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      Modeling interactions between Human Equilibrative Nucleoside Transporter-1 and other factors involved in the response to gemcitabine treatment to predict clinical outcomes in pancreatic ductal adenocarcinoma patients

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          Abstract

          Background

          Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy, characterized by largely unsatisfactory responses to the currently available therapeutic strategies. In this study we evaluated the expression of genes involved in gemcitabine uptake in a selected cohort of patients with PDAC, with well-defined clinical-pathological features.

          Methods

          mRNA levels of hENT1, CHOP, MRP1 and DCK were evaluated by means of qRT-PCR in matched pairs of tumor and adjacent normal tissue samples collected from PDAC patients treated with gemcitabine after surgical tumor resection. To detect possible interaction between gene expression levels and to identify subgroups of patients at different mortality/progression risk, the RECursive Partitioning and Amalgamation (RECPAM) method was used.

          Results

          RECPAM analysis showed that DCK and CHOP were most relevant variables for the identification of patients with different mortality risk, while hENT1 and CHOP were able to identify subgroups of patients with different disease progression risk. Conclusion: hENT1, CHOP, MRP1 and DCK appear correlated to PDAC, and this interaction might influence disease behavior.

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          Most cited references38

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          Cancer statistics, 2009.

          A. Jemal, R. Siegel, E. Ward … (2009)
          Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are standardized by age to the 2000 United States standard million population. A total of 1,479,350 new cancer cases and 562,340 deaths from cancer are projected to occur in the United States in 2009. Overall cancer incidence rates decreased in the most recent time period in both men (1.8% per year from 2001 to 2005) and women (0.6% per year from 1998 to 2005), largely because of decreases in the three major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and in two major cancer sites in women (breast and colorectum). Overall cancer death rates decreased in men by 19.2% between 1990 and 2005, with decreases in lung (37%), prostate (24%), and colorectal (17%) cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2005 decreased by 11.4%, with decreases in breast (37%) and colorectal (24%) cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates has resulted in the avoidance of about 650,000 deaths from cancer over the 15-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years of age. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment.
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            Pancreatic carcinoma.

            A L Warshaw, C Fernandez-del Castillo (1992)
            Article 0 comments Cited 163 times – based on 0 reviews     Review now
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              Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators.

