Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial

Oral capecitabine (Xeloda<sup>®</sup>) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings £3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings £1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK

El álbum poético en portugués y en español: sinergia estética entre palabras e ilustraciones

Este estudo procurou problematizar a relação textual que se observa entre a palavra e a imagem em um tipo de texto especialmente concebido para crianças: o álbum poético. Para tal, utilizamos alguns exemplos textuais significativos desse subgênero literário/editorial ainda em emergência tanto em Portugal quanto na Espanha, e propusemos uma definição e uma caracterização baseadas no comentário de sequências poéticas nas quais a ilustração sustenta o conteúdo verbal. Efetivamente, centrando a atenção no álbum poético de potencial recepção infanto-juvenil, sugere-se uma análise de diversos títulos de autoria portuguesa e espanhola, assente em uma leitura dialógica do texto verbal e do visual. A sinergia que se concretiza entre as duas componentes enunciadas alicerça essa nova construção estética que tem, na verdade e na sua essência, a poesia como matriz e, em larga medida, é devedora dos efeitos expressivos da metáfora.This study aimed to discuss the relation between words and images in a type of text especially directed to children: the picture-poetry book. From significant examples of this literary subgenre still emerging in both Portugal and Spain, we propose a definition and characterization based on the review of poetic sequences in which illustrations support the verbal content. By focusing on picture-poetry books potentially aimed for adolescents and children, we present an analysis of several titles by Portuguese and Spanish authors, based on the dialogic reading between verbal and visual texts. The synergy found between these two components creates de foundantions of a new aesthetic construction which, in truth and in essence, has poetry as its matrix and owes its expressive effects to metaphors.Este estudio ha tenido como objetivo discutir la relación textual que existe entre la palabra y la imagen en un tipo texto especialmente creado para niños: el álbum poético. Para ello, utilizamos algunos ejemplos textuales significativos de un subgénero literario en emergencia tanto en Portugal cuanto en España, y hemos propuesto una definición de este subgénero y su caracterización a partir del comentario de secuencias poéticas en las cuales la imagen sustenta el contenido verbal. De hecho, centrando la atención en el álbum poético de potencial recepción infantil y juvenil, proponemos un análisis de diversos títulos de autoría portuguesa y española basado en la lectura dialógica entre el texto verbal y el texto ilustrativo. La sinergia que se establece entre estos dos componentes enunciados facilita una nueva construcción estética que da pie, en su esencia, a un tipo de poesía que, en gran medida, es deudora de los efectos expresivos de la metáfora.CIEC - Centro de Investigação em Estudos da Criança, IE, UMinho (UI 317 da FCT), Portugal. Fundos Nacionais através da FCT (Fundação para a Ciência e a Tecnologia) e cofinanciado pelo Fundo Europeu de Desenvolvimento Regional (FEDER) através do COMPETE 2020 – Programa Operacional Competitividade e Internacionalização (POCI) no âmbito do CIEC (Centro de Investigação em Estudos da Criança, da Universidade do Minho) com a referência POCI-01-0145-FEDER-007562info:eu-repo/semantics/publishedVersio

Gene expression and immunohistochemical analyses identify SOX2 as major risk factor for overall survival and relapse in Ewing sarcoma patients

