Prognostic importance of the preoperative New-Naples prognostic score for patients with gastric cancer.

BACKGROUND: The wide applicability of the Naples prognostic score (NPS) is still worthy of further study in gastric cancer (GC). This study aimed to construct a New-NPS based on the differences in immunity and nutrition in patients with upper and lower gastrointestinal tumors to help obtain an individualized prediction of prognosis. METHODS: This study retrospectively analyzed patients who underwent radical gastrectomy from April 2014 to September 2016. The cutoff values of the preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), serum albumin (Alb), and total cholesterol (TC) were calculated by ROC curve analysis. ROC and t-ROC were used to evaluate the accuracy of the prognostic markers. The Kaplan-Meier method and log-rank test were used to analyze the overall survival probability. Univariate and multivariate analyses based on Cox risk regression were used to show the independent predictors. The nomogram was made by R studio. The predictive accuracy of nomogram was assessed using a calibration plot, concordance index (C-index), and decision curve. RESULTS: A total of 737 patients were included in training cohort, 411 patients were included in validation cohort. ROC showed that the New-NPS was more suitable for predicting the prognosis of GC patients. NPS = 2 indicated a poor prognosis. Multivariate analysis showed that CEA (P = 0.026), Borrmann type (P = 0.001), pTNM (P < 0.001), New-NPS (P < 0.001), and nerve infiltration (P = 0.035) were independent risk factors for prognosis. CONCLUSION: The New-NPS based on the cutoff values of NLR, LMR, Alb, and TC is not only suitable for predicting prognosis but can also be combined with clinicopathological characteristics to construct a nomogram model for GC patients.

Metastatic lymph nodes and prognosis assessed by the number of retrieved lymph nodes in gastric cancer.

BACKGROUND: The prognostic value of quantitative assessments of the number of retrieved lymph nodes (RLNs) in gastric cancer (GC) patients needs further study. AIM: To discuss how to obtain a more accurate count of metastatic lymph nodes (MLNs) based on RLNs in different pT stages and then to evaluate patient prognosis. METHODS: This study retrospectively analyzed patients who underwent GC radical surgery and D2/D2+ LN dissection at the Cancer Hospital of Harbin Medical University from January 2011 to May 2017. Locally weighted smoothing was used to analyze the relationship between RLNs and the number of MLNs. Restricted cubic splines were used to analyze the relationship between RLNs and hazard ratios (HRs), and X-tile was used to determine the optimal cutoff value for RLNs. Patient survival was analyzed with the Kaplan-Meier method and log-rank test. Finally, HRs and 95% confidence intervals were calculated using Cox proportional hazards models to analyze independent risk factors associated with patient outcomes. RESULTS: A total of 4968 patients were included in the training cohort, and 11154 patients were included in the validation cohort. The smooth curve showed that the number of MLNs increased with an increasing number of RLNs, and a nonlinear relationship between RLNs and HRs was observed. X-tile analysis showed that the optimal number of RLNs for pT1-pT4 stage GC patients was 26, 31, 39, and 45, respectively. A greater number of RLNs can reduce the risk of death in patients with pT1, pT2, and pT4 stage cancers but may not reduce the risk of death in patients with pT3 stage cancer. Multivariate analysis showed that RLNs were an independent risk factor associated with the prognosis of patients with pT1-pT4 stage cancer (P = 0.044, P = 0.037, P = 0.003, P < 0.001). CONCLUSION: A greater number of RLNs may not benefit the survival of patients with pT3 stage disease but can benefit the survival of patients with pT1, pT2, and pT4 stage disease. For the pT1, pT2, and pT4 stages, it is recommended to retrieve 26, 31 and 45 LNs, respectively.

Development and Validation of an Age-Related Gastric Cancer-Specific Immune Index.

Background: Aging has a negative impact on the immune function of patients. The purpose of this study was to construct an age-related specific immune index according to the immune aging phenomenon of gastric cancer (GC) and explore its prognostic value. Methods: This study retrospectively analyzed patients who underwent radical GC surgery in the Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Harbin Medical University, from August 2014 to December 2016 and divided them into a training cohort and a validation cohort. A new immune score, the GC-specific immune index (GSII), was developed as a series of lymphocyte subsets associated with the prognosis of patients with GC. Then, the receiver operating characteristic (ROC) curve was used to compare the prediction performance. The Kaplan‒Meier method and Log rank test were used to analyze the overall survival of patients. Cox hazard regression models were used to identify independent risk factors associated with prognosis. Finally, a nomogram model was constructed by combining the GSII and clinicopathological characteristics, and the calibration chart, consistency index, and decision curve were used to test the performance of the model. Results: Aging did not significantly affect CD8 cell counts but decreased CD4 and CD19 cell counts. Based on the Cox analysis, the GSII of patients ≤60 years old was 0.079×lg CD4+0.348×lg CD19, and the GSII of patients >60 years old was 0.058×lg CD4. A decreased GSII was indicative of a poor prognosis and was an independent risk factor associated with patient outcomes. The nomogram constructed based on the GSII and clinicopathological features accurately predicted patient prognosis. Furthermore, the GSII was well validated in the validation cohort. Conclusion: The GSII constructed for the special immune aging phenomenon of GC can accurately predict patient prognosis.

