RAS、BRAF基因突变及HER2基因扩增与结直肠癌患者临床病理特征及预后的关系北大核心CSCD

目的探讨结直肠癌RAS、BRAF基因突变及HER2基因扩增与患者的临床病理特征及预后的关系。方法回顾性分析268例结直肠癌患者的临床病理资料,检测KRAS、NRAS、BRAF基因突变及HER2基因扩增。结果 268例结直肠癌患者中KRAS基因突变率为53.4%,NRAS基因突变率为2.6%,BRAF基因突变率为3.0%,HER2基因扩增阳性率为6.7%。KRAS基因突变更容易发生在右半结肠癌和直肠癌,BRAF基因突变主要发生在右半结肠癌中,差异均有统计学意义(χ^(2)=10.824,P=0.004;P=0.044)。HER2基因扩增更容易出现在RAS、BRAF野生型的结直肠癌患者中,差异有统计学意义(OR=0.322,95%CI:0.117~0.887,P=0.027)。单因素分析显示,与野生型比较,RAS基因突变患者的无进展生存期缩短,差异有统计学意义(χ^(2)=6.153,P=0.013),而总生存期差异无统计学意义(χ^(2)=1.938,P=0.164)。与野生型比较,BRAF基因突变患者的无进展生存期与总生存期均短,差异均有统计学意义(χ^(2)=8.090,P=0.004;χ^(2)=11.125,P=0.001)。多因素分析结果显示BRAF基因突变是结直肠癌患者生存的独立影响因素(HR=3.536,95%CI:1.305~9.583,P=0.013)。结论 BRAF基因突变是结直肠癌患者不良预后的独立影响因素。     

结直肠癌肝转移不同治疗方式的预后比较

目的探讨不同治疗方式对结直肠癌肝转移生存时间和无复发生存时间的影响。方法回顾性分析2002年1月至2013年5月期间解放军总医院收治的71例结直肠癌肝转移患者的临床资料,分析干预对结直肠癌肝转移患者生存时间和无复发生存时间的影响。结果 71例结直肠癌肝转移患者的原发灶均行根治性切除。对肝转移灶,20例未予干预(未干预组);20例行肝转移灶切除,20例行射频消融,11例行肝转移灶切除+射频消融(所有接受干预的患者为干预组)。Cox比例风险模型结果显示,在控制其他因素的情况下,干预对生存(HR=1.724,P=0.043)和无复发生存(HR=0.701,P=0.048)均有影响,接受干预患者的生存情况和无复发生存情况较好。结论在对结直肠癌行根治性手术的条件下,对结直肠癌肝转移灶给予干预措施可以延长结直肠癌肝转移患者的生存时间和无复发生存时间。     

结直肠癌肝转移预后影响因素的分析

目的 探讨结直肠癌肝转移患者预后的相关影响因素.方法 回顾性分析5年间收治的71例结直肠癌肝转移患者的临床病理资料.选择患者性别、年龄、肝转移部位、肝转移时间、转移灶数目、转移灶大小、原发肿瘤分化程度、有无淋巴转移、有无肝外转移以及肝转移病灶治疗方法等10个因素,用SPSS 17.0软件进行结直肠癌肝转移单因素分析和多因素Cox回归分析,并对有意义的相关因素进行交互作用分析.结果 71例结直肠癌肝转移患者生存时间为(16.5±5.3)个月,3年生存率为12.7％.单因素分析显示肝转移部位、转移灶数目、转移灶大小、肿瘤分化程度、有无淋巴转移、有无肝外转移以及肝转移病灶治疗方法等7个因素与预后有关,它们的组间差异均具有统计学意义(x2 =11.279,9.600,8.076,17.376,19.817,24.310,32.267;P＜0.05).Cox回归模型表明原发肿瘤分化程度(RR=1.671,95％CI 1.236 ～2.345,P=0.026),淋巴转移(RR=1.658,95％ CI1.214 ～2.286,P=0.010),有无肝外转移(RR =2.586,95％ CI 1.758 ～6.326,P=0.000)以及肝转移病灶治疗方法(RR=6.846,95％CI3.624～13.032,P=0.000)与结直肠癌肝转移预后有密切关系.结论 肿瘤分化程度、有无淋巴转移、有无肝外转移以及肝转移病灶治疗方法是结直肠癌肝转移预后的独立危险因素.     

