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We thank Yang et al. for their attention to our work and concomitant description of their findings. In our investigation, we demonstrated a post-resection depletion of intra-platelet (IP) serotonin (5-HT) concentrations in patients with hepatocellular carcinoma (HCC) [1]. We observed an exhaustive pattern of post-resection platelet kinetics in patients with early HCC recurrence. While the post-resection serum and IP 5-HT levels were significantly depleted in patients with HCC recurrence, the preoperative concentration, although observed a similar tendency, this did not reach statistical significance. Interestingly, Yang et al. observed that the high serum 5-HT, high IP 5-HT and high IP 5-HT per platelet were all associated with poor overall and recurrence-free survival [2]. In accordance with it, Xia et al. reported that a preoperative elevated 5-HT was associated with advanced tumor node metastasis and poor recurrence-free survival and overall survival [3]. Similarly, in another study by Padickakudy et al., higher levels of preoperative IP 5-HT were found to be associated with improved postoperative liver regeneration, and an increase in early tumor recurrence suggesting a bivalent property of IP 5-HT in liver regeneration and post-resection recurrence [4]. Collectively, all the above-mentioned studies monitored the kinetics of IP 5-HT in post-resection cancer recurrence. Although there appears to be only a subtle difference between the designs of the studies, our study has some critical disparities. Our data explicitly refers to a post-resection time point (four weeks after liver resection), while the other studies focused on preoperative time points. Platelets exhibit a variety of qualitative abnormalities in patients with cancer (before or after surgery) [5,6]. These deviations comprise reduced, elevated or spontaneous platelet aggregation, and hypersensitivity to various platelet agonists. A state of oxidative stress was reported in resting blood platelets obtained from cancer patients [7]. Platelet proteome harbors differentially expressed proteins associated with tumors that were found normalized after tumor resection [8]. Likewise, partial hepatictomy also highly influences platelet functions. A hypercoagulable state elicited as a result of liver resection combined with the active promitogenic effect of platelets in liver regeneration stimulates platelet activation [9]. In this context, identifying an optimum time-point of blood sampling is crucial to aptly translate the prognostic or predictive value of post-resection platelet kinetics in cancer patients. Although our study on post-resection IP kinetics at four-weeks post-resection has not assessed the absolute advantage of this time point, it has technically minimized the biases from the confounding factors including the presence of tumor or immediate post-resection related stresses. Another issue that needs to be mentioned is the method of platelet preparation. Mussbacher et al. have stressed on a significant heterogeneity among anticoagulants used to prevent unwanted platelet activation [10]. Platelets are highly sensitive to changes in the microenvironment, they are prone to in vitro activation during platelet-preparation. Ivyspring

Intra-platelet Serotonin as a Biomarker in HCC Recurrence: When Time Matters