tbuckley/cabot-search huggingface dataset:
The effectiveness and medication costs of three anti-tumour necrosis factor agents in the treatment of rheumatoid arthritis from prospective clinical practice data
Authors: W Kievit, E M Adang, J Fransen, H H Kuper, M A F J van de Laar, T L Jansen, C M A De Gendt, D-J R A M De Rooij, H L M Brus, P C M Van Oijen, P C L M Van Riel
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Aim:</h3> to evaluate the effects of adalimumab, etanercept and infliximab on disease activity, functional ability and quality of life and the medication costs in a naturalistic design. <h3>Methods:</h3> All patients from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register starting on tumour necrosis factor (TNF)α-blocking agents for the first time were monitored and assessed by trained research nurses every 3 months. The primary outcome was the Disease Activity Score (DAS28) course over the 12 months follow-up, analysed by linear mixed models. Secondary outcomes were the Health Assessment Questionnaire (HAQ), EuroQol five dimensions (EQ-5D) and the Short-Form 36 items (SF36) scores, and medication-related total costs. <h3>Results:</h3> The DAS28 and SF-36 physical component scale decreased in all three medication groups over 12 months, but the decrease was larger for adalimumab and etanercept in comparison to infliximab (p&lt;0.001). The analyses of the HAQ and the EQ-5D scores showed the same (non-significant) trend, namely that at 12 months, the functionality and quality of life was better for adalimumab and etanercept patients. With regard to the medication costs, infliximab treatment resulted in significantly higher costs over the follow-up period than treatments with either adalimumab or etanercept. The comparison between adalimumab and etanercept showed a significant difference in the 12-month DAS28 course (p = 0.031). There were no additional indications for differences in effectiveness or costs between adalimumab and etanercept. <h3>Conclusion:</h3> The evaluation of the effectiveness and costs showed that adalimumab and etanercept are more or less equal and favourable compared to infliximab in the first year of treatment.
Abstract 11687: Cumulative Effect of Lesion Morphology and Location on the Functional Significance in Patient With Intermediate Stenotic Coronary Lesions
Authors: Hiroaki Takashima, Katsuhisa Waseda, Masahiko Gosho, Akiyoshi Kurita, Hirohiko Ando, Shinichiro Sakurai, Soichiro Kumagai, Akihiro Suzuki, Tetsuya Amano
Journal: Circulation (2014)

Introduction: Although identifying functional ischemia is important to decide revascularization, angiographic assessment alone is challenging in intermediate coronary stenosis. Previous studies have reported lesion-specific characteristics affected fractional flow reserve (FFR) values. However, the relationship between multiple lesion morphologies and FFR values has not been fully evaluated yet. Hypothesis: We hypothesized that cumulative impact of lesion complexity and lesion location affected FFR value as well as the degree of stenosis in intermediate stenotic coronary lesions. Methods: A total of 109 consecutive patients with 136 intermediate stenotic lesions (visual estimation 40%< diameter stenosis <70%) were assessed by quantitative coronary angiography, lesion-specific characteristics, and fractional flow reserve (FFR). According to the number of morphologies, lesion complexity was classified into 3 groups (mild-complex: 0 or 1 morphology, moderate-complex: 2 or 3 morphologies, and severe-complex: ...
Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma
Authors: Kei Satoh, Lisa Zhang, Yaqin Zhang, Raju Chelluri, Myriem Boufraqech, Naris Nilubol, Dhaval Patel, Min Shen, Electron Kebebew
Journal: Clinical Cancer Research (2016)

Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, and no current effective therapy is available for locally advanced and metastatic ACC. Drug repurposing is an emerging approach for identifying new indications for existing drugs, especially for rare cancers such as ACC. The objective of this study was to use quantitative high-throughput screening to identify agents with antineoplastic activity against ACC.A screening of 4,292 compounds was performed on three ACC cell lines: BD140A, SW-13, and NCI-H295R.Twenty-one active compounds were identified, with an efficacy of >80% in all three cell lines. Of these, niclosamide showed higher efficacy and lower IC50 than established anti-ACC drugs. We then validated niclosamide-inhibited cellular proliferation in all three ACC cell lines. Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G1 cell-cycle arrest. Niclosamide also decreased cellular migration and reduced the level of mediators of epithelial-to-mesenchymal transition, such as N-cadherin and vimentin. Furthermore, niclosamide treatment resulted in decreased expression of β-catenin. We also evaluated the effect of niclosamide on energy metabolism in ACC cell lines and found it resulted in mitochondrial uncoupling. Niclosamide treatment inhibited ACC tumor growth with no observed toxicity in mice in vivoOur findings suggest that niclosamide has anti-ACC activity through its inhibition of multiple altered cellular pathways and cellular metabolism in ACC. Our results provide a preclinical rationale for evaluating niclosamide therapy in a clinical trial for ACC. Clin Cancer Res; 22(14); 3458-66. ©2016 AACR.
High Incidence of Hepatocellular Carcinomas After Synthetic Estrogen Administration in Syrian Golden Hamsters Fed α-Naphthoflavone: A New Tumor Model234
Authors: Jonathan J. Li, Sara Antonia Li
Journal: JNCI Journal of the National Cancer Institute (1984)

