Loss of pRb2/p130 expression is associated with unfavorable clinical outcome in lung cancer.

Altered expression of cell cycle regulators represents a frequent event in both small cell and non-small cell lung cancer (NSCLC). Despite several studies that reported involvement of tumor suppressor genes, such as p53 and pRb, in the development and progression of lung cancer, contrasting opinions exist about the prognostic role of this protein in this neoplasm. We developed an immunohistochemical assay suitable for the detection of pRb2/p130, the last discovered member of the retinoblastoma gene family, on formalin-fixed and paraffin-embedded sections. We evaluated the immunohistochemical expression of pRb2/p130 in 135 lung cancer specimens, and performed Western blot analysis in a subset of 30 corresponding tumor lysates. A high correlation between immunohistochemical data and Western blot results (P = 0.0004) was found. We statistically analyzed the relationship between overall survival (OS) time and pRb2/p130 expression according to the different histological types in 105 patients. We did not find any correlation between pRb2/p130 expression and OS in small cell lung cancers, whereas in NSCLCs a direct relationship between pRb2 and OS was found in both adenocarcinoma (P = 0.0002) and squamous cell carcinoma (P = 0.0002) histotypes. According to univariate analysis, pRb2/p130 was a prognostic factor of which the lost or reduced expression correlated with a shorter OS (P < 0.0000). At multivariate analysis, pRb2/p130 expression was an independent predictor of OS (P = 0.0001) when considered together with histotype. This study demonstrates for the first time the potential independent prognostic value of pRb2/p130 expression on formalin-fixed, paraffin-embedded sections from lung cancer patients. pRb2/p130 immunoreactivity can be used to predict OS in patients with NSCLC and, therefore, may represent a new prognostic marker.     

pRb2/p130 protein expression is correlated with clinicopathologic findings in patients with oral squamous cell carcinoma

BACKGROUND: pRb2/p130 is one of the retinoblastoma (Rb) gene family and a suppressor oncogene. Immunohistochemically, the expression of pRb2/p130 was reported to be correlated inversely with the degree of malignancy in lung carcinoma and endometrial carcinoma. In the current study, the correlation between expression of pRb2/p130 and clinicopathologic factors in oral squamous cell carcinoma was investigated. METHODS: One hundred twenty-two specimens from patients with oral squamous cell carcinoma were investigated by staining with a polyclonal antibody against pRb2/p130. The correlation between the expression of pRb2/p130 and various clinicopathologic factors was studied. RESULTS: Positive staining for pRb2/p130 was observed in 61 of 122 cases (50.0%). pRb2/p130 expression was found to be correlated significantly with clinical stage (P = 0.050), cervical lymph node metastasis (P = 0.035), and tumor differentiation (P = 0.050). In the entire group a significantly reduced 5-year cumulative survival rate was observed in patients with pRb2/p130-negative tumors compared with patients whose tumors positively expressed pRb2/p130 (P = 0.0004). When tested with Cox proportional hazards regression analysis, the most significant independent prognostic factor for the entire group of 122 patients was found to be pRb2/p130 expression. CONCLUSIONS: Expression of pRb2/p130 may be a good prognostic indicator in patients with oral squamous cell carcinoma and also may be utilized for the subclassification of tumors with the Grade 3 mode of carcinoma invasion.     

Molecular prognostic factors in rectal cancer treated by preoperative chemoradiotherapy

