The Gastric Cancer Immune Prognostic Score (GCIPS) Shows Potential in Predicting an Unfavorable Prognosis for Gastric Cancer Patients Undergoing Immune Checkpoint Inhibitor Treatment.

(1) Background: This study aims to explore the predictive capability of the Gastric Cancer Immune Prognostic Score (GCIPS) for an unfavorable prognosis in gastric cancer patients undergoing immune checkpoint inhibitor (ICI) treatment. (2) Methods: This study included 302 gastric cancer patients who underwent treatment with ICIs at our institution from January 2017 to December 2022. The patients were randomly divided into a test set (201 cases) and a validation set (101 cases) using a random number table. Kaplan-Meier survival analysis and the log-rank test were used to investigate survival differences. Cox regression analysis and Lasso regression analysis were employed to establish the GCIPS and identify independent prognostic indicators. ROC curves, time-ROC curves, and nomograms were utilized to further explore the predictive performance of GCIPS. (3) Results: The test set and validation set showed no statistical differences in clinical and pathological features, as well as blood parameters (all p > 0.05). Cox regression analysis revealed that white blood cells (WBC), lymphocytes (LYM), and the international normalized ratio (INR) emerged as independent prognostic blood indicators after eliminating collinearity through Lasso analysis. The GCIPS was established using ß coefficients with the following formula: GCIPS = WBC (109/L) × 0.071 - LYM (109/L) × 0.375 + INR × 2.986. ROC curves based on death and time-ROC curves demonstrated that the GCIPS had higher AUCs than other classical markers at most time points. Survival analyses of all subgroups also revealed a significant correlation between the GCIPS and patients' progression-free survival (PFS) and overall survival (OS) (all p < 0.05). Furthermore, the GCIPS was identified as an independent prognostic factor for both PFS and OS. Analyses in the validation set further confirmed the reliability and stability of the GCIPS in predicting patient prognosis. Finally, nomograms incorporating the GCIPS exhibited high accuracy in both the test and validation sets. Additionally, the nomograms revealed that the GCIPS had a higher prognostic value than any other factor, including the TNM stage. (4) Conclusions: The GCIPS demonstrated its ability to predict adverse outcomes in gastric cancer patients undergoing ICIs treatment and had a high prognostic value. As a readily accessible and simple novel biomarker, it effectively identified high-risk patients.

An oxidative stress biomarkers predict prognosis in gastric cancer patients receiving immune checkpoint inhibitor.

Objective: The development and advance of gastric cancer are inextricably linked to oxidative and antioxidant imbalance. Although immunotherapy has been shown to be clinically effective, the link between oxidative stress and gastric cancer patients treated with immune checkpoint inhibitor (ICIs) remains unknown. This study aims at looking into the prognostic value of oxidative stress scores in gastric cancer patients treated with ICIs. Methods: By taking the propagation to receiver operating characteristic (ROC) we got the best cut-off values, and divided 265 patients receiving ICIs and chemotherapy into high and low GC-Integrated Oxidative Stress Score (GIOSS) groups. We also used Kaplan-Meier and COX regression models to investigate the relationship between oxidative stress biomarkers and prognosis. Results: Through both univariate and multivariate analyses, it's shown that GIOSS severs as an independent prognostic factor for progression-free survival (PFS) and Overall survival (OS). Based on GIOSS cutoff values, patients with high GIOSS levels, compared to those with low levels exhibited shorter PFS and OS, both in the high GIOSS group, which performed poorly in the ICIs subgroup and other subgroup analyses. Conclusion: GIOSS is a biomarker that responds to systemic oxidative stress in the body and can predict prognosis in patients with gastric cancer who are taking ICIs. Additionally, it might come to medical professionals' aid in making more effective or more suitable treatment plans for gastric cancer.

Combined with prognostic nutritional index and IgM for predicting the clinical outcomes of gastric cancer patients who received surgery.

