Cost-effectiveness analysis of stand-alone or combined non-invasive imaging tests for the diagnosis of stable coronary artery disease: results from the EVINCI study

Aim: This study aimed at evaluating the cost-effectiveness of different non-invasive imaging-guided strategies for the diagnosis of obstructive coronary artery disease (CAD) in a European population of patients from the Evaluation of Integrated Cardiac Imaging in Ischemic Heart Disease (EVINCI) study.Methods and results: Cost-effectiveness analysis was performed in 350 patients (209 males, mean age 59 ± 9 years) with symptoms of suspected stable CAD undergoing computed tomography coronary angiography (CTCA) and at least one cardiac imaging stress-test prior to invasive coronary angiography (ICA) and in whom imaging exams were analysed at dedicated core laboratories. Stand-alone stress-tests or combined non-invasive strategies, when the first exam was uncertain, were compared. The diagnostic end-point was obstructive CAD defined as > 50% stenosis at quantitative ICA in the left main or at least one major coronary vessel. Effectiveness was defined as the percentage of correct diagnosis (cd) and costs were calculated using country-specific reimbursements. Incremental cost-effectiveness ratios (ICERs) were obtained using per-patient data and considering “no-imaging” as reference. The overall prevalence of obstructive CAD was 28%. Strategies combining CTCA followed by stress ECHO, SPECT, PET, or stress CMR followed by CTCA, were all cost-effective. ICERs values indicated cost saving from − 969€/cd for CMR-CTCA to − 1490€/cd for CTCA-PET, − 3,09 €/cd for CTCA-SPECT and − 3776€/cd for CTCA-ECHO. Similarly when considering early revascularization as effectiveness measure.Conclusion: In patients with suspected stable CAD and low prevalence of disease, combined non-invasive strategies with CTCA and stress-imaging are cost-effective as gatekeepers to ICA and to select candidates for early revascularization.</p

Elaboração de fiambres com as carnes branca e escura de frango Chicken loaves prepared with broiler light and dark meat

O presente trabalho teve como objetivo específico a obtenção de fiambres com as carnes branca (do peito) e escura (das coxas e pernas) de frango, separadamente. Os cortes foram desossados manualmente e às carnes, após limpeza e corte, foram adicionados ingredientes não cárneos e aditivos, sendo elas moídas após 12 h. O processamento térmico foi realizado em defumador até a temperatura interna de 71&deg;C. Foram obtidos fiambres curados e defumados com boa qualidade sensorial, adequado nível de proteína e baixo conteúdo calórico, do tipo semi-conserva. O rendimento foi maior na elaboração do fiambre de carne branca, o qual foi preferido na avaliação sensorial, em relação ao produto de carne escura.<br>Chiken loaves were prepared with light and dark meat from broiler and deboned breasts and legs. The meat was cut, cured, ground, smoked and pasteurized (until 71&deg;C). The yield was greater for the loaf prepared with light meat, which was also ranked first in sensory analysis. The light and the dark meat loaves had the following chemical compositions: moisture 70.6 - 71.0%; protein 22.0 - 20.2%; moisture/protein ratio 3.2 - 3.5; fat 4.0 - 4.5%; sodium chloride 2.4 - 2.5%; sodium nitrite 51.5 - 69.0 ppm; pH 6.1 - 6.25, respectively

Expression Of Prox-1 In Oral Kaposi's Sarcoma Spindle Cells

Background: The histogenesis of neoplastic spindle cells of Kaposi's sarcoma is still uncertain, but some studies consider it a lymphatic vessel differentiation. Prox-1 is a nuclear transcription factor that plays a major role during embryonic lymphangiogenesis, and it has been considered a specific and sensitive lymphatic endothelial cell marker. The aim of this study was to determine the expression of Prox-1 in oral Kaposi's sarcoma comparing the results with oral benign vascular tumors including capillary hemangiomas and pyogenic granulomas. Methods: Expression of Prox-1 and HHV-8 was evaluated by immunohistochemistry in 30 oral Kaposi's sarcoma, 5 oral