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      The effect of propofol and sevoflurane on cancer cell, natural killer cell, and cytotoxic T lymphocyte function in patients undergoing breast cancer surgery: an in vitro analysis

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          Abstract

          Background

          To clarify the effect of anaesthetic agents on cancer immunity, we evaluated the effects of propofol and sevoflurane on natural killer (NK) cell, cytotoxic T lymphocyte (CTL) counts and apoptosis rate in breast cancer and immune cells co-cultures from patients who underwent breast cancer surgery.

          Methods

          Venous blood samples were collected after inducing anaesthesia and at 1 and 24 h postoperatively in patients who had undergone breast cancer surgery. The patients were allocated randomly to the propofol- or sevoflurane-based anaesthesia groups. We counted and detected apoptosis in cancer cell, NK cell and CTL of patients with breast cancer by co-culture with a breast cancer cell line in both groups. We also evaluated changes in the cytokines tumour necrosis factor-alpha, interleukin (IL)-6 and IL-10 during the perioperative period.

          Results

          Forty-four patients were included in the final analysis. No difference in NK cell count, CTL count or apoptosis rate was detected between the groups. Furthermore, the number of breast cancer cells undergoing apoptosis in the breast cancer cell co-cultures was not different between the groups. No changes in cytokines were detected between the groups.

          Conclusion

          Although basic science studies have suggested the potential benefits of propofol over a volatile agent during cancer surgery, propofol was not superior to sevoflurane, on the aspects of NK and CTL cells counts with apoptosis rate including breast cancer cell, during anaesthesia for breast cancer surgery in a clinical environment.

          Trial registration

          NCT02758249 on February 26, 2016.

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          Most cited references37

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          Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development.

          Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil. Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 micrograms.kg-1.min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y. The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were Ke0 = 0.516 min-1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and Ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic-pharmacodynamic model performed better than did the simple model when applied prospectively. This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.
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            Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures.

            Postoperative immunosuppression is partly ascribed to anesthesia and has been suggested to compromise patients' resistance to infection and tumor metastasis. We compared the effects of various anesthetics on natural killer (NK) cell activity and on resistance to experimental metastasis, and studied mediating mechanisms and prophylactic measures. Fischer 344 rats served as controls or were anesthetized for 1 h with ketamine, thiopental, halothane, or propofol. Anesthetized rats were either maintained in normothermia or left to spontaneously reach 33 degrees C-35 degrees C. Rats were then injected IV with MADB106 tumor cells, and 24 h later lung tumor retention was assessed, or 3 wk later, lung metastases were counted. Additionally, the number and activity of circulating NK cells were assessed after anesthesia. All anesthetics, except propofol, significantly reduced NK activity and increased MADB106 lung tumor retention or lung metastases. Hypothermia had no significant effects. Ketamine increased metastasis most potently, and this effect was markedly reduced in rats pretreated with a beta-adrenergic antagonist (nadolol) or with chronic small doses of an immunostimulator (polyriboinosinic:polyribocytidylic acid). Overall, the marked variation in the NK-suppressive effects of anesthetics seems to underlie their differential promotion of MADB106 metastasis. Prophylactic measures may include perioperative immunostimulation and the use of beta-blockers. This study in a rat model of pulmonary metastasis demonstrates that some anesthetics, but not others, increase susceptibility to tumor metastasis, apparently by suppressing natural killer cell activity. Ketamine was most deleterious, and its effects were prevented by peripheral blockade of beta-adrenoceptors combined with low levels of immunostimulation.
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              Effect of anaesthetic technique and other perioperative factors on cancer recurrence.

              Surgical excision is the mainstay of treatment for potentially curable solid tumours. Metastatic disease is the most important cause of cancer-related death in these patients. The likelihood of tumour metastases depends on the balance between the metastatic potential of the tumour and the anti-metastatic host defences, of which cell-mediated immunity, and natural killer cell function in particular, is a critical component. It is increasingly recognized that anaesthetic technique and other perioperative factors have the potential to effect long-term outcome after cancer surgery. Surgery can inhibit important host defences and promote the development of metastases. Anaesthetic technique and drug choice can interact with the cellular immune system and effect long-term outcome. The potential effect of i.v. anaesthetics, volatile agents, local anaesthetic drugs, opiates, and non-steroidal anti-inflammatory drugs are reviewed here. There is particular interest at present in the effect of regional anaesthesia, which appears to be beneficial. Retrospective analyses have shown an outcome benefit for paravertebral analgesia for breast cancer surgery and epidural analgesia for prostatectomy. Blood transfusion, pain, stress, and hypothermia are other potentially important perioperative factors to consider.
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                Author and article information

                Contributors
                limja@kuh.ac.kr
                ohcsik@naver.com
                ytg@kuh.ac.kr
                jasmin2778@naver.com
                shlee@kku.ac.kr
                0117652771@kuh.ac.kr
                20110364@kuh.ac.kr
                +82-2-2030-5454 , yshkim75@daum.net
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                7 February 2018
                7 February 2018
                2018
                : 18
                : 159
                Affiliations
                [1 ]ISNI 0000 0004 0532 8339, GRID grid.258676.8, Department of Anaesthesiology and Pain medicine, , Konkuk University Medical Centre, Konkuk University School of Medicine, ; 120-1 Neungdong-ro, Gwangjin-gu, Seoul, 05030 Republic of Korea
                [2 ]ISNI 0000 0004 0532 8339, GRID grid.258676.8, Department of Microbiology, , Konkuk University School of Medicine, ; Seoul, South Korea
                [3 ]ISNI 0000 0004 0532 8339, GRID grid.258676.8, Department of Surgery, , Konkuk University Medical Centre, Konkuk University School of Medicine, ; Seoul, South Korea
                [4 ]ISNI 0000 0004 0532 8339, GRID grid.258676.8, Research Institute of Medical Science, , Konkuk University School of Medicine, ; Seoul, South Korea
                Author information
                http://orcid.org/0000-0001-7764-9818
                Article
                4064
                10.1186/s12885-018-4064-8
                5803927
                29415668
                83886adf-23b3-40ae-affe-df3da64e754a
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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
                : 9 March 2017
                : 29 January 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea ;
                Award ID: 2015R1A2A2A01006779
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                breast cancer,propofol,sevoflurane,natural killer cell,cytotoxic t lymphocyte

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