The present study evaluated the expression of p53, pRb, hMLH1 and MDM2 prior to preoperative chemoradiotherapy (CRT) in patients with rectal cancer, and attempted to determine any correlation with treatment outcome. Forty-five patients with available pretreatment biopsy tissues and who received preoperative CRT were enrolled in this study. Preoperative CRT consisted of a median 50.4 Gy and 2 cycles of concurrent administration of 5-fluorouracil + leucovorin. Surgery was performed approximately seven weeks after CRT. Protein expression in formalin-fixed paraffin-embedded biopsy specimens was assessed by immunohistochemistry. A positive expression of p53, pRb, hMLH1 and MDM2 was found in 40, 46.7, 40 and 66.7% of the tissue specimens, respectively. The 5-year overall (OS), disease-free (DFS) and locoregional recurrence-free survival (LRFS) rates for patients included in the study were 71.3, 66.1 and 60.9%, respectively. p53 expression presented a significantly different OS (positive vs. negative, 45.8 vs. 86.2%; p=0.02). However, the expression of pRb, hMLH1 and MDM2 was not significant for OS. The expression of p53 was a borderline significant prognostic factor for DFS and for LRFS. Age, p53 and MDM2 expression were significant factors in the multivariate analysis performed for OS with 12 covariates, including 8 clinicopathological parameters and 4 proteins. No significant factor affected DFS or LRFS in the multivariate analysis. We suggest that the expression of p53 is a potential marker of survival. Determinations of this protein expression may be useful for selecting candidates from rectal cancer patients for more tailored treatment.     

Prognostic relevance of altered pRb and p53 protein expression in surgically treated non-small cell lung cancer patients

OBJECTIVE: The prognostic value of pRb and p53 altered expression in non-small cell lung cancer (NSCLC) remains debatable. We assessed the occurrence of altered pRb and p53 protein expression, and the prognostic value of these assays considered as separate and combined variables in operable NSCLC. The study group included 195 NSCLC consecutive patients from one institution who underwent curative pulmonary resection between 1994 and 1999. METHODS: Expression of pRb and p53 was assessed immunohistochemically with the use of monoclonal antibodies (LM95.1 and Pab 1801, Oncogene Science, respectively). RESULTS: A lack of pRb and abnormal p53 protein expression were found in 57 (29%) and 92 samples (47%), respectively, whereas both abnormalities (pRb-/p53+) occurred in 24 samples (12%). There was no relationship between altered pRb/p53 expression and major clinico-pathological characteristics, neither was there a significant difference in disease-free and overall survival between particular groups of patients with tumors carrying four possible pRb/p53 phenotypes. In uni- and multivariate analysis, the only variable associated with shortened disease-free and overall survival was stage of disease (p < 0.001) and degree of tumor differentiation (p = 0.005). CONCLUSION: These results suggest that altered pRb and p53 expression does not provide prognostic information in operable NSCLC patients.     

可溶性耐药相关钙结合蛋白在乳腺癌组织中的表达及其与预后关系

目的:探讨可溶性耐药相关钙结合蛋白(Soluble resistance-related calcium binding protein,Sorcin)在乳腺癌组织中的表达,评估其在乳腺癌预后中的作用.方法:采用免疫组织化学方法(IHC)检测60例手术切除的乳腺癌组织中Sorcin的表达,并分析其与临床、病理特征的关系及对预后的影响.结果:1)Sorcin在乳腺癌组织中的阳性表达率为56.7%(34/60);2)Sorcin与月经状况、肿瘤大小、淋巴结转移、组织分级和激素受体状况均无明显差异(P>0.05);3)Kaplan-Meier生存分析结果表明Sorcin表达与无瘤生存期和总生存期均无明显差异(P＞0.05);4)COX单因素分析和多因素分析显示肿瘤大小、淋巴结转移和ER与无瘤生存期及总生存期(P<0.05)明显相关,PR与总生存期(P<0.05)明显相关.结论:Sorcin在乳腺癌组织中具有高表达,与乳腺癌的无瘤生存期和总生存期皆无明显差异.     

