| [Background]The AJCC TNM stage was used as the most widely recognized criterion in evaluating the prognosis of patients with gastric cancer and the therapeutic efficacy of anti-tumor therapy.However,the efficacy of the TNM stage in predicting the prognosis of patients with gastric cancer is low(C-index is about 0.65),and it has been found in clinical practice that patients with the same stage also show great differences in clinical outcomes and therapeutic response to anti-tumor therapy.Therefore,it is not sufficient to consider the malignant biological behaviors of tumors for the evaluation of prognosis and efficacy of anti-tumor therapy in patients with gastric cancer(GC).Recent studies revealed that tumor immune microenvironment(TIME)played the important role in the development and progression of tumors,the differences between the abundance and function of the immune cells infiltrating in TIME can lead to differences in the prognosis of patients.For that,based on the TNM stage and effectively combined with the characteristics of TIME,prognostic risk stratification and efficacy evaluation of anti-tumor therapy in patients with GC can be better performed.Therefore,it is worth researching and exploring to find some markers that can effectively represent the TIME characteristics and effectively evaluate the prognosis of patients with gastric cancer and the response rate of anti-tumor therapy.Tertiary lymphoid structure(TLS)was a lymph node-like structure which comprised of highly aggregated immune cells,and provided a local environment for innate and adaptive immune cells to interaction for each other.Existing studies have taken TLS as one of the representative characteristics of TIME,and found a significant positive correlation between TLS and good prognosis of various tumors and the effectiveness of immunotherapy.There is an assessment of TLS status,including its quantity,density,spatial distribution,and maturity.Compared with other parameters,maturity can better represent TLS status.However,the correlation between the maturity of TLS and the prognosis of GC and the benefit of antitumor therapy has not been explained in the present studies.Therefore,this study intends to review the TLS maturity changes in tumor tissues of patients with gastric cancer through pathology,and then analyze its prognostic prediction and efficacy evaluation of anti-tumor therapy.On this basis,combined with TLS maturity and the TNM stage,a new prognosis prediction model for patients with gastric cancer was constructed,and the constructed model was verified.[Objectives]1.Based on the prospective gastric cancer follow-up cohort established by Xijing Digestive Disease Hospital and the pathological tissue sample bank of Pathology Department of Xijing Digestive Disease Hospital,the existence and maturity of TLS in primary tumor tissues of patients with gastric cancer were retrospectively analyzed,and the correlation between TLS and overall postoperative survival and risk of disease progression of patients with gastric cancer was analyzed,and the prognosis of patients with gastric cancer was accurately stratified.2.Based on the inpatient information system of Xijing Digestive Disease Hospital,the follow-up system of gastric cancer and the pathological tissue sample bank of Pathology Department,the existence and maturity of TLS in the tumor tissues of patients with gastric cancer were retrospectively analyzed,and the correlation between TLS and the benefits of postoperative adjuvant chemotherapy in patients with gastric cancer was analyzed to observe whether TLS could be used to guide postoperative chemotherapy in patients with gastric cancer.3.Based on the retrospective analysis cohort,combined with TLS maturity and the TNM stage,a prognostic model for gastric cancer patients was constructed,and the prognostic efficacy and consistency of the model were verified,to analyze the clinical application value of the constructed model.[Methods]Based on the prospective gastric cancer follow-up cohort established by Xijing Digestive Disease Hospital,patients who underwent radical resection of gastric cancer in Xijing Digestive Disease Hospital from 2010 to 2016 and were confirmed as primary gastric tumor by postoperative pathology were included.Routine clinicopathological data such as basic information,surgical pathology,chemotherapy and prognosis of patients were collected from the database.The missing data were supplemented and improved through electronic medical records and outpatient records,excluding patients receiving neoadjuvant chemotherapy,positive incisal margin,gastric stump cancer,and lost followup,and 1493 gastric cancer patients were finally included.For enrolled patients,hematoxylin-eosin(HE)stained sections of primary tumor tissue in surgical excised specimens were borrowed from the Pathology Department of Xijing Digestive Disease Hospital.Judging by TLS morphology,TLS was divided into three kinds of maturity:(1)Early TLS(Neg/E-TLS),which consists of lymphocyte clusters with blurred boundaries;(2)Primary Follicle-like TLS(FL-TLS),rounded lymphocyte clusters with clear boundaries,but without germinal centers;(3)the secondary Follicle sample TLS(Follicle-like the TLS,FL-TLS),lymphocyte accumulation center visible light dye germinal center.The presence,density and spatial distribution of TLS in tumor tissue will also be evaluated.Early and primary follicular TLS belong to immature TLS,while secondary follicular TLS belongs to mature TLS.According to the existence of TLS structures in tumor tissues,TLS positive(at least one early TLS exists in tumor tissues)and TLS negative(no TLS structures exist in tumor tissues at any mature stage)were classified.To observe the value of the presence status and maturity of TLS in the