Prognostic value of preoperative prognostic nutritional index and its associations with systemic inflammatory response markers in patients with stage Ⅲ colon cancer

Background: The prognostic nutritional index(PNI) has been widely applied for predicting survival outcomes of patients with various malignant tumors. Although a low PNI predicts poor prognosis in patients with colorectal cancer after tumor resection, the prognostic value remains unknown in patients with stage Ⅲ colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy. This study aimed to investigate the prognostic value of PNI in patients with stage III colon cancer.Methods: Medical records of 274 consecutive patients with stage Ⅲ colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy with oxaliplatin and capecitabine between December 2007 and December2013 were reviewed. The optimal PNI cutoff value was determined using receiver operating characteristic(ROC) curve analysis. The associations of PNI with systemic inflammatory response markers, including lymphocyte-to-monocyte ratio(LMR), neutrophil-to-lymphocyte ratio(NLR), platelet-to-lymphocyte ratio(PLR), and C-reactive protein(CRP)level, and clinicopathologic characteristics were assessed using the Chi square or Fisher's exact test. Correlation analysis was performed using Spearman's correlation coefficient. Disease-free survival(DFS) and overall survival(OS)stratified by PNI were analyzed using Kaplan-Meier method and log-rank test, and prognostic factors were identified by Cox regression analyses.Results: The preoperative PNI was positively correlated with LMR(r= 0.483, P < 0.001) and negatively correlated with NLR(r =-0.441, P < 0.001), PLR(r =-0.607, P < 0.001), and CRP level(r =-0.333, P < 0.001). A low PNI(≤49.22)was significantly associated with short OS and DFS in patients with stage ⅢC colon cancer but not in patients with stage ⅢA/ⅢB colon cancer.In addition, patients with a low PNI achieved a longer OS and DFS after being treated with6-8 cycles of adjuvant chemotherapy than did those with < 6 cycles. Multivariate analyses revealed that PNI was independently associated with DFS(hazard ratios 2.001; 95% confidence interval 1.157-3.462; P = 0.013).Conclusion: The present study identified preoperative PNI as a valuable predictor for survival outcomes in patients with stage Ⅲ colon cancer receiving curative tumor resection followed by adjuvant chemotherapy.

Expression of voltage.gated sodium channel Nav1.5 in non.metastatic colon cancer and its associations with estrogen receptor(ER)-βexpression and clinical outcomes

Background: Voltage-gated sodium channel 1.5(Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β(ER-β)expression in non-metastatic colon cancer patients receiving radical resection.Methods: A total of 269 consecutive patients with pathologically confirmed stages Ⅰ-Ⅲ colon cancer who underwent radical resection were selected. Nav1.5 and ER-β expression was detected by using immunohistochemistry(IHC)on tissue microarray constructed from paraffin-embedded specimens. IHC score was determined according to the percentage and intensity of positively stained cells. Statistical analysis was performed with the X-tile method, k coefficient, Chi square test or Fisher's exact test, logistic regression, log-rank test, and Cox proportional hazards models.Results: We found that Nav1.5 was commonly expressed in tumor tissues with higher mean IHC score as compared with matched tumor-adjacent normal tissues(5.1 ± 3.5 vs. 3.5 ± 2.7, P < 0.001).The high expression of Nav1.5 in colon cancer tissues was associated with high preoperative carcinoembryonic antigen level [odds ratio(OR) = 2.980;95% confidential interval(CI)1.163-7.632; P = 0.023] and high ER-β expression(OR = 2.808; 95% CI 1.243-6.343;p = 0.00 3). Log-rank test results showed that high Nav1.5 expression contributed to a low 5-year disease-free survival(DFS) rate in colon cancer patients(77.2% vs. 92.1%, P = 0.048), especially in patients with high ER-β expression tumor(76.2% vs. 91.3%, P = 0.032). Analysis with Cox proportional hazards model demonstrated that high Nav1.5 expression[hazard ratio(HR) = 2.738; 95% CI 1.100-6.819;P = 0.030] and lymph node metastasis(HR = 2.633; 95% CI 1.632-4.248; P < 0.001) were prognostic factors for unfavorable DFS in colon cancer patients.Conclusions: High expression of Nav1.5 was associated with high expression of ER-β and indicated unfavorable oncologic prognosis in patients with non-metastatic colon cancer.

