فایل ورد کامل سورافنیب در آماس سرطانی هپاتوسلولی پیشرفته

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تعداد صفحات این فایل: ۲۵ صفحه

همان طور که در درمان بسیاری از سرطان های هپاتوسلولی قبلی مشاهده شد، رویداد های نامطلوب ناشی از  سرطان کبدُ رویداد های مربوط به سورافنیب موجب کاهش دوز و  ایجاد برخی اختلالات در زیر گروه بیماران شد. مطالعات قبلی خطرات قلبی و عروقی را در بیماران درمان شده با سورافنیب و دیگر بازدارنده های کیناز تیروزین گوشزد کرده اند. این مطالعهُ افزایش کلی را در خطرات ابتلا به خونریزی در دو گروه مطالعه شده را نشان داد و این در حالی است که این مطالعه  جامعی برای تثبیت وقوع برخی رویداد های نامطلوب نمی باشد. به طور خلاصه، این مطالعه نشان داد که  سورافنیب موجب افزایش طول عمر و مدت زمان بروز بیماری تا ۳ ماه در ی بیماران با  سرطان هپاتوسلولی شد. مطالعات آینده می توانند به ارزیابی سورافنیب به عنوان یک داروی جانبی پس از داروهای اصلی  بپردازند.  همچنین مطالعاتی برای ارزیابی سورافنیب همراه با درمان های هدفمند مولکولی و نیز معیارهای استاندارد بر اساس رهنمود های جدید برای طراحی آزمون های بالینی   نیاز هستند.

عنوان انگلیسی:Sorafenib in Advanced Hepatocellular Carcinoma~~en~~

Hepatocellular carcinoma is a major health problem, accounting for more than 626,000 new cases per year worldwide.1 The incidence of hepatocellular carcinoma is increasing in the United States and Europe, and it is the third highest cause of cancer-related death globally, behind only lung and stomach cancers.1 In the West, the disease is diagnosed in 30 to 40% of all patients at early stages and is amenable to potentially curative treatments, such as surgical therapies (resection and liver transplantation) and locoregional procedures (radiofrequency ablation).2 Five-year survival rates of up to 60 to 70% can be achieved in well-selected patients.2 However, disease that is diagnosed at an advanced stage or with progression after locoregional therapy has a dismal prognosis, owing to the underlying liver disease and lack of effective treatment options.2-4 No systemic therapy has improved survival in patients with advanced hepatocellular carcinoma.5,6 Sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals–Onyx Pharmaceuticals) is a small molecule that inhibits tumor-cell proliferation and tumor angiogenesis and increases the rate of apoptosis in a wide range of tumor models.7,8 It acts by inhibiting the serine–threonine kinases Raf-1 and B-Raf and the receptor tyrosine kinase activity of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3 and platelet-derived growth factor receptor (PDGFR-).7,8 Cellular signaling that is mediated by the Raf-1 and vascular endothelial growth factor (VEGF) pathways has been implicated in the molecular pathogenesis of hepatocellular carcinoma,9-12 providing a rationale for investigating sorafenib for this indication. In preclinical experiments, sorafenib had antiproliferative activity in liver-cancer cell lines, and it reduced tumor angiogenesis and tumor-cell signaling and increased tumor-cell apoptosis in a mouse xenograft model of human hepatocellular carcinoma.13 Results of an uncontrolled phase 2 study involving 137 patients with advanced hepatocellular carcinoma and Child–Pugh class A or B status indicated that single-agent sorafenib might have a beneficial therapeutic effect. Sorafenib treatment resulted in a median overall survival of 9.2 months and a median time to progression of 5.5 months (as assessed by independent radiologic evaluation).14 On the basis of these data, we conducted a large phase 3, randomized, double-blind, placebocontrolled trial to assess the efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma. Methods Patients The study population consisted of patients with advanced-stage hepatocellular carcinoma, as confirmed by pathological analysis. None of the patients had received previous systemic therapy. Patients were classified as having advanced disease if they were not eligible for or had disease progression after surgical or locoregional therapies. The eligibility criteria also included an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less (Table A1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org),15 Child–Pugh liver function class A (Table A2 in the Supplementary Appendix),16,17 a life expectancy of 12 weeks or more, adequate hematologic function (platelet count, 60×۱۰۹ per liter; hemoglobin, 85 g per deciliter; and prothrombin time international normalized ratio, 23; or prothrombin time, 6 seconds above control), adequate hepatic function (albumin, 28 g per deciliter; total bilirubin, 3 mg per deciliter [51.3 mol per liter]; and alanine aminotransferase and aspartate aminotransferase, 5 times the upper limit of the normal range), and adequate renal function (serum creatinine, 15 times the upper limit of the normal range). Patients were required to have at least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST) (Table A3 in the Supplementary Appendix).18 Concomitant antiviral systemic therapy was allowed. Patients were excluded if they had previously received molecularly targeted therapies or any other systemic treatment. All patients provided written informed consent before enrollment in the study. The study was approved by the institutional review board or ethics committee at each center and complied with the provisions of the Good Clinical Practice guidelines and the Declaration of Helsinki and local laws. Study Design This multicenter, randomized, double-blind, placebo-controlled, phase 3 trial was conducted at 121 centers in 21 countries in Europe, North America, South America, and Australasia.All eligible patients were randomly assigned in a 1:1 ratio to receive continuous oral treatment with either 400 mg of sorafenib (consisting of two 200-mg tablets) twice daily or matching placebo (both sup plied by Bayer HealthCare Pharmaceuticals). Study randomization was centralized, and assignment to study groups was conducted by computer to achieve a balance between the two groups, with stratification before randomization according to region, ECOG performance status (a score of 0 vs. a score of 1 or 2), and the presence or absence of macroscopic vascular invasion (portal vein or branches) or extrahepatic spread.

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