Objective: Although the survival rate of patients who undergo surgery for gastric cancer has greatly improved, still many patients have a poor prognosis. This retrospective study aimed to investigate the predictive ability of the PNI-IgM score, a combined prognostic nutritional index (PNI), and immunoglobulin M (IgM), on the prognosis of patients undergoing surgery for gastric cancer. Methods: 340 patients with gastric cancer who underwent surgery from January 2016 to December 2017 were selected. The PNI-IgM score ranged from 1 to 3: score of 1, low PNI (< 48.45) and low IgM (< 0.87); score of 2, low PNI and high IgM, or high PNI and low IgM; score of 3, high PNI and high IgM. We compared the differences in disease-free survival (DFS) and overall survival (OS) among the three groups, while univariate and multivariate analyses calculated prognostic factors for DFS and OS. In addition, the nomograms were constructed based on the results of multivariate analysis to estimate the 1-, 3- and 5-year survival probability. Results: There were 67 cases in the PNI-IgM score 1 group, 160 cases in the PNI-IgM score 2 group, and 113 cases in the PNI-IgM score 3 group. The median survival times of DFS in the PNI-IgM score group 1, the PNI-IgM score group 2, and the PNI-IgM score group 3 were 62.20 months, not reached, and not reached, and 67.57 months vs. not reached vs. not reached in three groups for OS. Patients in the PNI-IgM score group 1 had a lower DFS than the PNI-IgM score group 2 (HR = 0.648, 95% CI: 0.418-1.006, P = 0.053) and the PNI-IgM score group 3 (HR = 0.337, 95% CI: 0.194-0.585, P < 0.001). In stratified analysis, PNI-IgM score 1 had a worse prognosis in the age < 60 years group and CA724 < 2.11 U/m group. Conclusion: PNI-IgM score is a novel combination of nutritional and immunological markers that can be used as a sensitive biological marker for patients with gastric cancer who undergo surgery. The lower the PNI-IgM score, the worse the prognosis.

CD19 (+) B Cell Combined with Prognostic Nutritional Index Predicts the Clinical Outcomes of Patients with Gastric Cancer Who Underwent Surgery.

(1) Background: The aim of this study was to explore the predictive ability of lymphocyte subsets for the prognosis of gastric cancer patients who underwent surgery and the prognostic value of CD19 (+) B cell combined with the Prognostic Nutritional Index (PNI). (2) Methods: This study involved 291 patients with gastric cancer who underwent surgery at our institution between January 2016 and December 2017. All patients had complete clinical data and peripheral lymphocyte subsets. Differences in clinical and pathological characteristics were examined using the Chi-square test or independent sample t-tests. The difference in survival was evaluated using Kaplan-Meier survival curves and the Log-rank test. Cox's regression analysis was performed to identify independent prognostic indicators, and nomograms were used to predict survival probabilities. (3) Results: Patients were categorized into three groups based on their CD19 (+) B cell and PNI levels, with 56 cases in group one, 190 cases in group two, and 45 cases in group three. Patients in group one had a shorter progression-free survival (PFS) (HR = 0.444, p < 0.001) and overall survival (OS) (HR = 0.435, p < 0.001). CD19 (+) B cell-PNI had the highest area under the curve (AUC) compared with other indicators, and it was also identified as an independent prognostic factor. Moreover, CD3 (+) T cell, CD3 (+) CD8 (+) T cell, and CD3 (+) CD16 (+) CD56 (+) NK T cell were all negatively correlated with the prognosis, while CD19 (+) B cell was positively associated with the prognosis. The C-index and 95% confidence interval (CI) of nomograms for PFS and OS were 0.772 (0.752-0.833) and 0.773 (0.752-0.835), respectively. (4) Conclusions: Lymphocyte subsets including CD3 (+) T cell, CD3 (+) CD8 (+) T cell, CD3 (+) CD16 (+) CD56 (+) NK T cell, and CD19 (+) B cell were related to the clinical outcomes of patients with gastric cancer who underwent surgery. Additionally, PNI combined with CD19 (+) B cell had higher prognostic value and could be used to identify patients with a high risk of metastasis and recurrence after surgery.

Corrigendum: Controlling nutritional status (CONUT) predicts survival in gastric cancer patients with immune checkpoint inhibitor (PD-1/PD-L1) outcomes.

[This corrects the article DOI: 10.3389/fphar.2022.836958.].

Prognostic nutritional index for predicting the clinical outcomes of patients with gastric cancer who received immune checkpoint inhibitors.