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

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。

Synthetic lethal short hairpin RNA screening reveals that ring finger protein 183 confers resistance to trametinib in colorectal cancer cells

Background: The mitogen-activated extracellular signal-regulated kinase 1/2(MEK1/2) inhibitor trametinib has shown promising therapeutic effects on melanoma, but its efficacy on colorectal cancer(CRC) is limited. Synthetic lethality arises with a combination of two or more separate gene mutations that causes cell death, whereas individual mutations keep cells alive. This study aimed to identify the genes responsible for resistance to trametinib in CRC cells,using a synthetic lethal short hairpin RNA(shRNA) screening approach.Methods: We infected HT29 cells with a pooled lentiviral shRNA library and applied next-generation sequencing to identify shRNAs with reduced abundance after 8-day treatment of 20 nmol/L trametinib. HCT116 and HT29 cells were used in validation studies. Stable ring finger protein 183(RNF183)-overexpressing cell lines were generated by pcDNA4-myc/his-RNF183 transfection. Stable RNF 183-knockdown cell lines were generated by infection of lentiviruses that express RNF183 shRNA, and small interference RNA(siRNA) was used to knock down RNF183 transiently.Quantitative real-time PCR was used to determine the mRNA expression. Western blotting, immunohistochemical analysis, and enzyme-linked immunosorbent assay(ELISA) were used to evaluate the protein abundance. MTT assay,colony formation assay, and subcutaneous xenograft tumor growth model were used to evaluate cell proliferation.Results: In the primary screening, we found that the abundance of RNF183 shRNA was markedly reduced after treatment with trametinib. Trametinib induced the expression of RNF183, which conferred resistance to drug-induced cell growth repression and apoptotic and non-apoptotic cell deaths. Moreover, interleukin-8(IL-8) was a downstream gene of RNF183 and was required for the function of RNF183 in facilitating cell growth. Additionally, elevated RNF183 expression partly reduced the inhibitory effect of trametinib on IL-8 expression. Finally, xenograft tumor model showed the synergism of RNF183 knockdown and trametinib in repressing the growth of CRC cells in vivo.Conclusion: The RNF183-IL-8 axis is responsible for the resistance of CRC cells to the MEK1/2 inhibitor trametinib and may serve as a candidate target for combined therapy for CRC.

对可切除的中/低位直肠癌是/否进行术前放化疗的全直肠系膜切除术研究:一项前瞻性、单中心、随机试验的长期分析

背景与目的我们的Ⅱ期随机试验的初步研究结果显示,对进行全直肠系膜切除术(total mesorectal excision,TME)的患者是/否进行术前同步放化疗(concurrent chemoradiotherapy,CCRT),二者的功能性括约肌保留率和短期生存结局相近。在经过中位71个月的随访后,现报告这一长期试验的结果。方法在2008年3月23日至2012年8月2日期间,192例患有T3–T4或淋巴结阳性、可切除的中/低直肠腺癌患者被随机分为接受或不接受术前CCRT组,之后均进行TME。评估以下终点:局部复发和远处转移的累积率、无病生存(disease?free survival,DFS)和总生存(overall survival,OS)。结果对入组的184例患者资料进行分析,其中TME组有94例,CCRT+TME组有90例。在整个队列中,5年DFS和OS率分别为84.8%和85.1%。CCRT+TME组的5年DFS率为85.2%,TME组为84.3%(P=0.969);CCRT+TME组的5年OS率为83.5%,TME组为86.5%(P=0.719)。在CCRT+TME和TME组中,局部复发的5年累积率分别为6.3%和5.0%(P=0.681),远处转移的5年累积率分别为15.0%和15.7%(P=0.881)。通过亚组分析,接受CCRT未观察到5年DFS和OS的显著改善。结论两种治疗方案的长期结局相近。因此,如果可以进行高质量的TME手术和强化化疗,建议选择性地对直肠癌患者进行术前CCRT。

