PIN1在胃癌组织中的表达及其预后意义

目的 探讨肽基脯氨酰顺反异构酶（PIN1）在胃癌中的表达及其与临床病理学特征及预后的关系。方法 应用组织芯片、免疫组化技术检测134例胃癌组织及对应癌旁组织中PIN1蛋白的表达情况,分析其与临床病理特征及预后的关系。结果胃癌组织中PIN1阳性表达率为33.6％（45／134）,癌旁组织为21.6％（29／134）,差异有统计学意义（P＜0.05）。PIN1表达与胃癌患者TNM分期和远处转移有关（P=0.007,P=0.010）,与其他临床病理特征无关（P＞0.05）。PIN1阳性患者的5年生存率为35.7％,阴性患者为50.6％,差异有统计学意义（P＜0.05）。Cox多因素分析显示,PIN1表达不是胃癌的独立预后因素,而pTNM分期和Lauren分型是胃癌的独立预后因素。结论 胃癌组织中存在PIN1阳性表达,并与TNM分期和远处转移及预后密切相关,可能是潜在的胃癌治疗靶点。     

化疗相关性白细胞减少等因素对小细胞肺癌生存期的影响

目的 探讨影响小细胞肺癌（small cell lung cancer,SCLC）患者生存期的因素。方法 回顾性研究123例SCLC患者的临床资料,利用SPSS15.0统计软件Cox回归模型分析性别、年龄、吸烟、合并症、临床分期、ECOG评分、治疗方法、CEA、化疗相关性白细胞减少（chemotherapy induced leucopenia,CIL ）9个预后因素对生存期的影响。结果随访1～52月,死亡103例。6月、1年、2年、3年、4年存活率分别为70.7%、34.1%、8.94%、2.4%、0.8%,中位生存期11月[95%CI(9.328, 12.627)]。Cox回归多因素分析显示,影响预后的独立因素是：ECOG评分（P=0.000）、化疗联合放疗（P=0.000）、临床分期（P=0.024）、CIL(P=0.013)。结论临床分期早、ECOG评分低、接受化疗联合放疗且出现CIL的SCLC患者生存期长、预后好。     

p27表达水平与非小细胞肺癌预后关系的Meta分析

目的：采用Meta分析的方法，探讨p27在非小细胞肺癌（NSCLC）预后中的作用。方法：检索PubMed、CNKI中研究p27表达与NSCLC预后关系的文献，收集每篇文献的相对危险比（HR）及95％可信区间（95％CI），应用Meta分析Dersimonian—Laird模型对文献进行定量综合分析。结果：共入选7篇文献，累计NSCI。C病例888例，其中p27阳性表达443例，阳性率49．9％。对入选7篇文献进行一致性检验，文献具有异质性（Q=102．13，P=0．000），合并相对危险比为1．21（95％可信区间：1．13～1．29，P=0．000）。结论：p27的阳性表达可能是NSCLC的良好预后因素。     

影响晚期胃癌患者疗效和预后的相关因素分析

目的 分析影响晚期胃癌患者疗效和预后的相关因素。方法 回顾性分析临床病理特征、接受不同化疗方案的治疗情况及HER-2基因表达等因素对晚期胃癌患者疗效和预后的影响。结果 2008年12月至2011年8月共纳入192例晚期胃癌患者,182例接受联合方案一线治疗,其中156例可评价疗效,有效率（RR）为19.9％,三药方案的有效率优于两药方案（27.0％ vs.15.1％,P=0.008）,三药方案中含靶向药物优于不含靶向药物（33.3％ vs. 14.3％,P=0.012）;108例接受二线治疗,其中69例可评价疗效,RR为13.0％,单药方案与多药方案的有效率、中位疾病进展时间差异均无统计学意义。接受二线治疗者较仅行一线治疗者的中位生存时间明显延长（14.1个月 vs.7.3个月,P＜0.001）。HER-2阳性患者接受含曲妥珠单抗方案治疗的有效率显著高于单纯化疗方案,其中一线治疗的RR分别为45.4％和11.0％（P=0.008）,二线治疗的RR分别为50.0％和10.0％（P=0.009）。Cox多因素回归分析显示,ECOG评分、HER-2表达、肿瘤负荷以及是否接受二线治疗是晚期胃癌患者的预后独立因素。Logistic多元回归分析提示靶向治疗对疗效有显著影响。结论 一线治疗应用含靶向药物的三药联合方案可显著提高晚期胃癌的疗效,二线治疗使晚期胃癌的预后明显改善。HER-2表达情况将影响治疗的选择,从而影响患者的预后。     