capillary hemangiomas, and 10 oral pyogenic granulomas. The labeling index was expressed as the percentage of positive cells for each case studied. Statistical comparison was performed using the Wilcoxon-Mann-Whitney rank sum test. Results: Twenty-eight (93.3%) and 30 oral Kaposi's sarcoma cases were positive for Prox-1 and HHV-8, respectively, while all oral benign vascular tumors were negative for these markers. The number of Prox-1 and HHV-8 oral Kaposi's sarcoma-positive cells increased significantly from patch/plaque to nodular histological stages. Conclusion: The expression of Prox-1 in the neoplastic spindle cells supports the view of a lymphatic differentiation in oral Kaposi's sarcoma. Prox-1 may also be involved in the pathogenesis of oral Kaposi's sarcoma as the number of positive spindle cells increased progressively from patch to nodular stages and could be eventually useful as an additional diagnostic tool for differential diagnosis between oral Kaposi's sarcoma and benign oral vascular lesions. © 2013 John Wiley & Sons A/S.432132136Feller, L., Wood, N.H., Lemmer, J., HIV-associated Kaposi sarcoma: pathogenic mechanisms (2007) Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 104, pp. 521-529Ramírez-Amador, V., Martínez-Mata, G., González-Ramírez, I., Anaya-Saavedra, G., de Almeida, O.P., Clinical, histological and immunohistochemical findings in oral Kaposi's sarcoma in a series of Mexican AIDS patients. Comparative study (2009) J Oral Pathol Med, 38, pp. 328-333Beckstead, J.H., Wood, G.S., Fletcher, V., Evidence for the origin of Kaposi's sarcoma from lymphatic endothelium (1985) Am J Pathol, 119, pp. 294-300Hong, Y.K., Foreman, K., Shin, J.W., Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus (2004) Nat Genet, 36, pp. 683-685Wang, H.W., Trotter, M.W., Lagos, D., Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma (2004) Nat Genet, 36, pp. 687-693Pyakurel, P., Pak, F., Mwakigonja, A.R., Kaaya, E., Heiden, T., Biberfeld, P., Lymphatic and vascular origin of Kaposi's sarcoma spindle cells during tumor development (2006) Int J Cancer, 119, pp. 1262-1267Folpe, A.L., Veikkola, T., Valtola, R., Weiss, S.W., Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi's sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas (2000) Mod Pathol, 13, pp. 180-185Carroll, P.A., Brazeau, E., Lagunoff, M., Kaposi's sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation (2004) Virology, 328, pp. 7-18Rodriguez-Niedenführ, M., Papoutsi, M., Christ, B., Prox1 is a marker of ectodermal placodes, endodermal compartments, lymphatic endothelium and lymphangioblasts (2001) Anat Embryol (Berl), 204, pp. 399-406Lavado, A., Oliver, G., Prox1 expression patterns in the developing and adult murine brain (2007) Dev Dyn, 236, pp. 518-524Wigle, J.T., Oliver, G., Prox1 function is required for the development of the murine lymphatic system (1999) Cell, 98, pp. 769-778Wigle, J.T., Harvey, N., Detmar, M., An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype (2002) EMBO J, 21, pp. 1505-1513Lamovec, J., Knuutila, S., Kaposi sarcoma (2002) World Health Organization Classification of tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone, pp. 170-172. , Fletcher CDM, Unni KK, Mertens F, eds. Lyon: IARC PressReis, R.M., Reis-Filho, J.S., Longatto Filho, A., Tomarev, S., Silva, P., Lopes, J.M., Differential Prox-1 and CD 31 expression in mucousae, cutaneous and soft tissue vascular lesions and tumors (2005) Pathol Res Pract, 201, pp. 771-776Dadras, S.S., Skrzypek, A., Nguyen, L., Prox-1 promotes invasion of kaposiform hemangioendotheliomas (2008) J Invest Dermatol, 128, pp. 2798-2806Kahn, H.J., Bailey, D., Marks, A., Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi's sarcoma and a subset of angiosarcomas (2002) Mod Pathol, 15, pp. 434-440Le Huu, A.R., Jokinen, C.H., Rubin, B.P., Expression of prox1, lymphatic endothelial nuclear transcription factor, in Kaposiform hemangioendothelioma and tufted angioma (2010) Am J Surg Pathol, 34, pp. 1563-157

Effect of blood activity on dosimetric calculations for radiopharmaceuticals.

