Prognostic significance of perioperative tumor marker levels in stage Ⅱ/Ⅲ gastric cancer
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摘要
AIM To evaluate the prognostic significance of perioperative carcinoembryonic antigen(CEA) and carbohydrate antigen 19-9(CA19-9) levels in stage Ⅱ/Ⅲ gastric cancer.METHODS From a multi-institutional retrospective database compiled by integrating clinical data from nine institutions, data of 998 patients who underwent curative resection for stage Ⅱ/Ⅲ gastric cancer between 2010 and 2014 were retrieved and analyzed. The prognostic impact of the preoperative and postoperative levels and chronological changes in CEA, CA19-9 and their combination were evaluated. To test whether postoperative adjuvant chemotherapy alters the prognostic impact of perioperative CEA and CA19-9 levels, the hazard ratios for mortality were compared between patients who underwent surgery alone and patients who underwent surgery followed by adjuvant chemotherapy.RESULTS The prognostic impact of postoperative CEA and CA19-9 was superior to that of the preoperative levels. Multivariable analysis identified high postoperative CEA and CA19-9 levels as independent prognostic factors for overall survival.Disease-free survival rates clearly decreased in a stepwise manner in association with postoperative CEA and CA19-9 levels, and patients with high levels of both markers showed significantly poorer prognosis than other patient groups. When we analyzed perioperative changes in serum CEA and CA19-9 levels, patients with high levels before and after surgery had the worst disease-free survival rates among all patient groups. Patients with normalized CEA levels after surgery had a significantly lower disease-free survival rate than those with normal perioperative levels, whereas patients with normalized CA19-9 levels after surgery had equivalent survival to those with normal perioperative levels. The prognostic impact of high CEA levels was observably smaller in patients who underwent adjuvant chemotherapy than in patients who underwent surgery alone, whereas that of high CA19-9 was greater in patients who underwent adjuvant chemotherapy. High postoperative CEA levels were significantly associated with an increased prevalence of liver, lung and bone recurrences, and high postoperative CA19-9 levels were significantly associated with increased frequencies of lymph node and liver recurrences.CONCLUSION The evaluation of serum CEA and CA 19-9 levels both before and after surgery provides useful information for precise risk stratification after curative gastrectomy.
AIM To evaluate the prognostic significance of perioperative carcinoembryonic antigen(CEA) and carbohydrate antigen 19-9(CA19-9) levels in stage Ⅱ/Ⅲ gastric cancer.METHODS From a multi-institutional retrospective database compiled by integrating clinical data from nine institutions, data of 998 patients who underwent curative resection for stage Ⅱ/Ⅲ gastric cancer between 2010 and 2014 were retrieved and analyzed. The prognostic impact of the preoperative and postoperative levels and chronological changes in CEA, CA19-9 and their combination were evaluated. To test whether postoperative adjuvant chemotherapy alters the prognostic impact of perioperative CEA and CA19-9 levels, the hazard ratios for mortality were compared between patients who underwent surgery alone and patients who underwent surgery followed by adjuvant chemotherapy.RESULTS The prognostic impact of postoperative CEA and CA19-9 was superior to that of the preoperative levels. Multivariable analysis identified high postoperative CEA and CA19-9 levels as independent prognostic factors for overall survival.Disease-free survival rates clearly decreased in a stepwise manner in association with postoperative CEA and CA19-9 levels, and patients with high levels of both markers showed significantly poorer prognosis than other patient groups. When we analyzed perioperative changes in serum CEA and CA19-9 levels, patients with high levels before and after surgery had the worst disease-free survival rates among all patient groups. Patients with normalized CEA levels after surgery had a significantly lower disease-free survival rate than those with normal perioperative levels, whereas patients with normalized CA19-9 levels after surgery had equivalent survival to those with normal perioperative levels. The prognostic impact of high CEA levels was observably smaller in patients who underwent adjuvant chemotherapy than in patients who underwent surgery alone, whereas that of high CA19-9 was greater in patients who underwent adjuvant chemotherapy. High postoperative CEA levels were significantly associated with an increased prevalence of liver, lung and bone recurrences, and high postoperative CA19-9 levels were significantly associated with increased frequencies of lymph node and liver recurrences.CONCLUSION The evaluation of serum CEA and CA 19-9 levels both before and after surgery provides useful information for precise risk stratification after curative gastrectomy.
