tbuckley/cabot-search huggingface dataset:
Development of a performance status prediction model for use in administrative data analyses.
Authors: A. J. Davidoff, I. H. Zuckerman, N. B. Pandya, F. Hendrick, X. Ke, A. Hurria, S. M. Lichtman, A. Hussain, M. J. Edelman
Journal: Journal of Clinical Oncology (2010)

6006 Background: Performance status (PS) is one of the most important predictors of cancer outcomes, and a key determinant of treatment. Observational studies using administrative data represent an important component of comparative effectiveness research (CER). Data sources such as SEER-Medicare, used to study cancer treatment patterns, outcomes and costs, do not capture patient PS. Claims based indicators of service use associated with poor PS (e.g. home oxygen, wheelchair) were tested in CER studies in colon and lung cancer, and found to predict treatment and survival. The objective of this research is to further develop methods to incorporate PS into CER studies, using an approach similar to the Charlson Comorbidity Index. We report on initial phases in development of a multivariate regression model that will predict PS as a function of a broad set of claims based indicators. Methods: The Medicare Current Beneficiary Survey (MCBS), a nationally representative survey of community and facility based Medicare beneficiaries, includes self or proxy reported limitations to activities of daily living (ADL), instrumental ADL, and physical strength, and is linked to Medicare (Parts A and B) claims. We used MCBS question-response sets to measure key dimensions in the ECOG PS scale (self-care, light/sedentary activity, and strenuous activities), and developed an algorithm to assign PS scores to respondents from the 2005 MCBS (n = 10,565). Results: PS assignments in the MCBS were 77% ECOG PS 0-1, 16% PS 2, and 7.5% PS 3-4. Among the 1/3 of community residents reporting CHF, COPD, AMI, stroke, or rheumatoid arthritis, 29% were PS > = 2 vs. 2% among others. Facility based residents had higher prevalence of PS 3-4 (74%) vs. 3% in the community. Conclusions: Our research uses a rich source of data on health and functional status, independent of chronological age, for an elderly and disabled population. Application of these data through a model that predicts PS will strengthen CER research based on administrative data, in cancer and other chronic diseases. In ongoing research we are identifying potential claims based indicators of PS, estimating multivariate prediction models, and will validate our predicted PS value in SEER-Medicare CER studies. No significant financial relationships to disclose.
Targeting Toll like receptor 3 by double stranded RNA in breast cancer: Results from in vitro studies and randomized trial
Authors: F. Andre, J. C. Sabourin, H. Assi, I. Miran, D. Podolsky, M. Spielmann, L. Zitvogel
Journal: Journal of Clinical Oncology (2004)

9619 Background : Toll like receptor 3 (TLR3) is known to be expressed by myeloid dendritic cells (DC) and to induce their maturation following binding with double stranded RNA (dsRNA) or its synthetic homologues polyAU and polyI:C. Several clinical trials have reported that injection of dsRNA is associated with survival benefit in cancer patients. In the present study, we have asked whether dsRNA could act directly on tumor cells through TLR3. Patients and methods : 300 patients with early breast cancer have been included from 1972 to 1979 in a randomized trial comparing post-operative administration of polyAU with no treatment. Results have been reported that showed a trend for a survival benefit in patients with involved axillary lymph nodes (n=200). Tumor biopsies from these patients were stained with TLR3-specific mAb and correlation between TLR3 expression and polyAU efficacy was determined. To investigate directly the effects of dsRNA, both freshly isolated breast tumor cells and cancer cell lines were cultured with polyI:C, and apoptosis was measured. The involvement of TLR3 in cell response was established by TLR3 RNA interference. Results : 182 tumor samples (91%) were available from the 200 pTxN+M0 patients included in this randomized trial. TLR3 was strongly expressed by tumor cells in 18 patients (10%). Table 1 reports the 20-year survival rates according to treatment and TLR3 expression. In vitro studies showed that breast cancer cell lines can express TLR3, and that dsRNA can induce up to 80% apoptosis in TLR3+ tumor cell lines within 48h of culture. This pro-apoptotic effect of double stranded RNA was specifically abolished by RNA interference for TLR3. Conclusion : These data suggest that: i. TLR3 is expressed by breast cancer cells in a subset of patients, ii. its activation by dsRNA could lead to tumor cell apoptosis in vitro and survival benefit in patients with TLR3+ tumors. No significant financial relationships to disclose.
Efficacy and safety of continuous daily sunitinib dosing in previously treated advanced non-small cell lung cancer (NSCLC): Results from a phase II study
Authors: J. R. Brahmer, R. Govindan, S. Novello, R. Rosell, C. P. Belani, J. N. Atkins, H. H. Gillenwater, L. Tye, R. Chao, M. A. Socinski
Journal: Journal of Clinical Oncology (2007)

