The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study

IF 6.1 1区 医学 Q1 ONCOLOGY Breast Cancer Research Pub Date : 2024-03-11 DOI:10.1186/s13058-024-01801-0
Lotte MC Jacobs, Leonie S Helder, Kim I Albers, Josephine Kranendonk, Christiaan Keijzer, Leo AB Joosten, Luc JA Strobbe, Michiel C Warlé
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Abstract

Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival. In this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20). Ex vivo cytokine production capacity of TNF, IL-6 and IL-1β was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1β after BCS (p = .041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p = .045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p = .003 and p = .041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p = .038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1β and TNF on POD3 (r = .408; p = .011 and r = .500; p = .001, respectively). This pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation.
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手术组织损伤和术中交感神经激活在保乳手术与乳房切除术后免疫抑制中的作用:一项前瞻性观察研究
乳腺癌是全球妇女死于癌症的第二大常见病因。与直觉相反的是,基于人群的大型回顾性试验报告显示,在对肿瘤和患者变量进行校正后,保乳手术(BCS)的存活率高于乳房切除术。更广泛的手术组织损伤以及交感神经系统在痛觉刺激下的激活与免疫抑制有关。我们假设乳房切除术会导致血浆损伤相关分子模式(DAMPs)的更高表达和术中交感神经的更多激活,从而诱发术后免疫失调。免疫抑制可导致术后并发症并影响无瘤生存。在这项前瞻性观察研究中,比较了接受择期乳腺切除术(BCS)(20 人)和乳腺切除术(20 人)患者的血浆 DAMPs(HMGB1、HSP70、S100A8/A9 和 S100A12)、术中交感神经激活(Nociception Level (NOL) index,从 0 到 100)和术后免疫功能(血浆细胞因子浓度和体内外细胞因子生成能力)。术后一小时,两组患者体内TNF、IL-6和IL-1β的体外细胞因子生成能力几乎都不存在。术后第 3 天(POD3),TNF、IL-6 和 IL-1β 的水平出现恢复,与乳房切除术相比,BCS 术后 IL-1β 的体内外产生能力明显更高(p = .041)。乳房切除术后一小时,血浆中的 IL-6 浓度更高(p = 045)。乳房切除术后 POD3 的血浆抗原 S100A8/A9 和 S100A12 浓度明显更高(分别为 p = .003 和 p = .041)。回归分析表明,在乳房切除术期间,经去甲肾上腺素当量校正后,NOL 测量值≤ 8(无痛觉)的百分比明显降低(分别为 36% 和 45%,p = .038)。所有患者的 NOL 测量值≤ 8 的百分比与 POD3 上 IL-1β 和 TNF 的体外细胞因子生成能力相关(r = .408; p = .011 和 r = .500; p = .001)。这项试点研究显示,乳房局部切除术和乳房切除术后的早期免疫抑制很严重,但在随后几天似乎会恢复。乳房局部切除术和乳房切除术在 DAMPs 释放和术中交感神经激活方面的差异可能会影响术后免疫平衡,从而导致之前基于人群的大型回顾性试验中报告的乳房局部切除术后较好的存活率。这些结果支持进一步探索:(1) 将 S100 alarmins 作为乳腺癌手术的潜在治疗靶点;(2) 抑制术中交感神经激活,以证实观察到的与术后免疫失调的关联。
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来源期刊
Breast Cancer Research
Breast Cancer Research 医学-肿瘤学
自引率
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发文量
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期刊介绍: Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.
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