Objective: Although the application of immunotherapy in gastric cancer has achieved satisfactory clinical effects, many patients have no response. The aim of this retrospective study is to investigate the predictive ability of the prognostic nutrition index (PNI) to the prognosis of patients with gastric cancer who received immune checkpoint inhibitors (ICIs). Materials and methods: Participants were 146 gastric cancer patients with ICIs (PD-1/PD-L1 inhibitors) or chemotherapy. All patients were divided into a low PNI group and a high PNI group based on the cut-off evaluated by the receiver operating characteristic (ROC) curve. We contrasted the difference in progression-free survival (PFS) and overall survival (OS) in two groups while calculating the prognosis factors for PFS and OS by univariate and multivariate analyses. Moreover, the nomogram based on the results of the multivariate analysis was constructed to estimate the 1- and 3-year survival probabilities. Results: There were 41 (28.1%) cases in the low PNI group and 105 (71.9%) cases in the high PNI group. The median survival time for PFS in the low PNI group and high PNI group was 12.30 months vs. 33.07 months, and 18.57 months vs. not reached in the two groups for OS. Patients in low PNI group were associated with shorter PFS and OS in all patients [Hazard ratio (HR) = 1.913, p = 0.013 and HR = 2.332, p = 0.001]. Additionally, in subgroup analysis, low PNI group cases also had poorer PFS and OS, especially in patients with ICIs. In addition, the multivariate analysis found that carbohydrate antigen 724 (CA724) and TNM stage were independent prognostic factors for PFS. At the same time, indirect bilirubin (IDBIL), CA724, PNI, and TNM stage were independent prognostic factors for OS. Conclusion: Prognostic nutrition index was an accurate inflammatory and nutritional marker, which could predict the prognosis of patients with gastric cancer who received ICIs. PNI could be used as a biomarker for ICIs to identify patients with gastric cancer who might be sensitive to ICIs.

The Prognostic Value of Gastric Immune Prognostic Index in Gastric Cancer Patients Treated With PD-1/PD-L1 Inhibitors.

Objective: This study aimed to investigate the prognostic value of the gastric immune prognostic index (GIPI) in gastric cancer patients treated with programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. Methods: This study was conducted to elucidate the role of GIPI using the data from 146 gastric cancer patients treated with PD-1/PD-L1 inhibitors between August 2016 and December 2020 in Harbin Medical University Cancer Hospital. The GIPI calculation was based on dNLR and LDH. Patients were categorized into three groups: 1) GIPI good (LDH ≤250 U/L and dNLR ≤3); 2) GIPI intermediate (LDH >250 U/L and NLR >3); 3) GIPI poor (LDH >250 U/L and dNLR >3). The correlations between GIPI and clinicopathologic characteristics were determined by the Chi-square test or the Fisher's exact test. The Kaplan-Meier analysis and log-rank test were used to calculate and compare progression-free survival (PFS) and overall survival (OS). The univariate and multivariate Cox proportional hazards regression model was used to detect prognostic and predictive factors of PFS and OS. Results: 146 patients treated with PD-1/PD-L1 inhibitors were included in this study, of which, 72.6% were GIPI good, 23.3% were GIPI intermediate, and 4.1% were GIPI poor. The GIPI was associated with the common blood parameters, including neutrophils and lymphocytes. The multivariate analysis showed that platelet, TNM stage, and treatment were the independent prognostic factors for PFS and OS. Patients with GIPI intermediate/poor were associated with shorter PFS (median: 24.63 vs. 32.50 months; p = 0.078) and OS (median: 28.37 months vs. not reached; p = 0.033) than those with GIPI good. GIPI intermediate/poor was correlated with shorter PFS and OS than GIPI good, especially in subgroups of patients with ICI treatment and patients with PD-1/PD-L1 positive status. Conclusions: The GIPI correlated with poor outcomes for PD-1/PD-L1 expression status and may be useful for identifying gastric cancer patients who are unlikely to benefit from treatment.

Controlling Nutritional Status (CONUT) Predicts Survival in Gastric Cancer Patients With Immune Checkpoint Inhibitor (PD-1/PD-L1) Outcomes.

