Ⅲ期结肠癌患者术前预后营养指数的预后价值及其与全身炎症反应标志物的相关性
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摘要
背景与目的预后营养指数(prognostic nutritional index,PNI)已广泛应用于预测各种恶性肿瘤患者的生存结局。虽然低PNI预测肿瘤切除后的结直肠癌患者的预后不良,但对接受根治性肿瘤切除术后辅助化疗的Ⅲ期结肠癌患者的预后价值仍未知。本研究旨在探讨PNI对Ⅲ期结肠癌患者的预后价值。方法本文回顾了2007年12月至2013年12月期间,274例接受根治性肿瘤切除术后接受奥沙利铂和卡培他滨辅助化疗的Ⅲ期结肠癌的连续患者的医疗记录。采用受试者工作特征(receiver operating characteristic,ROC)曲线分析确定最佳PNI临界值。采用卡方检验或Fisher’s精确检验评估PNI与全身炎症反应标志物[包括淋巴细胞与单核细胞比值(lymphocyte-to-monocyte ratio,LMR)、中性粒细胞与淋巴细胞比值(neutrophil-to-lymphocyte ratio,NLR)、血小板与淋巴细胞比值(platelet-to-lymphocyte ratio,PLR)、C反应蛋白(C-reactive protein,CRP)水平]和临床病理特征的相关性。采用Spearman’s相关系数进行相关分析。采用Kaplan-Meier法和log-rank检验分析PNI分层的无病生存期(disease-free survival,DFS)和总生存期(overall survival,OS),并通过Cox回归分析确定预后因子。结果术前PNI与LMR呈正相关(r=0.483,P <0.001),与NLR(r=-0.441,P <0.001)、PLR(r=-0.607,P <0.001)和CRP水平(r=-0.333,P <0.001)呈负相关。在ⅢC期结肠癌患者中,低PNI(≤49.22)与短OS和DFS显著相关,而在ⅢA/ⅢB期结肠癌患者中则不相关。此外,在PNI低的患者中,接受6–8个疗程辅助化疗的患者比接受<6个疗程治疗的患者获得了更长的OS和DFS。多变量分析显示PNI与DFS独立相关(风险比=2.001;95%置信区间:1.157–3.462;P=0.013)。结论术前PNI是接受根治性肿瘤切除术后辅助化疗的Ⅲ期结肠癌患者生存结局的重要预测指标。
引文
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2.Torre LA,Bray F,Siegel RL,Ferlay J,Lortet-Tieulent J,Jemal A.Global cancer statistics,2012.CA Cancer J Clin.2015;65(2):87-108.
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9.Zhang Y,Ma J,Zhang S,Deng G,Wu X,He J,et al.A prognostic analysis of 895 cases of stage III colon cancer in different colon subsites.Int J Colorectal Dis.2015;30(9):1173-83.
10.Lin BR,Lin YL,Lai HS,Lee PH,Chang K J,Liang JT.Overall survival of stage III colon cancer with only one lymph node metastasis is independently predicted by preoperative carcinoembryonic antigen level and lymph node sampling status.PLoS ONE.2015;10(9):e137053.
11.Wang F,Bai L,Liu TS,Yu YY,He MM,Liu KY,et al.Right-sided colon cancer and left-sided colorectal cancers respond differently to cetuximab.Chin J Cancer.2015;34(9):384-93.
12.Schwegler I,von Holzen A,Gutzw i l ler JP,Schlumpf R,Muhlebach S,Stanga Z.Nutritional risk is a clinical predictor of postoperative mortality and morbidity in surgery for colorectal cancer.Br J Surg.2010;97(1):92-7.
13.Stotz M,Pichler M,Absenger G,Szkandera J,Arminger F,Schaberl-Moser R,et al.The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer.Br J Cancer.2014;110(2):435-40.
14.Lin G N,Liu P P,Liu DY,Peng J W,Xiao J J,Xia Z J.Prognostics ignificance of the pre-chemotherapy lymphocyte-to-monocyte ratio in patients with previously untreated metastatic colorectal cancer receiving FOLFOXchemotherapy.Chin J Cancer.2016;35:5.