7542 Background: Sunitinib malate (SU), an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, has demonstrated activity in recurrent advanced NSCLC on the 4/2 schedule (4 weeks [wks] on treatment followed by 2 wks off), with a partial response (PR) rate of 11% (Socinski, ESMO 2006). A continuous dosing (CD) schedule of SU was additionally evaluated for safety and efficacy in this multicenter phase II study. Methods: Eligible patients (pts) had stage IIIB/IV NSCLC previously treated with 1–2 chemotherapy regimens, ECOG PS =1, and adequate organ function. Pts with brain metastases or recent gross hemoptysis were excluded. Pts received oral SU 37.5 mg/day continuously in 4-wk cycles. The primary endpoint was objective response rate per RECIST. Secondary endpoints included progression-free survival (PFS), overall survival, and safety. Results: Forty-seven pts were treated on the CD schedule: median age 60 yrs (range 37–81); male 57%; ECOG PS 0/1/2 49%/49%/2%; adenocarcinoma 53%, squamous cell carcinoma 15%, other 32%; median number of SU cycles initiated: 3 (range 1–10). One pt (2%) had a confirmed PR and 8 pts (17%) had stable disease &gt;3 months. Median PFS was 12.1 wks (95% CI: 8.6–13.7). SU was generally well tolerated; most adverse events (AEs) were grade 1/2 and included fatigue/asthenia, pain/myalgia, nausea/vomiting, diarrhea, dyspnea, and stomatitis/mucosal inflammation. Grade =3 AEs included fatigue/asthenia (15%), hypertension (6%), hypoxia (6%), dyspnea (4%), and hemoptysis (2%). Treatment-related serious AEs included congestive heart failure (CHF; 1 pt), gastrointestinal bleeding (1 pt), hypomagnesemia (1 pt), and hypoxic respiratory failure (1 pt). One pt died due to possible treatment-related CHF. Conclusions: SU on a CD schedule is associated with an acceptable safety profile when administered to previously treated NSCLC pts, and there is documented preliminary evidence of activity, with 1 PR and a median PFS of 12.1 wks. These data support further study of continuous dosing of SU in combination with other treatments for NSCLC. No significant financial relationships to disclose.
Open, Single Arm Trial of Erlotinib As the 2Nd/3Rd Line Treatment in Advanced or Recurrent Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Wild Type and C-Met Negative Expression (Ml28941, C-Tong 1306)
Authors: Z. Li, T. Zhou, Y. Huang, H. Zhao, L. Chen, Y.Y. Zhao, W. Fang, P.Y. Yang, X. Hou, C. Xue, X.Y. Ma, Z. Hu, T. Qin, W. Liang, X. Wu, S. Hong
Journal: Annals of Oncology (2014)
Carboxylesterase 2 as a Determinant of Response to Irinotecan and Neoadjuvant FOLFIRINOX Therapy in Pancreatic Ductal Adenocarcinoma
Authors: Michela Capello, Minhee Lee, Hong Wang, Ingrid Babel, Matthew H. Katz, Jason B. Fleming, Anirban Maitra, Huamin Wang, Weihua Tian, Ayumu Taguchi, Samir M. Hanash
Journal: JNCI Journal of the National Cancer Institute (2015)

Serine hydrolases (SHs) are among the largest classes of enzymes in humans and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the prodrug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy.CES2 expression in PDAC and paired nontumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA and correlated with irinotecan IC50 values by means of Pearson's correlation. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. All statistical tests were two-sided.Statistically significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared with paired nontumor tissue (P < .001), with 48 of 118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in 11 PDAC cell lines was inversely correlated with irinotecan IC50 values (R = -0.68, P = .02). High CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.51, P = .02).Our findings suggest that CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy.
Vaccination with long NY-ESO-1 79-108 peptide and CpG-B leads to robust activation of CD4 and CD8 T cell responses in stage III/IV melanoma patients, and a new HLA-DR7 epitope
Authors: Petra Baumgartner, Carla Nunes, Amélie Cachot, Hélène Hajjami, Laurène Cagnon, Marion Braun, Laurent Derré, Jean-Paul Rivals, Donata Rimoldi, Emanuela Romano, Olivier Michielin, Pedro Romero, Camilla Jandus, Daniel E Speiser
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Although promising, the combination of long synthetic peptides and CpG-B oligodeoxynucleotides has not yet been tested as cancer vaccine. In this Phase I trial, 19 patients received a mean of 8 (range 1-12) monthly vaccines s.c. composed of the long synthetic NY-ESO79-108 peptide
Abstract 12930: Neutrophil Extracellular Traps Correlate With Impaired Myocardial Reperfusion in Patients With St Elevation Myocardial Infarction After Primary Percutaneous Coronary Intervention
Authors: Mie Kurata, Anouchska S Autar, Daniëlle Mensink, Dirk J Duncker, Hugo t Cate, José Govers-Riemslag, Chris Reutelingsperger, Evelyn Regar, Marco Valgimigli, Frank W Leebeek, Felix Zijlstra, Moniek P de Maat, Heleen M van Beusekom
Journal: Circulation (2014)