Objective: The controlling nutritional status (CONUT), based on total lymphocyte count (TL), total cholesterol level (T-CHOL), and serum albumin (ALB), can provide a useful immunological prognostic biomarker for cancer patients. The present study aims to investigate the correlation between CONUT and prognosis in gastric cancer patients receiving immune checkpoint inhibitor (ICI) treatment. Methods: We retrospectively enrolled 146 patients with gastric cancer treated with ICIs (PD-1/PD-L1 inhibitors) from August 2016 to December 2020. The clinicopathologic characteristics were analyzed by Chi-square test or Fisher's exact test. The Kaplan-Meier and log-rank test were used to calculate and compare progression-free survival (PFS) and overall survival (OS). The prognostic and predictive factors of PFS and OS were identified by univariate and multivariate analyses. A nomogram was developed to estimate 1-, 3-, and 5-year PFS and OS probability. Results: Through the CONUT score, there were 75 (51.37%) patients in the low CONUT group and 71 (48.63%) patients in the high CONUT group. There was a correlation between the CONUT score and age (p = 0.005), pathology (p = 0.043), ALB (p = 0.020), PALB (p = 0.032), and Hb (p = 0.001). The CA724, TNM stage, and treatment (ICIs vs. chemotherapy) were the independent prognostic factors for PFS and OS by multivariate analyses. Patients with high CONUT score had poorer PFS and OS (χ2 = 3.238, p = 0.072, and χ2 = 4.298, p = 0.038). In the subgroup analysis, the patients with high CONUT score were associated with shorter PFS and OS with ICIs or chemotherapy. With the PD-1/PD-L1 positive expression, the patients with high CONUT score had shorter PFS and OS than those with low CONUT score. Furthermore, the patients with high CA724 value were associated with shorter PFS and OS. The toxicity assessment in ICIs or chemotherapy was significantly associated with anemia. The nomograms were constructed to predict the probability of 1-, 3-, and 5-year PFS, and 1-, 3-, and 5-year OS with C-indices of 0.749 and 0.769, respectively. Conclusion: The CONUT, as a novel immuno-nutritional biomarker, may be useful in identifying gastric cancer patients who are unlikely to benefit from ICI treatment.

Macrophages on the Peritoneum are involved in Gastric Cancer Peritoneal Metastasis.

Tumor-associated macrophages (TAM) have been shown to support tumor growth and progression by various mechanisms. However, the roles of TAM in gastric cancer (GC) peritoneal metastasis remain elusive. To explore the roles of macrophages in the process of GC peritoneal metastasis, we performed the present study. Samples from the primary GC tumor beds, surgical margins, peritoneal metastatic lesions and surrounding tissue, and the Pouch of Douglas, were collected, fixed by formalin, and embedded with paraffin. Immunohistochemistry staining for macrophages markers was performed. The peritoneal lavage was obtained from a fraction of patients to analyze the ratios of epidermal growth factor (EGF)- and vascular endothelial growth factor (VEGF)-secreting macrophages in the peritoneal cavity. GC patients with peritoneal metastasis had increased levels of macrophages and alternatively activated macrophages in the peritoneum compared to those without dissemination. Patients bearing more macrophages in the peritoneum had a poorer prognosis. GC patients bearing peritoneal metastasis harbored an increased level of angiogenesis. Macrophages in the peritoneal cavity were a source of EGF and VEGF. Macrophages in the peritoneum of GC patients play a supportive role for peritoneal metastasis by producing EGF and VEGF. Macrophages in the peritoneum might be a therapeutic target in the future.

Lumican expression in gastric cancer and its association with biological behavior and prognosis.

The aim of the present study was to investigate the expression of lumican in human gastric cancer and adjacent normal gastric tissues, and study its association with clinicopathological characteristics and survival rate. By using immunohistochemistry, the lumican expression patterns in 146 cases of gastric cancer with various clinicopathological characteristics 55 adjacent normal gastric tissue specimens was studied. And the significance of lumican expression regarding the biological behavior and survival of patients was evaluated. In adjacent normal gastric tissues, lumican was expressed weakly in 10.9% (6/55) of samples. By contrast, the lumican expression rate was 66.4% (97/146) in gastric cancer tissues. Lumican protein expression was closely associated with organ metastasis, lymphatic metastasis and histological type (P<0.05), but not with the tumor location, size, invasion depth or Borrmann type (P>0.05). The median survival time in patients with negative, weakly positive and strongly positive lumican expression was 46.3, 39.6 and 24.3 months, respectively (χ2=8.492; P=0.014). There was a significant association between lumican expression and invasive potential in gastric cancer; therefore, lumican may represent an independent prognostic factor.