影响结直肠癌肝转移手术切除患者预后的多因素分析

目的 探讨影响结直肠癌肝转移患者手术切除的预后因素。方法 收集1995-2001年间收治的结直肠癌肝转移手术切除患者103例的资料，用Kaplan-Meier法计算术后生存率，以Cox模型进行多变量分析。结果 患者术后1、3年无瘤生存率分别为73．8％和43．7％，术后1、3年累积生存率分别为7g．6％和49．5％。单因素分析显示：术前血清CEA水平、转移灶与原发灶的治疗间隔时间、术中切缘情况、肝门淋巴结转移、肝内卫星灶的存在与否、肝转移灶的最大直径、数目及有无包膜影响患者的术后肝内复发和术后累积生存率，而术后化疗可以提高患者的累积生存率。多因素分析显示：转移灶与原发灶的治疗间隔时间、切缘情况、肝内卫星灶的存在与否和肝转移灶的最大直径是影响肝内复发和累积生存率的独立因素，而肝门淋巴结转移是影响累积生存率的独立因素，有无包膜是影响肝内复发的独立因素。结论 手术切除是结直肠癌肝转移有效的治疗手段。转移灶与原发灶的治疗间隔时间、切缘情况、肝内卫星灶、肝转移灶的大小和包膜、肝门淋巴结转移等是患者预后的独立影响因素。     

K-ras基因突变与结直肠癌肝转移及其预后关系的研究

目的探讨结直肠癌肿瘤原发灶中K-ras基因突变情况与肝转移及其预后的关系。方法回顾性选取2003年1月至2008年12月间经复旦大学附属中山医院普通外科手术治疗的结直肠癌病例,根据术时诊断和术后随访肝转移情况分为同时性肝转移、异时性肝脏转移和未发生肝脏转移的患者3组,每组各100例。运用PCR及Pyrosequencing法检测石蜡标本中肿瘤原发灶K-ras第2外显子突变情况．分析其与结直肠癌肝转移的发生及其预后的关系。结果300例样本中肿瘤原发灶K-1-as突变者120例（40．0％）,其中K-ras第2外显子G13D突变32例,而异时性肝转移组中K-ras的第2外显子G13D突变较同时性肝转移组多（17．0％比8．0％,P=0．041）。多因素回归模型提示,K-ras第2外显子的G13D突变是结直肠癌异时性肝转移的独立危险因素（P=0．048,HR=1．108．95％CI：1．032-5．062）。结直肠癌无肝转移组中K-ras基因突变者较无突变者总体生存期短（中位生存时间65比72个月,P=0．039）,而在结直肠癌肝转移切除的患者中,K-ras基因突变者无复发生存期短（中位时间18比24个月,P=0．048）,多因素分析提示,K-ras基因突变（HR=1．561,95％CI：1．022-6．422,P=0．045）是影响结直肠癌无肝转移组总体生存的独立危险因素。结论检测结直肠癌原发灶中的K-ras基因状态可以为预测肝脏的转移和预后情况提供参考。     

年龄校正的Charlson合并症指数与肝门部胆管癌患者腹腔镜手术切除后预后的关系

目的分析年龄校正的Charlson合并症指数(ACCI)对肝门胆部管癌患者腹腔镜手术切除后预后的影响。方法回顾分析郑州大学人民医院2013年1月至2018年1月行腹腔镜手术切除的136例肝门部胆管癌患者资料, 其中男性81例, 女性55例, 年龄(63.6±9.8)岁。根据ACCI中位数4.0将所有患者分为高ACCI组(ACCI>4.0, n=49)和低ACCI组(ACCI≤4.0, n=87)。比较两组预后。单因素和多因素Cox回归分析ACCI对患者腹腔镜手术切除后生存的影响。结果低ACCI组患者术后1、3年累积生存率分别为87.4%、48.3%, 高ACCI组分别为53.1%、4.1%, 低ACCI组术后累积生存率高于高ACCI组, 差异有统计学意义(χ2=27.97, P<0.001)。单因素Cox回归分析ACCI>4.0与生存预后相关(HR=3.73, 95%CI:2.44～5.68, P<0.001)。多因素Cox回归分析也显示ACCI>4.0(HR=2.69, 95%CI:1.65～4.37, P<0.001)的肝门部胆管癌患者腹腔镜手术...     