生物反馈训练对预防直肠癌患者保肛术后前切除综合征的效果评价

目的探讨生物反馈训练对预防中低位直肠癌患者保肛术后前切除综合征的效果。方法将拟接受术前放化疗、直肠前切除术和预防性造口的中低位直肠癌患者随机分为试验组(35例)和对照组(36例);试验组在盆底肌功能锻炼的基础上进行生物反馈训练,对照组进行盆底肌功能锻炼。用固态肛门直肠高分辨测压设备对患者进行肛门直肠测压,并评价患者直肠前切除综合征的发生情况。结果试验组的直肠最大耐受容量和直肠顺应性显著高于对照组(P<0.05);试验组直肠前切除综合征的发生率低于对照组(P<0.05)。结论生物反馈训练能促进中低位直肠癌患者术后感觉功能的恢复,并降低前切除综合征的发生率。

Total mesorectal excision with or without preoperative chemoradiotherapy for resectable mid/low rectal cancer: a long-term analysis of a prospective, single-center, randomized trial

Background:The preliminary results of our phase II randomized trial reported comparable functional sphincter pres-ervation rates and short-term survival outcomes between patients undergoing total mesorectal excision(TME)with or without preoperative concurrent chemoradiotherapy(CCRT).We now report the long-term results after a median follow-up of 71 months.Methods:Between March 23,2008 and August 2,2012,192 patients with T3-T4 or node-positive,resectable,mid/low rectal adenocarcinoma were randomly assigned to receive TME with or without preoperative CCRT.The following endpoints were assessed:cumulative rates of local recurrence and distant metastasis,disease-free survival(DFS),and overall survival(OS).Results:The data of 184 eligible patients were analyzed:94 patients in the TME group and 90 patients in the CCRT+TME group.In the whole cohort,the 5-year DFS and OS rates were 84.8%and 85.1%,respectively.The 5-year DFS rates were 85.2%in the CCRT+TME group and 84.3%in the TME group(P=0.969),and the 5-year OS rates were 83.5%in the CCRT+TME group and 86.5%in the TME group(P=0.719).The 5-year cumulative rates of local recur-rence were 6.3%and 5.0%(P=0.681),and the 5-year cumulative rates of distant metastasis were 15.0%and 15.7%(P=0.881)in the CCRT+TME and TME groups,respectively.No significant improvements in 5-year DFS and OS were observed with CCRT by subgroup analyses.Conclusions:Both treatment strategies yielded similar long-term outcomes.A selective policy towards preoperative CCRT is thus recommended for rectal cancer patients if high-quality TME surgery and enhanced chemotherapy can be performed.

Is there a survival benefit from adjuvant chemotherapy for patients with liver oligometastases from colorectal cancer after curative resection?

Background:Although colorectal oligometastases to the liver can potentially be cured with aggressive local abla-tion,the efficacy of adjuvant chemotherapy(ACT)for such metastasis remains unclear.The present study explored the effects of ACT on patients with colorectal liver oligometastases(CLO)after curative resections and aimed to iden-tify patients who could benefit from ACT.Methods:We retrospectively analyzed 264 eligible patients with CLO who underwent curative resection between September 1999 and June 2015.Recurrence-free survival(RFS)and overall survival(OS)were analyzed using the Kaplan-Meier method and log-rank test;prognostic factors were a by Cox regression modeling.Results:Among 264 patients,200(75.8%)patients received ACT and 64(24.2%)did not receive ACT.These two groups did not significantly differ in clinicopathologic characteristics,and had comparable 3-year OS and RFS rates(RFS:42.1%vs.45.7%,P=0.588;OS:69.7%vs.62.7%,P=0.446)over a median follow-up duration of 35.5 months,irrespective of preoperative chemotherapy.ACT markedly improved 3-year OS in high-risk patients with Memorial Sloan-Kettering Cancer Center clinical risk scores(MSKCC-CRS)of 3-5(68.2%vs.33.8%,P=0.015),but presented no additional benefit in patients with MSKCC-CRS of 0-2(72.2%vs.78.6%,P=0.834).In multivariate analysis,ACT was independently associated with improved OS in patients with MSKCC-CRS of 3-5.Conclusions:ACT might offer a prognostic benefit in high-risk patients with CLOs after curative liver resection,but not in low-risk patients.Therefore,patients’risk status should be determined before ACT administration to optimize postoperative therapeutic strategies.

