Somos estos nervios y esta sangre. Entrevista a Davide Enia

Davide Enia (Palermo, 1974) se inicia en la escena italiana en laboratorios teatrales de manos de Danio Manfredini, Rena Mirecka, Tapa Sudana y Laura Curino, pero es en 2002 cuando, con su Italia-Brasile 3 a 2, un monólogo en el que escenifica la partida de fútbol entre ambos equipos en el mundial de 1982, comienza a adentrarse en la modalidad del teatro como narrador solista. Su siguiente Maggio ‘43 (2003), sobre los bombardeos de su Palermo natal durante la Segunda Guerra Mundial, profundizará en las peculiaridades de su dramaturgia de estos años, caracterizada por un uso cada vez más pronunciado del dialecto y por un desarrollo de las influencias del cunto siciliano. Los premios recibidos los años siguientes (el Ubu y el Hystrio, entre otros), lo consolidan como uno de los miembros más destacados de su generación. Además de interesantísimos espectáculos teatrales en los que combina narración y música, como I capitoli dell'infanzia (2007) o Canti e cunti (2009), Davide Enia ha desarrollado los últimos años una notable producción novelística, con títulos como Così in terra (2012) y Uomini e pecore (2014)

Budget impact analysis of the use of daclatasvir in Italy for the treatment of Hepatitis C Virus (HCV) genotype 3 patients

BACKGROUND: Hepatitis C Virus (HCV) infection represents a global health problem, leading to chronic cirrhosis, hepatocellular carcinoma (HCC), hepatic decompensation and liver transplant. The aim of the study was the evaluation of the impact on the budget of the Italian National Health Service (INHS) of the use of Daclatasvir (DCV) for the treatment of HCV genotype 3 in patients with advanced fibrosis.METHODS: An analytical decision model with a five year time horizon was implemented. Two scenarios were considered: a. 100% of market share for Interferon (INF-α)+Ribavirin (RBV)+Sofosbuvir (SOF) for 12 weeks; b. SOF+DCV+RBV for 24 weeks with annual market shares of 50% in 2015 and 2016, 55% in 2017 and 2018, 60% in 2019, and INF-α+RBV+SOF for 12 weeks with the remaining market shares. Every annual cycle a percentage of patients equal to the effectiveness of the antiviral treatment reach a sustained virologic response and during the first year of treatment patients may experience treatment related adverse events. The costs considered (2015) are those of the antiviral therapy, and direct medical costs for health state and adverse events management. Univariate and multivariate sensitivity analyses were performed.RESULTS: DCV would lead to an increase of the costs for the INHS (year 1 +21.31 millions, year 2 +21.35 millions, year 3 + 23.37 millions, year 4 + 23.26 millions and year 5 +16.37 millions). The sensitivity analysis confirmed the robustness of the results.CONCLUSIONS: The use of DCV is likely to have a short term impact on the INHS budget increasing resources use compared to the sole use of INF-α+RBV+SOF. However, a trend of reduction of the costs increase is observed due to the management of health states and adverse events which may lead to the possibility to reduce costs in the long term

Safety and comfort of domestic bortezomib injection in real-life experience

Despite novel agents, multiple myeloma is still an incurable disease, especially for elderly and frail patients, who are difficult to manage for concomitant comorbidities as the therapeutic options are limited and the response to chemotherapy is often short. We report our evaluations upon safety and efficacy of domestic subcutaneous bortezomib in elderly and frail patients candidate to bortezomib-melphalan-prednisone (VMP) regimen. We confirmed that overall incidence of adverse events, including peripheral neuropathy, was low, and in no case required admission to emergency service, contributing to reduce the rate of therapy discontinuation. These results confirm the effectiveness and safety of subcutaneous bortezomib, in a real-life-experience, and define a new possibility of safe auto-administration in a comfortable domestic setting. We suggest that domestic treatment can significantly improve the quality of life of the patients, avoiding unnecessary transfer to the hospital without reducing treatment efficacy

Regulação da ativação epigenética do gene MMP2 diante da sinalização da fibronectina em linhagens tumorais de mama