胶质瘤中MicroRNA-184的表达及其预后价值

目的 研究人脑胶质瘤石蜡包埋组织（formalin-fixed paraffin-embedded, FFPE）中微小RNA-184（microRNA-184, miR-184）的表达及其与临床病理特征之间的关系,探讨其在预测胶质瘤患者预后中的价值。方法 采用微阵列芯片法和RT-PCR检测108例胶质瘤FFPE和32例正常脑组织中的miR-184表达,同时Kaplan-Meier法分析胶质瘤患者总生存期和无病生存期情况。结果 胶质瘤组织中miR-184的表达下调,并用RT-PCR进一步验证; miR-184低表达与WHO分级（P=0.007）、Karnofsky 评分（KPS）（P=0.029）、复发时间（P=0.037）和生存时间（P=0.019）显著相关;Kaplan-Meier 分析结果表明,miR-184低表达与高表达患者总生存期（OS）（P=0.001）和无病生存期（DFS）（P=0.006）差异有统计学意义,miR-184低表达患者预后较差。多因素分析显示胶质瘤中miR-184的差异表达是预测OS[风险比（HR）：7.52;95％CI：2.63~21.42;P=0.002]和DFS[HR：11.56;95％CI：5.17~25.93;P<0.001]的独立危险因素。结论 miR-184的表达与胶质瘤患者预后显著相关,表明miR-184可作为预测胶质瘤患者预后的独立标志物。     

P型铜转运ATP酶(ATP7B)在乳腺癌组织中的表达及与预后的关系

目的研究P型铜转运ATP酶(Copper-transporting P-type adenosine triphosphatese,ATP7B)在乳腺癌组织中的表达,评估其在乳腺癌预后中的作用.方法采用免疫组织化学方法(Immunohistochemistry,IHC)检测47例手术切除的乳腺癌组织中ATP7B的表达,并分析其与临床、病理特征的关系及对预后的影响.结果 (1)ATP7B在乳腺癌组织中的阳性表达率为34.0%(16/47例);(2)组织学分级低分化者ATP7B表达水平明显高于组织学分级中高分化患者(P＜0.05),ATP7B表达与月经状况、肿瘤大小、腋淋巴结转移和激素受体状况均无关(P＞0.05);(3)Kaplan-Meier生存分析结果表明ATP7B与无病生存期和总生存期均密切相关(P＜0.05);(4)在COX多因素分析中ATP7B表达、肿瘤大小、腋淋巴结转移和组织学分级与无病生存期和总生存期均明显相关(P＜0.01).结论 ATP7B在乳腺癌组织中具有一定的表达水平,可能是预测乳腺癌患者预后的独立因素.     

p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue.

PURPOSE: The INK4A-ARF locus at chromosome 9p21 is frequently altered in head and neck squamous cell carcinoma (SCC) and encodes two distinct tumor suppressors, p16(INK4A) and p14(ARF). This study addressed the role of p14(ARF) as a potential prognostic marker in this disease. EXPERIMENTAL DESIGN: p14(ARF) protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Cox's proportional hazards models, the outcomes examined were time to disease recurrence or death, with or without clinicopathologic covariates, including nodal status, disease stage, treatment status, Ki-67 staining, and molecular markers with known functional or genetic relationships with p14(ARF) (p16(INK4A), p53, pRb, p21(WAF1/CIP1), E2F-1). RESULTS: On multivariate analysis, p14(ARF) positivity (nucleolar p14(ARF) staining and/or nuclear p14(ARF) staining in >/=30% of tumor cells) was an independent predictor of improved disease-free survival (DFS; P = 0.002) and overall survival (OS; P = 0.002). This was further enhanced when p14(ARF) positivity was cosegregated with positive (>/=1%) p16(INK4A) staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14(ARF) negative and p53 positive (>50%) had the poorest outcome (DFS, P < 0.001; OS, P < 0.001) of any patient subgroup analyzed. CONCLUSIONS: These data show that in patients with SCC of the tongue, combined nuclear and nucleolar expression of p14(ARF) protein predicts for improved DFS and OS independent of established prognostic markers.     