15.Qi Q,Geng Y,Sun M,Wang P,Chen Z.Clinical implications of systemic inflammatory response markers as independent prognostic factors for advanced pancreatic cancer.Pancreatology.2015;15(2):145-50.
16.Roxburgh CS,McMillan DC.Role of systemic inflammatory response in predicting survival in patients with primary operable cancer.Future Oncol.2010;6(1):149-63.
17.Onodera T,Goseki N,Kosaki G.Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients.Nihon Geka Gakkai Zasshi.1984;85(9):1001-5.
18.Tokunaga R,Sakamoto Y,Nakagawa S,Miyamoto Y,Yoshida N,Oki E,et al.Prognostic nutritional index predicts severe complications,recurrence,and poor prognosis in patients with colorectal cancer undergoing primary tumor resection.Dis Colon Rectum.2015;58(11):1048-57.
19.Jiang N,Deng JY,Ding XW,Ke B,Liu N,Zhang RP,et al.Prognostic nutritional index predicts postoperative complications and long-term outcomes of gastric cancer.World J Gastroenterol.2014;20(30):10537-44.
20.Filip B,Scarpa M,Cavallin F,Cagol M,Alfieri R,Saadeh L,et al.Postoperative outcome after oesophagectomy for cancer:nutritional status is the missing ring in the current prognostic scores.Eur J Surg Oncol.2015;41(6):787-94.
21.Benson AR,Venook AP,Bekaii-Saab T,Chan E,Chen YJ,Cooper HS,et al.Colon cancer,version 3.2014.J Natl Compr Canc Netw.2014;12(7):1028-59.
22.Noble F,Hopkins J,Curtis N,Kelly JJ,Bailey IS,Byrne JP,et al.The role of systemic inflammatory and nutritional blood-borne markers in predicting response to neoadjuvant chemotherapy and sur vival in oesophagogastric cancer.Med Oncol.2013;30(3):596.
23.Illa P,Tomiskova M,Skrickova J.Nutritional risk screening predicts tumor response in lung cancer patients.J Am Coll Nutr.2015;34(5):425-9.
24.Condeelis J,Pollard JW.Macrophages:obligate partners for tumor cell migration,invasion,and metastasis.Cell.2006;124(2):263-6.
25.Lin EY,Pollard JW.Role of infiltrated leucocytes in tumour growth and spread.Br J Cancer.2004;90(11):2053-8.
26.Iseki Y,Shibutani M,Maeda K,Nagahara H,Tamura T,Ohira G,et al.The impact of the preoperative peripheral lymphocyte count and lymphocyte percentage in patients with colorectal cancer.Surg Today.2017;47(6):743-54.
27.Seebacher V,Grimm C,Reinthaller A,Heinze G,Tempfer C,Hefler L,et al.The value of serum albumin as a novel independent marker for prognosis inpatients with endometrial cancer.Eur J Obstet Gynecol Reprod Biol.2013;171(1):101-6.
28.Konigsbrugge O,Posch F,Riedl J,Reitter EM,Zielinski C,Pabinger I,et al.Association between decreased serum al bumin with risk of venous thromboembol i sm and mortality in cancer patients.Oncologist.2016;21(2):252-7.
29.Seaton K.Albumin concentration controls cancer.J Natl Med Assoc.2001;93(12):490-3.
30.Garcia-Martinez R,Andreola F,Mehta G,Poulton K,Oria M,Jover M,et al.Immunomodulator y and antioxidant f unct ion of al bumin stabilises the endothel ium and improves survival in a rodent model of chronic liver failure.J Hepatol.2015;62(4):799-806.
31.Zhang C,Wang H,Ning Z,Xu L,Zhuang L,Wang P,et al.Prognostic nutritional index serves as a predictive marker of sur vival and associates with systemic inflammator y response in metastatic intrahepatic cholangiocarcinoma.Onco Targets Ther.2016;9:6417-23.
32.Geng Y,Qi Q,Sun M,Chen H,Wang P,Chen Z.Prognostic nutritional index predicts sur vival and correlates with systemic inflammatory response in advanced pancreatic cancer.Eur J Surg Oncol.2015;41(11):1508-14.
33.Fontana L,Eagon JC,Colonna M,Klein S.Impaired mononuclear cell immune function in extreme obesity is corrected by weight loss.Rejuvenation Res.2007;10(1):41-6.
