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      Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma

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          Abstract

          Background

          Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC.

          Materials and methods

          Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS).

          Results

          All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses.

          Conclusion

          In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

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          Most cited references22

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          Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis.

          Inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis. In most cases, the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a hallmark of cancer cells. Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional oncogenic functions that endow cells with growth and survival advantages. Interestingly, mutations in the p53 gene were shown to occur at different phases of the multistep process of malignant transformation, thus contributing differentially to tumor initiation, promotion, aggressiveness, and metastasis. Here, the authors review the different studies on the involvement of p53 inactivation at various stages of tumorigenesis and highlight the specific contribution of p53 mutations at each phase of cancer progression.
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            Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

            As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.
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              ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas

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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: VisualizationRole: Writing – original draft
                Role: Data curationRole: InvestigationRole: ValidationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Funding acquisitionRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Project administrationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                7 November 2017
                2017
                : 12
                : 11
                : e0187667
                Affiliations
                [1 ] Department of Medical Sciences, Section of Endocrine Oncology, Uppsala University, Uppsala, Sweden
                [2 ] Department of Pathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
                [3 ] Department of Biopathology, Institut Gustave Roussy, Villejuif, France
                [4 ] Department of Oncology, Oslo University, Oslo, Norway
                [5 ] Department of Hepatology & Gastroenterology, Aarhus university Hospital, Aarhus, Denmark
                [6 ] Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
                [7 ] Department of Oncology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
                [8 ] Department of Oncology, Odense University Hospital, Odense, Denmark
                [9 ] Pathology, HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
                [10 ] Department of Oncology, Helsinki University Hospital and Helsinki University, Helsinki Finland
                [11 ] Department of Oncology, Tampere University Hospital, Tampere, Finland
                [12 ] Department of Surgery C and Endocrinology PE, Rigshospitalet, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark
                [13 ] Department of Oncology, Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
                [14 ] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
                Heinrich-Heine-Universitat Dusseldorf, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9881-769X
                Article
                PONE-D-17-25203
                10.1371/journal.pone.0187667
                5675414
                29112960
                dfa1f988-8c59-4cd5-ab3a-9ac811b58fd6
                © 2017 Ali et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 July 2017
                : 24 October 2017
                Page count
                Figures: 3, Tables: 5, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100002794, Cancerfonden;
                Award ID: CAN558/2014
                Award Recipient :
                Funded by: Lions Foundation for Cancer Research at the Uppsala University Hospital
                Award Recipient :
                Funded by: Selander foundation
                Award Recipient :
                Funded by: International Studies at the Faculty of Health Science at University of Copenhagen.
                Award Recipient :
                This work was supported by the Lion's Cancer foundation ( www.lcff.se, ETJ), the Swedish Cancer Society ( www.cancerfonden.se, ETJ CAN558/2014), the Selanders foundation (ETJ) and the foundation for International Studies at the Faculty of Health Science, University of Copenhagen (UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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