BACKGROUND: Up to 30-40% of Ewing sarcoma (EwS) patients with non-metastatic disease develop local or metastatic relapse within a time span of 2-10 years. This is in part caused by the absence of prognostic biomarkers that can identify high-risk patients and thus assign them to risk-adapted monitoring and treatment regimens. Since cancer stemness has been associated with tumour relapse and poor patient outcomes, we investigated in the current study the prognostic potential SOX2 (sex determining region Y box 2) - a major transcription factor involved in development and stemness - which was previously described to contribute to the undifferentiated phenotype of EwS. METHODS: Two independent patient cohorts, one consisting of 189 retrospectively collected EwS tumours with corresponding mRNA expression data (test-cohort) and the other consisting of 141 prospectively collected formalin-fixed and paraffin-embedded resected tumours (validation and cohort), were employed to analyse SOX2 expression levels through DNA microarrays or immunohistochemistry, respectively, and to compare them with clinical parameters and patient outcomes. Two methods were employed to test the validity of the results at both the mRNA and protein levels. FINDINGS: Both cohorts showed that only a subset of EwS patients (16-20%) expressed high SOX2 mRNA or protein levels, which significantly correlated with poor overall survival. Multivariate analyses of our validation-cohort revealed that high SOX2 expression represents a major risk-factor for poor survival (HR = 3·19; 95%CI 1·74-5·84; p < 0·01) that is independent from metastasis and other known clinical risk-factors at the time of diagnosis. Univariate analyses demonstrated that SOX2-high expression was correlated with tumour relapse (p = 0·002). The median first relapse was at 14·7 months (range: 3·5-180·7). INTERPRETATION: High SOX2 expression constitutes an independent prognostic biomarker for EwS patients with poor outcomes. This may help to identify patients with localised disease who are at high risk for tumour relapse within the first two years after diagnosis. FUNDING: The laboratory of T. G. P. Grünewald is supported by grants from the 'Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München (WiFoMed)', by LMU Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the 'Mehr LEBEN für krebskranke Kinder - Bettina-Bräu-Stiftung', the Walter Schulz Foundation, the Wilhelm Sander-Foundation (2016.167.1), the Friedrich-Baur foundation, the Matthias-Lackas foundation, the Barbara & Hubertus Trettner foundation, the Dr. Leopold & Carmen Ellinger foundation, the Gert & Susanna Mayer foundation, the Deutsche Forschungsgemeinschaft (DFG 391665916), and by the German Cancer Aid (DKH-111886 and DKH-70112257). J. Li was supported by a scholarship of the China Scholarship Council (CSC), J. Musa was supported by a scholarship of the Kind-Philipp foundation, and T. L. B. Hölting by a scholarship of the German Cancer Aid. M. F. Orth and M. M. L. Knott were supported by scholarships of the German National Academic Foundation. G. Sannino was supported by a scholarship from the Fritz-Thyssen Foundation (FTF-40.15.0.030MN). The work of U. Dirksen is supported by grants from the German Cancer Aid (DKH-108128, DKH-70112018, and DKH-70113419), the ERA-Net-TRANSCAN consortium (project number 01KT1310), and Euro Ewing Consortium (EEC, project number EU-FP7 602,856), both funded under the European Commission Seventh Framework Program FP7-HEALTH (http://cordis.europa.eu/), the Barbara & Hubertus Trettner foundation, and the Gert & Susanna Mayer foundation. G. Hardiman was supported by grants from the National Science Foundation (SC EPSCoR) and National Institutes of Health (U01-DA045300). The laboratory of J. Alonso was supported by Instituto de Salud Carlos III (PI12/00816; PI16CIII/00026); Asociación Pablo Ugarte (TPY-M 1149/13; TRPV 205/18), ASION (TVP 141/17), Fundación Sonrisa de Alex & Todos somos Iván (TVP 1324/15).The laboratory of T. G. P. Grünewald is supported by grants from the ‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München (WiFoMed)’, by LMU Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder – Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the Wilhelm Sander-Foundation (2016.167.1), the Friedrich-Baur foundation, the Matthias-Lackas foundation, the Barbara & Hubertus Trettner foundation, the Dr. Leopold und Carmen Ellinger foundation, the Gert & Susanna Mayer foundation, the Rolf M. Schwiete foundation, the Deutsche Forschungsgemeinschaft (DFG 391665916), and by the German Cancer Aid (DKH-111886 and DKH-70112257). J. Li was supported by a scholarship of the China Scholarship Council (CSC), J. Musa was supported by a scholarship of the Kind-Philipp foundation, and T. L. B. Hölting by a scholarship of the German Cancer Aid. M. F. Orth and M. M. L. Knott were supported by scholarships of the German National Academic Foundation. G. Sannino was supported from a scholarship from the Fritz-Thyssen Foundation (FTF-40.15.0.030MN). The work of U. Dirksen is supported by grants from the German Cancerr Aid (DKH-108128, DKH-70112018, and DKH-70113419), the ERA-Net-TRANSCAN consortium (project number 01KT1310), and Euro Ewing Consortium (EEC, project number EU-FP7 602856), both funded under the European Commission Seventh Framework Program FP7-HEALTH (http://cordis.europa.eu/), the Barbara & Hubertus Trettner foundation, and the Gert & Susanna Mayer foundation. G. Hardiman was supported by grants from the National Science Foundation (SC EPSCoR) and National Institutes of Health (U01-DA045300). The laboratory of J. Alonso was supported by Instituto de Salud Carlos III (PI12/00816; PI16CIII/00026); Asociación Pablo Ugarte (TPY-M 1149/13; TRPV 205/18), ASION (TVP 141/17), Fundación Sonrisa de Alex & Todos somos Iván (TVP 1324/15).S