34.R oshani R,McCar thy F,Hagemann T.Inf lammator y c y tok ines in human pancreat ic cancer.Cancer L ett.2014;345(2):157-63.
35.Des Guetz G,Uzzan B,Morere JF,Perret G,Nicolas P.Duration of adjuvant chemotherapy for patients with non-metastatic colorectal cancer.Cochrane Database Syst Rev.2010;1:D7046.
36.Chen B,Liu L,Xu H,Yang Y,Zhang L,Zhang F.Effectiveness of immunetherapy combined with chemotherapy on the immune function and recurrence rate of cervical cancer.Exp Ther Med.2015;9(3):1063-7.
37.Jin C,Li J,Wang Y,Chen X,Che Y,Liu X,et al.Impact of cellular immune function on prognosis of lung cancer patients after cytokine-induced killer cell therapy.Asian Pac J Cancer Prev.2014;15(15):6009-14.
38.Fu Y,Chen SW,Chen SQ,Ou-Yang D,Liu W W,Song M,et al.A preoperative nutritional index for predicting cancer-specific and overall sur vival in chinese patients with lar yngeal cancer:a retrospective study.Medicine(Baltimore).2016;95(11):e2962.
39.Migita K,Takayama T,Saeki K,Matsumoto S,Wakatsuki K,Enomoto K,et al.The prognostic nutritional index predicts long-term outcomes of gastric cancer patients independent of tumor stage.Ann Surg Oncol.2013;20(8):2647-54.
40.Jian-Hui C,Iskandar EA,Cai S,Chen CQ,Wu H,Xu JB,et al.Significance of Onodera’s prognostic nutritional index in patients with colorectal cancer:a large cohort study in a single Chinese institution.Tumour Biol.2016;37(3):3277-83.
41.Nozoe T,Kohno M,Iguchi T,Mori E,Maeda T,Matsukuma A,et al.The prognostic nutritional indexcanbea prognostic indicator in colorectal carcinoma.Surg Today.2012;42(6):532-5.
42.Mohri T,Mohri Y,Shigemori T,Takeuchi K,Itoh Y,Kato T.Impact of prognostic nutritional index on long-term outcomes in patients with breast cancer.World J Surg Oncol.2016;14(1):170.
43.Qiu M,Zhou YX,Jin Y,Wang Z X,Wei XL,Han HY,et al.Nutrition suppor t can bring sur v ival benefit to high nutrition risk gastric cancer patients who received chemotherapy.Support Care Cancer.2015;23(7):1933-9.
44.Gavazzi C,Colatr uglio S,Valor iani F,Mazzaferro V,Sabbatini A,Biffi R,et al.Impact of home enteral nutrition in malnourished patients w ith upper gastrointestinal cancer:a multicentre randomised clinical trial.Eur JCancer.2016;64:107-12.
45.Snaebjornsson P,Coupe VM,Jonasson L,Meijer GA,van Grieken NC,Jonasson JG.PT4 stage II and III colon cancers carry the worst prognosis in a nationwide survival analysis.Shepherd’s local peritoneal involvement revisited.Int J Cancer.2014;135(2):467-78.
46.Sugimoto K,Sakamoto K,Tomiki Y,Goto M,Kotake K,Sugihara K.Proposal of new classification for stage IIIcolon cancer based on the lymph node ratio:analysis of4,172 patients from multi-institutional database in Japan.Ann Surg Oncol.2015;22(2):528-34.
47.Hanna N N,Onukwugha E,Choti M A,Davidoff A J,Zuckerman IH,Hsu VD,et al.Comparative analysis of various prognostic nodal factors,adjuvant chemotherapy and survival among stage III colon cancer patients over65 years:an analysis using sur veillance,epidemiolog y and end results(SEER)-Medicare data.Colorectal Dis.2012;14(1):48-55.
48.Cheung WY,Shi Q,O’Connell M,Cassidy J,Blanke CD,Kerr DJ,et al.The predictive and prognostic value of sex in early-stage colon cancer:a pooled analysis of 33,345patients from the ACCENT database.Clin Colorectal Cancer.2013;12(3):179-87.