结直肠癌肝转移的临床病理特征与术后生存关系分析

目的通过分析结直肠癌肝转移临床病理学特征与术后生存因素的相互关系,寻找更多更准确的能够影响预后的指标对预后生存的影响,为结直肠癌肝转移患者的治疗策略提供参考。方法回顾性分析第二军医大学东方肝胆外科医院2006年1月至2009年12月期间收治并经手术治疗的233例结直肠癌肝转移患者的临床资料,采用Kaplan-Meier法计算生存率及生存曲线,并进行单因素分析,采用log-rank法进行统计学检验。将经单因素分析对预后有统计学意义的危险因素带入COX多因素回归模型,计算独立预后因素。结果本组患者术后中位生存期为37.0个月,术后1、3及5年累积生存率分别为93.0%、61.0%、17.0%。接受根治性手术患者的术后中位生存期、3及5年累积生存率优于姑息性手术者:40.53个月比27.20个月、59.0%比29.0%、20.0%比0(P0.05)。对于总体生存期而言,单因素分析结果显示,手术方式、肝转移瘤切除术后首次复发时间、肝内转移灶数目、肝内转移灶最大直径、手术切缘、肝外不可切除转移灶及周围组织或器官侵犯、是否合并慢性肝病(慢性肝炎、脂肪肝、肝硬变)、术前血清CEA水平、CA19-9水平、是否为同时性肝转移、原发灶TNM分期、肝转移瘤生长位置和肝转移瘤包膜是否完整这13项是影响预后的因素(P0.05);COX多因素分析结果显示,姑息性手术方式、同时性肝转移、肝转移瘤生长位置广泛、肝转移瘤无完整包膜、肝内转移灶多发、肝内转移灶最大直径3 cm、存在肝外不可切除转移灶及周围组织或器官侵犯和未合并慢性肝病(慢性肝炎、脂肪肝、肝硬变)这8项因素是对结直肠癌肝转移患者术后生存产生影响的独立危险因素(P0.05)。结论手术治疗可以使结直肠癌肝转移患者获得长期生存,姑息性手术方式、同时性肝转移、肝转移瘤生长位置广泛、肝转移瘤无完整包膜、肝内转移灶多发、肝内转移灶最大直径3 cm,存在肝外不可切除转移灶及周围组织或器官侵犯、未合并慢性肝病(慢性肝炎、脂肪肝、肝硬变)等是影响结直肠癌肝转移患者术后预后的独立危险因素。     

结直肠癌肝转移根治性切除预后因素分析

目的 分析影响结直肠癌肝转移患者根治性手术切除预后的临床病理因素,探讨改善患者预后的方法.方法 收集2005年1月至201 1年12月江苏省苏北人民医院和复旦大学附属肿瘤医院收治的103例结直肠癌肝转移根治性切除患者的临床资料.采用Kaplan-Meier法计算生存率,用Log-rank法分析患者生存情况,对各种影响预后的因素分别进行单变量和多变量Cox回归分析.结果 103例患者均获随访,随访时间10～ 60个月,术后1、3、5年生存率分别为90％、49％、39％.单因素分析结果显示:肝转移灶数目、大小、分布、术前CEA水平、手术并发症、术后化疗是肝转移灶切除术后的影响因素(x2值分别为24.732、9.461、9.568、25.948、25.370、5.701,P＜0.05);多因素分析显示,肝转移灶数目、肝转移灶切除术前CEA水平、手术并发症是影响预后的独立因素(Wald=7.974、12.051、11.547,P＜0.05).结论 肝转移灶数目、肝转移灶切除术前CEA水平和手术并发症是影响结直肠癌肝转移患者预后的独立因素.适当扩大手术切除的适应证,加强对高危患者的随访和术后辅助化疗,可能改善肝转移患者的预后.     