血小板与淋巴细胞比值对肝细胞癌患者预后影响的Meta分析

目的 评价血小板与淋巴细胞比值（Platelet-lymphocyte ratio, PLR）对肝细胞癌（Hepatocellular carcinoma, HCC）的预后价值。方法 以PubMed、Embase、Web of Science数据库中已发表的英文文献作为检索的主要来源,检索时限为数据库建立至2016年12月31日,按照拟定的纳入和排除标准,筛选符合系统评价标准的研究。采用Meta分析方法评PLR对HCC的预后意义。数据分析软件采用STATA 12.0。异质性检验采用Cochran’s Q检验,根据检验结果选择模型进行相应的效应量合并,最终将合并分析所得出的HR/OR值及其95%CI作为效应分析的统计量。结果 来自6篇文献的1 215例HCC患者纳入研究。对于总体HCC人群而言,高水平PLR的HCC患者OS明显较短（HR=1.55, 95%CI: 1.06-2.29, P=0.025）,但与DFS无相关性（P=0.222）。结论 PLR是影响HCC患者远期预后的独立风险因素。检测治疗前PLR水平对判断肝细胞癌患者的临床预后具有一定的意义。     

S100P在胃癌中的下调表达及意义

目的探讨S100P在胃癌组织中的表达情况及与胃癌临床病理参数间的关系。方法选取93例胃癌石蜡组织标本及相对应的部分冻存胃癌组织及其配对正常组织为研究对象,应用免疫组织化学、RT-PCR、Western Blot方法检测S100P在胃癌及癌旁组织中的表达。结果免疫组织化学分析表明,胃癌中S100P蛋白主要定位于胞质和胞核,在52.7% (49/93)的胃癌组织和几乎所有的正常胃黏膜中可检测到表达,与正常胃黏膜相比,胃癌组织中的表达明显下调,其下调表达与患者肿瘤的侵袭深度(P=0.006)及肿瘤的大小相关(P=0.001)。同时,S100P在核酸和蛋白水平的表达具有相关性（P=0.030）,不能够作为独立的预后因素（P=0.347）。结论S100P在胃癌组织中表达下调,其表达与肿瘤的侵袭转移及肿瘤大小相关,并可以作为判断患者预后的辅助指标。     

60例青年肺癌患者的临床特征及预后分析

目的探讨青年肺癌的临床特征及影响预后的因素。方法回顾性分析60例40岁以下肺癌患者的临床资料,分别对性别、年龄、吸烟史、病理类型、肿瘤部位、肿瘤大小、TNM分期、有无肿瘤家族史及治疗方法进行预后分析。Kaplan-Meier法计算生存率,Log-rank进行生存率显著性检验,Cox比例回归风险模型进行单因素、多因素分析,评价各因素对预后的影响。结果全部青年肺癌患者的1、2、3年生存率分别为：69.1％、50.0％、20.0％。单因素分析显示：病理类型（P=0.001）、吸烟史（P=0.0461）、TNM分期（P=0.0383）、治疗方法的选择（P=0.011）是影响预后的因素。多因素分析则显示：病理类型和TNM分期是影响预后的独立因素。结论青年肺癌的临床表现无特异性,提高对青年肺癌的认知程度,争取早期正确诊断,选择正确的治疗方法,是提高生存率的方法。     

老年人胃癌的浸润深度和术后化疗对预后的影响

目的探讨接受手术治疗的老年人胃癌临床病理因素与预后的关系。方法回顾性研究本院2002年1月至2005年12月胃癌手术患者,记录患者的年龄、性别、肿瘤位置、肿瘤大小、共存病（高血压及心脏病）、手术根治程度、胃切除范围、病理类型(WHO)、TNM分期、术后化疗情况,建立数据库。结果老年组中位生存时间为29月（平均44月）,明显低于中年组（78月,P=0.001）和青年组（72月,P=0.009）;老年患者原发肿瘤以T3/T4为主;较少的患者接受联合脏器切除;更多合并高血压及心脏病,而较少患者接受术后化疗。结论老年人胃癌手术患者原发灶的侵犯深度、术后较少接受化疗与预后差有关。     