Genetic variability in CYP3A4 and CYP3A5 in primary liver, gastric and colorectal cancer patients

<p>Abstract</p> <p>Background</p> <p>Drug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites. The role of gene polymorphisms of several cytochrome P450 enzymes in digestive cancer risk has been extensively investigated. However, the drug-metabolizing enzymes with the broader substrate specificity, CYP3A4 and CYP3A5, have not been analyzed so far. This study aims to examine associations between common CYP3A4 and CYP3A5 polymorphisms and digestive cancer risk.</p> <p>Methods</p> <p>CYP3A4 and CYP3A5 genotypes were determined in 574 individuals including 178 patients with primary liver cancer, 82 patients with gastric cancer, 151 patients with colorectal cancer, and 163 healthy individuals.</p> <p>Results</p> <p>The variant allele frequencies for patients with liver cancer, gastric cancer, colorectal cancer and healthy controls, respectively, were: <it>CYP3A4*1B</it>, 4.8 % (95% C.I. 2.6–7.0), 3.7 % (0.8–6.6) 4.3% (2.0–6.6) and 4.3% (2.1–6.5); <it>CYP3A5*3</it>, 91.8 % (93.0–97.4), 95.7% (92.6–98.8), 91.7% (88.6–94.8) and 90.8% (87.7–93.9). The association between <it>CYP3A4*1B </it>and <it>CYP3A5*3 </it>variant alleles did not significantly differ among patients and controls. No differences in genotypes, allele frequencies, or association between variant alleles were observed with regard to gender, age at diagnosis, tumour site or stage.</p> <p>Conclusion</p> <p>Common polymorphisms on <it>CYP3A4 </it>and <it>CYP3A5 </it>genes do not modify the risk of developing digestive cancers in Western Europe.</p

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Sensitivity of thermal power generation to climate change

Objectives: This phase I, dose-escalation study was conducted to determine the recommended dose of intermittent oral capecitabine in combination with a fixed dose of i.v. oxaliplatin. Secondary objectives included evaluation of the safety profile and antitumor activity. Patients and methods: Twenty-three patients with advanced or metastatic solid tumors received a 21-day regimen of oral capecitabine (500, 825, 1000 or 1250 mg/m(2) twice daily days 1-14) in combination with oxaliplatin (130 mg/m(2), 2-h i.v. infusion, day 1). Dose-limiting toxicities were determined during the first treatment cycle. and safety and efficacy were evaluated throughout treatment. Results: The recommended dosing schedule is oral capecitabine 1000 mg/m(2) twice daily (days 1-14) with i.v. oxaliplatin 130 mg/m(2) (day 1) in a 21-day treatment cycle. The principal dose-limiting toxicity was diarrhea. The most frequent treatment-related adverse events occurring during the study were gastrointestinal (nausea/vomiting, diarrhea) and neurological (dysesthesia, paresthesia). The majority, of treatment-related adverse events were mild to moderate in intensity, and no grade 4 adverse events occur-red in the 15 patients treated at or below the recommended dose. The most common grade 3/4 laboratory abnormalities were lymphocytopenia (52% of patients), thrombocytopenia (22%; grade 3 only). neutropenia (17%) and hyperbilirubinemia (17%). Among patient., treated at or below the recommended dose level (n = 15). only two patients experienced grade 3 neutropenia and no patients experienced grade 4 neutropenia. Partial tumor responses occurred in six patients (26%), including five of nine patients (55%) with colorectal cancer. All responding patients were pretreated with 5-fluorouracil and four responders had received prior irinotecan. Conclusions: Oral capecitabine with i.v. oxaliplatin is a feasible combination regimen that shows promising antitumor activity in patients with colorectal cancer. There is an ongoing. phase II study to further characterize the safety and efficacy of this combination as first-line therapy for metastatic colorectal cancer, using the recommended dose identified in this study