49.Yamauchi M,Morikawa T,Kuchiba A,Imamura Y,Qian ZR,Nishihara R,et al.Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum.Gut.2012;61(6):847-54.
50.Phipps AI,Limburg PJ,Baron JA,Burnett-Hartman AN,Weisenberger DJ,Laird PW,et al.Association between molecular subt y pes of colorectal cancer and patient survival.Gastroenterology.2015;148(1):77-87.
2.Torre LA,Bray F,Siegel RL,Ferlay J,Lortet-Tieulent J,Jemal A.Global cancer statistics,2012.CA Cancer J Clin.2015;65(2):87-108.
3.Chagpar R,Xing Y,Chiang YJ,Feig BW,Chang GJ,You YN,et al.Adherence to stage-specific treatment guidelines for patients with colon cancer.J Clin Oncol.2012;30(9):972-9.
4.Gunderson L L,Jessup J M,Sargent D J,Greene F L,Stewart AK.Revised TN categorization for colon cancer based on national survival outcomes data.J Clin Oncol.2010;28(2):264-71.
5.Shah MA,Renfro LA,Allegra CJ,Andre T,de Gramont A,Schmoll HJ,et al.Impact of patient factors on recurrence risk and time dependency of oxaliplatin benefit in patients with colon cancer:analysis from Modern-Era adjuvant studies in the adjuvant colon cancer end points(ACCENT)database.J Clin Oncol.2016;34(8):843-53.
6.Andre T,Boni C,Navarro M,Tabernero J,Hickish T,Topham C,et al.Improved overall survival with oxaliplatin,fluorouracil,and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.J Clin Oncol.2009;27(19):3109-16.
7.Saltz LB,Niedzwiecki D,Hollis D,Goldberg RM,Hantel A,Thomas JP,et al.Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer:results of CALGB 89803.J Clin Oncol.2007;25(23):3456-61.
8.Schmoll HJ,Tabernero J,Maroun J,de Braud F,Price T,Van Cutsem E,et al.Capecitabine plus oxaliplatin compared with Fluorouracil/Folinic acid as adjuvant therapy for stage III colon cancer:final results of the NO16968 randomized controlled phase III trial.J Clin Oncol.2015;33(32):3733-40.
9.Zhang Y,Ma J,Zhang S,Deng G,Wu X,He J,et al.A prognostic analysis of 895 cases of stage III colon cancer in different colon subsites.Int J Colorectal Dis.2015;30(9):1173-83.
10.Lin BR,Lin YL,Lai HS,Lee PH,Chang K J,Liang JT.Overall survival of stage III colon cancer with only one lymph node metastasis is independently predicted by preoperative carcinoembryonic antigen level and lymph node sampling status.PLoS ONE.2015;10(9):e137053.
11.Wang F,Bai L,Liu TS,Yu YY,He MM,Liu KY,et al.Right-sided colon cancer and left-sided colorectal cancers respond differently to cetuximab.Chin J Cancer.2015;34(9):384-93.
12.Schwegler I,von Holzen A,Gutzw i l ler JP,Schlumpf R,Muhlebach S,Stanga Z.Nutritional risk is a clinical predictor of postoperative mortality and morbidity in surgery for colorectal cancer.Br J Surg.2010;97(1):92-7.
13.Stotz M,Pichler M,Absenger G,Szkandera J,Arminger F,Schaberl-Moser R,et al.The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer.Br J Cancer.2014;110(2):435-40.
14.Lin G N,Liu P P,Liu DY,Peng J W,Xiao J J,Xia Z J.Prognostics ignificance of the pre-chemotherapy lymphocyte-to-monocyte ratio in patients with previously untreated metastatic colorectal cancer receiving FOLFOXchemotherapy.Chin J Cancer.2016;35:5.
15.Qi Q,Geng Y,Sun M,Wang P,Chen Z.Clinical implications of systemic inflammatory response markers as independent prognostic factors for advanced pancreatic cancer.Pancreatology.2015;15(2):145-50.
16.Roxburgh CS,McMillan DC.Role of systemic inflammatory response in predicting survival in patients with primary operable cancer.Future Oncol.2010;6(1):149-63.
17.Onodera T,Goseki N,Kosaki G.Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients.Nihon Geka Gakkai Zasshi.1984;85(9):1001-5.