Orientadora : Profª Drª Giseli KlassenCo-orientadora : Profª Drª Edneia A. S. R. CavalieriDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Microbiologia, Parasitologia e Patologia. Defesa: Curitiba, 02/12/2014Inclui referênciasÁrea de concentraçãoResumo: O câncer de mama é o tipo de câncer mais frequente entre as mulheres em todo o mundo. A enzima MMP-2 é uma metaloprotease capaz de degradar o colágeno tipo IV, um dos principais constituintes da matriz extracelular (MEC). Sua função é amplamente descrita por atuar no mecanismo de metástases em diversos tipos de câncer. Estudos recentes demonstraram que a linhagem tumoral de mama MCF7 possui o gene MMP2 regulado por metilação do DNA. Além disso, alguns estudos têm demonstrado que a fibronectina, uma importante proteína constituinte da MEC, é capaz de promover a expressão de MMP-2 em linhagens tumorais de mama. Resultados recentes do nosso grupo mostraram que a linhagem tumoral MCF7 quando tratada com fibronectina por 5 horas sofre 30% de desmetilação da região promotora do gene MMP2. Entretanto, observou-se também que tal processo foi transitório, porque houve a remetilação parcial do promotor quando o estímulo foi retirado. Ainda, a fibronectina induziu o aumento de uma marca de histona no promotor de MMP2 que sinaliza para a ativação da transcrição gênica. Diante disso, o objetivo deste trabalho foi dar continuidade a esse estudo, avaliando a regulação epigenética do gene MMP2 em linhagens tumorais de mama após o cultivo com fibronectina em diferentes tempos. Para isso, células da linhagem MCF7 submetidas ao tratamento com fibronectina por 8, 12 e 24 horas, e da linhagem MDA-MB-436 por 24 horas, tiveram seus níveis de expressão de MMP2, metilação do DNA e modificações de histonas do promotor do gene avaliados. Na linhagem MCF7, o tratamento por 8, 12 e 24 horas foi capaz de promover o aumento da expressão de MMP2 em 7, 25 e 9 vezes, respectivamente, comparado com o controle, assim como a redução da metilação do promotor de 90% (controle) para 70%, 40% e 52%, respectivamente. O tratamento por 24h também promoveu o aumento da marca de ativação gênica H3K4me3. Ainda, após 12h de cultivo com fibronectina, a linhagem MCF7 aumentou sua capacidade migratória. A fim de verificar se o efeito observado não era exclusivo da linhagem MCF7, foi incluída no estudo a linhagem MDA-MB-436 que foi submetida ao tratamento por 24h, e apresentou aumento na expressão gênica de MMP2 (4 vezes) e redução da metilação do promotor (de 90% para 22%). Por fim, as células tratadas foram mantidas em cultivo sem a fibronectina para avaliar a estabilidade das modificações. Essas células, chamadas de recultivo, apresentaram uma redução na expressão gênica e aumento na metilação do promotor quando comparadas com as células logo após os tratamentos, confirmando o efeito transitório da fibronectina nos eventos epigenéticos, que já tinha sido observado após 5 horas de tratamento. Esses dados corroboram e complementam os mecanismos observados pelo nosso grupo de pesquisa e contribuem para a compreensão dos mecanismos epigenéticos que regulam a expressão de um importante gene associado às metástases tumorais. Palavras-chave: Câncer de mama, MMP-2, epigenética, metilação do DNA.Abstract: Breast cancer is the most common cancer worldwide among women. The MMP- 2 enzyme is a metalloprotease capable of degrading type IV collagen, a major constituent of the extracellular matrix (ECM). Its function is widely described by acting in the mechanism of metastasis in various cancers. Recent data has shown that the MCF7 breast tumor cell line has the MMP2 gene regulated by DNA methylation. In addition, some studies have shown that fibronectin, an important constituent of the extracellular matrix, is capable of promoting MMP-2 expression in breast tumor cell lines. Recent results from our group showed that fibronectin was able to induce MMP2 expression by a 30% decrease in its promoter methylation in MCF7 tumor cell line. However, it was also noted that this process was transient, because a partial promoter remethylation was observed when the stimulus was removed. Moreover, a histone marker for an open chromatin conformation was significantly increased. Therefore, the aim of this work was to continue evaluating the epigenetic regulation of the MMP2 gene after cultivation of breast tumor cell lines with fibronectin at different times. To this reason, MCF7 cells subjected to treatment with fibronectin for 8, 12 and 24 hours and MDA-MB-436 cells subjected to treatment for 24 hours, were evaluated by the levels of MMP2 expression, gene promoter DNA methylation and histone modifications. In the MCF7 cell line, treatments for 8, 12 and 24 hours were able to promote 7, 9 and 25-fold increase in MMP2 expression, respectively, compared with the mock. In addition, promoter methylation was reduced from 90% (control) to 70%, 40% and 52%, respectively. Treatment for 24h also promoted an increase of the histone open chromatin conformation marker H3K4me3. Moreover, the migratory capacity of MCF7 cells treated for 12h was increased. In order to confirm the fibronectin effect, the MDA-MB-436 cell line was subjected to 24h fibronectin treatment, which showed an increase in MMP2 gene expression (4-fold) and a reduction of promoter methylation (from 90% to 22%). Finally, the treated cells were kept in culture without fibronectin to evaluate the modifications stability. These cells (recultivation) showed a gene expression reduction and promoter methylation increased when compared to the cells after treatments, confirming the fibronectin transient effect observed after the 5h treatment. These data support and complement the mechanisms observed by our research group and contribute to understand the epigenetic mechanisms that regulate the expression of an important gene associated with tumor metastasis. Keywords: Breast cancer, MMP-2, epigenetics, DNA methylation