The objective of this work was to investigate the influence of the definition of blood as a distinct source on organ doses, associated with the administration of a novel radiopharmaceutical for positron emission tomography-computed tomography (PET/CT) imaging-(S)-4-(3-(18)F-fluoropropyl)-L-glutamic acid ((18)F-FSPG). Personalised pharmacokinetic models were constructed based on clinical PET/CT images from five healthy volunteers and blood samples from four of them. Following an identifiability analysis of the developed compartmental models, person-specific model parameters were estimated using the commercial program SAAM II. Organ doses were calculated in accordance to the formalism promulgated by the Committee on Medical Internal Radiation Dose (MIRD) and the International Commission on Radiological Protection (ICRP) using specific absorbed fractions for photons and electrons previously derived for the ICRP reference adult computational voxel phantoms. Organ doses for two concepts were compared: source organ activities in organs parenchyma with blood as a separate source (concept-1); aggregate activities in perfused source organs without blood as a distinct source (concept-2). Aggregate activities comprise the activities of organs parenchyma and the activity in the regional blood volumes (RBV). Concept-1 resulted in notably higher absorbed doses for most organs, especially non-source organs with substantial blood contents, e.g. lungs (92% maximum difference). Consequently, effective doses increased in concept-1 compared to concept-2 by 3-10%. Not considering the blood as a distinct source region leads to an underestimation of the organ absorbed doses and effective doses. The pronounced influence of the blood even for a radiopharmaceutical with a rapid clearance from the blood, such as (18)F-FSPG, suggests that blood should be introduced as a separate compartment in most compartmental pharmacokinetic models and blood should be considered as a distinct source in dosimetric calculations. Hence, blood samples should be included in all pharmacokinetic and dosimetric studies for new tracers if possible

Agrin And Perlecan Mediate Tumorigenic Processes In Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma is the most common type of cancer in the oral cavity, representing more than 90% of all oral cancers. The characterization of altered molecules in oral cancer is essential to understand molecular mechanisms underlying tumor progression as well as to contribute to cancer biomarker and therapeutic target discovery. Proteoglycans are key molecular effectors of cell surface and pericellular microenvironments, performing multiple functions in cancer. Two of the major basement membrane proteoglycans, agrin and perlecan, were investigated in this study regarding their role in oral cancer. Using real time quantitative PCR (qRT-PCR), we showed that agrin and perlecan are highly expressed in oral squamous cell carcinoma. Interestingly, cell lines originated from distinct sites showed different expression of agrin and perlecan. Enzymatically targeting chondroitin sulfate modification by chondroitinase, oral squamous carcinoma cell line had a reduced ability to adhere to extracellular matrix proteins and increased sensibility to cisplatin. Additionally, knockdown of agrin and perlecan promoted a decrease on cell migration and adhesion, and on resistance of cells to cisplatin. Our study showed, for the first