284例原发乳腺癌c-erbB2蛋白的表达及其与预后的关系

目的探讨c-erbB2癌蛋白在原发乳腺癌组织中的表达情况及其与预后的关系。方法采用免疫组化SP法检测284例原发乳腺癌组织的c-erbB2表达,并用统计学分析其与预后的关系。结果284例原发乳腺癌c-erbB2的阳性表达率为26．8％（76／284）,其表达与淋巴结转移数目（P=0．003）密切相关。单因素分析表明,c-erbB2是总生存时间（OS,P=0．002）和无病生存时间（DFS,P=0．024）的重要预后因素;多因素分析表明,c-erbB2是影响Os（P=0．023）的独立预后因素。此外,c-erbB2阳性的肿瘤患者较阴性者更易于发生内脏转移。而对于不同的淋巴结转移和ER状态,c-erbB2也有不同的预后价值。结论c-erbB2是影响原发乳腺癌患者OS的独立因素;在不同的淋巴结转移和ER状态下,其预后价值不同。     

p-糖蛋白(pgp)在乳腺癌组织中的表达及与预后的关系

目的：研究P－糖蛋白（P－glycoprotein,Pgp)在乳腺癌组织中的表达,评估其在乳腺癌预后中的作用。方法：采用免疫组织化学方法（Immunohistochemistry,IHC)检测47例手术切除的乳腺癌组织中Pgp的表达,并分析其与临床、病理特征的关系及对预的的影响。结果：Pgp在乳腺癌组织中的总表达率为83．0％（39／47例）,高表达者占53．2％（25／47例）,其与月经状、肿瘤大小、淋巴结转移、组织分级和激素受体状况均无关（P＞0．05）;Kaplan-Meier生存分析结果表明Pgp表达与无病生存期和总生存期均显著相关（P＜0．01）,而多因素Cox分析却显著仅有Pgp和淋巴结转移是独立的预后因素,结论：Pgp在乳腺癌组织中具有较高的表达,有可能成为判断乳腺癌预后的有用指标。     

多药耐药性相关蛋白在乳腺癌组织中的表达及其与预后关系

目的:研究多药耐药相关蛋白（Multidrug　resistance-associated　protein　1,MRP1）在乳腺癌组织中的表达,评估其在乳腺癌预后中的作用。方法:采用免疫组织化学方法（IHC）检测47例手术切除的乳腺癌组织中MRP1的表达,并分析其与临床、病理特征的关系及对预后的影响。结果:（1）MRP1在乳腺癌组织中的阳性表达率为85.1％（40/47例）,其中高表达者占53.2％（25/47例）;（2）腋淋巴结阳性者MRP1表达水平明显高于腋淋巴结阴性者（P<0.05）,MRP1表达与月经状况、肿瘤大小、组织分级和激素受体状况均无关（P>0.05）;（3）Kaplan-Meier生存分析结果表明MRP1表达与无病生存期明显相关（P<0.05）,但和总生存期无关（P>0.05）;（4）Cox单因素分析显示肿瘤大小和MRP1表达与无病生存期明显相关（P<0.05）,但仅有肿瘤大小和总生存期明显相关（P<0.05）;而多因素分析却显示只有腋淋巴结转移和无病生存期（P<0.01）和总生存期（P<0.05）明显相关。结论:MRP1在乳腺癌组织中具有较高的表达水平,与乳腺癌患者的无病生存期有关,而与总生存期无关。     

Low BAX protein expression correlates with disease recurrence in preoperatively irradiated rectal carcinoma

