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BACKGROUND: Statins are cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, statins may possess anticancer properties and interact with receptor activator of nuclear factor κB ligand expression. We aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18. PATIENTS AND METHODS: ABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor-positive BC receiving a nonsteroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post hoc analysis, we investigated the effects of concomitant statin therapy on recurrence risk (RR) of BC, fracture risk and bone mineral density (BMD). RESULTS: In the study population (n = 3420), statin therapy (n = 824) was associated with worse disease-free survival (DFS) [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.04-1.75; P = 0.023]. While no significant effect of lipophilic statins (n = 710) on RR was observed (HR 1.30, 95% CI 0.99-1.72; P = 0.062), patients on hydrophilic statins (n = 87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; P = 0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21-5.68; P = 0.014). However, this effect subsided after correction for confounders in the sensitivity analysis. No association between statin use and fracture risk or osteoporosis was observed. CONCLUSION: According to this analysis, hydrophilic statins showed a detrimental effect on DFS in the main model, which was attenuated after correction for confounders. Our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins.
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Neoplasias de la Mama , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias de la Mama/terapia , Denosumab/efectos adversos , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Posmenopausia , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: MammaPrint is a prognostic assay based on gene expression in tumors from patients with early breast cancer. MammaPrint has been extensively validated and Food and Drug Administration cleared in fresh and formalin-fixed and paraffin-embedded (FFPE) tissue. We aimed to assess its prognostic performance in the biomarker cohort of the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG-8) patient population, and to obtain a higher level of evidence with regard to its clinical validity after RNA extraction from FFPE biobank tissue. PATIENTS AND METHODS: A prespecified retrospective analysis to test the prognostic performance of the MammaPrint test to predict distant recurrence-free survival at 5 and 10 years as primary end point was carried out. MammaPrint risk, clinicopathological factors (after central pathological review), and clinical risk (using a modified version of Adjuvant! Online) were evaluated by Cox regression analyses. RESULTS: From 1347 available samples, 607 (45%) failed quality control after RNA extraction. In total, 658 (49%) patients were included in survival analyses: MammaPrint low risk versus high risk is a significant prognostic factor for distant recurrence-free survival at 5 years (94.0% versus 91.6%) with a significant risk reduction of 6.5% at 10 years (log-rank P value = 0.017, low risk 91.3% versus high risk 84.8%). The multivariable models suggest that hazard ratio (HR) is primarily driven by tumor stage (5-year HR 3.89; confidence interval 1.97-7.71) and nodal status (5-year HR 1.73; confidence interval 0.91-3.21). After adjustment for clinical risk groups, MammaPrint HRs remain stable with values just below 2.0 after the first 3 years. CONCLUSIONS: The MammaPrint test showed significant prognostic performance at 5 and 10 years of follow-up. In the particular cohort of ABCSG-8, the statistical independence from clinically assessed covariates remains unclear, and no conclusions concerning the clinical validity of the test can be drawn.
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Neoplasias de la Mama , Neoplasias Colorrectales , Austria , Biomarcadores , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Femenino , Hormonas , Humanos , Estudios Retrospectivos , Estados UnidosRESUMEN
BACKGROUND AND PURPOSE: Numerous lifestyle factors are blamed for triggering migraine attacks. The reliability of assessing these factors retrospectively is unknown. Therefore, retrospective and prospective assessments of lifestyle in general and of migraine triggers in particular were compared in patients with migraine. METHODS: At baseline, the patients filled in two questionnaires covering the previous 90 days. Thereafter they kept a prospective 90-day diary. Questionnaires and diary included the same set of 45 factors. In the first questionnaire the patients assessed their lifestyle, in the second they rated for each factor the likelihood of triggering a migraine attack, and in the diary they recorded the daily presence of these factors irrespective of headache. Five categories were used for comparing frequencies in questionnaire and diary, defining agreement as identical categories in diary and questionnaire, minor disagreement and major disagreement as overestimation or underestimation by one category and two or more categories, respectively. RESULTS: In all, 327 patients (283 women, age 41.9 ± 12.1 years) who recorded 28,325 patient days were included. Calculating for each factor the percentage of patients with major disagreement the mean proportion was larger for trigger factors than for lifestyle (38.7% ± 6.6% vs. 16.9% ± 6.4%, P < 0.001). The proportion of factors showing major disagreement in more than 20% of the patients was 8.8% for lifestyle but 94.1% for trigger factors (P < 0.001). CONCLUSION: Comparing questionnaire and diary assessments of lifestyle and trigger factors in patients with migraine shows that questionnaire assessment of lifestyle is reliable, whereas trigger factors are overestimated and/or underestimated in retrospective questionnaires.