结直肠癌伴同时性肝转移的治疗

目的 探讨结直肠癌伴同时性肝转移患者的临床相关病理因素以及手术治疗.方法 回顾性分析1994年8月至2006年12月收治患者的临床资料及随访结果,比较结直肠癌无肝转移和有同时性肝转移患者的病理特点及不同程度肝转移患者和不同手术处理的预后.结果 2019例原发性结直肠癌患者中发生同时性肝转移者166例(8.10%).多因素分析显示:术前CEA水平、Ducks分期、肿瘤分化程度与浆膜浸润是同时性肝转移发生的高危因素;同时性肝转移术后1、3、5年生存率分别为69%、21%、9%;不同程度肝转移(H1、H2、H3)组间预后差异有统计学意义(X2=23.35,P<0.01).根治性手术切除组总体生存率明显高于姑息切除和未能切除组生存率(X2=21.18,P<0.01);姑息切除组和未切除组近期生存率差异有统计学意义(P<0.01),远期生存率差异无统计学意义(P=0.13).结论 结直肠癌伴同时性肝转移患者肝转移程度不同预后也不同.能够根治性切除的结直肠癌伴同时性肝转移预后较好,姑息切除原发病灶可提高近期预后和生活质量.     

规则性肝切除在结直肠癌术后肝转移治疗中的应用

影响结直肠癌患者术后生存率的主要因素之一是远处转移,其最常见的远处转移部位是肝脏。如不进行治疗．合并肝转移的结直肠癌患者仅有6～12个月的中位生存期．而行转移灶切除术的患者中位生存期可延长至24～46个月。目前多数学者认为．肝切除术可以显著提高结直肠癌术后肝转移患者的生存率。肝脏切除手术方式一般有规则性肝（段）切除或不规则性肝切除两种。     

Interval Period Tumor Progression: Does Delayed Hepatectomy Detect Occult Metastases in Synchronous Colorectal Liver Metastases?

Background  Rapid remnant liver recurrence in patients with synchronous colorectal liver metastases (CRLM) is occasionally experienced after simultaneous colorectal and liver resection. We evaluated the tumor progression during interval periods to determine whether delayed hepatic resection detects occult metastases. Methods  One hundred thirty-seven patients underwent hepatectomy for synchronous CRLM. Up to 2003, 116 patients underwent simultaneous colorectal and hepatic resection. From 2004 onward, we identified 21 patients undergoing delayed hepatectomy for synchronous CRLM. The tumor progression during interval was determined by a dynamic computed tomography scan. Results  Median/mean interval between the two evaluations prior to the first and second surgery was 2/2.4 months. The median/mean number of metastases detected at each evaluation was 2/3.3 and 3/4.6, respectively. Nine of the 21 (43%) patients had new detectable metastatic lesions after reevaluation. For 11 of the 21 patients, it was necessary to reconsider planned surgical procedure which was determined prior to colorectal surgery. Hepatic disease-free survival was significantly different between patients undergoing delayed and simultaneous hepatectomy. Multivariate analysis showed that the delayed hepatectomy was a significant independent prognostic factor in hepatic disease-free survival. Conclusion  Tumor progression was recognized and occult metastases were detected after the interval reevaluation. Delayed hepatectomy may be a useful approach to reduce rapid remnant liver recurrence in synchronous CRLM.     

Regional hepatic therapies: an important component in the management of colorectal cancer liver metastases

The treatment of colorectal cancer liver metastases (CRLM) has evolved significantly in the last 15 years. Currently, complete surgical resection remains the only potentially curative option; unfortunately, approximately 80% of patients with CRLM are not candidates for complete tumor resection. For patients with unresectable CRLM the available treatment options were historically limited; however, the development of regional hepatic therapies (RHT) and improvement of systemic chemotherapeutic regimens have emerged as viable options to improve overall survival and quality of life for this group of patients. The selection, sequence and integration of interventions into a multi-modal approach is a complex and evolving discipline. In this article, the currently available RHT modalities for CRLM are presented as a guide to the options for clinical treatment decisions.Key Words: Colorectal, liver metastases, tumor ablation     