time, a negative regulation on oral cancer-associated events by either targeting chondroitin sulfate content or agrin and perlecan levels.912Argiris, A., Karamouzis, M.V., Raben, D., Ferris, R.L., Head and neck cancer (2008) Lancet, 371, pp. 1695-1709Belcher, R., Hayes, K., Fedewa, S., Chen, A.Y., Current treatment of head and neck squamous cell cancer (2014) J Surg OncolMydlarz, W.K., Hennessey, P.T., Califano, J.A., Advances and Perspectives in the Molecular Diagnosis of Head and Neck Cancer (2010) Expert Opin Med Diagn, 4, pp. 53-65Da Silva, S.D., Ferlito, A., Takes, R.P., Brakenhoff, R.H., Valentin, M.D., Advances and applications of oral cancer basic research (2011) Oral Oncol, 47, pp. 783-791Pereira, M.C., Oliveira, D.T., Landman, G., Kowalski, L.P., Histologic subtypes of oral squamous cell carcinoma: Prognostic relevance (2007) J Can Dent Assoc, 73, pp. 339-344Van Kempen, L.C., Ruiter, D.J., Van Muijen, G.N., Coussens, L.M., The tumor microenvironment: A critical determinant of neoplastic evolution (2003) Eur J Cell Biol, 82, pp. 539-548Naba, A., Clauser, K.R., Hoersch, S., Liu, H., Carr, S.A., The matrisome: In silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices (2012) Mol Cell Proteomics, 11, pp. M111+014647Barash, U., Cohen-Kaplan, V., Dowek, I., Sanderson, R.D., Ilan, N., Proteoglycans in health and disease: New concepts for heparanase function in tumor progression and metastasis (2010) FEBS J, 277, pp. 3890-3903Theocharis, A.D., Skandalis, S.S., Tzanakakis, G.N., Karamanos, N.K., Proteoglycans in health and disease: Novel roles for proteoglycans in malignancy and their pharmacological targeting (2010) FEBS J, 277, pp. 3904-3923Iozzo, R.V., Sanderson, R.D., Proteoglycans in cancer biology, tumour microenvironment and angiogenesis (2011) J Cell Mol Med, 15, pp. 1013-1031Edwards, I.J., Proteoglycans in prostate cancer (2012) Nat Rev Urol, 9, pp. 196-206Tatrai, P., Dudas, J., Batmunkh, E., Mathe, M., Zalatnai, A., Agrin, a novel basement membrane component in human and rat liver, accumulates in cirrhosis and hepatocellular carcinoma (2006) Lab Invest, 86, pp. 1149-1160Mundhenke, C., Meyer, K., Drew, S., Friedl, A., Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 receptor binding in breast carcinomas (2002) Am J Pathol, 160, pp. 185-194Sharma, B., Handler, M., Eichstetter, I., Whitelock, J.M., Nugent, M.A., Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo (1998) J Clin Invest, 102, pp. 1599-1608Savore, C., Zhang, C., Muir, C., Liu, R., Wyrwa, J., Perlecan knockdown in metastatic prostate cancer cells reduces heparin-binding growth factor responses in vitro and tumor growth in vivo (2005) Clin Exp Metastasis, 22, pp. 377-390Iozzo, R.V., Cohen, I.R., Grassel, S., Murdoch, A.D., The biology of perlecan: The multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices (1994) Biochem J, 302, pp. 625-639Noonan, D.M., Fulle, A., Valente, P., Cai, S., Horigan, E., The complete sequence of perlecan, a basement membrane heparan sulfate proteoglycan, reveals extensive similarity with laminin A chain, low density lipoprotein-receptor, and the neural cell adhesion molecule (1991) J Biol Chem, 266, pp. 22939-22947Murdoch, A.D., Liu, B., Schwarting, R., Tuan, R.S., Iozzo, R.V., Widespread expression of perlecan proteoglycan in basement membranes and extracellular matrices of human tissues as detected by a novel monoclonal antibody against domain III and by in situ hybridization (1994) J