Preoperative Platelet-Lymphocyte Ratio (PLR) as a prognostic inflammation biomarker in Asian HIV-infected patients with gastric cancer: a single-center study

We conducted a retrospective study of 41 HIV-infected patients with preoperative pathologically diagnosed gastric adenocarcinoma who underwent gastrectomy (with or without standard lymphadenectomy) between January 2015 and December 2021 at Shanghai Public Health Clinical Center (SHPHC) in China. The study included characteristics such as gender, age, body mass index (BMI), disease history (hypertension, diabetes, tuberculosis infection, smoking, and alcohol abuse), duration of HIV infection and treatment (cART), preoperative tests (routine laboratory tests, tumor markers, and plasma lipids), tumor location, pathological stage (using the AJCC 8th edition), human epidermal growth factor receptor 2 (Her2) status (using immunohistochemical results of Her2 proteins), and surgical resection with or without tumor residuals. For comparison, we also retrospectively recruited 127 non-HIV infected patients diagnosed with gastric adenocarcinoma who underwent surgery treatment in our hospital during the same period. This study was conducted in accordance with the Declaration of Helsinki and approved by the Shanghai Public Health Clinical Center.

Regular follow-ups were conducted every three months during the first year after surgery and every six months for the following two years. Patients were admitted to the hospital for routine blood examination, enhanced chest and abdominal CT scans, and other necessary tests. After three years, the follow-up visits were scheduled annually. Progression was defined as the first detection of local recurrence, enlargement of unresected tumor lesions, and distant organ metastases. Death was confirmed through relevant information provided by the hospital or by notification from the patient's family during a telephone follow-up. The last censoring date for evaluating survival time was March 2022. Overall survival (OS) was defined as the time interval from surgery to death from any cause or the last censoring date. Progression-free survival (PFS) was defined as the time interval from surgery to progression or the last censoring date. Two of the 41 patients were lost to follow-up during the study period.

The laboratory tests from each patient were obtained within 1-week before surgical resection of the primary tumour. In recent reports, neutrophil (N; × 10^9/L) to lymphocyte (L; × 10^9/L) ratio (NLR), lymphocyte (L; × 10^9/L) to monocyte (M; × 10^9/L) ratio (LMR) and platelet (P; × 10^9/L) to lymphocyte (L; × 10^9/L) ratio (PLR) had been evaluated as useful prognostic biomarkers of GC patients [14, 15]. The prognostic nutritional index (PNI) was calculated as serum albumin value (g/L) + 5 × lymphocyte (L; × 10^9/L) [16]. The systemic immune-inflammation index (SII) was calculated based on platelet (P; × 10^9/L), neutrophil (N; × 10^9/L), and lymphocyte (L; × 10^9/L) blood counts using the following formula: SII = P × N/L [17]. The systemic inflammation score (SIS) definition was based on the combination of the preoperative albumin level and LMR [9]. The SIS was defined as follows: patients with albumin level < 40 g/L and LMR < 4.44 were assigned a score of 2; patients with either albumin level ≥ 40 g/L or LMR ≥ 4.44 were assigned a score of 1; and patients with both albumin level ≥ 40 g/L and LMR ≥ 4.44 were assigned a score of 0.

Categorical variables were reported as integers and proportions, and continuous variables were reported as medians, means (standard deviations), and maximum ranges. We used Wilcoxon rank-sum test for continuous variables and chi-square for classified variables. To analyze the survival differences, patients were categorized into two group based on the continuous variables best-cutoff using the “MaxStat” R package (maximally selected log-rank statistics) [18]. The Kaplan–Meier survival curves were constructed according to differences in group, which were analyzed using the log-rank test. Variables that significantly affected survival were estimated by univariate and multivariate analysis according to the Cox regression model. Stratifified survival analysis results were discussed based on clinicopathological features. A two-tailed P < 0.05 was considered statistically significant. All statistical analyses were determined using R software (version 3.6.3, http://​www.​r-project.​org).