Introduction: Impaired myocardial reperfusion after successful percutaneous coronary intervention (PCI) is an important determinant of prognosis of patients with ST elevation myocardial infarction (STEMI). Neutrophil extracellular traps (NETs) are toxic DNA-protein complexes, upregulated in pro-thrombotic states and may induce endothelial injury. Aim: We aimed to assess in systemic and culprit coronary plasma, the level of NETs and their relationship with microvascular perfusion after PCI. Methods: Forty-nine STEMI patients treated with thrombectomy and PCI were enrolled. Patients with past history of coronary revascularization were excluded. Systemic blood was drawn at baseline and post PCI, and from the culprit lesion during thrombectomy. NETs and extracellular histone-DNA (E-DNA) were measured by capture ELISA (myeloperoxidase-DNA complex, histone-DNA complex, respectively). Corrected thrombolysis in MI (TIMI) frame count (cTFC) was calculated from coronary angiography. Results: The relation between NETs and cTFC is summarized in the figure. Both NETs and E-DNA were highest in culprit lesion plasma (p&lt;0.05). Baseline and post-PCI levels of NETs were similar (p=0.56). Baseline, aspirate, and post-PCI NETs levels were inversely correlated with cTFC (ρ=-0.43, -0.31, -0.39, respectively, all p&lt;0.05), and baseline NETs was an independent predictor of cTFC (β=-0.40, p=0.04), not age, gender, total ischemia time or troponin T level at admission. All E-DNA levels positively correlated with troponin T at admission (ρ=0.58, 0.47, 0.38, p&lt;0.05, respectively), and were higher post PCI than at baseline (p&lt;0.01), suggesting a reflection of myocardial damage. E-DNA showed no correlation with cTFC. Conclusions: Prior to PCI, baseline NETs level predict impaired reperfusion and may assist in tailored therapy and follow up.
EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer
Authors: Katherine R. Amato, Shan Wang, Li Tan, Andrew K. Hastings, Wenqiang Song, Christine M. Lovly, Catherine B. Meador, Fei Ye, Pengcheng Lu, Justin M. Balko, Daniel C. Colvin, Justin M. Cates, William Pao, Nathanael S. Gray, Jin Chen
Journal: Cancer Research (2016)

Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors.
Managing HBV in pregnancy. Prevention, prophylaxis, treatment and follow-up: position paper produced by Australian, UK and New Zealand key opinion leaders
Authors: Kumar Visvanathan, Geoff Dusheiko, Michelle Giles, May-Ling Wong, Nghi Phung, Susan Walker, Suong Le, Seng Gee Lim, Ed Gane, Meng Ngu, Winita Hardikar, Ben Cowie, Scott Bowden, Simone Strasser, Miriam Levy, Joe Sasaduesz
Journal: Gut (2015)

Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These include the lack of a current cohesive strategy for treatment and follow-up of mothers and their babies; the uncertain risk of postpartum HBV flares; the lack of randomised trial data on the safety and efficacy of antiviral treatment in pregnancy; the lack of head-to-head studies comparing different antivirals in pregnancy; and the lack of epidemiologic information regarding infection across different populations globally. This position paper provides a comprehensive review of the management of women with HBV infection prior to conception, throughout each stage of pregnancy and postpartum, as well as recommendations and clinical approaches for the follow-up of children born to infected mothers, based on available evidence in the literature and recommendations from international experts. Prevention of perinatal transmission is an important component of global efforts to reduce the burden of chronic HBV since vertical transmission is responsible for most of the chronic infection worldwide.
P16 Non-invasive detection of oesophageal varices: comparison of non-invasive assessment of systemic haemodynamics with laboratory parameters and predictive scores
Authors: Kara Rye, Gerri Mortimore, Andrew Austin, Jan G. Freeman
Journal: Gut (2010)