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Estilo de Vida , Trastornos Migrañosos/etiología , Encuestas y Cuestionarios , Adulto , Austria/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/epidemiología , Factores Desencadenantes , Estudios Prospectivos , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
BACKGROUND: Patients treated with TNF-α inhibitors (TNFi) are at high risk of reactivation of latent tuberculosis (LTB). Prospective studies on monitoring of TB reactivation and/or infection in this risk group are lacking. AIM: To test the conversion and reversion rate of screening tests for latent TB serial tuberculin skin test (TST) and interferon-γ release assay (IGRA) under ongoing TNFi therapy. METHODS: We retested consecutive patients with IBD receiving TNFi therapy for a minimum of 5 months for LTB using IGRA and TST. A detailed patient history and concomitant therapy were recorded for each subject. RESULTS: After a median of 34.9 weeks (20.7177.7), IGRA was retested in 184/227 patients (81.1%; Crohn's disease n = 139, ulcerative colitis n = 45) still under index TNFi. TST was available in 144/184 subjects (78.2%). The majority of patients were TNFi naïve (147/184, 79.9%). In a subgroup of patients who received isoniazid due to diagnosis of latent TB at baseline (n = 32), 6/13 patients (46.2%) with baseline positive IGRA and 3/22 patients (13.6%) with baseline positive TST reverted to negative at retesting. In patients without diagnosis of LTB at baseline no permanent IGRA conversion was observed, but there were 6/144 (4.2%) TST conversions from negative to positive. No single case of TB reactivation or infection was recorded during the observation period. CONCLUSIONS: During treatment TNF-α inhibitors conversion was observed for tuberculin skin test, but not interferon-γ release assay. As compared with tuberculin skin test, interferon-γ release assay reverted in nearly half of isoniazid-treated patients for latent tuberculosis. However, the fact that patients in whom the interferon-γ release assay test result remained positive did not develop active tuberculosis during follow-up questions the utility of interferon-γ release assay as a monitoring tool during chemoprevention.
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Fármacos Gastrointestinales/uso terapéutico , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Tuberculosis Latente/diagnóstico , Prueba de Tuberculina/métodos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adolescente , Adulto , Femenino , Humanos , Inmunosupresores/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Ensayos de Liberación de Interferón gamma , Tuberculosis Latente/complicaciones , Tuberculosis Latente/inmunología , Masculino , Adulto JovenRESUMEN
Molecular dynamics is a commonly used technique in computational biology. One key issue of each molecular dynamics simulation is: When does this simulation reach equilibrium state? A widely used way to determine this is the visual and intuitive inspection of root mean square deviation (RMSD) plots of the simulation. Although this technique has been criticized several times, it is still often used. Therefore, we present a study proving that this method is not reliable at all. We conducted a survey with participants from the field in which we illustrated different RMSD plots to scientists in the field of molecular dynamics. These plots were randomized and repeated, using a statistical model and different variants of the plots. We show that there is no mutual consent about the point of equilibrium. The decisions are severely biased by different parameters. Therefore, we conclude that scientists should not discuss the equilibration of a molecular dynamics simulation on the basis of a RMSD plot.
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Biología Computacional , Modelos Estadísticos , Simulación de Dinámica Molecular/normas , Algoritmos , Sesgo , Biología Computacional/métodos , Biología Computacional/estadística & datos numéricos , Recolección de Datos , Humanos , Simulación de Dinámica Molecular/estadística & datos numéricos , Variaciones Dependientes del ObservadorRESUMEN
BACKGROUND/AIMS: RCAS-1 is a transmembrane protein that is involved in the evasion of host immune surveillance by tumor cells. It has been found to be a valuable prognostic and diagnostic marker in a number of different malignancies. The objective of the study was to analyze the potency of RCAS-1 as a biomarker in the serum of patients with head and neck squamous cell carcinoma (HNSCC). METHODS: ELISA was performed with prospectively collected serum samples from 60 patients with HNSCC (taken at the time of diagnosis, after 3 and 12 months) and from 31 healthy controls. To correlate serum levels with RCAS-1 expression in the tumor, immunohistochemical staining of RCAS-1 was done using a tissue microarray. RESULTS: Surprisingly, median sRCAS-1 levels were basically identical between tumor patients and controls. Interestingly, patients with low RCAS-1 values at the time of diagnosis had better disease-free survival. 62% of tumor samples expressed RCAS-1 but we could not demonstrate a correlation between protein expression and serum levels. CONCLUSION: This study was the first to correlate RCAS-1 levels in the serum and in the tumor of the same patients. RCAS-1 seems to have prognostic properties although larger studies will be necessary to fully evaluate its role in HNSCC.