Safety and efficacy of a modified XELOX adjuvant regimen for patients with operated stage III colon cancer:a Chinese single-center experience

Background:A fixed 8-cycle oxaliplatin and capecitabine(XELOX)regimen has been the standard adjuvant therapy for patients with stage III colon cancer.However,completing the full-cycle of oxaliplatin is often associated with severe neurotoxicity.To spare patients from the toxic effects,without comprising the required efficacy,we evaluated the safety and efficacy of a modified XELOX(mXELOX)adjuvant chemotherapy regimen with 6 cycles of oxaliplatin and a full cycle of capecitabine.Methods:We retrospectively analyzed 330 eligible patients with stage III colon cancer who underwent cura-tive tumor resection followed by mXELOX,standard XELOX or unfinished XELOX adjuvant chemotherapy between December 2007 and April 2015.Associated prognostic factors were investigated and their disease-free survival(DFS)and overall survival(OS)rates were also determined and compared among the different regimen groups.Results:Compared with the standard XELOX group,the mXELOX group had lower total incidence rates of neuro-toxicity(39.3%vs.76.2%,P<0.001),leucopenia(53.6%vs.69.8%,P=0.017)and thrombocytopenia(38.1%vs.56.3%,P=0.011).The standard XELOX and mXELOX adjuvant chemotherapy regimens presented with comparable 3-year DFS rates(86.3%vs.89.2%;P=0.838)and 3-year OS rates(92.7%vs.97.6%;P=0.227).Compared to unfinished XELOX chemotherapy,the oncologic benefits of the mXELOX regimen were greater for patients with T4 tumors(3-year DFS:Hazard ratio[HR],2.184;95%confidence interval[CI],1.051-4.540;P=0.036;3-year OS:HR,4.529;95%CI 1.245-16.479;P=0.022)and for high-risk patients(3-year DFS:HR,1.962;95%CI 0.964-3.993;P=0.044;3-year OS:HR,4.193;95%CI 1.182-14.874;P=0.026).Conclusions:The mXELOX adjuvant chemotherapy presented a comparable survival benefit and lower incidence of toxicity than standard XELOX chemotherapy.It could be an alternative treatment for high-risk patients with operated stage III colon cancer.

CACA guidelines for holistic integrative management of rectal cancer

Purpose Colorectal cancer is a common malignant tumor worldwide.In China,the ratio of rectal cancer to coloncancer in terms of incidence is close to 1:1.Low rectal cancer accounts for more than half of all cases of rectal cancer.In recent years,the proportion of rectal cancer has trended downward,however the incidence of rectal cancer inyounger adults is increasing.The CACA Guidelines for Holistic Integrative Management of Rectal Cancer were editedto help improve the diagnosis and comprehensive treatment in China.Methods This guideline has been prepared by consensuses reached by the CACA Committee of Colorectal CancerSociety,based on a careful review of the latest evidence including China’s studies,and referred to domestic and internationalrelative guidelines,also considered China’s specific national conditions and clinical practice.Results The CACA Guidelines for Holistic Integrative Management of Rectal Cancer include the epidemiology of rectalcancer,prevention and screening,diagnosis,treatment of nonmetastatic and metastatic rectal cancer,follow-up,and whole-course rehabilitation management.Conclusion Committee of Colorectal Cancer Society,Chinese Anti-Cancer Association,standardizes the diagnosisand treatment of rectal cancer in China through the formulation of the CACA Guidelines.