Association of the TGFß gene family with microenvironmental features of gastric cancer and prediction of response to immunotherapy.

In the complex tumor microenvironment, TGFß is a pleiotropic cytokine involved in regulating cellular processes such as cancer cell proliferation, apoptosis and metastasis. TGFß defines three subtypes (TGFß1, TGFß2, and TGFß3), of which TGFß is highly expressed in many cancers, especially those showing high dissemination potential. In addition, increased expression of TGFß in multiple cancers is usually positively correlated with epithelial mesenchymal transition (EMT) and coordinated with the expression of genes driving EMT-related genes. TGFß signaling in the tumor microenvironment inhibits the antitumor function of multiple immune cell populations, including T cells and natural killer cells, and the resulting immunosuppression severely limits the efficacy of immune checkpoint inhibitors and other immunotherapeutic approaches. As a major pathway to enhance the efficacy of cancer immunotherapy effects, the role of TGFß signaling inhibitors have been evaluated in many clinical trials. However, the potential functions and mechanisms of TGFß1, TGFß2 and TGFß3 in gastric cancer progression and tumor immunology are unclear. In this study, we comprehensively analyzed TGFß1, TGFß2 and TGFß3 and gastric cancer microenvironmental features, including immune cell infiltration, EMT, hypoxia, mutation, immunotherapy and drug treatment, based on HMUCH sequencing data (GSE184336) and public databases. We also validated the protein expression levels of TGFß in gastric cancer tissues as well as the role of TGFß factor in cytology experiments. This report reveals the important role of the TGFß gene family in gastric cancer and provides possible relationships and potential mechanisms of TGFß in gastric cancer.

TGFß2 is a Prognostic Biomarker for Gastric Cancer and is Associated With Methylation and Immunotherapy Responses.

TGFß signaling plays a key role in cancer progression and by shaping tumor architecture and inhibiting the anti-tumor activity of immune cells. It was reported that high expression of TGFß can promote the invasion and metastasis of cancer cells in a variety of tumors. However, there are few studies on TGFß2 and its methylation in gastric cancer. We analyzed the Harbin Medical University Cancer Hospital (HMUCH) sequencing data and used public data to explore the potential function and prognostic value of TGFß2 and its methylation in gastric cancer. In this study, we used the ssGSEA algorithm to quantify 23 methylation sites related to TGFß2. Survival analysis showed that high expression of TGFß2 and hypomethylation levels of TGFß2 were negative factors in the prognosis of gastric cancer. Functional enrichment analysis of methylation revealed that methylation of different TGFß2 methylation scores was mainly involved in energy metabolism, extracellular matrix formation and cell cycle regulation. In the gastric cancer microenvironment TGFß2 was associated with high levels of multiple immune cell infiltration and cytokine expression, and high TGFß2 expression was significantly and positively correlated with stemness markers, stromalscore and EMT. Gene set enrichment analysis also revealed an important role of TGFß2 in promoting EMT. In addition, we discussed the relationship between TGFß2 and immunotherapy. The expression of PD-1, PD-L1 and CTLA-4 was elevated in the TGFß2 high expression group. Also when TGFß2 was highly expressed, the responsiveness of immune checkpoint blockade (ICB) was significantly enhanced. This indicates that TGFß2 may become an indicator for predicting the efficacy of immunosuppressive agents and a potential target for immunotherapy.

Comprehensive Characterization of RNA Processing Factors in Gastric Cancer Identifies a Prognostic Signature for Predicting Clinical Outcomes and Therapeutic Responses.