The clinicopathological characteristics of 41 HIV-infected patients with gastric cancer (GC) who underwent gastrectomy are summarized in Table S1. Of the 41 patients, 39 were male and two were female, with a median age of 59 years (range: 44–76 years) at the time of surgery. The median body mass index (BMI) was 21.1 (range: 15.1–26.6), and 22.0% of patients had a history of hypertension, 17.1% had diabetes, 4.9% had tuberculosis infection, and 17.1% had hyperlipidemia. Eight patients (19.5%) had a history of smoking, and five (12.2%) had a history of alcohol abuse. The median duration of HIV infection was one month, and most patients had not received anti-HIV treatment. The preoperative test showed a mean CD4 + T lymphocyte count of 323.4 cell/µL and a CD8 + T lymphocyte count of 663.3 cell/µL. Based on postoperative pathology, 7 patients (17.1%) had an upper gastric tumor, 31 (75.6%) had a middle gastric tumor, and 3 (7.3%) had a tumor in the lower part of the stomach. According to the eighth edition of the AJCC TNM staging system, 9 (22.0%), 8 (19.5%), 19 (46.3%), and 5 (12.2%) of patients had stages I, II, III, and IV, respectively.

The follow-up time for overall survival (OS) and progression-free survival (PFS) ranged from 3 to 94 months. The cumulative three-year OS rate was 46.0%, and the cumulative three-year PFS rate was 44%. HIV-infected GC patients had significantly worse OS and PFS outcomes compared to non-HIV infected GC patients (Figure S1). Univariate analysis identified several inflammatory indicators associated with OS, including PLR, PNI, and Alb level (P < 0.05, Table 1). Variables such as BMI, history of signet ring cell, R0 resection, and TNM stage also significantly affected OS (P < 0.05, Table 1). In multivariate analyses, PLR ≤ 199.0 (HR: 0.038, 95% CI: 0.006–0.258), histology of signet ring cell (HR: 41.178, 95% CI: 6.287–269.722), and no R0 resection (HR: 277.461, 95% CI: 10.475–7349.318) were associated with OS (both P < 0.05, Table 1). Additionally, the prognostic effect of NLR, PLR, PNI, SII, BMI, histology of signet ring cell, R0 resection, TNM stage, and Alb level was significantly related to PFS in univariate analysis (Table 2). In multivariate analysis of PFS, PLR ≤ 199.0 (HR: 0.027, 95% CI: 0.004–0.201), histology of signet ring cell (HR: 42.638, 95% CI: 6.245–291.092), and no R0 resection (HR: 136.565, 95% CI: 8.048–2317.405) were independently associated with PFS outcomes (both P < 0.05, Table 2). In non-HIV infected GC patients, inflammatory indicators such as PLR were not associated with OS (Table S2) or PFS (Table S3) in univariate analysis. The Kaplan–Meier survival analysis and log-rank tests were conducted to investigate the association between PLR groups and postoperative survival time. Our results showed that PLR (> 199) was significantly associated with decreased OS and PFS (Fig. 1). We also evaluated the OS and PFS subgroups of HIV-infected GC patients. The Kaplan–Meier curves revealed that CD3 + count > 1022 cells/µL, both CD8 + groups, and CD4 + count > 323.4 cells/µL in the high PLR group (> 199) were closely associated with poor OS (Fig. 2). Additionally, CD3 + count > 998.8 cells/µL, both CD8 + groups, CD4 + count > 291.3 cells/µL, and CD4/CD8 > 0.6 in the high PLR group (> 199) were also associated with poor PFS rate (Fig. 3).

The relationship between clinicopathological variables and PLR was summarized in Table 3. Higher PLR values were associated with lower BMI (19.7 vs 21.7, P = 0.005), a longer duration of HIV treatment (32.2 months vs 20.9 months, P = 0.113), and a higher tendency for advanced stages (III-IV: 76.9% vs 50.0%, P = 0.173). The comparison of PLR with preoperative laboratory tests was shown in Table 4. In addition to platelet and lymphocyte counts, mean values of hemoglobin (126.9 g/L vs 104.2 g/L, P = 0.008), albumin (39.7 g/L vs 36.5 g/L, P = 0.041), CD3 + cells count (1196.1 per uL vs 646.9 per uL), CD4 + cells count (373 per uL vs 216.5 per uL), and CD8 + cells counts (784.2 per uL vs 402.8 per uL) were significantly higher in the low PLR group than in the high PLR group. However, neutrophil counts were significantly higher in the high PLR group (4.7 × 10^3/uL) than in the low PLR group (3 × 10^3/uL).