Prognostic relevance of proliferating cell nuclear antigen and p53 expression in non-small cell lung cancer.

Prognostic value of p53 and PCNA expression in non-small cell lung cancer (NSCLC) remains controversial. In this study we determined the relevance of these abnormalities in terms of overall survival and disease-free survival in 95 NSCLC patients who underwent curative pulmonary resection. Expression of p53 was found in 44 samples (45%), expression of PCNA-in 79 samples (83%), and expression of both markers-in 35 samples (36%). There was no relationship between expression of either protein and major clinicopathological characteristics. Median survival for patients with and without p53 expression was 36 and 33 months, respectively and 5-year survival probability-29 and 37%, respectively (P=0.73). Median survival for patients with and without PCNA expression was 36 and 27 months, respectively and 5-year survival probability-35 and 25%, respectively (P=0.60). There was no significant difference in overall survival between particular groups of patients with tumors carrying four possible p53/PCNA phenotypes. In multivariate analysis including patient age, sex, tumor stage, tumor type and differentiation, p53 and PCNA expression, the only variable important for survival was stage of disease. These results suggest the lack of prognostic relevance of p53 and PCNA expression in surgically treated NSCLC patients.     

Prognostic evaluation of the expression of p53 and bcl-2 oncoproteins in patients with surgically resected non-small cell lung cancer

BACKGROUND: Tumor staging remains the most important prognostic predictor in patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of expression of oncoproteins involved in regulation of cellular uncontrolled proliferation remains controversial. METHODS: In this retrospective study, we investigated the expression of bcl-2 and p53 oncoproteins in 114 surgically resected NSCLC patients (46 stage I, 39 stage II and 29 stage IIIa) using immunohistochemical analysis and correlated the molecular markers with survival. RESULTS: Positive bcl-2 immunoreactivity was detected in 26 of 114 (22.8%) NSCLC, including 15 of 43 (34.9%) squamous cell carcinoma and 11 of 71 (15.5%) adenocarcinoma cases. Nuclear staining for p53 was observed in 59 of 114 (51.8%) NSCLC, including 26 of 43 (60.5%) squamous cell carcinoma and 33 of 71 (46.5%) adenocarcinoma patients. There was no correlation between pathological staging and expression of bcl-2 and p53. However, the expression frequency of bcl-2 was significantly higher in squamous cell carcinoma than in adenocarcinoma (P < 0.02). The presence of bcl-2 expression did not provide a favorable prognosis (P = 0.23) and the overexpression of p53 oncoprotein was also not significantly associated with adverse prognosis (P = 0.09). No inverse relationship was found between bcl-2 and p53 expression (P = 0.83). CONCLUSION: Expressions of bcl-2 and p53 using immunohistochemical staining are not independent prognostic predictors in patients undergoing surgery for NSCLC.     

凋亡和p53突变对非小细胞肺癌预后的影响

目的:研究细胞凋亡及凋亡相关蛋白p53在肺癌组织中的表达水平,及其对预后的影响。方法:应用DNA缺口末端标记技术和免疫组化方法检测111例肺癌患者组织中细胞凋亡和突变型p53蛋白表达水平。结果:111例肺癌组织中,细胞凋亡数量≥1%的病例有47·7%(53/111),突变型p53蛋白阳性表达率为40·5%(45/111);单因素分析肺癌患者预后的影响因素有凋亡(χ2=6·77,P<0·01)、突变型p53(χ2=6·56,P<0·05)、淋巴结转移(χ2=16·31,P<0·01)和TNM分期(χ2=15·86,P<0·01);COX模型多因素分析显示,肿瘤大小(χ2=4·12,P<0·05)、淋巴结转移(χ2=12·94,P<0·01)和细胞凋亡(χ2=4·61,P<0·05)是肺癌患者的预后不良因素。结论:凋亡及凋亡相关蛋白p53影响肺癌患者的生物学行为及预后。     

Prognostic factors for the survival of surgically treated patients for non-small cell lung cancer