PURPOSE: To determine the prognostic impact of BAX in correlation to its upstream effector p53 as well as clinicopathologic variables and patient outcome in preoperatively irradiated rectal carcinoma. METHODS AND MATERIALS: We investigated 92 rectal carcinoma patients treated by preoperative radiotherapy to a total dose of 30 Gy followed by surgery. Median follow-up was 71 months. Immunohistochemistry was performed on paraffin sections of pretreatment biopsy samples for BAX protein. Also, we considered the previously determined p53 expression data from this cohort. RESULTS: BAX protein expression was classified as high and low in 63 (68.5%) and 29 (31.5%) tumors, respectively. Unlike clinicopathologic variables, high BAX expression was significantly associated with improved disease-free survival by univariate analysis (p = 0.048). Moreover, in multivariate analyses, high BAX expression was an independent prognostic indicator for both improved local recurrence-free interval and improved disease-free survival (p = 0.03 and 0.047, respectively). Concerning the p53/BAX pathway, subgroup analysis yielded no association between p53 immunonegative/BAX high vs. p53 immunopositive/BAX low expressing tumors with regard to overall, disease-free, or local recurrence-free survival in either univariate (p = 0.88, 0.54, and 0.16, respectively) or multivariate analysis. CONCLUSIONS: This study demonstrates that BAX protein expression might help to predict disease recurrence in preoperatively irradiated rectal carcinoma, whereas determination of p53, the proposed upstream regulator of BAX-induced apoptosis, did not provide additional prognostic information.     

Proapoptotic Bad and Bid protein expression predict survival in stages II and III colon cancers.

PURPOSE: Proapoptotic BH3-only proteins Bad and Bid initiate apoptosis by binding to regulatory sites on prosurvival Bcl-2 proteins to directly neutralize their function. We determined if expression of these proteins in colon cancers may account for differences in patient survival. EXPERIMENTAL DESIGN: Tumor-node-metastasis stages II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bad and Bid proteins was done in tumors (n = 379) and adjacent normal mucosa. Expression was correlated with clinicopathologic variables, disease-free survival rates (DFS), and overall survival (OS) rates. RESULTS: High expression of the Bad protein [hazard ratio (HR), 0.64; 95% confidence interval (95% CI), 0.43-0.96; P = 0.031] in the cytoplasm of tumor cells was significantly associated with more favorable OS in a univariate analysis. The combined Bad and Bid variable was prognostic for DFS (P = 0.027) and OS (P = 0.006). Stage and histologic grade, but not DNA mismatch repair status, were also prognostic for OS. Multivariate Cox analysis showed that high expression of Bad (HR, 0.64; 95% CI, 0.43-0.97; P = 0.027) and Bid (HR, 0.68; 95% CI, 0.49-0.97; P = 0.034) were independent predictors of OS after adjustment for stage, grade, age, treatment, and study. The combined variable of Bad + Bid was independently associated with DFS (P = 0.020) and OS (P = 0.004). CONCLUSION: Proapoptotic Bad and Bid proteins are independent prognostic variables in colon cancer patients receiving adjuvant treatment. If validated, Bad and Bid expression may assist in risk stratification and selection of patients to receive adjuvant chemotherapy.     

p53 and Bcl-2 as significant predictors of recurrence and survival in rectal cancer

The aim of this study was to evaluate the prognostic value of p53 nuclear accumulation and Bcl-2 expression after curative surgery for rectal cancer. Immunohistochemistry was performed using monoclonal antibodies (MAb) (DO-1 for p53; anti-human Bcl-2 MAb, clone 124, for Bcl-2) on formalin-fixed, paraffin-embedded tissues of 160 rectal carcinomas (UICC stages I-III), and results were compared with data from the prospective registry of rectal cancer by univariate and multivariate logistic regression model focusing specifically on recurrence. Survival was calculated by the Kaplan-Meier method and proportional hazards model. p53 nuclear accumulation was documented in 39% (n=63) of tumours and was associated with a higher incidence of tumour progression (local or distant recurrence) and poorer disease-free survival (P<0.0001). Bcl-2 expression was detected in 29% (n=47), and was associated with longer disease-free survival and lower incidence of recurrence (P<0.0086). Multivariate logistic regression analysis demonstrated that gender (P=0.0136), UICC stage (P=0.0002), p53 expression (P=0.0002) and Bcl-2 expression (P=0. 0243) were independent factors predictive of recurrence. The proportional hazards model identified p53 (P=0.0009), UICC stage (P=0.0480), gender (P=0.0049), but not Bcl-2 (P=0.1503), as independently related to disease-free survival. Looking at the p53/Bcl-2 subgroups, the poorest prognosis was observed in the p53+/Bcl-2- subgroup, whereas patients whose tumours were p53-/Bcl-2+ had the best prognosis (P<0.0001). Immunohistochemical assessment of both p53 and Bcl-2 status may be valuable in predicting recurrence and survival after curative surgery for rectal cancer. Therefore, they play a role as prognostic factors in rectal cancer. p53 is a stronger predictor of prognosis than Bcl-2.     