Whole-body radioiodine effective half-life in patients with differentiated thyroid cancer

Background: Radioactive 131I (RAI) therapy is used in patients with differentiated thyroid cancer (DTC) after total thyroidectomy for remnant ablation, adjuvant treatment or treatment of persistent disease. 131I retention data, which are used to indicate the time at which a 131I treated DTC patient can be released from the hospital, may bring some insights regarding clinical factors that prolong the length of hospitalization. The aim of this study was to investigate the 131I whole-body retention in DTC patients during 131I therapy. Methods: We monitored 166 DTC patients to follow the 131I whole-body retention during 131I therapy with a radioactivity detector fixed on the ceiling of each protected room. A linear regression fit permitted us to estimate the whole-body 131I effective half-life in each patient, and a relationship was sought between patients’ clinical characteristics and whole-body effective 131I half-life. Results: The effective 131I half-life ranged from 4.08 to 56.4 h. At multivariable analysis, longer effective 131I half-life was related to older age and extensive extra-thyroid disease. Conclusions: 131I effective half-life during 131I treatment in DTC patients is highly variable among patients and is significantly longer in older and in patients with RAI uptake in large thyroid remnants or in extrathyroidal disease that significantly prolongs the whole-body retention of 131I

Initial Testing of an Approximated, Fast Calculation Procedure for Personalized Dosimetry in Radionuclide Therapy Based on Planar Whole-Body Scan and Monte-Carlo Specific Dose Rates from the OpenDose Project

Individualized dosimetry in nuclear medicine is currently at least advisable in order to obtain the best risk–benefit balance in terms of the maximal dose to lesions and under-threshold doses to radiosensitive organs. This article aims to propose a procedure for fast dosimetric calculations based on planar whole-body scintigraphy (WBS) images and developed to be employed in everyday clinical practice. Methods: For simplicity and legacy reasons, the method is based on planar imaging dosimetry, complemented with some assumptions on the radiopharmaceutical kinetics empirically derived from single-photon emission tomography/computed tomography (SPECT/CT) image analysis. The idea is to exploit a rough estimate of the time-integrated activity as has been suggested for SPECT/CT dosimetry but using planar images. The resulting further reduction in dose estimation accuracy is moderated by the use of a high-precision Monte-Carlo S-factor, such as those available within the OpenDose project. Results: We moved the problem of individualized dosimetry to a transformed space where comparing doses was imparted to the ICRP Average Male/Female computational phantom, resulting from an activity distribution related to patient’s pharmaceutical uptake. This is a fast method for the personalized dosimetric evaluation of radionuclide therapy, bearing in mind that the resulting doses are meaningful in comparison with thresholds calculated in the same framework. Conclusion: The simplified scheme proposed here can help the community, or even the single physician, establish a quantitative guide-for-the-eye approach to individualized dosimetry

Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin

Simple Summary Gemtuzumab Ozogamicin (GO) is a drug approved for the treatment of acute myeloid leukemia (AML). It targets leukemic cells that express the CD33 molecule on their surface and brings the toxic agent calicheamicin inside the cell to kill it. Several studies have shown that AML patients can benefit of the addition of GO to chemotherapy during induction regimens, pre- and post-transplantation. Moreover, some disease features have been addressed or are under investigation for their capacity to predict response to GO, with the future aim of selecting AML patients that can mostly benefit of GO treatment. Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33(+) AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response