The survival and outcome rates of 284 patients who underwent surgical treatment for non-small cell lung cancer were assessed retrospectively. Resectability rate was 94.1%, hospital mortality 3.9% (n=11) and the mortality rates in patients who underwent pneumonectomy or lobectomy were 8.9% and 0.6%, respectively. The overall 5-year survival was 43.6%. Female gender, earlier stages of disease and a complete resection were strongly predictive for a long-term survival. Women in stage IA disease had a 5-year survival rate of 92.7%. The 5-year survival rate for patients in stages IIIA and N2 disease who underwent a complete resection was 21.9%, and 9% for those who did not undergo a complete resection. It is concluded that the best surgical results were observed in women who were operated on at an early stage of disease. A complete resection also contributed to a better outcome, even for patients in stage IIIA and N2 disease.     

非小细胞肺癌脑转移手术治疗预后相关因素分析

目的 非小细胞肺癌(non-small cell lung cancer,NSCLC)一旦发生脑转移往往提示预后不良,对于一些脑转移瘤患者,手术仍然是其可选择的治疗方法,但是就如何选择手术获益人群,仍然是神经外科医生面临的难题.本研究就NSCLC脑转移瘤手术切除后组织亚型对患者术后生存期预后影响进行分析.方法 选取2005-01-01-2013-12-31天津医科大学肿瘤医院脑系科收治的78例手术治疗NSCLC脑转移瘤患者的临床病例资料.其中男40例,女38例.年龄38～81岁,中位年龄55岁.以发现脑转移病灶首发44例,发现肺原发病灶首发34例.病灶位于幕上43例,幕下9例,幕上下均累及26例.颅内病灶单发28例,颅内病灶≥2个50例,有颅外其他部位转移26例,仅有颅内部位转移52例,患者术前功能状态评分(karnofsky,KPS)均≥70.结果 患者研究终点是术后生存期,从患者手术之日计算.中位生存期为8.40个月,本研究中只有2例(2.56％)患者其生存期分别为39和52个月,1、2、3年生存率分别为34.5％、11.9％和5.2％.单因素分析显示,性别(x2=5.918,P=0.015)、NSCLC组织亚型(x2=5.361,P=0.021)、脑转移瘤是否首发(x2 =3.932,P=0.047)、脑转移瘤术前化疗与否(x2=4.810,P=0.028)、原发灶控制与否(x2=21.452,P＜0.001)、脑转移术后全脑放疗与否(x2=32.454,P＜0.001)和脑转移术后化疗与否(x2=7.690,P=0.006)对术后生存期有影响.多因素分析显示,NSCLC组织亚型(P=0.001)、原发灶控制与否(P=0.015)、脑转移瘤是否首发(P=0.026)和术后是否行全脑放疗(P＜0.001)是其独立的预后因素.NSCLC中鳞癌脑转移瘤患者中位生存期7.98个月,并且无一例鳞癌脑转移瘤患者生存期＞2年,明显低于NSCLC中腺癌脑转移瘤患者.因此,术后全脑放疗是脑转移瘤患者良好预后因素.结论 在选取手术治疗NSCLC脑转移瘤患者时,考虑由预后等级评估所确定的脑转移个数、KPS评分、年龄以及颅外转移有无等4个参数时,也应该把NSCLC组织亚型对术后预后影响考虑在内.     