AIM To evaluate the prognostic significance of perioperative carcinoembryonic antigen(CEA) and carbohydrate antigen 19-9(CA19-9) levels in stage Ⅱ/Ⅲ gastric cancer.METHODS From a multi-institutional retrospective database compiled by integrating clinical data from nine institutions, data of 998 patients who underwent curative resection for stage Ⅱ/Ⅲ gastric cancer between 2010 and 2014 were retrieved and analyzed. The prognostic impact of the preoperative and postoperative levels and chronological changes in CEA, CA19-9 and their combination were evaluated. To test whether postoperative adjuvant chemotherapy alters the prognostic impact of perioperative CEA and CA19-9 levels, the hazard ratios for mortality were compared between patients who underwent surgery alone and patients who underwent surgery followed by adjuvant chemotherapy.RESULTS The prognostic impact of postoperative CEA and CA19-9 was superior to that of the preoperative levels. Multivariable analysis identified high postoperative CEA and CA19-9 levels as independent prognostic factors for overall survival.Disease-free survival rates clearly decreased in a stepwise manner in association with postoperative CEA and CA19-9 levels, and patients with high levels of both markers showed significantly poorer prognosis than other patient groups. When we analyzed perioperative changes in serum CEA and CA19-9 levels, patients with high levels before and after surgery had the worst disease-free survival rates among all patient groups. Patients with normalized CEA levels after surgery had a significantly lower disease-free survival rate than those with normal perioperative levels, whereas patients with normalized CA19-9 levels after surgery had equivalent survival to those with normal perioperative levels. The prognostic impact of high CEA levels was observably smaller in patients who underwent adjuvant chemotherapy than in patients who underwent surgery alone, whereas that of high CA19-9 was greater in patients who underwent adjuvant chemotherapy. High postoperative CEA levels were significantly associated with an increased prevalence of liver, lung and bone recurrences, and high postoperative CA19-9 levels were significantly associated with increased frequencies of lymph node and liver recurrences.CONCLUSION The evaluation of serum CEA and CA 19-9 levels both before and after surgery provides useful information for precise risk stratification after curative gastrectomy.
引文
1 Van Cutsem E,Sagaert X,Topal B,Haustermans K,Prenen H.Gastric cancer.Lancet 2016;388:2654-2664[PMID:27156933 DOI:10.1016/S0140-6736(16)30354-3]
2 Wadhwa R,Song S,Lee JS,Yao Y,Wei Q,Ajani JA.Gastric cancer-molecular and clinical dimensions.Nat Rev Clin Oncol 2013;10:643-655[PMID:24061039 DOI:10.1038/nrclinonc.2013.170]