Prognostic impact of bim, puma, and noxa expression in human colon carcinomas

PURPOSE: Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurrence and survival rates. EXPERIMENTAL DESIGN: Archival tumor-node-metastasis stage II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bim, Puma, and Noxa proteins was done using tissue microarrays (n = 431). Immunoscores were determined and correlated with clinicopathologic variables and disease-free survival (DFS) and overall survival (OS) rates. RESULTS: Elevated expression of proapoptotic Bim (hazard ratio, 0.65; 95% confidence interval, 0.44-0.97; P = 0.033) and Puma (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.022), but not Noxa, proteins in the tumor cytoplasm was significantly associated with more favorable OS in a univariate analysis, and elevated Bim expression was also associated with better DFS (P = 0.023). Patient age, tumor stage, and histologic grade were also prognostic. Multivariate Cox analysis showed that Bim (DFS, P = 0.030; OS, P = 0.045) and Puma (OS, P = 0.037) expression were independent predictors of OS after adjustment for histologic grade, tumor stage, age, and treatment. Furthermore, the combined variable of Bim and Puma was highly discriminant for both DFS (P = 0.0034) and OS (P = 0.0011). CONCLUSIONS: The proapoptotic BH3-only proteins Bim and Puma can provide prognostic information for stage II and III colon cancer patients receiving 5-fluorouracil-based adjuvant chemotherapy. Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs.     

pRb2/p130, vascular endothelial growth factor, p27(KIP1), and proliferating cell nuclear antigen expression in hepatocellular carcinoma: their clinical significance.

Hepatocarcinoma (HCC) is the fifth most common cancer, with more than one million fatalities occurring annually worldwide. Multiple risk factors are associated with HCC disease etiology, the highest incidence being in patients with chronic hepatitis B virus and hepatitis C virus, although other factors such as genetic makeup and environmental exposure are involved. Multiple genetic alterations including the activation of oncogenes and inactivation of tumor suppressor genes are required for malignancy in human cancers and are correlated with increased stages of carcinogenesis and further tumor progression. In this study of 21 HCC patients, we analyzed pRb2/p130, vascular endothelial growth factor (VEGF), p27((KIP1)), and proliferating cell nuclear antigen as potential HCC molecular biomarkers. In our sample set, we found that p27((KIP1)) was absent. Univariate survival analysis showed that proliferating cell nuclear antigen expression (diffuse staining >50% of positive cells in tumor) was confirmed as a significant HCC prognostic biomarker for determining patient survival agreeing with previous studies (P = 0.0126, log-rank test). Lower pRb2/p130 expression was associated to a borderline P value of inverse correlation with tumor malignancy and to a positive correlation with respect to the time from HCC diagnosis (Spearman coefficient = 0.568; P < 0.05). Conversely, higher VEGF expression was associated with a poor survival (P = 0.0257, log-rank test). We demonstrate for the first time that pRb2/p130 is inversely correlated with VEGF expression and tumor aggressiveness (P < 0.05) in p27((KIP1))-negative HCC patients. pRb2/p130 and VEGF expression are independent from tumor staging, suggesting their possible role as independent prognostic molecular biomarkers in HCC. Furthermore, we have evidence that VEGF together with pRb2/p130 may act as new HCC biomarkers in a p27((KIP1))-independent manner. Additional studies with larger numbers of patient data would allow the use of multivariable techniques and would be able to further identify patients with poorer survival.     