Prognostic relevance of p53 protein expression in glioblastoma

TP53 plays a key role in cellular response to DNA-damaging agents, and mutation of this gene, which is associated with immunohistochemically detectable p53 protein accumulation, may influence response to chemo- and radiotherapy. We investigated immunohistochemically the influence of p53 protein accumulation in 114 consecutive cases of primary glioblastoma treated by surgery and adjuvant radio- and chemotherapy. In addition, we determined cellular proliferation index using the antibody MIB-1 and apoptotic index of tumor cells using the TUNEL-assay. Twenty-nine patients (25.4%) were considered as positive with regard to p53 protein expression (>50% p53 immunostained tumor cells). Patients with p53 positive glioblastomas were significantly younger (mean age 54.4+/-2 years) than those with p53 negative tumors (mean age 61.4+/-1.1 years) (p=0.002, Mann-Whitney test). While no significant difference in apoptotic index was found, we observed a significantly higher MIB-1 labeling index (LI) in patients with p53 positive tumors (median LI: 36.4%) compared to p53 negative ones (median LI: 23.8%) (p=0.005, Mann-Whitney test). p53 protein expression was associated with significantly longer survival in univariate analysis (p=0.0399, log-rank test). In multivariate analysis of overall survival (Cox regression) only postoperative Karnofsky performance status remained as independent prognostic factor. We conclude that glioblastoma patients with immunohistochemically detectable p53 protein expression, who received adjuvant radio- and chemotherapy, have a significantly better overall survival, possibly due to increased sensitivity to this adjuvant treatment.     

Prognostic impact of p53 Pro72 homozygous genotype in non-small cell lung cancer patients

Mutations of the p53 gene represent the most common genetic alterations in human cancer. Several reports have focused on p53 polymorphisms as risk factors in lung cancer, in particular at codon 72 of exon 4, encoding either an arginine (Arg72R) or a proline (Pro72P) amino acid. Polymorphisms at codon 72 of the p53 gene were determined using a PCR-RFLP-based method. We analysed the relationship of this polymorphism to patient survival in 121 non-small cell lung cancer (NSCLC) cases. Interestingly, the 72P homozygous NSCLC patients often presented high-grade tumours and had significantly poorer survival rates than patients with R72 homozygotes or heterozygotes. Our results may help clarify discrepancies in the literature concerning the prognostic role of p53 codon 72 variants.     

Prognostic value of serum p53 antibodies in patients with resected non-small cell lung cancer

BACKGROUND: Serum antibodies against p53 protein (p53-Abs) have been detected in some cancer patients. The significance and use of p53-Abs as a marker of the clinical behavior of lung cancer is currently under investigation. PURPOSE: In this study, we measured the serum p53-Abs in 84 patients with operable non-small cell lung cancer (NSCLC) and evaluated potential association between the presence of these antibodies and prognosis. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to detect p53-Abs in serum. Survival and disease-free survival curves related to initial p53-Abs status were estimated using the Kaplan-Meier method. RESULTS: At the time of diagnosis 19 (22.6%) of 84 analyzed patients had positive result from the serum p53 antibodies (p53-Abs) test. No association was found between p53-Abs, histological types of tumors and clinical stage of disease. We found that patients with a positive result from the p53-Abs test had lower probability of overall and disease-free survival. The unfavorable effect was significant both in the univariate analysis, as well as in the multivariate analysis (after adjustment for sex, histopathological type of tumor. TNM stage). CONCLUSION: The results of the present study indicate that serum p53 antibodies may be an independent prognostic factor in NSCLC, especially in the squamous cell carcinoma (SqCC) patients and may be useful in identifying resected lung cancer patients at high risk for treatment failure.     

The clinical relevance of Bcl-2, Rb and p53 expression in advanced non-small cell lung cancer

PURPOSE: The aim of this study was to evaluate the impact of Bcl-2, retinoblastoma (Rb) and p53 proteins on overall survival of 102 patients with locally advanced and metastatic NSCLC who underwent cisplatin-based chemotherapy. MATERIALS AND METHODS: Paraffin-embedded bronchial biopsy and fine-needle biopsy specimens were evaluated by an immunostaining method. RESULTS: Median age of analyzed patients was 61 years. Male/female ratio was 88/14. There were 10 (10%) patients with stage IIIA, 37 (36%) with stage IIIB and 55 (54%) with stage IV NSCLC. Only 15 (15%) tumor specimens had no detectable alterations for analyzed factors. Forty-six samples (45%) had positive immunostaining for p53, 61 (60%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for Bcl-2. Median and 5-year survival of analyzed population was 12 months and 6%, respectively. In univariate analysis Bcl-2 overexpression, stage (III versus IV) and normal lactate dehydrogenase (LDH) serum levels were associated with better overall survival (P<0.02, 0.001 and 0.03). In multivariate analysis, only stage was identified as an independent predictive factor. CONCLUSION: High frequency of Rb and Bcl-2 loss was detected in patients with advanced NSCLC. P53, Rb and Bcl-2 have not been shown to be independent predictors of survival even if Bcl-2 might have a particular relevance in patients with advanced NSCLC and should be better explored in this setting.     

p53 gene mutation and protein expression in operable non-small cell lung cancer in Poland.