18.Tokunaga R,Sakamoto Y,Nakagawa S,Miyamoto Y,Yoshida N,Oki E,et al.Prognostic nutritional index predicts severe complications,recurrence,and poor prognosis in patients with colorectal cancer undergoing primary tumor resection.Dis Colon Rectum.2015;58(11):1048-57.
19.Jiang N,Deng JY,Ding XW,Ke B,Liu N,Zhang RP,et al.Prognostic nutritional index predicts postoperative complications and long-term outcomes of gastric cancer.World J Gastroenterol.2014;20(30):10537-44.
20.Filip B,Scarpa M,Cavallin F,Cagol M,Alfieri R,Saadeh L,et al.Postoperative outcome after oesophagectomy for cancer:nutritional status is the missing ring in the current prognostic scores.Eur J Surg Oncol.2015;41(6):787-94.
21.Benson AR,Venook AP,Bekaii-Saab T,Chan E,Chen YJ,Cooper HS,et al.Colon cancer,version 3.2014.J Natl Compr Canc Netw.2014;12(7):1028-59.
22.Noble F,Hopkins J,Curtis N,Kelly JJ,Bailey IS,Byrne JP,et al.The role of systemic inflammatory and nutritional blood-borne markers in predicting response to neoadjuvant chemotherapy and sur vival in oesophagogastric cancer.Med Oncol.2013;30(3):596.
23.Illa P,Tomiskova M,Skrickova J.Nutritional risk screening predicts tumor response in lung cancer patients.J Am Coll Nutr.2015;34(5):425-9.
24.Condeelis J,Pollard JW.Macrophages:obligate partners for tumor cell migration,invasion,and metastasis.Cell.2006;124(2):263-6.
25.Lin EY,Pollard JW.Role of infiltrated leucocytes in tumour growth and spread.Br J Cancer.2004;90(11):2053-8.
26.Iseki Y,Shibutani M,Maeda K,Nagahara H,Tamura T,Ohira G,et al.The impact of the preoperative peripheral lymphocyte count and lymphocyte percentage in patients with colorectal cancer.Surg Today.2017;47(6):743-54.
27.Seebacher V,Grimm C,Reinthaller A,Heinze G,Tempfer C,Hefler L,et al.The value of serum albumin as a novel independent marker for prognosis inpatients with endometrial cancer.Eur J Obstet Gynecol Reprod Biol.2013;171(1):101-6.
28.Konigsbrugge O,Posch F,Riedl J,Reitter EM,Zielinski C,Pabinger I,et al.Association between decreased serum al bumin with risk of venous thromboembol i sm and mortality in cancer patients.Oncologist.2016;21(2):252-7.
29.Seaton K.Albumin concentration controls cancer.J Natl Med Assoc.2001;93(12):490-3.
30.Garcia-Martinez R,Andreola F,Mehta G,Poulton K,Oria M,Jover M,et al.Immunomodulator y and antioxidant f unct ion of al bumin stabilises the endothel ium and improves survival in a rodent model of chronic liver failure.J Hepatol.2015;62(4):799-806.
31.Zhang C,Wang H,Ning Z,Xu L,Zhuang L,Wang P,et al.Prognostic nutritional index serves as a predictive marker of sur vival and associates with systemic inflammator y response in metastatic intrahepatic cholangiocarcinoma.Onco Targets Ther.2016;9:6417-23.
32.Geng Y,Qi Q,Sun M,Chen H,Wang P,Chen Z.Prognostic nutritional index predicts sur vival and correlates with systemic inflammatory response in advanced pancreatic cancer.Eur J Surg Oncol.2015;41(11):1508-14.
33.Fontana L,Eagon JC,Colonna M,Klein S.Impaired mononuclear cell immune function in extreme obesity is corrected by weight loss.Rejuvenation Res.2007;10(1):41-6.
34.R oshani R,McCar thy F,Hagemann T.Inf lammator y c y tok ines in human pancreat ic cancer.Cancer L ett.2014;345(2):157-63.
35.Des Guetz G,Uzzan B,Morere JF,Perret G,Nicolas P.Duration of adjuvant chemotherapy for patients with non-metastatic colorectal cancer.Cochrane Database Syst Rev.2010;1:D7046.
