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      Therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: State-of-the-art and future perspectives

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          Abstract

          Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have always been considered rare tumors, their incidence has risen over the past few decades. They represent a highly heterogeneous group of neoplasms with several prognostic factors, including disease stage, proliferative index (Ki67), and tumor differentiation. Most of these neoplasms express somatostatin receptors on the cell surface, a feature that has important implications in terms of prognosis, diagnosis, and therapy. Although International Guidelines propose algorithms aimed at guiding therapeutic strategies, GEP-NEN patients are still very different from one another, and the need for personalized treatment continues to increase. Radical surgery is always the best option when feasible; however, up to 80% of cases are metastatic upon diagnosis. Regarding medical treatments, as GEP-NENs are characterized by relatively long overall survival, multiple therapy lines are adopted during the lifetime of these patients, but the optimum sequence to be followed has never been clearly defined. Furthermore, although new molecular markers aimed at predicting the response to therapy, as well as prognostic scores, are currently being studied, their application is still far from being part of daily clinical practice. As they represent a complex disease, with therapeutic protocols that are not completely standardized, GEP-NENs require a multidisciplinary approach. This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.

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          Most cited references179

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          Mutational heterogeneity in cancer and the search for new cancer genes

          Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.
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            Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States.

            The incidence and prevalence of neuroendocrine tumors (NETs) are thought to be rising, but updated epidemiologic data are lacking.
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              Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.

              The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).
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                Author and article information

                Contributors
                Journal
                World J Gastrointest Surg
                WJGS
                World Journal of Gastrointestinal Surgery
                Baishideng Publishing Group Inc
                1948-9366
                27 February 2022
                27 February 2022
                : 14
                : 2
                : 78-106
                Affiliations
                Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy. elettra.merola@ 123456apss.tn.it
                Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
                Department of Radiology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
                Department of Nuclear Medicine, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
                Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
                Department of Surgery, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
                Department of Pathology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
                Department of Medical Oncology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
                Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
                Department of Nuclear Medicine, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
                Author notes

                Author contributions: All authors performed the literature research, wrote the manuscript, and read and approved the final manuscript.

                Corresponding author: Elettra Merola, MD, PhD, Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Largo Medaglie D’Oro 9, Trento 38122, Italy. elettra.merola@ 123456apss.tn.it

                Article
                jWJGS.v14.i2.pg78
                10.4240/wjgs.v14.i2.78
                8908345
                f3096a72-4b96-488a-991d-ee843e190ced
                ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

                History
                : 20 March 2021
                : 18 October 2021
                : 25 January 2022
                Categories
                Frontier

                gastroenteropancreatic neuroendocrine neoplasms,therapeutic strategies,radical surgery,medical treatments,overview,future perspectives

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