P8 80-100% incidence of multinodular hepatocellular carcinomas was observed in castrated male hamsters following synthetic estrogen treatment in the presence of 0.2-0.4% alpha-naphthoflavone (ANF) in the diet after 8.5-10 months. Induction of these liver tumors was detected as early as 3.5-4.0 months in low frequency. Of the synthetic estrogens studied, ethynylestradiol (CAS: 57-63-6) was a more potent inducer of these hepatic carcinomas than either diethylstilbestrol (CAS: 56-53-1) or hexestrol (CAS: 84-16-2). ANF, considered an inhibitor of P450-dependent multisubstrate monooxygenases, did not produce any liver tumors when administered alone for up to 12 months. Neither concomitant androgen nor progesterone (CAS: 57-83-0) treatment resulted in any hepatic carcinomas in animals maintained on ANF. Moreover, beta-naphthoflavone (CAS: 6051-87-2) treatment alone or in combination with these synthetic estrogens also resulted in no hepatic tumors. This new estrogen-induced liver tumor model could be useful to elucidate the casual relationship that exists between estrogenic hormones and hepatic tumors in humans.
Molecular evolution of rodent insulins.
Authors: J J Beintema, R N Campagne
Journal: Molecular Biology and Evolution (1987)

Several trees of amino acid sequences of rodent insulins were derived with the maximum-parsimony procedure. Possible orthologous and paralogous relationships were investigated. Except for a recent gene duplication in the ancestor of rat and mouse, there are no strong arguments for other paralogous relationships. Therefore, a tree in agreement with other biological data is the most reasonable one. According to this tree, the capacity to form zinc-binding hexamers was lost once in the ancestor of the hystricomorph rodents, followed by moderately increased evolutionary rates in the lineages to African porcupine and chinchilla but highly increased rates in at least three independent lines to other taxa of this suborder: guinea pig, cuis, and Octodontoidea (coypu and casiragua).
&lt;italic&gt;Brief Communication:&lt;/italic&gt; Endotoxin-Stimulated Immune Response to Modified Lymphoma Cells&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: M D Prager, C M Ludden, W J Mandy, J P Allison, G B Kitto
Journal: JNCI Journal of the National Cancer Institute (1975)

Bacterial endotoxin was administered with iodoacetamide-modified P1798 lymphoma cells to immunize syngenic BALB/cJ mice against this lymphoma to which they are naturally unresponsive. Three or four vaccinations with endotoxin (6.6 mug/injection) alone or the modified cells alone did not produce host resistance. A significant number (30 percent) of mice receiving both endotoxin and modified cells rejected a subsequent implant of viable tumor cells. Even those mice having progressive tumor growth exhibited prolonged survival. High doses of endotoxin given with the modified P1798 cells caused 70-75 percent of the mice to reject the tumor implants. When resistance developed, antibodies reacting with tumor cell membrane were demonstrable. These results indicate that B-lymphocyte stimulators can produce an effective immune response against lymphoma cells.
Antineoplastic effects of tumor necrosis factor alone and in combination with gamma-interferon on tumor biopsies in clonogenic assay.
Authors: S E Salmon, L Young, P Scuderi, B Clark
Journal: Journal of Clinical Oncology (1987)