PARP-1在舌鳞癌组织中的表达及意义

目的检测PARP-1在舌鳞癌中的表达水平,分析与舌鳞癌患者临床病理因素及预后的相关性,初步探讨PARP-1在舌鳞癌的预后价值。方法采用免疫组织化学法检测155例舌鳞癌组织及13例邻近正常舌组织的石蜡组织切片中PARP-1的表达水平,分析PARP-1的表达水平与舌鳞癌患者的临床病理因素及预后的相关性。结果155例舌鳞癌组织中,PARP-1阳性表达率为89.0%(138/155),其中58.1%(90/155)呈高表达,41.9%(65/155)呈低表达;13例邻近正常舌组织均无PARP-1表达,两者比较差异有统计学意义(χ²=64.815,P=0.000)。PARP-1的表达水平与患者的T分期(χ² =10.841,P=0.002)、N分期(χ²=8.962,P=0.007)、病理分期(χ²=17.151,P=0.000)呈正相关。PARP-1高表达者总生存时间(P=0.037)与无瘤生存时间(P=0.026)比低表达者短。结论PARP-1可能是促进舌鳞癌发生发展的癌基因,具有预测舌鳞癌预后的临床价值。     

Prognostic significance of sphingosine kinase 2 expression in non-small cell lung cancer

Sphingosine kinase 2 (SphK2) as a conserved lipid kinase has not been thoroughly elucidated in non-small cell lung cancer (NSCLC). The aim of the present study was to evaluate the expression of SphK2 in NSCLC tissues and to determine its correlation with clinicopathologic characteristics and its impact on patient prognosis. We assessed the expression of SphK2 and proliferating cell nuclear antigen (PCNA) (as a proliferative index) by immunohistochemistry in 180 NSCLC patient's formalin-fixed paraffin-embedded tissue blocks. Relationship between the expression of SphK2 and PCNA and various clinicopathological features in these patients was evaluated. We detected that expression of SphK2 was gradually upregulated from normal, metaplasia/dysplasia tissues to NSCLC tissues. At the same time, PCNA expression followed a similar pattern. Statistical analysis showed that expression of SphK2 in NSCLC tissues was strongly associated with PCNA expression, histology grade, live vaccine strain invasion, lymph node status, clinical stage, tumors size, and histology type. Patients with SphK2 overexpression in their tissues had lower overall survival (OS) and disease-free survival (DFS) rates than those with low SphK2 expression. Using uni- and multivariate analysis, we found that SphK2 overexpression was an independent prognostic factor for both OS and DFS. The expression of SphK2 parallels the progression of NSCLC, and SphK2 overexpression may represent a novel and potentially independent biomarker for the prognosis of patients with NSCLC.     

Prognostic significance of clinical parameters and biological markers in patients with squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy.

Concurrent chemoradiotherapy is reported to have a fair clinical outcome with organ preservation for patients with squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to determine whether biological markers are related to proliferative activity or apoptosis of tumor cells and whether clinical factors are associated with a clinical outcome in SCCHN patients treated with concurrent chemoradiotherapy. Immunostaining with antibodies specific for p53, bcl-2, bax, and MIB-1 was performed to evaluate expression of these proteins in formalin-fixed, paraffin-embedded specimens of 111 SCCHN patients treated with concurrent chemoradiotherapy (carboplatin, 100 mg/m2, four to six times every week; total radiation therapy dose of 40-65 Gy over 4-6.5 weeks). Multivariate analysis indicated that nodal status was a significant indicator of overall survival (OS; P = 0.001) and locoregional control (LRC; P = 0.002). In a univariate analysis, patients with a low MIB-1-positive index (< 40%) had better OS than those with a high MIB-1-positive index (> or = 40%; P = 0.013), although the difference was not statistically significant in a multivariate analysis (P = 0.060). Patients with bcl-2-positive tumors had better LRC than those with bcl-2-negative tumors, based on a multivariate analysis (P = 0.017). No statistically significant association was found between p53 or bax expression and clinical outcome. These results indicate that nodal status is the major prognostic factor in SCCHN patients treated with concurrent chemoradiotherapy. In addition, our findings suggest that bcl-2 positivity is associated with better LRC and that the proliferative activity of tumor cells might be prognostic for OS.     