45例间变性大细胞淋巴瘤临床病理特点及疗效分析

目的 分析间变性大细胞淋巴瘤（ALCL）的临床病理特点、远期效果和影响预后的因素。方法 回顾性分析2000年1月—2008年12月我院收治的45例ALCL患者的临床资料,并分析远期疗效, 用Cox模型分析预后因素。结果 原发皮肤和系统性ALCL分别有7例（84.4%）和38例（15.6%）。20例（44.4%）伴有B症状者,乳酸脱氢酶升高者8例（21.6%）,低危组、中低危组共31例（68.9%）,28例（62.2%）ALK阳性。26例（57.8%）为T细胞来源,6例（13.3%）为B细胞来源,11例（22.2%）T细胞和B细胞标记均为阴性,为null型,2例T细胞和B细胞标记均为阳性。原发皮肤和系统性ALCL治疗后的有效率分别为100%和92.1%,5年OS率分别为83.3%和63.9%（χ²=0.707,P＝0.401）。ALK阳性和阴性患者的5年OS率分别87.5%和46.9%（χ²=10.992,P＝0.01）。单因素分析ALK表达状况（P＝0.01）、国际预后指数评分（P＝0.000）、临床分期（P＝0.005）对生存期的影响有统计学意义,ALK的表达状况（P＝0.012）和国际预后指数评分（P＝0.000）是影响总生存期的独立因素。结论 ALCL中约80%为原发系统性,近期和远期疗效较好,约60%的患者ALK阳性,ALK和国际预后指数为独立的预后因素。     

HDAC6在胃癌组织中的表达及意义

目的 检测胃癌及胃良性病变组织中组蛋白去乙酰化酶6（HDAC6）的表达及其与胃癌的发生及各种临床病理因素之间的关系。方法 采用免疫组织化学方法,检测40例胃癌组织及36例胃良性病变组织中HDAC6的表达,分析其与临床病理因素间的关系。结果 在40例胃癌组织中HDAC6呈高表达的有25例,而在36例胃良性病变组织中呈高表达的仅有10例,两者相比差异均有统计学意义（χ²=9.915,P=0.003）。HDAC6在胃癌组织中的表达与分化程度（χ²=7.116,P=0.022）、临床分期有相关性（r_s=0.442,P=0.001）,相反,HDAC6的表达和其他的临床病理因素无关,如年龄、性别、浸润深度、淋巴结转移。结论 HDAC6在胃癌组织中呈过表达状态,其表达水平可以作为判断胃癌患者恶性程度的一个潜在指标,也可以作为一个预后指标。     

Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival.

The prognostic role of epidermal growth factor receptor (EGFR) and HER2-neu remains controversial in patients with non-small cell lung cancer (NSCLC). We studied the association between the mRNA expression of EGFR, HER2-neu, and survival in primary tumor and matching nonmalignant tissues from 83 patients with NSCLC. Analysis was performed using a quantitative real-time PCR system (Taqman). EGFR and HER2-neu mRNA expression was detectable in all (100%) specimens analyzed. Twenty-nine (34.9%) patients had high HER2-neu expression, and 28 (33.7%) patients had high EGFR expression. A high HER2-neu and EGFR coexpression was detectable in 14 (16.9%) patients. High HER2-neu expression was associated with inferior survival (P = 0.004), whereas high EGFR expression showed a trend toward inferior survival (P = 0.176). The impact of HER2-neu and EGFR coexpression on patients' survival was additive (P = 0.003). Multivariate analysis determined high HER2-neu expression (P = 0.041), and high EGFR/HER2-neu coexpression (P = 0.030) as significant and independent unfavorable prognostic factors. These findings indicate that HER2-neu and EGFR play a crucial role in the biological behavior of NSCLCs. Testing of molecular marker coexpression (EGFR and HER2-neu) improves the estimation of prognosis and appears to define low- and high-risk groups for treatment failure in curatively resected NSCLC.     

Survey of Her2-neu Expression and its Correlation with Histology of Gastric Carcinoma and Gastroesophageal Junction Adenocarcinoma

Background: There is increasing evidence that HER2-neu is an important biomarker in gastric carcinomas (GC) and gastroesophageal junction (GEJ) adenocarcinomas. The aim of this study was to evaluate HER2-neu expression and also some clinicopathological features of these neoplasms. Materials and Methods: We selected 211 paraffin-embedded blocks, 193 GC and 18 GEJ. Then 4 micron sections were prepared for staining with hematoxylin and eosin and also for IHC (Her2-neu). The Chi-square test was used for significance between expression of HER2-neu and clinicopathological parameters. Results: In patients with advanced cancer of GC and GEJ, HER2-neu overexpression was more associated with the intestinal cancer subtype. Conclusions: This could be a guide to new complementary therapy for affected patients.     

