to build an infrastructure for surgical quality assurance (QA) in clinical trials (SURCARE) and advance the surgical research agenda in Europe. Benchmarking is a critical step to achieve this. Their first project is CLIMB, a prospective study to evaluate complications and identify indicators for improvement in surgery for unresectable or borderline resectable colorectal liver metastasis (CRLM). Methods: CLIMB (NCT02218801) opened in 2015 in 9 countries and 14 specialised centers for liver surgery. Eligible patients were registered after multidisciplinary evaluation and before surgery. Primary endpoint was 30 and 90 day surgical complication rate. On-site visits and central review ensured prospective data inclusion of the following: biomarker, imaging, chemotherapy, surgery, complications graded by Clavien-Dindo classification and survival. Data until post op day 90 were analysed but long term outcome will be reported after all patients were followed for two years after registration. Results: Among 210 patients registered, 126 (60%) who had at least one liver surgery were analysed. 73% had left-sided or rectal primary tumor, 95.2% had synchronous primary and liver metastasis, 19.8% had extra-hepatic lesions and CRLM. Most patients (N = 95, 75.4%) had one stage liver surgery while 30 (23.8%) had two stage liver surgery, 10 of whom had ALPSS. Over-all complication rates for one stage was 53.7% (95% CI [43%, 64%]), 17.9% (95% CI [11%, 27%]) with grade≥3 and 93.3% (95% CI [78%, 99%]) for two stage, 46.7% (95% CI [28%, 66%]) with grade≥3 including two deaths. Intra-abdominal, wound and urinary tract infections, bile leak and post hepatectomy liver failure grade A were most commonly reported over-all. Conclusions: CLIMB prospectively collected data from complex surgery for unresectable CRLM. Two stage surgery had more grade≥3 complications. Harmonizing standards in multidisciplinary evaluation, biomarker testing and imaging may improve this outcome. SURCARE will use these indicators to develop trials with enhanced QA methods to improve cancer surgery. Clinical trial information: NCT02218801.
Comparison of efficacy and safety of first-line palliative chemotherapy with TX and XELOX regimens in patients with metastatic gastric adenocarcinoma: A randomized phase II trial.
Authors: Xiaodong Zhu, Jin Li, Zhao Xiaoying, Weijian Guo, Xin Liu, Wen Zhang, Zhiyu Chen, Lixin Qiu, Wenhua Li, Mingzhu Huang, Xiaowei Zhang
Journal: Journal of Clinical Oncology (2017)

4070 Background: Docetaxel has shown antitumor activity in the treatment of MGC as a single or combination chemotherapy. This study was designed to compare the clinical outcome of docetaxel based and platinum based doublet regimen as first-line treatment in MGC patients. Methods: In an open, randomized, single center phase II trial, 134 pts were randomly assigned and treated with either TX (capecitabine 1g/m2/twice daily/ 1-14 days and docetaxel 75mg/m2 in 1st day) or XELOX (capecitabine 1g/m2/twice daily/ 1-14 days and oxaliplatin 130 mg/m2 in 1st day) as first-line chemotherapy. The primary endpoint is finding potential predictive factors, secondary endpoint is ORR, PFS, OS and safety. After progression, patients were switched into the other group. Results: Now, the potential predictive factors are testing in genomics and proteomics. In 134 randomly assigned and treated pts (TX = 69; XELOX = 65). Most pts were male (87pts).Overall survival was longer with TX versus XELOX (13.1m vs. 9.6m, p = 0.173), but no statistical differences. Progression free survival was similar with TX versus XELOX (4.57m vs. 5.27m, p = 0.297). Overall response rate was equal with TX versus XELOX (50.8% vs. 47.6%, p = 0.72). G3-4 treatment-related AE occurred in 60.6% (TX) v 55.4% (XELOX) of patients. Frequent G3-4 toxicities for TX v XELOX were: neutropenia (60.6% v 15.4%), febrile granulocyte deficiency (17.4% v 1.5%), anemia (10.1% v 10.8%), thrombocytopenia (1.4% v 15.4%), and all grade peripheral neurotoxicity (11.6% v 38.5%).After first-line treatment failure, 35 patients in the TX group switched to XELOX, and 27 patients in the XELOX group switched to TX, and there is also no significant difference in survival time from the first-line treatment between the two groups (p = 0.129). Conclusions: Although TX led to more neutropenia, first-line palliative chemotherapy with docetaxel based doublet regimens provides a new choice and can gain almost the same response rate and survival time as frequently-used fluorouracil and platinum based regimen. And potential predictive factors will indicate who will get more benefit from taxanes or platinums. Clinical trial information: NCT01963702.
Incorporating geriatric patient reported outcomes into novel screening tool of distress and supportive care concerns.
Authors: James I Gerhart, Ana Gordon, Betty Roggenkamp, Paramjeet Khosla, Julia Rachel Trosman, Joanna Martin, Amy Scheu, Lauren Allison Wiebe, Rosa Berardi, Selina Lai-ming Chow, Mary Pasquinelli, Lawrence Eric Feldman, William Dale, Sean O'Mahony, Patricia B. Mumby, Catherine Deamant, Christine B. Weldon
Journal: Journal of Clinical Oncology (2018)

37 Background: The Institute of Medicine (IOM) 2013 Report recommends that supportive oncology care start at cancer diagnosis; the Commission on Cancer (CoC) Standard 3.2 requires distress screening and indicated action. The Supportive Oncology Collaborative, collaborative of 100+ clinicians funded by The Coleman Foundation, developed a patient-centric screening tool (CSOC-ST) adapted from ASCO Distress, NCCN Distress Problem List, IOM report and CoC standards, and other validated sub-tools (Weldon, ASCO-Q 2017). The Collaborative then revised the CSOC-ST tool to align with geriatric guidelines. Methods: Literature and guidelines review of geriatric screening, added items to CSOC-ST, and piloted at 4 sites. Descriptive statistics and Fisher’s exact test used. Results: 473 patients screened with added geriatric relevant items to CSOC-ST: self-care concerns (PROMIS Instrumental Support), living alone (ASCO Distress 2014), and memory / cognition (PROMIS item bank). Treatment/care concern items were revised to identify health care power of attorney and advance directive interest. Geriatric related items endorsed by patients, see Table. PHQ4, Anxiety and Depression, average score 2.4 (mild &gt; 3). Higher scores on the PHQ-4 were significantly associated with each of the following: self-care concerns, memory/cognition concerns and specific treatment/care concerns (p &lt; .0001). Conclusions: Pilot results and comparison to geriatric guidelines identified important items to support geriatric patient reported outcomes screening. After pilot, added 3 items for falls/frailty. Eight sites implementing this CSOC-ST.[Table: see text]