Resecting large numbers of hepatic colorectal metastases

Background : Despite the widespread use of surgical resection as a treatment for hepatic colorectal metastases, the value of resecting more than three metastases remains controversial. It was the objective of this study to determine if resection of larger numbers of metastases affects patient survival. Method : The survival of 123 consecutive patients who underwent curative hepatic resection for colorectal metastases between 1989 and 1999 by a single surgeon was analysed retrospectively. Kaplan–Meier survival statistics and Cox regression were used to determine the factors that affected survival, and logistic regression was used to determine the factors that affected the risk of recurrence of hepatic disease. Results : The median survival rate for the whole group of patients was 38 months, with 1, 3 and 5 year survival rates of 88%, 53% and 31% respectively. The survival rate of patients undergoing resection of four to seven metastases (n = 22; 5 year survival = 39%) was not significantly different to that of patients undergoing resection of one to three metastases (n = 91; 5 year survival = 30%), P = 0.9. Age, sex, primary cancer site, hepatic disease distribution, resection margins and adjuvant hepatic arterial chemotherapy (HAC) did not affect survival. Local invasion of the hepatic metastases (relative risk (RR) = 2.9; P = 0.001) and hepatic disease recurrence (RR = 2.1; P = 0.007) were the only factors that independently affected survival. Local invasion of the hepatic metastasis was the only factor associated with an increased risk of hepatic recurrence (RR = 2.8; P = 0.03). Adjuvant HAC did not affect the risk of hepatic recurrence (RR = 1.5, P = 0.4). Conclusion : Although there are no randomized trials that quantify any survival benefit from resection of liver metastases, the comparison of our results with well documented historical evidence indicates that surgical resection of up to seven colorectal liver metastases can result in a significant survival benefit.     

A new scoring system to classify patients with colorectal liver metastases: proposal of criteria to select candidates for hepatic resection

Background Although many studies have reported the beneficial effects of hepatic resection for colorectal liver metastases on survival rates, it is still difficult to preoperatively select good candidates for hepatectomy.Methods Fifteen clinicopathological features, which were recognized only before or during surgery, were selected retrospectively in 81 consecutive patients in one hospital (Group I). These features were entered into a multivariate analysis to determine independent and significant variables affecting long-term prognosis after hepatectomy. Using selected variables, we created a scoring formula to classify patients with colorectal liver metastases to select good candidates for hepatic resection. The usefulness of the new scoring system was examined in a series of 70 patients from another hospital (Group II).Results Multivariate analysis, i.e., Cox regression analysis, showed that serosa invasion of primary cancers (P = 0.0720, risk ratio = 2.238); local lymph node metastases of primary cancers, i.e., Dukes C (P = 0.0976, risk ratio = 2.311); multiple nodules of hepatic metastases (P = 0.0461, risk ratio = 2.365); nodules of hepatic metastases greater than 5cm in diameter (P =0.0030, risk ratio = 4.277); and resectable extrahepatic distant metastases (P = 0.0080, risk ratio = 4.038) were significant and independent prognostic factors for poor survival after hepatectomy. Using thsee five variables, we created a new scoring formula to classify patients with colorectal liver metastases. Finally, our new scoring system classified patients in Group II and Group I well, according to long-term outcomes after hepatic resection.Conclusions Our new scoring system to classify patients with colorectal liver metastases is simple and useful in the preoperative selection of good candidates for hepatic resection.     

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??Risk and prognostic factors of colorectal liver metastases LIANG Li, LIU Tian-shu. Department of Medical Oncology??Zhongshan Hospital, Fudan University??Shanghai 200032, China
Corresponding author: LIU Tian-shu, E-mail: liu.tianshu@
zs-hospital.sh.cn
Abstract Liver is the most common metastasis site of colorectal cancer, and the prognosis of colorectal liver metastases (CRLM)is poor. CRLM are divided into synchronous metastasis and metachronous metastasis. Single factor and multiple factor regression analyses show that the risk factors of CRLM include the depth of invasion, lymph node metastasis, tumor node, differentiation degree, tumor antigen and carbohydrate antigen. The factors influencing the prognosis of CRLM include the size and quantity of liver metastases, primary resection, surgical resection of liver metastases, systemic drug therapy and so on. Therefore, the surgical resection of liver metastases as well as drug therapy to get the opportunity of resection can maximize the survival of patients with CRLM. For a combination of a number of factors, the scoring system can better predict the prognosis of CRLM.     