We investigated the association of p53 abnormalities (gene mutations by DNA sequencing and protein over-expression by immunostaining) with clinical data and prognosis in 74 patients with resected non-small cell lung cancer (NSCLC). DNA analysis of exons 5-8 of the p53 gene showed 34 mutations in 74 resected primary NSCLC (45.9%). Immunohistochemical study of the p53 protein revealed that 41 of 74 (55.4%) samples had positive staining. We found strong agreement between the results of the p53 protein expression test (p53-PE) and the p53 gene mutation test (p53-M) (Cohen's kappa = 0.65, 95% CI 0.48-0.82). Joint distribution of the results (analysed using the bivariate Dale model) was mainly influenced by, histological type of tumour. A positive result for the p53-PE test significantly increased (estimated odds ratio 84.5; 95% CI 8.89-803.03) the odds of observing a positive result in the p53-M test. In the univariate analysis (log rank test), positive results in the p53-M test and the p53-PE test were significantly associated with overall survival (P < 0.001 and P = 0.005, respectively). In the multivariate analysis (Cox's proportional hazard model), a positive result for the p53-M test significantly increased relative risk for overall survival (RR 9.56; 95% CI 2.62-34.87; P < 0.001). When the result of the p53-M test was accounted for, a positive result for the p53-PE test did not offer any additional prognostic information due to the strong dependence of results of the tests. However, when the result of the p53-M test was removed from the model, a positive result for the p53-PE test became a significant unfavourable prognostic factor (P = 0.009). We conclude that p53 gene mutation and protein expression analyses are in a strong agreement. Joint distribution of the results depends mainly on histological type of tumour. When considered separately, both tests are unfavourable prognostic factors in NSCLC. When the result of the p53-M test is taken into account, the p53-PE test does not offer any additional prognostic information.     

p53和PCNA与非小细胞肺癌

p53基因和增殖细胞核抗原(PCNA)均与非小细胞肺癌(NSCIE)的放疗有密切关系.两者同时高表达的NSCLC患者的生存期低于同时阴性者.研究p53基因和PCNA在NSCLC中的表达,及其与NSCLC放射敏感性和预后的关系,可以对临床制定个体化治疗方案和提高疗效起到积极作用.     

Prognostic significance of p53 alterations in patients with non-small cell lung cancer: a meta-analysis.

There is great controversy as to whether alteration of the p53 gene adversely affects survival of non-small cell lung cancer patients. The aim of this study was to qualitatively review the association between p53 alterations and patient outcome by reviewing published papers. Forty-three articles were used. Survival difference was combined by use of the DerSimonian-Laird method. p53 alteration was either detected as overexpression by the protein studies or as mutation by the DNA studies. The incidence of p53 alteration in DNA studies (381 of 1031; 37%) was lower than that in protein studies (1725 of 3579; 48%; P < 0.0001, chi2 test). The incidence of p53 overexpression and mutation in adenocarcinoma (36 and 34%) was significantly lower than that in squamous cell carcinoma (54 and 52%; P < 0.0001). Combined survival differences at 5 years (survival in patients with alteration minus that in patients without alteration) by protein and DNA studies were -9.1% (P = 0.0091) and -22.0% (P = 0.0026), respectively. The negative prognostic effect of p53 alteration was highly significant in patients with adenocarcinoma [-21.8% at 5 years (P = 0.0000039) by protein studies and -48.0% (P = 0.000031) by DNA studies] but not in patients with squamous cell carcinoma [-15.6% (P = 0.4241) by protein studies and 2.0% (P = 0.8864) by DNA studies]. In the light of these results, p53 alteration was a significant marker of poor prognosis in patients with pulmonary adenocarcinoma. Whether p53 alteration also provides information that can alter treatment decisions should be asked in clinical trials.     

