Prediction Of The Efficacy Of Neoadjuvant Chemotherapy In Locally Advanced Gastric Cancer By H19 And HOTTIP In Plasma

Objective:To study the value of plasma long non-coding RNA H19 and HOTTIP in predicting the efficacy of neoadjuvant chemotherapy for locally advanced gastric cancer.Methods:A total of 76 patients with stage T3～4aN-M0 gastric cancer and 44 patients with benign gastric diseases who were treated in Yantai Yuhuangding Hospital Affiliated to Qingdao University from August 2020 to February 2022 were included,and the expression levels of plasma H19 and HOTTIP were detected before treatment.All gastric cancer patients received neoadjuvant chemotherapy with CAPEOX regimen.After 2 cycles,the expression levels of H19 and HOTTIP in plasma were detected again.Combined with abdominal contrast-enhanced CT examination,RECIST v1.1 scoring standard was used to evaluate the efficacy of neoadjuvant chemotherapy,which was divided into complete remission(CR),partial remission(PR),stable disease(SD),and progressive disease(PD);CR and PR were classified as objective response(ORR).Indications for surgery were also evaluated.According to the pathological results after surgery,the tumor regression grading AJCC/CAP criteria were used:TRG 0:no residual tumor(complete regression);TRG 1:few residual tumor cells;TRG 2:more fibrosis than residual tumor cells;TRG 3:More residual tumor cells than fibrosis or no regressive changes.To analyze the value of plasma H19 and HOTTIP before treatment in the diagnosis of gastric cancer and prediction of the efficacy of neoadjuvant chemotherapy.According to the median of the expression levels of the two lncRNAs in gastric cancer patients as the threshold,higher than the threshold is called high expression,and lower than or equal to the threshold is called low expression.Result:1.Based on bioinformatics analysis of 407 tissue samples from the TCGA gastric cancer database,both H19 and HOTTIP belong to lncRNAs that are significantly highly expressed in gastric cancer tissues.The expression levels of H19 and HOTTIP in gastric cancer tissues were significantly higher than those in adjacent tissues(P<0.001).Both H19 and HOTTIP have high diagnostic value in diagnosing gastric cancer tissue and adjacent tissue(cut-off value=1.36,AUC=0.673,CI=0.570-0.776;cut-off value=0.10,AUC=0.864,CI=0.796-0.931).2.The expression levels of plasma H19 and HOTTIP in patients with gastric cancer were higher than those in patients with benign gastric diseases[1.36(0.61)vs.0.98(0.38),Z=-4.793,P<0.001;1.91(1.19)vs.1.03(0.89),Z=-5.615,P<0.001].The diagnostic value of H19 and HOTTIP for gastric cancer(cut-off value=1.28,AUC=0.763,95%CI=0.673-0.853;cut-off value=1.17,AUC=0.808,95%CI=0.726-0.890)was significantly higher than CEA,CA19-9,CA72-4 and CA125.Regardless of whether H19 and HOTTIP were used as single or combined diagnostic indicators,the area under the ROC curve(AUC value)was greater than 0.75.3.The expression level of H19 in plasma before treatment was higher in patients with poorly differentiated tumors,deep infiltration,and more lymph node metastasis than in patients with well-differentiated tumors,shallow invasion,and few lymph node metastases[1.42(0.61)vs.1.21(0.45),Z=-2.538,P=0.011;1.56(0.66)vs.1.24(0.55),Z=-3.472,P=0.001;1.80(1.08)vs.1.48(0.64)vs.1.24(0.46),H=16.180,P<0.001].The expression level of HOTTIP in plasma before neoadjuvant chemotherapy in patients with poorly differentiated tumor and more lymph node metastasis was higher than that of patients with well differentiated tumor and less lymph node metastasis[1.97(1.17)vs.1.50(0.93),Z=-2.105,P=0.035;2.49(1.24)vs.1.95(1.63)vs.1.61(0.93),H=9.630,P=0.008].4.After neoadjuvant chemotherapy in 76 patients with advanced gastric cancer,according to RECIST v1.1 scoring criteria,1 case(1.32%)of CR,41 cases of PR(53.94%),31 cases of SD(40.79%),and 3 cases of PD(3.95%),objective remission was achieved in 42 cases(55.26%).The expression levels of H19 and HOTTIP were positively correlated with the RECIST v1.1 scoring criteria.The expression levels of H19 and HOTTIP were lower in patients with better curative effect,and higher in patients with poor curative effect.Construction of ROC curve to assess the objective response rate of H19 and HOTTIP before chemotherapy in predicting disease after neoadjuvant chemotherapy(cut-off value=1.54,AUC=0.786,CI=0.681-0.891;cut-off