Monocyte to lymphocyte ratio predicts survival in patients with advanced gastric cancer undergoing neoadjuvant chemotherapy.

BACKGROUND: Currently, precise predictors in gastric cancer patients undergoing neoadjuvant chemotherapy are lacking. The study aims to investigate the prognostic value of the monocyte to lymphocyte ratio (MLR) in patients with advanced gastric cancer receiving S-1 plus oxaliplatin (SOX) or oxaliplatin and capecitabine (XELOX) neoadjuvant chemotherapy regimen. METHODS: The data from Harbin Medical University Cancer Hospital from August 2008 to September 2015 were retrospectively collected. Ninety-one patients with advanced gastric cancer treated with neoadjuvant chemotherapy were included. The blood samples were collected before neoadjuvant chemotherapy. The MLR was divided into two groups: Low-MLR <0.27 group and high-MLR ≥0.27 group. Survival curves were performed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazards regression model were evaluated to determine independent prognostic factors. RESULTS: The univariate analysis showed that median disease free survival (DFS) and overall survival (OS) for all patients were better in low-MLR value group than high-MLR value group (median DFS 26.80 and 23.73 months, P=0.653, respectively; median OS 27.93 and 26.87 months, P=0.807, respectively). Multivariate analysis showed that MLR level was not an independent prognostic factor of DFS and OS. Nevertheless, median DFS and OS for all patients were better for patients with low monocyte values compared to those with high monocyte values (median DFS 30.23 and 21.03 months, P=0.645, respectively; median OS 37.97 and 25.83 months, P=0.509, respectively); in patients with high lymphocyte values compared with low lymphocyte values median DFS was 26.87 and 21.03 months, (P=0.624) respectively; median OS was 27.93 and 26.37 months, (P=0.584) respectively. However, the patients with low level MLR had better 5-year DFS and OS rates. CONCLUSION: MLR may be used as a convenient and cheap prognostic marker in patients with advanced gastric cancer undergoing neoadjuvant chemotherapy with SOX or XELOX. Low level MLR as a prognostic marker may help doctors in terms of efficient measures to treat gastric cancer.

Peripheral venous blood neutrophil-to-lymphocyte ratio predicts survival in patients with advanced gastric cancer treated with neoadjuvant chemotherapy.

BACKGROUND: Accurate and useful predictors of gastric carcinoma treated with neoadjuvant chemotherapy are lacking at present. We aim to explore the potential prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) in advanced gastric cancer receiving S-1 plus oxaliplatin (SOX) or oxaliplatin and capecitabine (XELOX) regimen. METHODS: We enrolled 91 patients with advanced gastric cancer treated with neoadjuvant chemotherapy from August 2008 to September 2015. The peripheral venous blood samples were collected before neoadjuvant chemotherapy. The NLR was divided into two groups: low NLR <2.17 group and high NLR ≥2.17 group. Univariate analysis on disease-free survival (DFS) and overall survival (OS) were generated using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors were assessed by univariate analyses, and the independent prognostic factors were evaluated using multivariate analysis (Cox's proportional-hazards regression model). RESULTS: The univariate analysis showed that median DFS and median OS were worse for high NLR values than low NLR values before neoadjuvant chemotherapy (median DFS: 19.97 and 26.87 months, respectively, P=0.299; median OS: 25.83 and 29.73 months, respectively, P=0.405). Multivariate analysis showed that the NLR before neoadjuvant chemotherapy was not an independent prognostic factor for DFS and OS. However, median DFS and median OS were worse for high neutrophil values than for low neutrophil values (median DFS: 21.03 and 26.87 months, respectively, P=0.396; median OS: 24.43 and 29.37 months, respectively, P=0.534); for low lymphocyte values than for high lymphocyte values before neoadjuvant chemotherapy (median DFS: 22.33 and 26.87 months, respectively, P=0.624; median OS: 26.37 and 27.93 months, respectively, P=0.584). Nevertheless, patients with low NLR had better 1-year, 3-year, and 5-year DFS and OS rates. CONCLUSION: NLR may serve as a cheap and convenient prognostic indicator in gastric carcinoma patients receiving SOX or XELOX neoadjuvant chemotherapy. Low NLR may help the doctors to take efficient treatment measures for gastric cancer.