Tumor colony-forming cells were grown from fresh biopsy specimens from 102 patients with a variety of nonhematologic malignant neoplasms and exposed in vitro to pharmacologically achievable doses of recombinant human tumor necrosis factor (rTNF). In 68 instances, the tumor specimens were also tested against recombinant human gamma-interferon (rIFN-gamma), as well as the combination of rTNF and rIFN-gamma. rTNF exhibited dose-dependent and tumor-type-dependent antitumor effects. Sensitivity to rTNF at doses of less than 100 U was observed in 28% of the tumors tested. A higher than average frequency of sensitivity was observed in colorectal and lung cancer. Resistance to rTNF was observed in 42% of the tumors, including 52% of the ovarian cancer specimens tested. In paired experiments, exposure of tumor specimens to rTNF and rIFN-gamma in combination often resulted in a greater antitumor effect than was observed with either agent alone, with at least subadditive effects seen in 62% of the specimens tested against the combination. Antagonism between rTNF and rIFN-gamma was observed in 18% of the studies. Overall, exposure to the combination of rTNF and rIFN-gamma reduced the dose of rTNF required for significant antitumor activity by about threefold. Normal bone marrow granulocyte-macrophage colony-forming cells were also tested against both rTNF and rIFN-gamma and the combination. The bone marrow progenitors were more sensitive to rTNF and the combination with rIFN-gamma than were the tumor cells; however, the significance of this comparison between two different in vitro assay systems is indeterminate. Based on our observations, rTNF warrants phase II clinical trials in selected solid tumors with definite emphasis on colorectal and lung cancer. Additionally, studies of the combination of rTNF and rIFN-gamma are indicated and will be of particular interest in endometrial and breast cancer.
Transcutaneous Electrical Nerve Stimulation for Treating Neurogenic Lower Urinary Tract Dysfunction: A Systematic Review
Authors: Tobias Gross, Marc P. Schneider, Lucas M. Bachmann, Bertil F.M. Blok, Jan Groen, Lisette A. ‘t Hoen, David Castro-Diaz, Bárbara Padilla Fernández, Giulio Del Popolo, Stefania Musco, Rizwan Hamid, Hazel Ecclestone, Gilles Karsenty, Véronique Phé, Jürgen Pannek, Thomas M. Kessler
Journal: European Urology (2016)
Vaginal brachytherapy versus external beam pelvic radiotherapy for high-intermediate risk endometrial cancer: Results of the randomized PORTEC-2 trial
Authors: R. A. Nout, H. Putter, I. M. Jürgenliemk-Schulz, J. J. Jobsen, L. C. Lutgens, E. M. van der Steen-Banasik, J. W. Mens, A. Slot, V. T. Smit, C. L. Creutzberg
Journal: Journal of Clinical Oncology (2008)

LBA5503 Background: Pelvic external beam radiotherapy (EBRT) reduces the risk of vaginal and pelvic recurrence for stage I endometrial carcinoma (EC), but without survival benefit. In the PORTEC1-trial, the 5-year risk of vaginal and pelvic recurrence for high- intermediate risk patients was 19% without further treatment, compared to 5% after EBRT. Most recurrences were located in the upper vagina. Phase II trials suggested vaginal brachytherapy (VBT) to be as effective as EBRT. PORTEC-2 is the first randomized trial comparing the efficacy of VBT and EBRT to determine which treatment provides optimal local control with best quality of life. Methods: The PORTEC-2 trial was a multicenter phase-III trial. After surgery, patients were randomly allocated (1:1) to pelvic EBRT (46 Gy in 23 fractions) or VBT (21 Gy HDR in 3 fractions, or 30 Gy LDR). Eligible patients had a high-intermediate risk EC: age > 60 and stage 1C grade 1–2 or stage 1B grade 3; any age and stage 2A grade 1–2 or grade 3 with < 50% invasion. Primary endpoint was vaginal relapse (VR), which was expected to be 2% at 3 yrs in the EBRT group. The aim was to estimate the difference in VR with sufficient precision (SE <2%). An accrual of 400 patients in 4 years would provide the study with adequate power (> 80%) for detecting a difference of 6% (8% vs. 2%) in VR between both arms (one-sided). Analysis was done by intention-to-treat, using the competing risk method for VR, pelvic (PR) and distant relapse, and KM for overall (OS) and relapse free survival (RFS). Results: 427 patients were randomized between 2002–2006 (214 to EBRT and 213 to VBT). At a median follow-up of 34 months, 3-year actuarial rates of vaginal relapse were 0.9% in the VBT arm and 2.0% after EBRT (p=0.97), with SE of the difference 1.4%. Three-year rates of PR were 3.6% and 0.7% (p=0.03). Three-year rates of vaginal, pelvic and distant relapse as first failure were 0%, 1.3% and 6.4% in the VBT group, and 1.6%, 0.7% and 6.0% in the EBRT group. There were no significant differences in 3-year OS (90.4% vs. 90.8% p=0.55) and RFS (89.5% vs. 89.1% p=0.38). Conclusions: Vaginal brachytherapy is effective in preventing vaginal recurrence. Despite the slightly but significantly increased pelvic failure rate in the VBT arm, rates of distant metastases, OS and RFS were similar. As patient reported quality of life after VBT was shown to be better than after EBRT, VBT should be the treatment of choice for patients with high-intermediate risk endometrial carcinoma. No significant financial relationships to disclose.
Intravitreal Aflibercept Injection in Diabetic Macular Edema Patients with and without Prior Anti–Vascular Endothelial Growth Factor Treatment
Authors: Diana V. Do, Quan Dong Nguyen, Robert Vitti, Alyson J. Berliner, Andrea Gibson, Namrata Saroj, Yuhwen Soo, David S. Boyer
Journal: Ophthalmology (2016)
Spirometry during public events
Authors: Uta Butt, Carl-Peter Criée
Journal: European Respiratory Journal (2013)