RNA processing converts primary transcript RNA into mature RNA. Altered RNA processing drives tumor initiation and maintenance, and may generate novel therapeutic opportunities. However, the role of RNA processing factors in gastric cancer (GC) has not been clearly elucidated. This study presents a comprehensive analysis exploring the clinical, molecular, immune, and drug response features underlying the RNA processing factors in GC. This study included 1079 GC cases from The Cancer Genome Atlas (TCGA, training set), our hospital cohort, and two other external validation sets (GSE15459, GSE62254). We developed an RNA processing-related prognostic signature using Cox regression with the least absolute shrinkage and selection operator (LASSO) penalty. The prognostic value of the signature was evaluated using a multiple-method approach. The genetic variants, pathway activation, immune heterogeneity, drug response, and splicing features associated with the risk signature were explored using bioinformatics methods. Among the tested 819 RNA processing genes, we identified five distinct RNA processing patterns with specific clinical outcomes and biological features. A 10-gene RNA processing-related prognostic signature, involving ZBTB7A, METTL2B, CACTIN, TRUB2, POLDIP3, TSEN54, SUGP1, RBMS1, TGFB1, and PWP2, was further identified. The signature was a powerful and robust prognosis factor in both the training and validation datasets. Notably, it could stratify the survival of patients with GC in specific tumor-node-metastasis (TNM) classification subgroups. We constructed a composite prognostic nomogram to facilitate clinical practice by integrating this signature with other clinical variables (TNM stage, age). Patients with low-risk scores were characterized with good clinical outcomes, proliferation, and metabolism hallmarks. Conversely, poor clinical outcome, invasion, and metastasis hallmarks were enriched in the high-risk group. The RNA processing signature was also involved in tumor microenvironment reprogramming and regulating alternative splicing, causing different drug response features between the two risk groups. The low-risk subgroup was characterized by high genomic instability, high alternative splicing and might benefit from the immunotherapy. Our findings highlight the prognostic value of RNA processing factors for patients with GC and provide insights into the specific clinical and molecular features underlying the RNA processing-related signature, which may be important for patient management and targeting treatment.

The Ratio of the Hemoglobin to Red Cell Distribution Width Combined with the Ratio of Platelets to Lymphocytes Can Predict the Survival of Patients with Gastric Cancer Liver Metastasis.

BACKGROUND: Hemoglobin/red cell distribution width (HR) and platelet/lymphocyte (PLR) ratios are considered effective prognostic markers in various cancers. We have proposed a new prognostic parameter: HR+PLR. The aim of this study is to explore the prognostic value of the HR+PLR scoring system in patients with gastric cancer liver metastasis. METHODS: This study retrospectively analyzed the clinical data of 306 patients with gastric cancer liver metastases admitted to our hospital from 2007 to 2014. According to the size of HR value and PLR value, we will divide the patients into three groups, namely, HR+PLR: (1) 0 points: HR > 1.02 and PLR < 128; (2) 1 point: HR > 1.02 and PLR > 128 and HR < 1.02 and PLR < 128; and (3) 2 points: HR < 1.02 and PLR > 128. RESULTS: The HR+PLR score was statistically different from age (P = 0.049), T stage (P < 0.001), N stage (P = 0.017), number of liver metastases (P = 0.018), gastrectomy (P < 0.001), hepatectomy (P = 0.001), peritoneal metastasis (P = 0.012), prognostic nutritional index (PNI) (P = 0.028), and neutrophil/lymphocyte ratio (NLR) (P = 0.045). The HR+PLR scoring system has a higher area under the ROC curve (AUC value) than PNI, PLR, HR, and PLR (AUC = 0.798, P < 0.001). In multivariate analysis, gastrectomy (P = 0.001), hepatectomy (P < 0.001), chemotherapy (P = 0.014), and HR+PLR score (P < 0.001) were considered independent prognostic factors. CONCLUSION: For patients with gastric cancer liver metastasis, the HR+PLR score is a simple, reliable, and economic prognostic marker.

Changing trends of clinicopathologic features and survival duration after surgery for gastric cancer in Northeast China.

BACKGROUND: Through analyzing the data from a single institution in Northeast China, this study revealed the possible clinicopathologic characteristics that influence the prognosis of patients with gastric cancer (GC). AIM: To evaluate the changing trends of clinicopathologic features and survival duration after surgery in patients with GC in Northeast China, which is a high-prevalence area of GC. METHODS: The study analyzed the difference in clinicopathologic features and survival duration after surgery of 5887 patients who were histologically diagnosed with GC at the Harbin Medical University Cancer Hospital. The study mainly analyzed the data in three periods, 2000 to 2004 (Phase 1), 2005 to 2009 (Phase 2), and 2010 to 2014 (Phase 3). RESULTS: Over time, the postoperative survival rate significantly increased from 2000 to 2014. In the past 15 years, compared with Phases 1 and 2, the tumor size was smaller in Phase 3 (P < 0.001), but the proportion of high-medium differentiated tumors increased (P < 0.001). The proportion of early GC gradually increased from 3.9% to 14.4% (P < 0.001). A surprising improvement was observed in the mean number of retrieved lymph nodes, ranging from 11.4 to 27.5 (P < 0.001). The overall 5-year survival rate increased from 24% in Phase 1 to 43.8% in Phase 3. Through multivariate analysis, it was found that age, tumor size, histologic type, tumor-node-metastasis stage, depth of invasion, lymph node metastasis, surgical approach, local infiltration, radical extent, number of retrieved lymph nodes, and age group were independent risk factors that influenced the prognosis of patients with GC. CONCLUSION: The clinical features of GC in Northeast China changed during the observation period. The increasing detection of early GC and more standardized surgical treatment effectively prolonged lifetimes.

