There is growing evidence that preoperative nutritional status and inflammatory response may be a potentially powerful predictor of the prognosis of cancer patients. Consistent with previous research, the present study found that preoperative inflammation scores, such as NLR and PLR, were associated with the prognosis of GIST patients, both before and after PSM^{[14, 16, 30, 31]} (Figure S1). However, LMR seemed to have no effect on the RFS of GIST patients (Figure S1), which differs from findings of previous studies^[14]. In addition, the PNI, a nutritional score based on albumin levels and lymphocytes, was also related to RFS of GIST patients, both before and after PSM in the present study^{[11, 12]} (Figure S1).

In this study, we also found that preoperative HALP was significantly correlated with tumor site, tumor size, mitosis, Ki67, NIH risk category, and adjuvant therapy (Table 1). To balance the patient characteristics and standard prognostic factors between groups, we utilized the PSM method to balance patient's age, tumor size, tumor site, mitosis, and adjuvant targeted therapy. After PSM, sex, Ki67, PNI, NLR, LMR, and PLR were still associated with HALP (Table S1). Notably, there was no difference in standard prognostic factors (i.e. tumor site, tumor size, mitosis, NIH risk category, and adjuvant therapy) between the low and high HALP groups (Table 1). Given that HALP shared several parameters with PNI, NLR, LMR, and PLR, their statistically significant correlation is unsurprising. The correlation between HALP and sex may be due to the fact that the male and female patients had significantly different hemoglobin levels (123.22 ± 2.08 g/L for males and 105.46 ± 1.84 g/L for females, P < 0.001). Remarkably, recurrence was not associated with either sex or histologic subtype (Table S1). Subgroup analysis by sex revealed that a low level of HALP was associated with recurrence in both male and female patients (P = 0.048 and P = 0.018, respectively) (Figure S2).

Finally, consistent with previous research on HALP in other tumors^[18-24], our findings revealed prognostic value of HALP in GIST. HALP was an independent risk factor for GIST patients before PSM, after PSM, and in high-risk subgroups (Table 2 and Table S3). Thus, HALP can be used to not only evaluate GIST patients' postoperative risk prior to surgery but also to assess their prognosis. Notably, the HALP index can be utilized to predict the prognosis of patients in a convenient and cost-effective manner.

Although the underlying mechanism of systemic inflammation in tumorigenesis, progression and metastasis remains obscure, some theories suggest that it stimulates angiogenesis, immunosuppression, and formation of the supporting microenvironment. Lymphocytes are well known to play a critical role in tumor growth inhibition^[32-34]. A higher lymphocyte signature is associated with improved prognosis in a variety of tumors^[34], whereas platelets can infiltrate the tumor microenvironment and interact directly with cancer cells, assisting circulating tumor cells in adhering to endothelial cells and establishing a niche environment prior to metastasis^[35-41].

Anemia is one of the most common symptoms of GIST, which can be caused by both gastrointestinal bleeding and intratumoral bleeding^[42]. Yang et al^[43] identified GIST with gastrointestinal bleeding as an independent prognostic predictor of poor RFS. Several studies have demonstrated that low hemoglobin levels can result in tumor hypoxia, which is associated with an increased risk of local failure and distant metastasis^{[31, 44]}. Furthermore, a hypoxic tumor environment may result in limited drug accumulation and hinder drug efficacy^[45]. Most importantly, anemia is a common adverse effect of imatinib^[46], which may require the prescribing physician to stop the drug or reduce the dose. High levels of preoperative hemoglobin may help to prevent this adverse effect.

Low levels of serum albumin are also associated with poor long-term survival in GIST patients^{[44, 45]}, which is consistent with our findings. Serum albumin is generally considered as associated with nutritional status and liver or renal function, both of which may affect the prescribing physician's decision-making, similar to hemoglobin. Additionally, tumor tissues have abnormal vascular endothelial gaps and lack effective lymphatic drainage, allowing macromolecules, such as albumin, to accumulate more readily in tumor tissue than in normal tissue^{[47, 48]}. Consequently, serum albumin is suspected of being a possible nutritional source for tumor growth, due to its elevated accumulation in tumors^[49-51]. This effect is referred to as the ‘enhanced permeability and retention effect’. Moreover, about 95% of imatinib is bound to serum proteins, mainly albumin and 1-acid glycoprotein, which may facilitate drug accumulation in tumors and improve therapeutic effect^{[52, 53]}. Subsequently, serum albumin levels have been shown to be an independent prognostic factor of survival in a variety of cancers, including those of colorectal^[54], gastric^[55], pancreatic^[56], and breast^[57]. As a result, it is unsurprising that HALP, which reflects systemic inflammation and nutritional status simultaneously, is associated with the risk and prognosis of GIST.

There are some limitations to this study. First, because this is a retrospective study, biases in the data collection process are possible. Second, our cases were collected between 2008 and 2016, the period during which imatinib was used for adjuvant treatment of GIST in China. Despite the adverse reaction and high costs, 201/591 (34.0%) of GIST patients still received adjuvant imatinib therapy. As an important treatment after GIST, adjuvant imatinib therapy can significantly improve the prognosis of GIST patients^[58], and its benefits are also shown in the present study (Figure S3). However, there was no adequate collection and analysis of the time, dose, and adverse reactions of patients with imatinib or sunitinib therapy, which may also be related to HALP. Moreover, this study did not evaluate other clinicopathological factors related to prognosis, especially gene mutation status. Furthermore, the effect of preoperative or postoperative improvement of nutritional status or inflammation response on the prognosis of GIST remains obscure, and will require further confirmation in clinical studies.