Histochem Cytochem, 42, pp. 239-249Mishra, M., Chandavarkar, V., Naik, V.V., Kale, A.D., An immunohistochemical study of basement membrane heparan sulfate proteoglycan (perlecan) in oral epithelial dysplasia and squamous cell carcinoma (2013) J Oral Maxillofac Pathol, 17, pp. 31-35Ida-Yonemochi, H., Ikarashi, T., Nagata, M., Hoshina, H., Takagi, R., The basement membrane-type heparan sulfate proteoglycan (perlecan) in ameloblastomas: Its intercellular localization in stellate reticulum-like foci and biosynthesis by tumor cells in culture (2002) Virchows Arch, 441, pp. 165-173Ikarashi, T., Ida-Yonemochi, H., Ohshiro, K., Cheng, J., Saku, T., Intraepithelial expression of perlecan, a basement membrane-type heparan sulfate proteoglycan reflects dysplastic changes of the oral mucosal epithelium (2004) J Oral Pathol Med, 33, pp. 87-95Iozzo, R.V., Zoeller, J.J., Nystrom, A., Basement membrane proteoglycans: Modulators Par Excellence of cancer growth and angiogenesis (2009) Mol Cells, 27, pp. 503-513Winzen, U., Cole, G.J., Halfter, W., Agrin is a chimeric proteoglycan with the attachment sites for heparan sulfate/chondroitin sulfate located in two multiple serine-glycine clusters (2003) J Biol Chem, 278, pp. 30106-30114Somoracz, A., Tatrai, P., Horvath, G., Kiss, A., Kupcsulik, P., Agrin immunohistochemistry facilitates the determination of primary versus metastatic origin of liver carcinomas (2010) Hum Pathol, 41, pp. 1310-1319Batmunkh, E., Tatrai, P., Szabo, E., Lodi, C., Holczbauer, A., Comparison of the expression of agrin, a basement membrane heparan sulfate proteoglycan, in cholangiocarcinoma and hepatocellular carcinoma (2007) Hum Pathol, 38, pp. 1508-1515Agostini, M., Almeida, L.Y., Bastos, D.C., Ortega, R.M., Moreira, F.S., The Fatty Acid synthase inhibitor orlistat reduces the growth and metastasis of orthotopic tongue oral squamous cell carcinomas (2014) Mol Cancer Ther, 13, pp. 585-595Aragao, A.Z., Belloni, M., Simabuco, F.M., Zanetti, M.R., Yokoo, S., Novel processed form of syndecan-1 shed from SCC-9 cells plays a role in cell migration (2012) PLoS One, 7, p. e43521Silva, H., Frezard, F., Peterson, E.J., Kabolizadeh, P., Ryan, J.J., Heparan sulfate proteoglycan-mediated entry pathway for charged tri-platinum compounds: Differential cellular accumulation mechanisms for platinum (2012) Mol Pharm, 9, pp. 1795-1802Terp, M.G., Lund, R.R., Jensen, O.N., Leth-Larsen, R., Ditzel, H.J., Identification of markers associated with highly aggressive metastatic phenotypes using quantitative comparative proteomics (2012) Cancer Genomics Proteomics, 9, pp. 265-273Noguti, J., De Moura, C.F., De Jesus, G.P., Da Silva, V.H., Hossaka, T.A., Metastasis from oral cancer: An overview (2012) Cancer Genomics Proteomics, 9, pp. 329-335O'Donnell, R.K., Kupferman, M., Wei, S.J., Singhal, S., Weber, R., Gene expression signature predicts lymphatic metastasis in squamous cell carcinoma of the oral cavity (2005) Oncogene, 24, pp. 1244-1251Chang, K.P., Yu, J.S., Chien, K.Y., Lee, C.W., Liang, Y., Identification of PRDX4 and P4HA2 as metastasis-associated proteins in oral cavity squamous cell carcinoma by comparative tissue proteomics of microdissected specimens using iTRAQ technology (2011) J Proteome Res, 10, pp. 4935-4947Chai, Y.D., Zhang, L., Yang, Y., Su, T., Charugundla, P., Discovery of potential serum protein biomarkers for lymph-node metastasis in oral cancer (2014) Head NeckFeller, L.L.J., Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment (2012) Journal of Cancer Therapy, 3, pp. 263-268Afratis, N., Gialeli, C., Nikitovic, D., Tsegenidis, T., Karousou, E., Glycosaminoglycans: Key players in cancer cell biology and treatment (2012) FEBS J, 279, pp. 1177-1197Fuster, M.M., Esko, J.D., The sweet and sour of cancer: Glycans as novel therapeutic targets (2005) Nat Rev Cancer, 5, pp. 526-542Vlodavsky, I., Friedmann, Y., Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis (2001) J Clin Invest, 108, pp. 341-347Goldshmidt, O., Zcharia, E., Abramovitch, R., Metzger, S., Aingorn, H., Cell surface expression and secretion of heparanase markedly promote tumor angiogenesis and metastasis (2002) Proc Natl Acad Sci U S A, 99, pp. 10031-10036Pantazaka, E., Papadimitriou, E., Chondroitin sulfate-cell membrane effectors as regulators of growth factor-mediated vascular and cancer cell migration (2014) Biochim Biophys Acta, 1840, pp. 2643-2650Cattaruzza, S., Perris, R., Proteoglycan control of cell movement during wound healing and cancer spreading (2005) Matrix Biol, 24, pp. 400-417Zhou, Z., Wang, J., Cao, R., Morita, H., Soininen, R., Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice (2004) Cancer Res, 64, pp. 4699-4702Whitelock, J.M., Graham, L.D., Melrose, J., Murdoch, A.D., Iozzo, R.V., Human perlecan immunopurified from different endothelial cell sources has different adhesive properties for vascular cells (1999) Matrix Biol, 18, pp. 163-178Klein, G., Conzelmann, S., Beck, S., Timpl, R., Muller, C.A., Perlecan in human bone marrow: A growth-factor-presenting, but anti-adhesive, extracellular matrix component for hematopoietic cells (1995) Matrix Biol, 14, pp. 457-465Bix, G., Iozzo, R.V., Matrix revolutions: Tail of basement-membrane components with angiostatic functions (2005) Trends Cell Biol, 15, pp. 52-60Hayashi, K., Madri, J.A., Yurchenco, P.D., Endothelial cells interact with the core protein of basement membrane perlecan through beta 1 and beta 3 integrins: An adhesion modulated by glycosaminoglycan (1992) J Cell Biol, 119, pp. 945-959Martin, P.T., Sanes, J.R., Integrins mediate adhesion to agrin and modulate agrin signaling (1997) Development, 124, pp. 3909-3917Yip, G.W., Smollich, M., Gotte, M., Therapeutic value of glycosaminoglycans in cancer (2006) Mol Cancer Ther, 5, pp. 2139-2148Zhang, J.S., Anraku, M., Kadowaki, D., Imai, T., Suenaga, A., Spectroscopic studies of interactions of chondroitin sulfates with cisplatin (2011) Carbohydr Res, 346, pp. 631-637Rabik, C.A., Dolan, M.E., Molecular mechanisms of resistance and toxicity associated with platinating agents (2007) Cancer Treat Rev, 33, pp. 9-23Galluzzi, L., Senovilla, L., Vitale, I., Michels, J., Martins, I., Molecular mechanisms of cisplatin resistance (2012) Oncogene, 31, pp. 1869-1883Dasari, S., Bernard Tchounwou, P., Cisplatin in Cancer therapy: Molecular mechanisms of action (2014) Eur J PharmacolBarr, M.P., Gray, S.G., Hoffmann, A.C., Hilger, R.A., Thomale, J., Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature (2013) PLoS One, 8, p. e54193Eberle, K.E., Sansing, H.A., Szaniszlo, P., Resto, V.A., Berrier, A.L., Carcinoma matrix controls resistance to cisplatin through talin regulation of NF-kB (2011) PLoS One, 6, p. e21496Teng, P.N., Wang, G., Hood, B.L., Conrads, K.A., Hamilton, C.A., Identification of candidate circulating cisplatin-resistant biomarkers from epithelial ovarian carcinoma cell secretomes (2014) Br J Cancer, 110, pp. 123-13