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      Primary Thromboprophylaxis in Pancreatic Cancer Patients: Why Clinical Practice Guidelines Should Be Implemented

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          Abstract

          Exocrine pancreatic ductal adenocarcinoma, simply referred to as pancreatic cancer (PC) has the worst prognosis of any malignancy. Despite recent advances in the use of adjuvant chemotherapy in PC, the prognosis remains poor, with fewer than 8% of patients being alive at 5 years after diagnosis. The prevalence of PC has steadily increased over the past decades, and it is projected to become the second-leading cause of cancer-related death by 2030. In this context, optimizing and integrating supportive care is important to improve quality of life and survival. Venous thromboembolism (VTE) is a common but preventable complication in PC patients. VTE occurs in one out of five PC patients and is associated with significantly reduced progression-free survival and overall survival. The appropriate use of primary thromboprophylaxis can drastically and safely reduce the rates of VTE in PC patients as shown from subgroup analysis of non-PC targeted placebo-controlled randomized trials of cancer patients and from two dedicated controlled randomized trials in locally advanced PC patients receiving chemotherapy. Therefore, primary thromboprophylaxis with a Grade 1B evidence level is recommended in locally advanced PC patients receiving chemotherapy by the International Initiative on Cancer and Thrombosis clinical practice guidelines since 2013. However, its use and potential significant clinical benefit continues to be underrecognized worldwide. This narrative review aims to summarize the main recent advances in the field including on the use of individualized risk assessment models to stratify the risk of VTE in each patient with individual available treatment options.

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          Epidemiology of cancer-associated venous thrombosis.

          Cancer-associated venous thrombosis is a common condition, although the reported incidence varies widely between studies depending on patient population, start and duration of follow-up, and the method of detecting and reporting thrombotic events. Furthermore, as cancer is a heterogeneous disease, the risk of venous thrombosis depends on cancer types and stages, treatment measures, and patient-related factors. In general, cancer patients with venous thrombosis do not fare well and have an increased mortality compared with cancer patients without. This may be explained by the more aggressive type of malignancies associated with this condition. It is hypothesized that thromboprophylaxis in cancer patients might improve prognosis and quality of life by preventing thrombotic events. However, anticoagulant treatment leads to increased bleeding, particularly in this patient group, so in case of proven benefit of thromboprophylaxis, only patients with a high risk of venous thrombosis should be considered. This review describes the literature on incidence of and risk factors for cancer-associated venous thrombosis, with the aim to provide a basis for identification of high-risk patients and for further development and refinement of prediction models. Furthermore, knowledge on risk factors for cancer-related venous thrombosis may enhance the understanding of the pathophysiology of thrombosis in these patients.
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            Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer

            Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second most common cause of death within the next 10 years. The prognosis for this disease is poor despite diagnostic progress and new chemotherapeutic regimens. The oncogenic KRAS mutation is the major event in pancreatic cancer; it confers permanent activation of the KRAS protein, which acts as a molecular switch to activate various intracellular signalling pathways and transcription factors inducing cell proliferation, migration, transformation and survival. Several laboratory methods have been developed to detect KRAS mutations in biological samples, including digital droplet PCR (which displays high sensitivity). Clinical studies have revealed that a KRAS mutation assay in fine-needle aspiration material combined with cytopathology increases the sensitivity, accuracy and negative predictive value of cytopathology for a positive diagnosis of pancreatic cancer. In addition, the presence of KRAS mutations in serum and plasma (liquid biopsies) correlates with a worse prognosis. The presence of mutated KRAS can also have therapeutic implications, whether at the gene level per se, during its post-translational maturation, interaction with nucleotides and after activation of the various oncogenic signals. Further pharmacokinetic and toxicological studies on new molecules are required, especially small synthetic molecules, before they can be used in the therapeutic arsenal for pancreatic ductal adenocarcinoma.
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              The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

