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      The Prognostic Significance of Novel Pancreas Cancer Prognostic Index in Unresectable Locally Advanced Pancreas Cancers Treated with Definitive Concurrent Chemoradiotherapy

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          Abstract

          Purpose

          We evaluated the prognostic quality of the novel pancreas cancer prognostic index (PCPI), a combination of CA 19-9 and systemic inflammation response index (SIRI), on the outcomes of locally advanced pancreas adenocarcinoma (LAPAC) patients who received concurrent chemoradiotherapy (C-CRT).

          Methods

          This retrospective analysis covered 152 unresectable LAPAC patients treated from 2007 to 2019. Receiver operating characteristic (ROC) curve analysis was used to define ideal cutoff thresholds for the pretreatment CA 19-9 and SIRI measurements, individually. The associations between the PCPI groups and progression-free- (PFS) and overall survival (OS) comprised the respective primary and secondary endpoints.

          Results

          The ROC curve analysis distinguished the respective rounded optimal cutoffs at 91 U/m/L (< versus ≥90) and 1.8 (< versus ≥1.8) for CA 19-9 and SIRI, arranging the study cohort into two significantly different survival groups for each, with resultant four likely groups: Group-1: CA 19-9<90 U/m/L and SIRI<1.8, Group-2: CA 19-9<90 U/m/L but SIRI≥1.8, Group-3: CA 19-9≥90 U/m/L but SIRI<1.8, and Group-4: CA 19-9≥90 U/m/L and SIRI≥1.8. Since the PFS (P=0.79) and OS (P=0.86) estimates of the groups 2 and 3 were statistically indistinct, we merged them as one group and created the novel three-tiered PCPI: PCPI-1: CA 19-9<90 U/m/L and SIRI<1.8, PCPI-2: CA 19-9<90 U/m/L but SIRI≥1.8 or CA 19-9≥90 U/m/L but SIRI<1.8, and PCPI-3: CA 19-9≥90 U/m/L and SIRI≥1.8, respectively. Comparative analyses unveiled that the PCPI-1 and PCPI-3 groups had the respective best and worst PFS (17.0 versus 7.5 versus 4.4 months; P<0.001) and OS (26.1 versus 15.1 versus 7.4 months; P<0.001) outcomes, while the PCPI-2 group posed in between. The multivariate analysis outcomes confirmed the novel three tired PCPI’s independent prognostic significance on either of the PFS [HR: 5.38 (95% confidence interval (CI): 4.96-5.80); P<0.001)] and OS [HR: 5.67 (95% CI: 5.19-6.15); P<0.001] endpoints, separately.

          Conclusion

          The new PCPI introduced here can be used as an independent and reliable prognostic indicator to divide LAPAC patients into three subgroups with discrete survival results.

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          Most cited references45

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Cancer-related inflammation.

            The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
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              Pancreatic cancers require autophagy for tumor growth.

              Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.
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                Author and article information

                Journal
                J Inflamm Res
                J Inflamm Res
                jir
                jinres
                Journal of Inflammation Research
                Dove
                1178-7031
                04 September 2021
                2021
                : 14
                : 4433-4444
                Affiliations
                [1 ]Department of Radiation Oncology, Baskent University Medical Faculty , Adana, Turkey
                [2 ]Department of Radiation Oncology, Koc University Faculty of Medicine , Istanbul, Turkey
                [3 ]Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX, USA
                [4 ]Department of Radiation Oncology, Bahcesehir University , Istanbul, Turkey
                [5 ]Radiation Oncology Clinics, Mersin City Hospital , Mersin, Turkey
                [6 ]Clinics of Medical Oncology, Medline Hospital , Adana, Turkey
                Author notes
                Correspondence: Erkan Topkan Department of Radiation Oncology, Baskent University Medical Faculty , Adana, 01120, TurkeyTel +90 533-7381069Fax +90 322-3444452 Email docdretopkan@gmail.com
                Article
                329611
                10.2147/JIR.S329611
                8427684
                cffddb18-9d3b-4b12-8d3d-5080533da511
                © 2021 Topkan et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 2, Tables: 14, References: 45, Pages: 12
                Funding
                Funded by: no funding;
                There is no funding to report.
                Categories
                Original Research

                Immunology
                locally advanced pancreas cancer,concurrent chemoradiotherapy,prognosis,survival outcomes,pancreas cancer prognostic index

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