              T Sohn, Darren Yeo, J L Cameron … (2015)
              This large-volume, single-institution review examines factors influencing long-term survival after resection in patients with adenocarcinoma of the head, neck, uncinate process, body, or tail of the pancreas. Between January 1984 and July 1999 inclusive, 616 patients with adenocarcinoma of the pancreas underwent surgical resection. A retrospective analysis of a prospectively collected database was performed. Both univariate and multivariate models were used to determine the factors influencing survival. Of the 616 patients, 526 (85%) underwent pancreaticoduodenectomy for adenocarcinoma of the head, neck, or uncinate process of the pancreas, 52 (9%) underwent distal pancreatectomy for adenocarcinoma of the body or tail, and 38 (6%) underwent total pancreatectomy for adenocarcinoma extensively involving the gland. The mean age of the patients was 64.3 years, with 54% being male and 91% being white. The overall perioperative mortality rate was 2.3%, whereas the incidence of postoperative complications was 30%. The median postoperative length of stay was 11 days. The mean tumor diameter was 3.2 cm, with 72% of patients having positive lymph nodes, 30% having positive resection margins, and 36% having poorly differentiated tumors. Patients undergoing distal pancreatectomy for left-sided lesions had larger tumors (4.7 vs. 3.1 cm, P < 0.0001), but fewer node-positive resections (59% vs. 73%, P = 0.03) and fewer poorly differentiated tumors (29% vs. 36%, P < 0.001), as compared to those undergoing pancreaticoduodenectomy for right-sided lesions. The overall survival of the entire cohort was 63% at 1 year and 17% at 5 years, with a median survival of 17 months. For right-sided lesions the 1- and 5-year survival rates were 64% and 17%, respectively, compared to 50% and 15% for left-sided lesions. Factors shown to have favorable independent prognostic significance by multivariate analysis were negative resection margins (hazard ratio [HR] = 0.64, confidence interval [CI] = 0.50 to 0.82, P = 0.0004), tumor diameter less than 3 cm (HR = 0.72, CI = 0.57 to 0.90, P = 0.004), estimated blood loss less than 750 ml (HR = 0.75, CI = 0.58 to 0.96, P = 0.02), well/moderate tumor differentiation (HR = 0.71, CI = 0.56 to 0.90, P = 0.005), and postoperative chemoradiation (HR = 0.50, CI = 0.39 to 0.64, P < 0.0001). Tumor location in head, neck, or uncinate process approached significance in the final multivariate model (HR = 0.60, CI = 0.35 to 1.0, P = 0.06). Pancreatic resection remains the only hope for long-term survival in patients with adenocarcinoma of the pancreas. Completeness of resection and tumor characteristics including tumor size and degree of differentiation are important independent prognostic indicators. Adjuvant chemoradiation is a strong predictor of outcome and likely decreases the independent significance of tumor location and nodal status.
              Article 0 comments Cited 137 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Francesca Tavano: f.tavano@operapadrepio.it
                Andrea Fontana: a.fontana@operapadrepio.it
                Fabio Pellegrini: fdimola1@hotmail.com
                Francesca Paola Burbaci: f.burbaci@operapadrepio.it
                Francesca Rappa: francyrappa@hotmail.com
                Francesco Cappello: francapp@hotmail.com
                Massimiliano Copetti: m.copetti@operapadrepio.it
                Evaristo Maiello: e.maiello@operapadrepio.it
                Lucia Lombardi: lombardilucia@hotmail.com
                Paolo Graziano: p.graziano@operapadrepio.it
                Manlio Vinciguerra: m.vinciguerra@operapadrepio.it
                Fabio Francesco di Mola: f.dimola@operapadrepio.it
                Pierluigi di Sebastiano: p.disebastiano@asl2abruzzo.it
                Angelo Andriulli: a.andriulli@operapadrepio.it
                Valerio Pazienza: pazienza_valerio@yahoo.it
                Journal
                Journal ID (nlm-ta): J Transl Med
                Journal ID (iso-abbrev): J Transl Med
                Title: Journal of Translational Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1479-5876
                Publication date (Electronic): 10 September 2014
                Publication date PMC-release: 10 September 2014
                Publication date Collection: 2014
                Volume: 12
                Issue: 1
                Electronic Location Identifier: 248
                Affiliations
                [ ]Gastroenterology Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG) Italy, viale dei Cappuccini n.1, San Giovanni Rotondo, FG 71013 Italy
                [ ]Unit of Biostatistics I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG) Italy, viale dei Cappuccini n.1, San Giovanni Rotondo, FG 71013 Italy
                [ ]Unit of Biostatistics, DCPE, Consorzio Mario Negri Sud, Santa Maria Imbaro, CH Italy
                [ ]Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
                [ ]Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
                [ ]Oncology Unit I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG) Italy, viale dei Cappuccini n.1, San Giovanni Rotondo, FG 71013 Italy
                [ ]Pathology Unit I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG) Italy, viale dei Cappuccini n.1, San Giovanni Rotondo, FG 71013 Italy
                [ ]University College London, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, London, UK
                [ ]Division of Surgical Oncology “SS Annunziata” Hospital, Chieti, Italy
                Article
                Publisher ID: 248
                DOI: 10.1186/s12967-014-0248-4
                PMC ID: 4172900
                PubMed ID: 25199538
                SO-VID: ca3d3f16-edf2-4887-be0d-ad661b0a6612
                Copyright © © Tavano et al.; licensee BioMed Central Ltd. 2014
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 6 May 2014
                Date accepted : 29 August 2014
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2014

                ScienceOpen disciplines: Medicine
                Keywords: pancreatic ductal adenocarcinoma,hent1,chop,mrp1,dck,recpam
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: pancreatic ductal adenocarcinoma, hent1, chop, mrp1, dck, recpam

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