BACKGROUND & AIMS Besides its critical role during liver regeneration, serotonin (5-HT) has been found to act as a mitogenic factor in several neoplastic entities. Accordingly, we aimed to evaluate whether intra-platelet 5-HT (IP5-HT) was associated with oncological outcome after liver resection and concomitantly evaluate its ability to serve as a therapeutic target to promote liver regeneration. METHODS A total of 96 patients undergoing liver resection for malignant liver tumors were prospectively included. Optimized plasma and serum preparation were performed and IP5-HT levels were determined. Patients were followed up for postoperative liver dysfunction (LD), morbidity, disease free and overall survival (OS). RESULTS We found increased preoperative IP5-HT levels in patients with disease recurrence at 6 and 12months (p=0.046, p=0.020, respectively). In clear contrast, patients suffering from postoperative morbidity, severe morbidity or LD had significantly reduced IP5-HT levels (p=0.011, p=0.035, p=0.003, respectively). Patients with high IP5-HT levels (>134ng/ml) suffered from an increased incidence of postoperative disease recurrence at 6 and 12months (p=0.045, p=0.006, respectively) but exhibited a reduction in morbidity, severe morbidity, and LD (p=0.006, p=0.008, p=0.005, respectively). We confirmed these results in our two largest subgroups, demonstrating that they were independent of tumor type. This bivalent effect of IP5-HT was also reflected in patients receiving selective serotonin reuptake inhibitor treatment, who displayed a reduction in disease recurrence accompanied by an increase in postoperative morbidity. Yet, both early disease recurrence and morbidity worsened OS. CONCLUSION Herein, we present first clinical evidence for IP5-HT being associated with early disease recurrence after liver resection in humans. Thus, pharmacological intervention at the level of platelets and platelet-derived 5-HT to promote liver regeneration should be considered with caution. A careful definition of indications and timing is needed to promote liver regeneration without inducing deleterious effects. LAY SUMMARY Preoperative intra-platelet serotonin (IP5-HT) levels seem to substantially affect patient outcomes after liver resection for liver tumors. While there is a narrow window of IP5-HT levels where liver regeneration and tumor progression is balanced, excessively high IP5-HT levels (>134ng/ml IP5-HT) lead to an increased incidence of early tumor recurrence and excessively low IP5-HT levels (<73ng/ml IP5-HT) lead to a higher rate of morbidity. Ultimately, overall survival is negatively affected by both postoperative early disease recurrence and morbidity. ClinicalTrials.gov-Identifier: NCT01700231.

中文翻译：

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血小板内血清素在人类肝脏再生和肿瘤复发中的二价作用

背景和目的 除了在肝再生过程中的关键作用外，5-羟色胺 (5-HT) 已被发现在几种肿瘤实体中充当促有丝分裂因子。因此，我们旨在评估血小板内 5-HT (IP5-HT) 是否与肝切除术后的肿瘤学结果相关，并同时评估其作为促进肝脏再生的治疗靶点的能力。方法前瞻性纳入因恶性肝脏肿瘤行肝切除术的96例患者。进行了优化的血浆和血清制备，并确定了 IP5-HT 水平。随访患者术后肝功能障碍（LD）、发病率、无病生存率和总生存率（OS）。结果 我们发现在 6 个月和 12 个月时疾病复发的患者术前 IP5-HT 水平升高（p=0.046，p=0.020，分别）。与此形成鲜明对比的是，患有术后发病率、严重发病率或 LD 的患者的 IP5-HT 水平显着降低（分别为 p=0.011、p=0.035、p=0.003）。IP5-HT 水平高 (>134ng/ml) 的患者术后 6 个月和 12 个月的疾病复发率增加（分别为 p=0.045、p=0.006），但发病率、重度发病率和 LD 均有所降低。分别为 p=0.006、p=0.008、p=0.005）。我们在两个最大的亚组中证实了这些结果，证明它们与肿瘤类型无关。IP5-HT 的这种二价效应也反映在接受选择性 5-羟色胺再摄取抑制剂治疗的患者中，这些患者表现出疾病复发的减少以及术后发病率的增加。然而，早期疾病复发和发病率均使 OS 恶化。结论在此，我们提出了 IP5-HT 与人类肝切除术后早期疾病复发相关的第一个临床证据。因此，应谨慎考虑在血小板和血小板衍生的 5-HT 水平进行药物干预以促进肝脏再生。需要仔细定义适应症和时机，以促进肝脏再生而不引起有害影响。概述 术前血小板内血清素 (IP5-HT) 水平似乎对肝脏肿瘤肝切除术后患者的预后有重大影响。虽然在肝脏再生和肿瘤进展平衡的情况下，IP5-HT 水平的窗口很窄，但 IP5-HT 水平过高 (> 134ng/ml IP5-HT）导致早期肿瘤复发的发生率增加，过低的 IP5-HT 水平（<73ng/ml IP5-HT）导致更高的发病率。最终，总生存率受到术后早期疾病复发和发病率的负面影响。ClinicalTrials.gov-标识符：NCT01700231。