3 Kanda M,Kobayashi D,Tanaka C,Iwata N,Yamada S,Fujii T,Nakayama G,Sugimoto H,Koike M,Nomoto S,Murotani K,Fujiwara M,Kodera Y.Adverse prognostic impact of perioperative allogeneic transfusion on patients with stage Ⅱ/Ⅲ gastric cancer.Gastric Cancer 2016;19:255-263[PMID:25563579 DOI:10.1007/s10120-014-0456-x]
4 Wong RK,Jang R,Darling G.Postoperative chemoradiotherapy vs.preoperative chemoradiotherapy for locally advanced(operable)gastric cancer:clarifying the role and technique of radiotherapy.J Gastrointest Oncol 2015;6:89-107[PMID:25642342 DOI:10.3978/j.issn.2078-6891.2014.089]
5 Kanda M,Kodera Y,Sakamoto J.Updated evidence on adjuvant treatments for gastric cancer.Expert Rev Gastroenterol Hepatol 2015;9:1549-1560[PMID:26414453 DOI:10.1586/17474124.2015.1094373]
6 Shen L,Shan YS,Hu HM,Price TJ,Sirohi B,Yeh KH,Yang YH,Sano T,Yang HK,Zhang X,Park SR,Fujii M,Kang YK,Chen LT.Management of gastric cancer in Asia:resource-stratified guidelines.Lancet Oncol 2013;14:e535-e547[PMID:24176572 DOI:10.1016/S1470-2045(13)70436-4]
7 Kanda M,Tanaka C,Kobayashi D,Mizuno A,Tanaka Y,Takami H,Iwata N,Hayashi M,Niwa Y,Yamada S,Fujii T,Sugimoto H,Murotani K,Fujiwara M,Kodera Y.Proposal of the Coagulation Score as a Predictor for Short-Term and Long-Term Outcomes of Patients with Resectable Gastric Cancer.Ann Surg Oncol 2017;24:502-509[PMID:27600621 DOI:10.1245/s10434-016-5544-1]
8 Marrelli D,Pinto E,De Stefano A,de Manzoni G,Farnetani M,Garosi L,Roviello F.Preoperative positivity of serum tumor markers is a strong predictor of hematogenous recurrence of gastric cancer.J Surg Oncol 2001;78:253-258[PMID:11745820 DOI:10.1002/jso.1163]
9 Nam DH,Lee YK,Park JC,Lee H,Shin SK,Lee SK,Lee YC,Cheong JH,Hyung WJ,Noh SH,Kim CB.Prognostic value of early postoperative tumor marker response in gastric cancer.Ann Surg Oncol 2013;20:3905-3911[PMID:23807661 DOI:10.1245/s10434-013-3066-7]
10 Wang W,Seeruttun SR,Fang C,Chen J,Li Y,Liu Z,Zhan Y,Li W,Chen Y,Sun X,Li Y,Xu D,Guan Y,Zhou Z.Prognostic Significance of Carcinoembryonic Antigen Staining in Cancer Tissues of Gastric Cancer Patients.Ann Surg Oncol 2016;23:1244-1251[PMID:26620645 DOI:10.1245/s10434-015-4981-6]
11 Park SH,Ku KB,Chung HY,Yu W.Prognostic significance of serum and tissue carcinoembryonic antigen in patients with gastric adenocarcinomas.Cancer Res Treat 2008;40:16-21[PMID:19688060 DOI:10.4143/crt.2008.40.1.16]
12 Liu X,Qiu H,Liu J,Chen S,Xu D,Li W,Zhan Y,Li Y,Chen Y,Zhou Z,Sun X.Combined preoperative concentrations of CEA,CA 19-9,and 72-4 for predicting outcomes in patients with gastric cancer after curative resection.Oncotarget 2016;7:35446-35453[PMID:27147574 DOI:10.18632/oncotarget.9060]
13 Wang W,Chen XL,Zhao SY,Xu YH,Zhang WH,Liu K,Chen XZ,Yang K,Zhang B,Chen ZX,Chen JP,Zhou ZG,Hu JK.Prognostic significance of preoperative serum CA125,CA19-9 and CEA in gastric carcinoma.Oncotarget 2016;7:35423-35436[PMID:27097114 DOI:10.18632/oncotarget.8770]