肝切除治疗结直肠癌肝转移预后影响因素研究进展

结直肠癌是我国最常见的恶性肿瘤之一。临床上，结直肠癌病人首次确诊时已有15%～25%发生肝脏转移，中位生存期约为6个月，然而行手术切除肝转移灶后5年存活率可达60%。近年来，虽然在新辅助化疗和外科技术等方面取得迅速发展，使得病人获得较长的生存时间，但肝切除仍是治愈结直肠癌肝转移（CRLM）病人的主要治疗方式。肝切除术能够改善病人预后，手术应做到R0切除或者达到无疾病证据状态（NED）；若有复发应积极施行二次手术；原发病灶部位以及淋巴结转移情况对预后影响尚有待研究；结直肠癌确诊至发生肝转移时间间隔越长预后较好（＞2年）。然而，肝转移灶的大小、数目、部位情况等，并不是影响手术预后的主要因素。总之，肝切除对CRLM病人具有良好的预后，同时需要结合病人的切缘状态、残余肝体积、原发病灶及淋巴结转移等因素综合考虑。     

Outcomes after resection of synchronous or metachronous hepatic and pulmonary colorectal metastases

BACKGROUND: Surgical resection of isolated hepatic or pulmonary colorectal metastases prolongs survival in selected patients. But the benefits of resection and appropriate selection criteria in patients who develop both hepatic and pulmonary metastases are ill defined. STUDY DESIGN: Data were prospectively collected from 131 patients with colorectal cancer who underwent resection of both hepatic and pulmonary metastases over a 20-year period. Median followup was 6.6 years from the time of resection of the primary tumor. Patient, treatment, and outcomes variables were analyzed using log-rank, Cox regression, and Kaplan-Meier methods. RESULTS: The site of first metastasis was the liver in 65% of patients, the lung in 11%, and both simultaneously in 24%. Multiple hepatic metastases were present in 51% of patients, and multiple pulmonary metastases were found in 48%. Hepatic lobectomy or trisegmentectomy was required in 61% of patients; most lung metastases (80%) were treated with wedge excisions. Median survival rates from resection of the primary disease, first site of metastasis, and second site of metastasis were 6.9, 5.0, and 3.3 years, respectively. After resection of disease at the second site of metastasis, the 1-, 3-, 5-, and 10-year disease-specific survival rates were 91%, 55%, 31%, and 19%, respectively. An analysis of prognostic factors revealed that survival was significantly longer when the disease-free interval between the development of the first and second sites of metastases exceeded 1 year, in patients with a single liver metastasis, and in patients younger than 55 years old. CONCLUSIONS: Surgical resection of both hepatic and pulmonary colorectal metastases is associated with prolonged survival in selected patients. Patients with a longer disease-free interval between metastases and those with single liver lesions had the best outcomes.     

结直肠癌肝转移危险及预后因素分析

肝脏是结直肠癌最常见的远处转移器官,结直肠癌病人出现肝转移一般预后较差。结直肠癌肝转移分为同时性肝转移和异时性肝转移,对众多的临床以及病理学特征进行的单因素和多因素回归分析提示,影响结直肠癌发生肝转移的危险因素有：浸润深度、淋巴结转移、癌结节、分化程度、癌胚抗原和糖类抗原等。影响结直肠癌肝转移病人预后的因素有：肝转移灶大小及数目、肝外器官转移、原发灶手术切除、肝转移灶手术切除、全身药物治疗等。因此,手术切除肝转移灶、药物治疗获得手术切除机会等治疗模式能够最大程度地提高结直肠癌肝转移病人的存活率。由众多因素组合起来的评分系统,能够较好地预测结直肠癌肝转移病人的预后。     

Therapeutic Efficacy of Combined Intraoperative Ablation and Resection for Colorectal Liver Metastases: An International,Multi-institutional Analysis

Background  

Only 10–25% of patients presenting with colorectal liver metastases (CRLM) are amenable to hepatic resection. By combining resection and ablation, the number of patients eligible for surgery can be expanded. We sought to determine the efficacy of combined resection and ablation for CRLM.