prognosis assessment of gastric cancer patients based on the follow-up outcome analysis of patients.The correlation between the existence status and maturity of TLS and the efficacy of postoperative adjuvant chemotherapy in patients with gastric cancer was further analyzed based on the information of postoperative adjuvant chemotherapy.Finally,based on the above analysis results,a prognostic model for gastric cancer patients was constructed and the predictive efficacy of the model was verified.Statistical methods:Chi-square test or Fisher exact probability method were used to compare the differences of categorical variables between different coorgroups,and T-test was used to analyze the differences between continuous variables.Kaplan-Meier method was used to draw the postoperative survival curves of patients,and Log-rank test was used to compare the differences in the survival curves of different groups.The clinicopathological factors associated with TLS maturity were analyzed by Logistic regression.COX univariate and multivariate analyses were used to identify independent risk factors associated with prognosis.This Nomogram was used to visualize the results of COX multifactor analysis to construct a prognostic model for gastric cancer patients.ROC curves were used to compare the predictive efficacy of different prognostic evaluation methods,and calibration curves were used to evaluate the consistency of prognostic prediction.P<0.05 was statistically significant..[Results]1.According to the principle of 2:1:1,the enrolled patients were randomly divided into one discovery cohort and two validation cohorts.(1)By comparing the difference in prognosis between positive and negative patients,the prognosis of TLS positive patients in the three cohorts was significantly better than that of TLS negative patients(all P<0.05);(2)In the three cohorts,prognostic analysis showed that compared with Negative/EarlyTLS(Neg/E-TLS)patients,In patients with positive Follicle-like TLS(FL-TLS),both OS and DFS were significantly improved after surgery(P<0.05).(3)Multivariate COX analysis showed that FL-TLS positive patients had 42.3%and 42.6%lower overall risk of postoperative death and disease progression than Neg/E-TLS patients.Multivariate Logistic regression showed that preoperative elevated serum CEA,larger tumor size and late TNM stage were negatively correlated with FL-TLS positives in tumor tissue.2.(1)The survival analysis of gastric cancer patients combined with whether chemotherapy and TLS maturity after surgery showed that 5-year OS and DFS of patients with FLTLS present in tumor tissues were 21%and 17%higher in the chemotherapy group than in the non-chemotherapy group(OS:59%VS in the chemotherapy group).In the group without chemotherapy,38%(P<0.001);DFS:61%in chemotherapy group VS.44%in non-chemotherapy group,(P<0.001);Among patients with tumor tissue negative/E-TLS,5-year OS and DFS were 13%and 10%better in the chemotherapy group than in the no-chemotherapy group,respectively(OS:41%VS.In the group without chemotherapy,28%,P<0.001;DFS:41%in chemotherapy group VS.32%in nonchemotherapy group,P=0.039).Interaction analysis showed that compared with Neg/ETLS patients,patients with FL-TLS positive in tumor tissue benefited more from postoperative chemotherapy.(2)Further subgroup analysis combined with TNM staging and prognostic correlation analysis showed that although the postoperative chemotherapy benefit trend was observed in both Neg/E-TLS patients and FL-TLS patients in stage Ⅱpatients,there was no significant correlation between TLS maturity and postoperative adjuvant chemotherapy benefit.In stage Ⅲ patients,both Neg/E-TLS patients and FLTLS patients showed significant chemotherapy benefit after surgery,and compared with Neg/E-TLS patients,patients with FL-TLS positive tumor tissue showed more significant chemotherapy benefit after surgery.3.(1)Univariate and multivariate COX risk regression analysis showed that eight clinicopathological variables,including preoperative serum CEA,serum CA19-9,pathological differentiation,tumor size,vascular invasion,TNM stage,TLS maturity and chemotherapy status,were independent correlated factors for postoperative OS in patients with stage Ⅰ-Ⅲ gastric cancer.Seven clinicopathological variables,including preoperative serum CEA,serum CA19-9,pathological differentiation,tumor size,TNM stage,TLS maturity and chemotherapy status,were independent correlated factors for postoperative DFS in patients with stage Ⅰ-Ⅲ gastric cancer.(2)The C-index of postoperative OS prediction model for gastric cancer patients constructed based on the results of COX multifactor analysis was 0.735,and the C-index of DFS prediction model was 0.723.The predictive efficacy of the model was evaluated in the validation cohort,and the C-index of the postoperative OS and DFS prediction models were 0.803 and 0.795,respectively,indicating a high consistency in predicting 3-year and 5-year survival of gastric cancer patients.[Conclusions]1.TLS maturity was significant positive related to the prognosis of gastric cancer patients.Compared with Neg/E-TLS patients,the OS and DFS for those with FL-TLS were significantly improved.This result indicated that FL-TLS could bring long-term effective tumor control effect in tumor tissues,2.Combined with the postoperative chemotherapy status of patients,both Neg/E-TLS patients and FL-TLS patients showed significant benefits from postoperative adjuvant chemotherapy,but FL-TLS patients had more significant benefits than Neg/E-TLS patients.3.Combined with conventional clinicopathological factors related to prognosis,the prediction model of OS and DFS for Ⅰ-Ⅲ gastric cancer patients has high prognostic efficacy and consistency. |
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