14 Feng F,Tian Y,Xu G,Liu Z,Liu S,Zheng G,Guo M,Lian X,Fan D,Zhang H.Diagnostic and prognostic value of CEA,CA19-9,AFP and CA125 for early gastric cancer.BMC Cancer 2017;17:737[PMID:29121872 DOI:10.1186/s12885-017-3738-y]
15 Uda H,Kanda M,Tanaka C,Kobayashi D,Inaoka K,Tanaka Y,Hayashi M,Iwata N,Yamada S,Fujii T,Sugimoto H,Murotani K,Fujiwara M,Kodera Y.Perioperative Serum Carcinoembryonic Antigen Levels Predict Recurrence and Survival of Patients with Pathological T2-4 Gastric Cancer Treated with Curative Gastrectomy.Dig Surg 2018;35:55-63[PMID:28441659 DOI:10.1159/000471931]
16 Kanda M,Murotani K,Kobayashi D,Tanaka C,Yamada S,Fujii T,Nakayama G,Sugimoto H,Koike M,Fujiwara M,Kodera Y.Postoperative adjuvant chemotherapy with S-1 alters recurrence patterns and prognostic factors among patients with stage Ⅱ/Ⅲ gastric cancer:A propensity score matching analysis.Surgery 2015;158:1573-1580[PMID:26120068 DOI:10.1016/j.surg.2015.05.017]
17 Liu JY,Peng CW,Yang XJ,Huang CQ,Li Y.The prognosis role of AJCC/UICC 8th edition staging system in gastric cancer,a retrospective analysis.Am J Transl Res 2018;10:292-303[PMID:29423014]
18 Japanese Gastric Cancer Association.Japanese gastric cancer treatment guidelines 2014(ver.4).Gastric Cancer 2017;20:1-19[PMID:27342689 DOI:10.1007/s10120-016-0622-4]
19 Kanda M,Shimizu D,Tanaka H,Tanaka C,Kobayashi D,Hayashi M,Iwata N,Niwa Y,Yamada S,Fujii T,Sugimoto H,Murotani K,Fujiwara M,Kodera Y.Significance of SYT8 For the Detection,Prediction,and Treatment of Peritoneal Metastasis From Gastric Cancer.Ann Surg2018;267:495-503[PMID:28026832 DOI:10.1097/SLA.0000000000002096]
20 Sasako M,Sakuramoto S,Katai H,Kinoshita T,Furukawa H,Yamaguchi T,Nashimoto A,Fujii M,Nakajima T,Ohashi Y.Five-year outcomes of a randomized phase Ⅲ trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage Ⅱ or Ⅲ gastric cancer.J Clin Oncol2011;29:4387-4393[PMID:22010012 DOI:10.1200/JCO.2011.36.5908]
21 Noh SH,Park SR,Yang HK,Chung HC,Chung IJ,Kim SW,Kim HH,Choi JH,Kim HK,Yu W,Lee JI,Shin DB,Ji J,Chen JS,Lim Y,Ha S,Bang YJ;CLASSIC trial investigators.Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy(CLASSIC):5-year follow-up of an open-label,randomised phase 3 trial.Lancet Oncol 2014;15:1389-1396[PMID:25439693DOI:10.1016/S1470-2045(14)70473-5]
22 Chen S,Feng XY,Li YF,Zhao BW,Zhou ZW,Chen YB.The prognosis of gastric cancer patients with marginally elevated carcinoembryonic antigen(CEA)values after D2 radical gastrectomy.JSurg Oncol 2013;107:641-645[PMID:23297055 DOI:10.1002/jso.23300]
23 Deng K,Yang L,Hu B,Wu H,Zhu H,Tang C.The prognostic significance of pretreatment serum CEA levels in gastric cancer:a meta-analysis including 14651 patients.PLoS One 2015;10:e0124151[PMID:25879931 DOI:10.1371/journal.pone.0124151]
24 Zhang Q,Qu H,Sun G,Li Z,Ma S,Shi Z,Zhao E,Zhang H,He Q.Early postoperative tumor marker responses provide a robust prognostic indicator for N3 stage gastric cancer.Medicine(Baltimore)2017;96:e7560[PMID:28796039 DOI:10.1097/MD.0000000000007560]