p53、p27、bcl-2在非小细胞肺癌中表达的研究

目的　研究p53、p2 7、bcl 2三种基因蛋白与非小细胞肺癌 (NSCLC)临床病理特征的关系。方法　应用S P免疫组化法检测 76例手术切除NSCLC标本中三种基因蛋白的表达。结果　 76例标本中 2 8例(36 .84% )p53过度表达 ,34例 (44.74% )p2 7过度表达 ,37例bcl 2过度表达 (48.68% ) ,7例患者p53、p2 7、bcl 2均过度表达。p53阳性表达率随分化程度降低而升高 ,bcl 2和p2 7阳性表达率随分化程度降低而降低 ,且高、低分化组间均有显著性差异 (P <0 .0 5)。但是三种蛋白阳性表达率均与肺癌组织学类型、淋巴结转移及病理分期无明显关系 (P >0 .0 5)。结论　p53、p2 7和bcl 2基因过度表达可能与NSCLC的发生、发展有关     

clusterin、Bax及p53在非小细胞肺癌中的表达及相关性研究

背景与目的已有的研究表明簇集蛋白(clusterin)是近年新发现的凋亡相关因子,在多种肿瘤中上调表达,在肿瘤的发生发展中起重要作用。clusterin的抗凋亡作用与其他抗凋亡因子有相关性。本文旨在探讨clusterin、Bax和p53在非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达情况及其与肺癌发生发展的关系。方法采用SP免疫组化方法和Western blot法,检测NSCLC组织中clusterin、Bax和p53的表达情况,并结合临床和病理资料进行分析。结果免疫组化显示clusterin在79.25%(42/53)的NSCLC组织中阳性表达。NSCLC组织中clusterin表达阳性率明显高于正常肺组织(χ2=23.68,P<0.05),与肿瘤的分化程度(rs=0.464,P<0.01)、临床分期(rs=0.320,P<0.01)及有无淋巴结转移(rs=0.255,P<0.05)呈正相关,但与年龄、性别及病理分型无关。clusterin与p53的表达呈正相关(rs=0.589,P<0.01),与Bax的表达呈负相关(rs=-0.346,P<0.01)。Western blot法显示clusterin在NSCLC组织中的表达水平明显高于正常肺组织(0.541±0.010比0.201±0.020,P<0.05)。结论clusterin可能通过抗凋亡机制在肺癌的生物学特性中发挥重要作用。     

Clinical relevance of galectin-1 expression in non-small cell lung cancer patients

Background

Identification of biomarkers in lung cancer, a leading cause of cancer-related mortality, has a meaningful clinical relevance in the quest of novel prognostic factors and therapeutic targets. The glycan-binding protein galectin-1 (Gal-1) modulates tumor progression by mediating cell–cell and cell–extracellular matrix interactions, as well as angiogenesis and tumor immune-escape. Previous works reported the expression of Gal-1 in lung cancer, although its clinical significance remains uncertain.

Objective

To assess the clinicopathologic relevance and prognostic value of Gal-1 expression in a cohort of 103 Stage I–III non-small cell lung cancer (NSCLC) patients.

Methods

Gal-1 expression was determined by immunohistochemistry in tumor tissue samples. The percentage of immunoreactive tumor cells and stroma, as well as the presence of blood vessels with positively stained endothelium in the tumor and surrounding normal tissue, were recorded. Results were correlated with the clinicopathologic factors of the patients (Spearman's rank correlation coefficient, chi-square test) and overall survival by univariate (Kaplan Meier) and multivariate analyses (Cox regression hazard model).