The main cause to offer spirometry during public events is to increase the awareness of lung diseases. However, in some participants an impairment of lung function is detected in absence of known cardiac or lung diseases.  Method: At the world spirometry day in 2012 and the german lung day in 2011 we analysed 2182 lung function tests and questionnaires, which are supplied by the European lung foundation (ELF).  Results: In 1321 participants (55 % woman, 45 % men) spirometry and questionnaires were of sufficient quality. The mean age was 58 ±. 20 yrs. 15 % were smokers, 29 % were ex-smokers und 56 % non smokers. 21 % of smokers and ex-smokers and 11 % of non smokers showed an obstructive impairment. In 13% and 14 % of smokers and ex-smokers, respectively, and 11 % of non smokers lung function showed a restrictive impairment. In 30 % of the participants a pulmonary disease had already been diagnosed. However, in 9 % of the participants without a known cardiac or pulmonary disease spirometry was abnormal.  Conclusion: In 9 % of participants without a known pulmonary or cardiac disease spirometric impairment was detected. Unfortunately there is no information about follow-up testings and underlying diagnosis.
Population pharmacokinetics (PK) of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in cancer patients
Authors: J. Li, M. B. Jameson, B. C. Baguley, R. Pili, S. D. Baker
Journal: Journal of Clinical Oncology (2006)

13076 Background: DMXAA (AS1404) is a small-molecule vascular-disrupting agent that selectively disrupts established tumor blood vessels. It is being evaluated in phase II trials in combination with cytotoxics. DMXAA is extensively metabolized, predominantly by UDP-glucuronosyltransferase (UGT) 2B7 and 1A9, and exhibits concentration-dependent protein binding. The study aim was to develop a population PK model for DMXAA and to examine covariates influencing drug disposition. Methods: 3,050 DMXAA total plasma concentrations were measured in 124 cancer patients receiving DMXAA monotherapy as a 20-min iv infusion weekly or every three weeks at doses from 6 to 4900 mg/m 2 in 3 phase I trials. PK models were fitted to the data from all patients simultaneously using the program NONMEM. Potential covariates including age, body weight, height, body surface area (BSA), sex, and liver and kidney function tests were screened with general additive model analysis and tested in the PK model. Results: DMXAA concentration-time profiles after multiple-dose administration were well described by a 3-compartment model with saturable elimination (Michaelis-Menten kinetic) from the central compartment. BSA and sex were significant covariates on the volume of distribution of the central compartment (V1) and the maximum elimination capacity (Vm), respectively, accounting for 10 and 12% of interindividual variation (IIV) in these parameters. Population estimates for Vm, Km (concentration at which half-maximal elimination rate is achieved), and V1 were 122 × (1 + 0.502 × (2-SEX)) (μM/h) [females had lower Vm than males; SEX = 1 for males, 2 for females], 103 μM, and 8.15 × (BSA/1.8) 0.69 (L), respectively. In the final model, IIV in Vm was 52%. Conclusions: DMXAA plasma disposition is characterized by a saturable elimination process. BSA-guided dosing for DMXAA is important. Evaluation of other covariates that reflect drug glucuronidation (e.g., UGT polymorphisms) may account for a greater fraction of the substantial unexplained PK variability. The population PK model will aid development of limited PK sampling strategies and investigation of PK-pharmacodynamic relationships in further trials. [Table: see text]
Glutathione pathway genes predict quality of life (QOL) in lung cancer patients: A NCCTG-97–24–51 based study
Authors: P. Yang, S. Mandrekar, S. Hillman, K. Allen, J. Jett, E. Perez, A. Adjei
Journal: Journal of Clinical Oncology (2007)