Introduction  Endoscopic screening for varices (OV) is advised in cirrhosis, repeated every 1–3 years, with primary prophylaxis given to large OV. This is costly to endoscopy units, unpleasant for patients and multiple procedures may affect compliance. Cirrhosis is characterised by a hyperdynamic circulation; novel tools make non-invasive assessment possible.  Aim  Toassess accuracy of non-invasive tests of systemic haemodynamics (Cardiac output and index (CO, CI), systemic vascular resistance (SVR), baroreceptor sensitivity (BRS) to detect OV and compare with other non-invasive methods (Child–Pugh score (CPS), albumin, platelet count, prothrombin time (PT), AST/ALT ratio, platelet count/spleen diameter ratio).  Method  Prospective study of 29 cirrhotic patients. Systemic haemodynamics were assessed non-invasively with the Finometer®, hepatic venous pressure gradient (HVPG) assessed portal pressure and gastroscopy for variceal size (none/small (absent), medium/large (large)).  Results  69% male, median age 47 (42–55) years, CPS 6 (Class A 18, B 10, C 1) and MELD 10 (8–13). Prevalence OV 79%, large 38%. Significant differences in haemodynamics were seen between patients classified as absent or large OV (CO 5.6 vs 8.0lpm, CI 3.0 vs 4.5 l/min/m2, SVR 1.17 vs 0.77MU, HVPG 14 vs 19 mm Hg, BRS 5.8 vs 3.2 ms/mm Hg, CPS 5 vs 7, respectively). Comparisons summarised in the Abstract P16 Table 1. At a cutoff of 7.15lpm, CO predicted large OV with 73% sensitivity, 78% specificity and correctly classified 76% of patients. At a cutoff of 3.66 l//min/m2, CI predicted large OV with 82% sensitivity, 83% specificity and correctly classified 79% of patients. This compares to 78% correctly classified using HVPG, 76% CPS and 59% PT.  Conclusion  Non-invasive assessment of systemic haemodynamics appears a promising technique to identify cirrhotic patients at risk of having large oesophageal varices. Larger prospective validation studies need to be performed. Standard laboratory tests and predictive scores (except Child–Pugh score) are not reliable to accurately predict large oesophageal varices.
Abstract 11582: Association Between Cardiorespiratory Fitness and Stroke: Investigating Possible Mediators of Disease
Authors: Minesh R Patel, Ang Gao, Ethan Halm, David Leonard, Sandeep Das, Benjamin Willis, Laura DeFina, Jarett D Berry
Journal: Circulation (2012)

BACKGROUND: Cardiorespiratory fitness (fitness) is inversely associated with stroke. The extent to which this association is explained by the development of stroke risk factors such as diabetes (DM) and hypertension (HTN) is unknown. We hypothesized that the association between fitness and stroke would be attenuated after adjustment for incident DM & HTN. METHODS: Linking participant data from the Cooper Center Longitudinal Study with Medicare claims files, we studied 20,838 individuals (20.7% women, mean age 49) without prior stroke, who underwent baseline examination from 1970 to 2009 and survived to receive Medicare coverage from 1999-2009. Fitness in metabolic equivalents was estimated at baseline by Balke protocol treadmill time and categorized into age and sex specific quintiles (Q1=low fitness). Stroke hospitalization, incident DM & HTN were determined using Medicare data. Associations between fitness and stroke hospitalization after age 65 were assessed by applying a proportional hazards model to ...
Abnormal DNA double strand break repair in human oral cancer cells: implication of p53 in the efficacy of DNA end-joining
Authors: Ki-Hyuk Shin, Mo K. Kang, Philip K. Lim, Felix K. Yip, Ji Min Yochim, Marcel A. Baluda, No-Hee Park
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

4436 

In human cells, double-strand DNA breaks (DSBs) are repaired primarily by non-homologous DNA end-joining (NHEJ). This is a potentially error-prone process which can cause abnormal DNA end-joining (EJ) and lead to an accumulation of chromosomal mutations and/or aneuploidy. Since cancer cells are genetically unstable, we compared the DNA EJ activities of normal, immortalized but non-tumorigenic and malignant human oral epithelial cells to investigate whether abnormal DNA EJ is at the basis of carcinogenesis. We found a significant diminution of precise DNA EJ activities in HPV-16 infected non-malignant immortalized human oral keratinocytes (HOK-16B) and in human oral squamous cell carcinoma (HOSCC) cells compared with that in normal human oral keratinocytes (NHOK). Moreover, abnormal DNA EJ activities were detected exclusively in HOK-16B and HOSCC cells due to microhomology-mediated and nonmicrohomology-mediated end-joining activities. Also since all the analyzed transformed cells were defective in p53, the contribution of p53 in DNA EJ was investigated. For this latter purpose, we investigated the perturbation of DNA EJ activity with small interfering RNAs (siRNAs) targeted against p53 mRNA in RKO diploid colorectal carcinoma cells, which express normal p53 activity. The p53 siRNAs specifically inhibited expression of p53 and significantly impaired the efficiency and fidelity of DNA EJ activity. Elevated cellular exonuclease activity was observed in p53 knockdown RKO cells and cellular extract of the p53 knockdown RKO cells appeared to be defective in protecting the termini of a DNA substrate against nuclease digestion. These results suggested that p53 directly inhibited cellular exonuclease activity. Thus, p53 inhibition of exonuclease activity by DNA end protection played a critical role in the efficacy and fidelity of DNA EJ to precisely repair DSBs and prevent oncogenesis by maintaining genetic integrity.