25 Gold P,Freedman SO.Specific carcinoembryonic antigens of the human digestive system.J Exp Med 1965;122:467-481[PMID:4953873 DOI:10.1084/jem.122.3.467]
26 Del Villano BC,Brennan S,Brock P,Bucher C,Liu V,McClure M,Rake B,Space S,Westrick B,Schoemaker H,Zurawski VR Jr.Radioimmunometric assay for a monoclonal antibody-defined tumor marker,CA 19-9.Clin Chem 1983;29:549-552[PMID:6825270]
27 Koprowski H,Steplewski Z,Mitchell K,Herlyn M,Herlyn D,Fuhrer P.Colorectal carcinoma antigens detected by hybridoma antibodies.Somatic Cell Genet 1979;5:957-971[PMID:94699DOI:10.1007/BF01542654]
28 Kim JH,Jun KH,Jung H,Park IS,Chin HM.Prognostic Value of Preoperative Serum Levels of Five Tumor Markers(Carcinoembryonic Antigen,CA19-9,Alpha-fetoprotein,CA72-4,and CA125)in Gastric Cancer.Hepatogastroenterology 2014;61:863-869[PMID:26176088]
29 He CZ,Zhang KH,Li Q,Liu XH,Hong Y,Lv NH.Combined use of AFP,CEA,CA125 and CAl9-9 improves the sensitivity for the diagnosis of gastric cancer.BMC Gastroenterol 2013;13:87[PMID:23672279 DOI:10.1186/1471-230X-13-87]
30 Goonetilleke KS,Siriwardena AK.Systematic review of carbohydrate antigen(CA 19-9)as a biochemical marker in the diagnosis of pancreatic cancer.Eur J Surg Oncol 2007;33:266-270[PMID:17097848 DOI:10.1016/j.ejso.2006.10.004]
31 Park JK,Paik WH,Ryu JK,Kim YT,Kim YJ,Kim J,Song BJ,Park JM,Yoon YB.Clinical significance and revisiting the meaning of CA 19-9 blood level before and after the treatment of pancreatic ductal adenocarcinoma:analysis of 1,446 patients from the pancreatic cancer cohort in a single institution.PLoS One 2013;8:e78977[PMID:24250822 DOI:10.1371/journal.pone.0078977]
32 Kanda M,Shimizu D,Tanaka H,Tanaka C,Kobayashi D,Hayashi M,Takami H,Niwa Y,Yamada S,Fujii T,Sugimoto H,Kodera Y.Synaptotagmin expression and peritoneal metastasis in gastric cancer.Br J Surg 2018;105:1349-1358[PMID:29741294 DOI:10.1002/bjs.10876]
33 Kanda M,Tanaka H,Shimizu D,Miwa T,Umeda S,Tanaka C,Kobayashi D,Hattori N,Suenaga M,Hayashi M,Iwata N,Yamada S,Fujiwara M,Kodera Y.SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells.Oncogene 2018;37:5355-5366[PMID:29858600 DOI:10.1038/s41388-018-0335-8]
34 Hasegawa H,Fujitani K,Nakazuru S,Hirao M,Yamamoto K,Mita E,Tsujinaka T.Optimal treatment change criteria for advanced gastric cancer with non-measurable peritoneal metastasis:symptom/tumor marker-based versus CT-based.Anticancer Res 2014;34:5169-5174[PMID:25202110]
35 Wada N,Kurokawa Y,Miyazaki Y,Makino T,Takahashi T,Yamasaki M,Nakajima K,Takiguchi S,Mori M,Doki Y.The characteristics of the serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels in gastric cancer cases.Surg Today 2017;47:227-232[PMID:27566604 DOI:10.1007/s00595-016-1408-3]
