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      Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met.

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          Abstract

          Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26-amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met-expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.

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          Most cited references 30

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          Global cancer statistics.

          The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
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            A genetic model for colorectal tumorigenesis

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              Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial.

              Colorectal cancer is the third most common cancer worldwide and has a high mortality rate. We tested the hypothesis that only one flexible sigmoidoscopy screening between 55 and 64 years of age can substantially reduce colorectal cancer incidence and mortality. This randomised controlled trial was undertaken in 14 UK centres. 170 432 eligible men and women, who had indicated on a previous questionnaire that they would accept an invitation for screening, were randomly allocated to the intervention group (offered flexible sigmoidoscopy screening) or the control group (not contacted). Randomisation by sequential number generation was done centrally in blocks of 12, with stratification by trial centre, general practice, and household type. The primary outcomes were the incidence of colorectal cancer, including prevalent cases detected at screening, and mortality from colorectal cancer. Analyses were intention to treat and per protocol. The trial is registered, number ISRCTN28352761. 113 195 people were assigned to the control group and 57 237 to the intervention group, of whom 112 939 and 57 099, respectively, were included in the final analyses. 40 674 (71%) people underwent flexible sigmoidoscopy. During screening and median follow-up of 11.2 years (IQR 10.7-11.9), 2524 participants were diagnosed with colorectal cancer (1818 in control group vs 706 in intervention group) and 20 543 died (13 768 vs 6775; 727 certified from colorectal cancer [538 vs 189]). In intention-to-treat analyses, colorectal cancer incidence in the intervention group was reduced by 23% (hazard ratio 0.77, 95% CI 0.70-0.84) and mortality by 31% (0.69, 0.59-0.82). In per-protocol analyses, adjusting for self-selection bias in the intervention group, incidence of colorectal cancer in people attending screening was reduced by 33% (0.67, 0.60-0.76) and mortality by 43% (0.57, 0.45-0.72). Incidence of distal colorectal cancer (rectum and sigmoid colon) was reduced by 50% (0.50, 0.42-0.59; secondary outcome). The numbers needed to be screened to prevent one colorectal cancer diagnosis or death, by the end of the study period, were 191 (95% CI 145-277) and 489 (343-852), respectively. Flexible sigmoidoscopy is a safe and practical test and, when offered only once between ages 55 and 64 years, confers a substantial and longlasting benefit. Medical Research Council, National Health Service R&D, Cancer Research UK, KeyMed. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Nat. Med.
                Nature medicine
                1546-170X
                1078-8956
                Aug 2015
                : 21
                : 8
                Affiliations
                [1 ] Centre for Human Drug Research, Leiden, the Netherlands.
                [2 ] GE Healthcare, Oslo, Norway.
                [3 ] GE Global Research Centre, Niskayuna, New York, USA.
                [4 ] Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
                [5 ] Pathology Diagnostics Ltd., St. John's Innovation Centre, Cambridge, UK.
                [6 ] Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
                [7 ] Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
                [8 ] GE Healthcare, Amersham, UK.
                Article
                nm.3641
                10.1038/nm.3641
                26168295

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