Prognostic significance of Borrmann type combined with vessel invasion status in advanced gastric cancer.

BACKGROUND: Borrmann classification (types I-IV) for the detection of advanced gastric cancer has been accepted worldwide, and lymphatic and/or blood vessel invasion (LBVI) status is related to the poor prognosis after gastric cancer. AIM: To evaluate the significance of Borrmann type combined with LBVI status in predicting the prognosis of advanced gastric cancer. METHODS: We retrospectively studied the clinicopathological characteristics and long-term survival data of 2604 patients who were diagnosed with advanced gastric adenocarcinoma at Harbin Medical University Cancer Hospital from January 2009 to December 2013. Categorical variables were evaluated by the Pearson's χ 2 test, the Kaplan-Meier method was used to identify differences in cumulative survival rates, and the Cox proportional hazards model was used for multivariate prognostic analysis. RESULTS: A total of 2604 patients were included in this study. The presence of LVBI [LBVI (+)] and Borrmann type (P = 0.001), tumor location (P < 0.001), tumor size (P < 0.001), histological type (P < 0.001), tumor invasion depth (P < 0.001), number of metastatic lymph nodes (P < 0.001), and surgical method (P < 0.001) were significantly correlated with survival. When analyzing the combination of the Borrmann classification and LBVI status, we found that patients with Borrmann type III disease and LBVI (+) had a similar 5-year survival rate to those with Borrmann IV + LBVI (-) (16.4% vs 13.1%, P = 0.065) and those with Borrmann IV + LBVI (+) (16.4% vs 11.2%, P = 0.112). Subgroup analysis showed that the above results were true for any pT stage and any tumor location. Multivariate Cox regression analysis showed that Borrmann classification (P = 0.023), vascular infiltration (P < 0.001), tumor size (P = 0.012), pT stage (P < 0.001), pN stage (P < 0.001), and extent of radical surgery (P < 0.001) were independent prognostic factors for survival. CONCLUSION: Since patients with Borrmann III disease and LBVI (+) have the same poor prognosis as those with Borrmann IV disease, more attention should be paid to patients with Borrmann III disease and LBVI (+) during diagnosis and treatment, regardless of the pT stage and tumor location, to obtain better survival results.

Prognostic Nutritional Index and Neutrophil-to-Lymphocyte Ratio Are Respectively Associated with Prognosis of Gastric Cancer with Liver Metatasis Undergoing and without Hepatectomy.

Background. To clarify the efficacy of hepatectomy for gastric cancer liver metastasis (GCLM) and to investigate the association between prognostic nutrition index (PNI) or neutrophil-to-lymphocyte ratio (NLR) and prognosis of GCLM undergoing or without hepatectomy. Methods. We retrospectively studied 374 patients with GCLM. The ROC curve was used to determine the optimal cut-off of PNI and NLR. Patients were divided into groups based on whether hepatectomy was performed, and survival analysis was conducted before and after grouping. The overall survival (OS) time and 1, 3, 5-year survival rates were also compared. Results. Multivariate analysis of all GCLM patients revealed that hepatectomy (p = 0.001) was an independent prognosis factor. And there were statistical differences in OS and 1, 3, 5-year survival rates (p = 0.001 of all) between hepatectomy group and nonhepatectomy group. Multivariate analysis of GCLM undergoing hepatectomy showed that PNI was an independent prognosis factor (p = 0.001). And there were statistical differences in OS and 1, 3, 5-year survival rates (p = 0.001p = 0.005, p = 0.001 and p = 0.020, respectively) between high PNI group and low PNI group. Multivariate analysis of GCLM without hepatectomy showed that NLR was an independent prognosis factor (p = 0.001). And there were statistical differences in OS and 1, 3, 5-year survival rates (p = 0.001p = 0.008p = 0.031 and p = 0.026, respectively) between low NLR group and high NLR group. Conclusions. GCLM has a better prognosis with hepatectomy. High preoperative PNI is a benign prognostic predictor for patients undergoing hepatectomy. And high preoperative NLR is an adverse prognostic factor for patients without hepatectomy.