36 Cheong JH,Yang HK,Kim H,Kim WH,Kim YW,Kook MC,Park YK,Kim HH,Lee HS,Lee KH,Gu MJ,Kim HY,Lee J,Choi SH,Hong S,Kim JW,Choi YY,Hyung WJ,Jang E,Kim H,Huh YM,Noh SH.Predictive test for chemotherapy response in resectable gastric cancer:a multicohort,retrospective analysis.Lancet Oncol 2018;19:629-638[PMID:29567071 DOI:10.1016/S1470-2045(18)30108-6]
2 Wadhwa R,Song S,Lee JS,Yao Y,Wei Q,Ajani JA.Gastric cancer-molecular and clinical dimensions.Nat Rev Clin Oncol 2013;10:643-655[PMID:24061039 DOI:10.1038/nrclinonc.2013.170]
3 Kanda M,Kobayashi D,Tanaka C,Iwata N,Yamada S,Fujii T,Nakayama G,Sugimoto H,Koike M,Nomoto S,Murotani K,Fujiwara M,Kodera Y.Adverse prognostic impact of perioperative allogeneic transfusion on patients with stage Ⅱ/Ⅲ gastric cancer.Gastric Cancer 2016;19:255-263[PMID:25563579 DOI:10.1007/s10120-014-0456-x]
4 Wong RK,Jang R,Darling G.Postoperative chemoradiotherapy vs.preoperative chemoradiotherapy for locally advanced(operable)gastric cancer:clarifying the role and technique of radiotherapy.J Gastrointest Oncol 2015;6:89-107[PMID:25642342 DOI:10.3978/j.issn.2078-6891.2014.089]
5 Kanda M,Kodera Y,Sakamoto J.Updated evidence on adjuvant treatments for gastric cancer.Expert Rev Gastroenterol Hepatol 2015;9:1549-1560[PMID:26414453 DOI:10.1586/17474124.2015.1094373]
6 Shen L,Shan YS,Hu HM,Price TJ,Sirohi B,Yeh KH,Yang YH,Sano T,Yang HK,Zhang X,Park SR,Fujii M,Kang YK,Chen LT.Management of gastric cancer in Asia:resource-stratified guidelines.Lancet Oncol 2013;14:e535-e547[PMID:24176572 DOI:10.1016/S1470-2045(13)70436-4]
7 Kanda M,Tanaka C,Kobayashi D,Mizuno A,Tanaka Y,Takami H,Iwata N,Hayashi M,Niwa Y,Yamada S,Fujii T,Sugimoto H,Murotani K,Fujiwara M,Kodera Y.Proposal of the Coagulation Score as a Predictor for Short-Term and Long-Term Outcomes of Patients with Resectable Gastric Cancer.Ann Surg Oncol 2017;24:502-509[PMID:27600621 DOI:10.1245/s10434-016-5544-1]
8 Marrelli D,Pinto E,De Stefano A,de Manzoni G,Farnetani M,Garosi L,Roviello F.Preoperative positivity of serum tumor markers is a strong predictor of hematogenous recurrence of gastric cancer.J Surg Oncol 2001;78:253-258[PMID:11745820 DOI:10.1002/jso.1163]
9 Nam DH,Lee YK,Park JC,Lee H,Shin SK,Lee SK,Lee YC,Cheong JH,Hyung WJ,Noh SH,Kim CB.Prognostic value of early postoperative tumor marker response in gastric cancer.Ann Surg Oncol 2013;20:3905-3911[PMID:23807661 DOI:10.1245/s10434-013-3066-7]
10 Wang W,Seeruttun SR,Fang C,Chen J,Li Y,Liu Z,Zhan Y,Li W,Chen Y,Sun X,Li Y,Xu D,Guan Y,Zhou Z.Prognostic Significance of Carcinoembryonic Antigen Staining in Cancer Tissues of Gastric Cancer Patients.Ann Surg Oncol 2016;23:1244-1251[PMID:26620645 DOI:10.1245/s10434-015-4981-6]
11 Park SH,Ku KB,Chung HY,Yu W.Prognostic significance of serum and tissue carcinoembryonic antigen in patients with gastric adenocarcinomas.Cancer Res Treat 2008;40:16-21[PMID:19688060 DOI:10.4143/crt.2008.40.1.16]