              Summary Background Worldwide, both the incidence and death rates of pancreatic cancer are increasing. Evaluation of pancreatic cancer burden and its global, regional, and national patterns is crucial to policy making and better resource allocation for controlling pancreatic cancer risk factors, developing early detection methods, and providing faster and more effective treatments. Methods Vital registration, vital registration sample, and cancer registry data were used to generate mortality, incidence, and disability-adjusted life-years (DALYs) estimates. We used the comparative risk assessment framework to estimate the proportion of deaths attributable to risk factors for pancreatic cancer: smoking, high fasting plasma glucose, and high body-mass index. All of the estimates were reported as counts and age-standardised rates per 100 000 person-years. 95% uncertainty intervals (UIs) were reported for all estimates. Findings In 2017, there were 448 000 (95% UI 439 000–456 000) incident cases of pancreatic cancer globally, of which 232 000 (210 000–221 000; 51·9%) were in males. The age-standardised incidence rate was 5·0 (4·9–5·1) per 100 000 person-years in 1990 and increased to 5·7 (5·6–5·8) per 100 000 person-years in 2017. There was a 2·3 times increase in number of deaths for both sexes from 196 000 (193 000–200 000) in 1990 to 441 000 (433 000–449 000) in 2017. There was a 2·1 times increase in DALYs due to pancreatic cancer, increasing from 4·4 million (4·3–4·5) in 1990 to 9·1 million (8·9–9·3) in 2017. The age-standardised death rate of pancreatic cancer was highest in the high-income super-region across all years from 1990 to 2017. In 2017, the highest age-standardised death rates were observed in Greenland (17·4 [15·8–19·0] per 100 000 person-years) and Uruguay (12·1 [10·9–13·5] per 100 000 person-years). These countries also had the highest age-standardised death rates in 1990. Bangladesh (1·9 [1·5–2·3] per 100 000 person-years) had the lowest rate in 2017, and São Tomé and Príncipe (1·3 [1·1–1·5] per 100 000 person-years) had the lowest rate in 1990. The numbers of incident cases and deaths peaked at the ages of 65–69 years for males and at 75–79 years for females. Age-standardised pancreatic cancer deaths worldwide were primarily attributable to smoking (21·1% [18·8–23·7]), high fasting plasma glucose (8·9% [2·1–19·4]), and high body-mass index (6·2% [2·5–11·4]) in 2017. Interpretation Globally, the number of deaths, incident cases, and DALYs caused by pancreatic cancer has more than doubled from 1990 to 2017. The increase in incidence of pancreatic cancer is likely to continue as the population ages. Prevention strategies should focus on modifiable risk factors. Development of screening programmes for early detection and more effective treatment strategies for pancreatic cancer are needed. Funding Bill & Melinda Gates Foundation.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                06 March 2020
                March 2020
                : 12
                : 3
                : 618
                Affiliations
                [1 ]Institut Universitaire d’Hématologie, Université de Paris, EA 3518, F-75010 Paris, France
                [2 ]Assistance Publique Hôpitaux de Paris, Saint-Louis Hospital, Internal Medicine, Autoimmune and Vascular Disease Unit, F-75010 Paris, France
                [3 ]Department of Medicine, McGill University, Montreal, Québec, QC H4A 3J1, Canada
                [4 ]University of Toulouse, F-31059 Toulouse, France; bournet.b@ 123456chu-toulouse.fr (B.B.); buscail.l@ 123456chu-toulouse.fr (L.B.)
                [5 ]CHU de Toulouse, Department of Gastroenterology and Pancreatology, F-31059 Toulouse, France
                [6 ]Institut de Cancérologie de Lorraine, Department of Medical Oncology, Université de Lorraine, APEMAC, EA4360, F-54519 Vandoeuvre-lès-Nancy, France; t.conroy@ 123456nancy.unicancer.fr
                [7 ]Department of Biostatistics, Université de Paris, F-75010 Paris, France; eric.vicaut@ 123456aphp.fr
                [8 ]Assistance Publique Hôpitaux de Paris, Department of Biostatistics, Fernand Widal Hospital, F-75010 Paris, France
                [9 ]McGill University and the Research Institute of the McGill University Health Centre, Montreal, Québec, QC H4A 3J1, Canada; janusz.rak@ 123456mcgill.ca (J.R.);
                [10 ]Department of Digestive, Oncological, Endocrine, and Hepatic Surgery, and Hepatic Transplantation, Trousseau Hospital, CHRU Trousseau, F-37170 Chambray-les-Tours, France; m.ouaissi@ 123456chu-tours.fr
                [11 ]Institute of Cardiometabolism and Nutrition, Sorbonne Université, INSERM UMRS_1166, GRC 27 GRECO, F-75013 Paris, France; corinne.frere@ 123456aphp.fr
                [12 ]Assistance Publique Hôpitaux de Paris, Department of Haematology, Pitié-Salpêtrière Hospital, F-75013 Paris, France
                Author notes
                Author information
                https://orcid.org/0000-0002-3679-9454
                https://orcid.org/0000-0002-0906-4428
                https://orcid.org/0000-0003-4276-1003
                https://orcid.org/0000-0001-6303-4732
                Article
                cancers-12-00618
                10.3390/cancers12030618
                7139861
                32155940
                9d6ba5f8-dfc1-45c3-a75e-d466a12817e5
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 February 2020
                : 04 March 2020
                Categories
                Review

                pancreatic cancer,venous thromboembolism,thromboprophylaxis,low-molecular weight heparin,direct oral anticoagulant,survival

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