Expression of cell-cycle-regulated proteins pRb2/p130, p107, p27(kip1), p53, mdm-2, and Ki-67 (MIB-1) in prostatic gland adenocarcinoma.

PURPOSE: The quest for prognostic molecular markers in prostatic carcinoma is still in progress. Many proteins have already been screened by immunohistochemistry with the aim to find the most reliable indicator of progressive disease. In this study, we evaluated the expression of pRb2/p130, p107, p27(kip1), p53, mdm-2, and Ki-67 (MIB-1) by immunohistochemistry in 24 prostate carcinomas compared with the paired expression of normal prostates. EXPERIMENTAL DESIGN: Expression of the different proteins in normal and pathological specimens was evaluated by the Wilcoxon test. A matrix of correlation (Spearman coefficient) was used to evaluate the possible association in expression among the different proteins. Logistic regression analysis was used to test the multivariable prognostic value of the levels of protein expression for the probability of disease development. RESULTS: p53 and Ki-67 (MIB-1) showed a higher expression in cancer than in normal tissue (P = 0.006 and <0.001, respectively). pRb2/p130, p107, and p27(kip1) showed an overall lower expression in cancer, but the difference between cytoplasmic and nuclear expression was always higher for cancer (Ps, from <0.001 to 0.016). mdm-2 expression was lower in cancer, but the difference between cytoplasmic and nuclear expression was not significant (P = 0.571) when compared with that in normal tissue. A positive correlation between p27 and pRb2/p130 levels expressed, in normal and cancer counterparts in the same sample, as the difference between cytoplasmic and nuclear protein concentrations (P = 0.045) was found. Additionally, p107 expression showed an inverse correlation with Ki-67 (MIB-1) expression in the most aggressive tumors (P = 0.046). Logistic regression output showed that Ki-67 (MIB-1) and pRb2/p130 (expressed as differences between cytoplasmic and nuclear concentrations) were the variables associated with a higher risk of cancer. The highest value was reported for Ki-67 (MIB-1) (odds ratio, 2.11), followed by pRb2/p130 (odds ratio, 1.01). pRb2/p130 alone was associated with a sensitivity (rate of cases having a posterior probability of disease >/=0.5) of 61% with a false positive rate of 22%. Ki-67 (MIB-1) alone yielded a sensitivity of 69% and a false positive rate of 14%. The combined model (Ki-67 + pRb2/p130) yielded a sensitivity of 83% with a false positive rate of 17%. Interestingly, one specimen in which we also found a high-grade prostatic intraepithelial neoplasia showed the progressive loss of pRb2/p130 from normal prostatic cells to prostatic intraepithelial neoplasia cells, suggesting that in prostatic cancer, lack of expression of the tumor suppressor gene pRb2/p130 could be involved in the progression of the disease, from an early stage. CONCLUSIONS: This study showed that all of the proteins but mdm-2 were expressed at a different rate in normal and pathological prostate specimens. Multivariate analysis showed that pRb2/p130 and p107 may be involved in the pathogenesis and progression of prostate cancers, and that the expression of the retinoblastoma-related protein pRb2/p130 along with Ki-67 (MIB-1), expressed as differences between cytoplasmic and nuclear concentrations, could be considered new parameters to be evaluated in discriminating patients at a higher risk for prostate cancer.