12 Liu X,Qiu H,Liu J,Chen S,Xu D,Li W,Zhan Y,Li Y,Chen Y,Zhou Z,Sun X.Combined preoperative concentrations of CEA,CA 19-9,and 72-4 for predicting outcomes in patients with gastric cancer after curative resection.Oncotarget 2016;7:35446-35453[PMID:27147574 DOI:10.18632/oncotarget.9060]
13 Wang W,Chen XL,Zhao SY,Xu YH,Zhang WH,Liu K,Chen XZ,Yang K,Zhang B,Chen ZX,Chen JP,Zhou ZG,Hu JK.Prognostic significance of preoperative serum CA125,CA19-9 and CEA in gastric carcinoma.Oncotarget 2016;7:35423-35436[PMID:27097114 DOI:10.18632/oncotarget.8770]
14 Feng F,Tian Y,Xu G,Liu Z,Liu S,Zheng G,Guo M,Lian X,Fan D,Zhang H.Diagnostic and prognostic value of CEA,CA19-9,AFP and CA125 for early gastric cancer.BMC Cancer 2017;17:737[PMID:29121872 DOI:10.1186/s12885-017-3738-y]
15 Uda H,Kanda M,Tanaka C,Kobayashi D,Inaoka K,Tanaka Y,Hayashi M,Iwata N,Yamada S,Fujii T,Sugimoto H,Murotani K,Fujiwara M,Kodera Y.Perioperative Serum Carcinoembryonic Antigen Levels Predict Recurrence and Survival of Patients with Pathological T2-4 Gastric Cancer Treated with Curative Gastrectomy.Dig Surg 2018;35:55-63[PMID:28441659 DOI:10.1159/000471931]
16 Kanda M,Murotani K,Kobayashi D,Tanaka C,Yamada S,Fujii T,Nakayama G,Sugimoto H,Koike M,Fujiwara M,Kodera Y.Postoperative adjuvant chemotherapy with S-1 alters recurrence patterns and prognostic factors among patients with stage Ⅱ/Ⅲ gastric cancer:A propensity score matching analysis.Surgery 2015;158:1573-1580[PMID:26120068 DOI:10.1016/j.surg.2015.05.017]
17 Liu JY,Peng CW,Yang XJ,Huang CQ,Li Y.The prognosis role of AJCC/UICC 8th edition staging system in gastric cancer,a retrospective analysis.Am J Transl Res 2018;10:292-303[PMID:29423014]
18 Japanese Gastric Cancer Association.Japanese gastric cancer treatment guidelines 2014(ver.4).Gastric Cancer 2017;20:1-19[PMID:27342689 DOI:10.1007/s10120-016-0622-4]
19 Kanda M,Shimizu D,Tanaka H,Tanaka C,Kobayashi D,Hayashi M,Iwata N,Niwa Y,Yamada S,Fujii T,Sugimoto H,Murotani K,Fujiwara M,Kodera Y.Significance of SYT8 For the Detection,Prediction,and Treatment of Peritoneal Metastasis From Gastric Cancer.Ann Surg2018;267:495-503[PMID:28026832 DOI:10.1097/SLA.0000000000002096]
20 Sasako M,Sakuramoto S,Katai H,Kinoshita T,Furukawa H,Yamaguchi T,Nashimoto A,Fujii M,Nakajima T,Ohashi Y.Five-year outcomes of a randomized phase Ⅲ trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage Ⅱ or Ⅲ gastric cancer.J Clin Oncol2011;29:4387-4393[PMID:22010012 DOI:10.1200/JCO.2011.36.5908]
21 Noh SH,Park SR,Yang HK,Chung HC,Chung IJ,Kim SW,Kim HH,Choi JH,Kim HK,Yu W,Lee JI,Shin DB,Ji J,Chen JS,Lim Y,Ha S,Bang YJ;CLASSIC trial investigators.Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy(CLASSIC):5-year follow-up of an open-label,randomised phase 3 trial.Lancet Oncol 2014;15:1389-1396[PMID:25439693DOI:10.1016/S1470-2045(14)70473-5]