Type 2 diabetes mellitus and prognosis in early stage breast cancer women

It has been suggested that type 2 diabetes mellitus may affect breast cancer prognosis, possibly due to increased diabetes-related comorbidity, or direct effects of insulin resistance and/or hyperinsulinemia. The aim of this study was to determine the impact of diabetes on disease-free survival (DFS) following mastectomy for breast cancer patients. The cases included in this retrospective study were selected from breast cancer women who had undergone mastectomy and completed adjuvant chemotherapy from 1998 to 2010. Patients were classified into two groups: diabetic and non-diabetic. Patients' age, sex, menopausal status, body mass index (BMI), histopathological features, tumor size, lymph node involvement, hormone receptor and HER2-neu status, and treatment types were recorded. There were 483 breast cancer patients included in the study. Postmenopausal patients' rate (53.7% vs. 36.8%, P = 0.016) and mean BMI levels were statistically higher (32.2 vs. 27.9, P = 0.007) in diabetic patients. There was no statistical difference for histological subgroup, grade, ER and PR positivity, HER2-neu overexpression rate, and tumor size between the diabetic and non-diabetic group. Lymph node involvements were statistically higher in diabetic patients compared with non-diabetic patients (P = 0.013). Median disease-free survival is 81 months (95% CI, 61.6-100.4) in non-diabetic patients and 36 months (95% CI, 13.6-58.4) in diabetic patients (P < 0.001). The odds ratio of recurrence was significantly increased in those with HER2-neu overexpression and lymph node involvement and decreased with PR-positive tumors. Our results suggest that diabetes is an independent prognostic factor for breast cancer.     

Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer.

PURPOSE: Recent studies have indicated that expression of chemokine receptors CXCR4 and CCR7 could be an indicator of the metastatic potential of breast cancer. Expression of CXCR4 and CCR7 along with the biomarkers HER2-neu and epidermal growth factor receptor (EGFR) was investigated in inflammatory breast cancer (IBC) to evaluate their prognostic implications. EXPERIMENTAL DESIGN: CXCR4, CCR7, and EGFR were evaluated by immunohistochemical staining (IHC) of paraffin-embedded tissue sections. HER2-neu amplification was assessed by FISH and/or IHC. All patients received chemotherapy, surgery, and radiation. RESULTS: Forty-four cases diagnosed with IBC from 1994 to 2002 were included in the study. In all, 18 (40.9%) patients had positive CXCR4, 10 (22.7%) had positive CCR7, 21 (47.7%) had positive HER2-neu, and EGFR was positive in 12 of 40 patients (30%). The 5-year overall survival (OS) was 24.8% for CXCR4-positive disease versus 42.3% for CXCR4-negative patients (P = 0.53) and 20.0% for CCR7-positive disease versus 41.9% for CCR7-negative patients (P = 0.24). EGFR-positive disease had significantly worse OS compared with EGFR-negative disease (P = 0.01). CONCLUSIONS: These data demonstrate the expression of growth factor and chemokine receptors in IBC. The expression of these receptors is associated with increased risk of recurrence and death, and thus, they may represent potential therapeutic targets in IBC.     

CXCL-12/stromal cell-derived factor-1alpha transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation

Experimental evidence suggests that CXCR4, a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1alpha (SDF-1alpha), plays a role in breast cancer metastasis. Transactivation of HER2-neu by G protein-coupled receptor activation has been reported as a ligand-independent mechanism of activating tyrosine kinase receptors. We found that SDF-1alpha transactivated HER2-neu in the breast cancer cell lines MDA-MB-361 and SKBR3, which express both CXCR4 and HER2-neu. AMD3100, a CXCR4 inhibitor, PKI 166, an epidermal growth factor receptor/HER2-neu tyrosine kinase inhibitor, and PP2, a Src kinase inhibitor, each blocked SDF-1alpha-induced HER2-neu phosphorylation. Blocking Src kinase, with PP2 or using a kinase-inactive Src construct, and inhibiting epidermal growth factor receptor/HER2-neu signaling with PKI 166 each inhibited SDF-1alpha-stimulated cell migration. We report a novel mechanism of HER2-neu transactivation through SDF-1alpha stimulation of CXCR4 that involves Src kinase activation.     

CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer.