36.Chen B,Liu L,Xu H,Yang Y,Zhang L,Zhang F.Effectiveness of immunetherapy combined with chemotherapy on the immune function and recurrence rate of cervical cancer.Exp Ther Med.2015;9(3):1063-7.
37.Jin C,Li J,Wang Y,Chen X,Che Y,Liu X,et al.Impact of cellular immune function on prognosis of lung cancer patients after cytokine-induced killer cell therapy.Asian Pac J Cancer Prev.2014;15(15):6009-14.
38.Fu Y,Chen SW,Chen SQ,Ou-Yang D,Liu W W,Song M,et al.A preoperative nutritional index for predicting cancer-specific and overall sur vival in chinese patients with lar yngeal cancer:a retrospective study.Medicine(Baltimore).2016;95(11):e2962.
39.Migita K,Takayama T,Saeki K,Matsumoto S,Wakatsuki K,Enomoto K,et al.The prognostic nutritional index predicts long-term outcomes of gastric cancer patients independent of tumor stage.Ann Surg Oncol.2013;20(8):2647-54.
40.Jian-Hui C,Iskandar EA,Cai S,Chen CQ,Wu H,Xu JB,et al.Significance of Onodera’s prognostic nutritional index in patients with colorectal cancer:a large cohort study in a single Chinese institution.Tumour Biol.2016;37(3):3277-83.
41.Nozoe T,Kohno M,Iguchi T,Mori E,Maeda T,Matsukuma A,et al.The prognostic nutritional indexcanbea prognostic indicator in colorectal carcinoma.Surg Today.2012;42(6):532-5.
42.Mohri T,Mohri Y,Shigemori T,Takeuchi K,Itoh Y,Kato T.Impact of prognostic nutritional index on long-term outcomes in patients with breast cancer.World J Surg Oncol.2016;14(1):170.
43.Qiu M,Zhou YX,Jin Y,Wang Z X,Wei XL,Han HY,et al.Nutrition suppor t can bring sur v ival benefit to high nutrition risk gastric cancer patients who received chemotherapy.Support Care Cancer.2015;23(7):1933-9.
44.Gavazzi C,Colatr uglio S,Valor iani F,Mazzaferro V,Sabbatini A,Biffi R,et al.Impact of home enteral nutrition in malnourished patients w ith upper gastrointestinal cancer:a multicentre randomised clinical trial.Eur JCancer.2016;64:107-12.
45.Snaebjornsson P,Coupe VM,Jonasson L,Meijer GA,van Grieken NC,Jonasson JG.PT4 stage II and III colon cancers carry the worst prognosis in a nationwide survival analysis.Shepherd’s local peritoneal involvement revisited.Int J Cancer.2014;135(2):467-78.
46.Sugimoto K,Sakamoto K,Tomiki Y,Goto M,Kotake K,Sugihara K.Proposal of new classification for stage IIIcolon cancer based on the lymph node ratio:analysis of4,172 patients from multi-institutional database in Japan.Ann Surg Oncol.2015;22(2):528-34.
47.Hanna N N,Onukwugha E,Choti M A,Davidoff A J,Zuckerman IH,Hsu VD,et al.Comparative analysis of various prognostic nodal factors,adjuvant chemotherapy and survival among stage III colon cancer patients over65 years:an analysis using sur veillance,epidemiolog y and end results(SEER)-Medicare data.Colorectal Dis.2012;14(1):48-55.
48.Cheung WY,Shi Q,O’Connell M,Cassidy J,Blanke CD,Kerr DJ,et al.The predictive and prognostic value of sex in early-stage colon cancer:a pooled analysis of 33,345patients from the ACCENT database.Clin Colorectal Cancer.2013;12(3):179-87.
49.Yamauchi M,Morikawa T,Kuchiba A,Imamura Y,Qian ZR,Nishihara R,et al.Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum.Gut.2012;61(6):847-54.
50.Phipps AI,Limburg PJ,Baron JA,Burnett-Hartman AN,Weisenberger DJ,Laird PW,et al.Association between molecular subt y pes of colorectal cancer and patient survival.Gastroenterology.2015;148(1):77-87.