22 Chen S,Feng XY,Li YF,Zhao BW,Zhou ZW,Chen YB.The prognosis of gastric cancer patients with marginally elevated carcinoembryonic antigen(CEA)values after D2 radical gastrectomy.JSurg Oncol 2013;107:641-645[PMID:23297055 DOI:10.1002/jso.23300]
23 Deng K,Yang L,Hu B,Wu H,Zhu H,Tang C.The prognostic significance of pretreatment serum CEA levels in gastric cancer:a meta-analysis including 14651 patients.PLoS One 2015;10:e0124151[PMID:25879931 DOI:10.1371/journal.pone.0124151]
24 Zhang Q,Qu H,Sun G,Li Z,Ma S,Shi Z,Zhao E,Zhang H,He Q.Early postoperative tumor marker responses provide a robust prognostic indicator for N3 stage gastric cancer.Medicine(Baltimore)2017;96:e7560[PMID:28796039 DOI:10.1097/MD.0000000000007560]
25 Gold P,Freedman SO.Specific carcinoembryonic antigens of the human digestive system.J Exp Med 1965;122:467-481[PMID:4953873 DOI:10.1084/jem.122.3.467]
26 Del Villano BC,Brennan S,Brock P,Bucher C,Liu V,McClure M,Rake B,Space S,Westrick B,Schoemaker H,Zurawski VR Jr.Radioimmunometric assay for a monoclonal antibody-defined tumor marker,CA 19-9.Clin Chem 1983;29:549-552[PMID:6825270]
27 Koprowski H,Steplewski Z,Mitchell K,Herlyn M,Herlyn D,Fuhrer P.Colorectal carcinoma antigens detected by hybridoma antibodies.Somatic Cell Genet 1979;5:957-971[PMID:94699DOI:10.1007/BF01542654]
28 Kim JH,Jun KH,Jung H,Park IS,Chin HM.Prognostic Value of Preoperative Serum Levels of Five Tumor Markers(Carcinoembryonic Antigen,CA19-9,Alpha-fetoprotein,CA72-4,and CA125)in Gastric Cancer.Hepatogastroenterology 2014;61:863-869[PMID:26176088]
29 He CZ,Zhang KH,Li Q,Liu XH,Hong Y,Lv NH.Combined use of AFP,CEA,CA125 and CAl9-9 improves the sensitivity for the diagnosis of gastric cancer.BMC Gastroenterol 2013;13:87[PMID:23672279 DOI:10.1186/1471-230X-13-87]
30 Goonetilleke KS,Siriwardena AK.Systematic review of carbohydrate antigen(CA 19-9)as a biochemical marker in the diagnosis of pancreatic cancer.Eur J Surg Oncol 2007;33:266-270[PMID:17097848 DOI:10.1016/j.ejso.2006.10.004]
31 Park JK,Paik WH,Ryu JK,Kim YT,Kim YJ,Kim J,Song BJ,Park JM,Yoon YB.Clinical significance and revisiting the meaning of CA 19-9 blood level before and after the treatment of pancreatic ductal adenocarcinoma:analysis of 1,446 patients from the pancreatic cancer cohort in a single institution.PLoS One 2013;8:e78977[PMID:24250822 DOI:10.1371/journal.pone.0078977]
32 Kanda M,Shimizu D,Tanaka H,Tanaka C,Kobayashi D,Hayashi M,Takami H,Niwa Y,Yamada S,Fujii T,Sugimoto H,Kodera Y.Synaptotagmin expression and peritoneal metastasis in gastric cancer.Br J Surg 2018;105:1349-1358[PMID:29741294 DOI:10.1002/bjs.10876]
33 Kanda M,Tanaka H,Shimizu D,Miwa T,Umeda S,Tanaka C,Kobayashi D,Hattori N,Suenaga M,Hayashi M,Iwata N,Yamada S,Fujiwara M,Kodera Y.SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells.Oncogene 2018;37:5355-5366[PMID:29858600 DOI:10.1038/s41388-018-0335-8]
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