value=1.77,AUC=0.682,CI=0.561-0.804).Regardless of whether H19 and HOTTIP are used alone or in combination,their predictive value of ORR is higher than that of traditional tumor markers.5.76 patients with advanced gastric cancer underwent surgery as of 2022-02.Postoperative pathological results were obtained,and tumor regression was graded according to AJCC/CAP criteria.Among them,3 people(3.95%)were at TRG level 0,8 people(10.52%)at TRG level 1,29 people(38.16%)at TRG level 2,and 36 people(47.37%)at TRG level 3.The expression levels of H19 and HOTTIP in plasma before neoadjuvant chemotherapy were positively correlated with TRG grade,and HOTTIP was significantly different in patients with pathological complete regression(pCR)and pathological incomplete regression(Non-pCR).Construction of ROC curve to evaluate the value of H19 and HOTTIP before chemotherapy in predicting the degree of tumor regression to TRG 0 and TRG 1(cut-off value=1.31,AUC=0.806,CI=0.688-0.923;cut-off value=1.69,AUC=0.718,CI=0.573-0.863).Regardless of whether H19 and HOTTIP were used alone or in combination,their predictive values for TRG 0 and TRG 1 were higher than those of traditional tumor markers.6.After 2 cycles of neoadjuvant chemotherapy in 76 patients with advanced gastric cancer,1 case(1.32%)of CR,42 cases of PR(55.26%),28 cases of SD(36.84%),and 5 cases of PD(6.58%),objective remission in 43 cases(56.58%).The expression levels of H19 and HOTTIP were positively correlated with the RECIST v1.1 scoring criteria.The expression levels of H19 and HOTTIP were lower in patients with better curative effect,and higher in patients with poor curative effect.Construction of ROC curv e to evaluate the objective response rate of H19 and HOTTIP before chemotherapy in predicting disease after 2 cycles of neoadjuvant chemotherapy(cut-off value=1.31,AUC=0.837,CI=0.747-0.926;cut-off value=1.77,AUC=0.765,CI=0.657-0.874).Regardless of whether H19 and HOTTIP were used alone or in combination,their value in predicting ORR after 2 cycles of neoadjuvant chemotherapy was higher than that of traditional tumor markers.7.After 2 cycles of neoadjuvant chemotherapy,the relative expression levels of H19 and HOTTIP in plasma were 1.12(0.632)and 1.22(0.981),respectively,which were lower than those before neoadjuvant chemotherapy,respectively[respectively 1.37(0.614),1.91(1.194),Z=-4.877,P<0.001,Z=-6.430,P<0.001].8.The median of H19 before treatment was 1.37,and the median of H19 after 2 cycles of chemotherapy was 1.12;the median of HOTTIP before treatment was 1.91,and the median of HOTTIP after 2 cycles of chemotherapy was 1.22.The median was used as the threshold,above the threshold was high expression,and below the threshold was low expression.The postoperative follow-up time has been 16 months so far.The prognosis of patients with low H19 expression before neoadjuvant chemotherapy was not significantly different from that of patients with high H19 expression before neoadjuvant chemotherapy[HR 1.82(0.76-4.34),P=0.177].There was no significant difference in the prognosis of patients with low H19 expression after 2 cycles of neoadjuvant chemotherapy compared with patients with high H19 expression after 2 cycles of neoadjuvant chemotherapy[HR 1.94(0.81-4.63),P=0.135].The prognosis of patients with low HOTTIP expression before neoadjuvant chemotherapy was not significantly different from that of patients with high HOTTIP expression before neoadjuvant chemotherapy[HR 2.22(0.91-5.45),P=0.081].The prognosis of patients with low HOTTIP expression after 2 cycles of neoadjuvant chemotherapy was not significantly different from that of patients with high HOTTIP expression after 2 cycles of neoadjuvant chemotherapy[HR 1.40(0.60-3.28),P=0.438].Conclusion:1.H19 and HOTTIP are highly expressed in tumor tissue and plasma of gastric cancer patients,which may be a potential tumor diagnostic marker for gastric cancer patients.Patients with higher levels of H19 and HOTTIP expression in plasma before neoadjuvant chemotherapy may be associated with higher tumor aggressiveness.2.The expression levels of H19 and HOTTIP in plasma before neoadjuvant chemotherapy may have a role in predicting the efficacy of neoadjuvant chemotherapy.Patients with lower levels of H19 and HOTTIP expression in plasma had better response to neoadjuvant chemotherapy and had better postoperative pathological regression.