[Comparison of clinicopathological features and prognosis between adenocarcinoma of esophagogastric junction and adenocarcinoma of gastric antrum].

OBJECTIVE: To compare the clinicopathological features and the prognosis between patients with adenocarcinoma of esophagogastric junction (AEG) and with adenocarcinoma of gastric antrum (AGA), and to investigate the prognostic factors of AEG and AGA. METHODS: A retrospective cohort study was performed on clinicopathological data of 239 AEG patients (AEG group) and 313 AGA patients selected simultaneously (AGA group) undergoing operation at Harbin Medical University Cancer Hospital from January 2001 to December 2012. INCLUSION CRITERIA: (1) receiving radical surgery (R0 resection); (2) AEG or AGA confirmed by pathological examination of postoperative tissue specimens; (3) without preoperative neoadjuvant radiotherapy or chemotherapy; (4) complete clinicopathological and follow-up data; (5) patients who died of non-tumor-related causes were excluded. Chi-square test and independent samples t-test were used to determine differences in clinicopathological factors between two groups. The overall survival (OS) of patients was compared by Kaplan-Meier method and Log-rank test. Multivariate prognosis analysis was performed using Cox proportional hazards regression model. RESULTS: As compared to AGA group, AEG group had higher proportion of male [82.0%(196/239) vs. 65.2%(204/313),χ²=19.243,P<0.001], older age [(60±10) years vs. (55±12) years, t=4.895, P<0.001], larger tumor diameter [(5.6±2.4) cm vs. (5.0±3.3) cm, t=2.480,P=0.013], more T4 stage[64.8%(155/239) vs. 55.6%(174/313),Z=-3.998, P<0.001], and more advanced tumor stage [stage III:60.7%(145/239) vs. 55.6%(174/313),Z=-2.564,P=0.010]. There were no statistically significant differences in serum albumin or hemoglobin between two groups (all P>0.05). The 5-year OS rate was 33.5% and 56.9% in AEG group and AGA group respectively and the median OS was 60.0(3.0-60.0) months and 33.6(3.0-60.0) months respectively; the difference was statistically significant (P<0.001). In AEG group, univariate analysis showed that differences of hemoglobin level (5-year OS rate: 24.0% for <130 g/L, 39.9% for ≥130 g/L, P=0.006), tumor diameter (5-year OS rate: 41.9% for <5 cm,28.8% for ≥5 cm, P=0.014), N stage (5-year OS rate: 42.2% for N0, 40.9% for N1, 31.7% for N2, 15.8% for N3a, 9.0% for N3b, P<0.001) and TNM stage (5-year OS rate: 56.2% for stage I, 38.5% for stage II, 28.3% for stage III,P=0.017) were statistically significant (all P<0.05); multivariate analysis revealed that the worse N stage was an independent risk factor of prognosis survival for AEG patients(HR=1.404,95%CI:1.164-1.693, P<0.001), and serum hemoglobin level ≥130 g/L was an independent protective factor of prognosis survival for AEG patients (HR=0.689,95%CI:0.501-0.946,P=0.021). In AGA group, univariate analysis showed that differences of serum albumin (5-year OS rate: 49.1% for <40 g/L, 61.1% for ≥ 40 g/L, P=0.021), tumor diameter (5-year OS rate: 74.2% for <5 cm, 39.9% for ≥ 5 cm, P<0.001), T stage (5-year OS rate: 98.3% for T1,83.3% for T2,50.0% for T3,36.8% for T4, P<0.001), N stage (5-year OS rate: 89.0% for N0, 62.3% for N1, 50.0% for N2, 33.9% for N3a, 10.3% for N3b, P<0.001) and TNM stage (5-year OS rate: 97.3% for stage I, 75.8% for stage II, 32.8% for stage III, P<0.001) were statistically significant (all P<0.05); multivariate analysis revealed that the worse T stage (HR=1.516,95%CI:1.060-2.167,P=0.023) and the worse N stage (HR=1.453,95%CI:1.209-1.747,P<0.001) were independent risk factors for prognosis of AGA patients. CONCLUSIONS: As compared to AGA, AEG presents have poorer prognosis,and is easier to present with later pathological stage and larger tumor diameter. N stage and hemoglobin level are independent factors associated with the OS of AEG patients. T stage and N stage are independent factors associated with the OS of AGA patients.