Results

We did not observe significant associations between Gal-1 expression and relevant clinicopathologic features at diagnosis of NSCLC. However, Kaplan Meier analysis revealed a significant association between Gal-1 expression and overall survival, when Gal-1 expression was analyzed on tumor cells alone (“tumor cell percentage”) or when an integrated score accounting for tumor cell as well as stromal expression of Gal-1 (“total score”) was assessed. Patients showing high Gal-1 expression evidenced a poorer clinical outcome. Furthermore, “total score” remained significantly associated with survival by multivariate Cox regression analysis in the whole cohort of patients, even when controlling for the classical predictors and prognostic factors of NSCLC.

Conclusion

We conclude that Gal-1 expression may be a useful biomarker for better prediction of the clinical outcome and management of NSCLC patients.     

Prognostic relevance of c-Myc and caspase-3 for patients with non-small cell lung cancer

This analysis attempted to ascertain whether combining the expression of c-Myc and caspase-3 can improve the available prognostic information for patients with non-small cell lung carcinomas. To this purpose, the expression of c-Myc and caspase-3 was determined in 128 cases of non-small cell lung carcinoma. The median survival time for patients with c-Myc-negative carcinomas was 89 weeks; it was only 43 weeks for patients with c-Myc-positive tumors (p=0.03). The estimated increased relative risk for patients with c-Myc-positive tumors was 1.6. The median survival time for patients with caspase-3-negative carcinomas was 41 weeks while patients with caspase-3-positive carcinomas survived for 79 weeks (p=0.06). The relative risk for patients with caspase-3-negative tumors was 1.5. A significant inverse relationship between the expression of c-Myc and caspase-3 was observed (p=0.04). To determine whether the combination of c-Myc and caspase-3 expression has a higher prognostic significance, patients were grouped based on their expressions of both variables. Patients with c-Myc-negative and caspase-3-positive tumors had the most favorable prognosis (102 weeks) while c-Myc-positive and caspase-3-negative carcinomas had the most unfavorable prognosis (22 weeks; p=0.01).     

Prognostic factors for patients in postoperative brain metastases from surgically resected non-small cell lung cancer

Background

Postoperative recurrence in non-small cell lung cancer (NSCLC) reduces the life expectancy of patients. In this retrospective study, we investigated the prognostic factors in patients with postoperative brain metastases from surgical resected non-small cell lung cancer (NSCLC).

Methods

We conducted a retrospective chart review of patients who had undergone resection for NSCLC between April 2004 and February 2009 and found 65 had experienced postoperative brain metastases by March 2010. We reviewed these patients for clinicopathological information, treatments and responses to treatment, and overall survival.

Results

The 5-year survival rate after the diagnosis of brain metastases was 15.4 %. Significantly favorable prognostic factors for patients after a diagnosis of brain metastases included female gender, adenocarcinoma, a small number (1–3) of brain metastases, no extracranial metastasis at the diagnosis of brain metastases, radiation treatment (whole-brain radiation and/or stereotactic irradiation), and local treatment [stereotactic irradiation and/or surgical operation (craniotomy)]. Furthermore, in patients with only brain metastases as the postoperative initial recurrence, the favorable positive prognostic factors included a small number (1–3) of brain metastases, adjuvant chemotherapy, chemotherapy (including adjuvant and other chemotherapy and excluding epidermal growth factor receptor–tyrosine kinase inhibitors), and local treatment.

Conclusions

Our study found that the foregoing clinical characteristics in postoperative brain metastases and the administration of treatment contributed to patient life expectancy.     

p53蛋白在非小细胞肺癌中的表达及意义

目的 :探讨非小细胞肺癌中p5 3蛋白的表达及意义。方法 :应用SP免疫组化法检测 5 2例肺癌组织中p5 3蛋白的表达。结果 :非小细胞肺癌中p5 3蛋白阳性表达率为 78 8% ,其中鳞癌与腺癌分别为 75 0 %和 82 1% ,p5 3蛋白阳性病人的预后较阴性者差。结论 :p5 3蛋白在非小细胞肺癌中有较高的表达 ,有可能作为评估预后、指导治疗的指标。