18037 Background: Platinum compounds are major chemotherapeutic agents in lung cancer and are metabolized by the glutathione pathway enzymes. We reported that genotypes of glutathione-related enzymes, especially GCLC, may be host factors in predicting survival of patients with stage IIIB/IV non-small cell lung cancer who were stable or responding from prior platinum-based chemotherapy (Yang et al., ASCO 2006). NCCTG investigators previously correlated allelic variants in 5-FU metabolizing genes with QOL in colorectal cancer patients (Sloan et al., ASCO 2004). We sought to evaluate the role of glutathione pathway genotypes on QOL. Methods: DNA samples were analyzed using 6 polymorphic DNA markers in the glutathione metabolic pathway. The contrasting genotypes in the analysis were GSTM1 and GSTT1 (null vs. present), GSTP1-I105V (AA vs. GA/GG), GSTP1-A114V (CC vs. CT/TT), GPX1 (CC vs. TT/TC), and GCLC (homozygous repeat 77 vs. heterozygous 7*). Forty-six patients completed the FACT-L and the UNISCALE QOL questionnaires at baseline and week-8, and we have results for all 6 genotypes. A clinically significant decline (CSD) in QOL was defined as a 10% decrease from baseline to week-8. A multivariate logistic regression model was used to evaluate the association of all 6 genotypes with a CSD in QOL. Results: Patients carrying the GPX1-CC genotype had a CSD in the UNISCALE (Odds Ratio (OR): 10.0; p=0.02), total FACT-L score (OR: 7.9; p=0.03), the FACT-L physical well being construct (OR: 13.7; p=0.02), and the FACT-L functional well being construct (OR: 5.3; p=0.05). Other constructs, i.e., emotional, social and family, and additional concerns were not significantly associated with the genotypes. Conclusions: Genotypes of glutathione-related enzymes, especially GPX1 may be inherited factors in predicting patients’ QOL after platinum-based chemotherapy. Further investigation to define and measure the direct or indirect effects of these genes on QOL is critical, particularly, via drug responses, toxicities, and disease recurrence. (This work was partly supported by NIH grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.
Correlation of a family history of cancer with risk of relapse and death in pediatric cancer patients
Authors: S. L. Eichstadt, G. V. Dahl, P. G. Fisher, J. M. Ford, J. D. Schiffman
Journal: Journal of Clinical Oncology (2009)

10029 Background: The association between family history of cancer (FHC) and outcome remains uncertain. Relapse and survival of children with FHC has not been well studied. Such information would be valuable for prognosis, refining treatment protocols, and long-term follow-up in pediatric patients with FHC. Methods: An historical cohort study of all pediatric patients diagnosed with cancer at Lucile Packard Children's Hospital at Stanford from 1999 - 2002 was performed (n = 363, mean age: 8.4 yrs [0–28 yrs]). FHC among 1st, 2nd and 3rd degree relatives was obtained from the first 10 consecutive encounters in the electronic medical record. Relapse, secondary malignancy, and survival data were also acquired. The relative risks for these endpoints were calculated between patients with FHC among 1st and/or 2nd degree relatives and those with negative FHC. Patients without documented FHC were excluded (n = 100). Results: 108 (41%) newly diagnosed pediatric patients had reported FHC (1st Degree: n = 14 [5%], 2nd Degree: n = 58 [22%], 3rd Degree: n = 36 [14%]). Patients with reported FHC among 1st and/or 2nd degree relatives were at increased relative risk [RR] for relapse (1.96, 95% confidence interval [CI] 1.27–3.02) compared to patients with negative FHC (n = 191). In particular, patients with Hodgkin Disease (HD) and FHC (n = 12) were more likely to relapse (RR 1.79, 95% CI 1.19–2.72) and at increased risk of death (RR 1.72, 95% CI 1.18–2.53), compared to HD with negative FHC (n = 8). Similarly, patients diagnosed with ALL and FHC (n = 22) had increased risk of death (RR 2.25, 95% CI 1.06–4.8) compared to ALL patients with negative FHC (n = 56). For patients diagnosed with any pediatric cancer and positive FHC in 1st degree relative, RR of death was significantly elevated (3.74, 95% CI 1.20–11.70). Conclusions: Pediatric cancer patients with positive FHC among 1st and/or 2nd degree relatives appear to have higher relative risk of relapse compared to those with negative FHC. Additionally, an increased risk of death was associated with HD and ALL patients with positive FHC. Patients with 1st degree relative with malignancy had an increased risk for death compared to those without cancer among 1st degree relatives. These findings may reflect underlying genetic predispositions in children which contribute to outcome. No significant financial relationships to disclose.