PURPOSE: The chemokine receptors CCR7 and CXCR4 have been shown to play an important role in cancer metastasis. We therefore studied the differential expression of CCR7 and CXCR4, along with that of the biomarker HER2-neu, to evaluate whether these biomarkers could predict axillary lymph node metastasis in breast cancer. EXPERIMENTAL DESIGN: Biomarker expression levels were evaluated using paraffin-embedded tissue sections of lymph node-negative (n = 99) and lymph node-positive (n = 98) T1 breast cancer by immunohistochemical staining. RESULTS: Lymph node-positive tumors showed higher rates of high cytoplasmic CCR7 staining (21.5% versus 8.5%, P = 0.013) and HER2-neu overexpression (21.5% versus 9.3%, P = 0.019) than did lymph node-negative tumors. Similarly, high cytoplasmic CXCR4 expression occurred more commonly in lymph node-positive tumors (11.2% versus 5.1%, P = 0.113). In contrast, predominantly nuclear CXCR4 staining was more likely to be found in lymph node-negative tumors (54.5% versus 37.8%, P = 0.018). Furthermore, cytoplasmic CXCR4 coexpressed with HER2-neu was the only factor associated with involvement of four or more lymph nodes (16.7% versus 1.2%, P = 0.04) among lymph node-positive tumors. When all three biomarkers (CCR7, CXCR4, HER2-neu) were utilized together, 50.0% of lymph node-positive tumors highly expressed one of these biomarkers compared with 18.8% of the lymph node-negative tumors (P < 0.0001). CONCLUSIONS: Our results suggest that the chemokine receptor CCR7 is a novel biomarker that can predict lymph node metastases in breast cancer. Utilization of additional markers, such as CXCR4 and HER2-neu, further improves the prediction of the presence and extent of lymph node involvement.     

The Role of HER2 Testing in Advanced Colorectal Cancer

Purpose of Review

About 1/3 of all metastatic colorectal cancer (mCRC) patients may harbor a mutation in the KRAS or NRAS gene suggesting inefficacy of EGFR inhibitors cetuximab and panitumumab. In spite of tailoring treatment in RAS wild-type patients to receive EGFR inhibitors, not all show response.

Recent Findings

Studies have shown that HER2-neu amplification/alteration in addition to alteration in BRAF and PI3KA may explain resistance to EGFR inhibitors. Several pre-clinical studies have identified that HER2-neu amplification can result in both de novo and acquired resistance to EGFR inhibitors. Recently, several clinical studies have highlighted the use of single or combination HER2-neu directed therapies in HER2-neu amplified/overexpressed mCRC.

Summary

About 5% mCRC patients will demonstrate HER2-neu overexpression and response to HER2-neu-directed therapies can be in the range of 30–38%. Patients not responding to EGFR-inhibitors warrant testing for HER2-neu testing to explain resistance. In the near future, HER2-neu testing is likely to be integrated into our routine clinical practice for management of metastatic colorectal cancer patients.

     

Prognostic significance of HER2 expression based on trastuzumab for gastric cancer (ToGA) criteria in gastric cancer: an updated meta-analysis

The prognostic significance of HER2 expression in patients with gastric cancer remains controversial, partially due to the significant heterogeneity of the approaches and criteria used for HER2 assessment among different studies. We therefore conducted a meta-analysis enrolling only studies defining HER2 status by trastuzumab for gastric cancer (ToGA) criteria. Published studies investigating the association between HER2 expression and survival were identified. Only publications that defined HER2 expression using ToGA criteria were enrolled. Meta-analyses were performed by Revman 5.2. Pooled hazard ratio (HR) and its 95 % confidence interval (CI) were calculated to evaluate the risk of disease. A total of 11 studies were enrolled in meta-analyses. Pooled data of nine studies using univariate analysis showed that HER2 expression is not associated with overall survival (OS; pooled HR, 0.97; 95 % CI, 0.84–1.12; P?=?0.63), which are maintained in six studies of multivariate analysis (pooled HR, 1.01; 95 % CI, 0.75–1.35; P?=?0.95). The Q statistic test for nine studies of univariate analysis and for six studies of multivariate analysis showed no and low heterogeneity (I ²?=?22 % and P?=?0.25; I ²?=?41 % and P?=?0.13, respectively). Furthermore, pooled data of four studies without heterogeneity (I ²?=?0 %, P?=?0.74) showed that HER2 expression were not associated with relapse-free survival as well, with a pooled HR of 1.08 (95 % CI, 0.84–1.37; P?=?0.55) in patients with HER2 expression. In conclusion, this meta-analysis indicated that HER2 expression based on ToGA criteria is not related to the survival in patients with gastric cancer.