p63 expression as a new prognostic marker in Merkel cell carcinoma

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin tumor, mostly affecting elderly individuals. The histogenesis of this rare tumor as well as its prognostic criteria are a matter of dispute. METHODS: An immunohistochemical analysis of markers of proliferation (Ki-67/MIB-1), neuroendocrine differentiation (chromogranin A and synaptophysin), and basal cell differentiation (p63) was performed in a series of 47 cases of MCC. The significance of pathologic data and of immunoreactivity with different markers was evaluated using the chi-square test. Survival curves were calculated using the Kaplan-Meyer method. The survival difference was estimated using the Wilcoxon or Mantel-Cox test. RESULTS: Immunohistochemical evidence of neuroendocrine differentiation and immunopositivity for cytokeratin 20 were observed in all cases, whereas positivity for p63 was detected in approximately half of the cases (25 of 47 cases; 53.2%). Cases that were positive for p63 demonstrated a more aggressive clinical course than those that were negative (Z value of 2.93; P = .0003; hazards ratio of 22.22). CONCLUSIONS: Data from the current study indicate that p63 expression is associated with a worse prognosis in patients with MCC and represents a new independent marker of clinical evolution.     

Histologic coagulative tumor necrosis as a prognostic indicator of renal cell carcinoma aggressiveness

BACKGROUND: Prognostic markers for renal cell carcinoma (RCC), such as patient symptoms, tumor stage, tumor size, and tumor grade, are useful for determining appropriate follow-up and selecting patients for adjuvant therapy. Histologic coagulative tumor necrosis, also reported to be a prognostic marker for RCC, has not previously been extensively described or investigated. Hence, the objective of the current study was to characterize tumor necrosis as a prognostic feature of RCC. METHODS: The authors of the current study identified 3009 patients treated surgically for RCC between 1970 and 2002 from the Mayo Clinic Nephrectomy Registry (Rochester, MN). Associations of tumor necrosis with clinical, laboratory, and pathologic features were examined with chi-square, Fisher exact test, and Wilcoxon rank-sum tests. Cancer-specific survival was estimated with the Kaplan-Meier method, and associations with outcome were assessed with Cox proportional hazard models. RESULTS: Tumor necrosis was present in 690 of 2445 (28%) clear cell, 196 of 421 (47%) papillary, and 28 of 143 (20%) chromophobe RCCs. The risk ratio for death from RCC in patients with necrotic compared with non-necrotic tumors was 5.27 (95% confidence interval [CI]: 4.56-6.09; P < 0.001) for clear cell, 4.20 (CI: 1.65-10.68; P < 0.001) for chromophobe, and 1.49 (CI: 0.81-2.74; P = 0.199) for papillary RCC. The survival difference for clear cell RCC persisted even after multivariate adjustment for tumor stage, size, and grade (risk ratio 1.90; P < 0.001). CONCLUSIONS: Histologic coagulative tumor necrosis is an independent predictor of outcome for clear cell and chromophobe RCC, and it should be routinely reported and used in clinical assessment.     

Validation of CRP as prognostic marker for renal cell carcinoma in a large series of patients

ABSTRACT: BACKGROUND: To evaluated the prognostic significance of the pre-operative C-reactive protein (CRP) serum level in patients with renal cell cancer (RCC). METHODS: We evaluated 1,161 RCC patients with complete patient and tumour specific characteristics as well as information about their pre-operative CRP-level, who had undergone either radical nephrectomy or nephron-sparing surgery at two German high-volume centres (University Hospitals of Hannover and Ulm). The mean follow-up was 54 months. RESULTS: The CRP-level, stratified to three subgroups (CRP <= 4, 4--10, and >10 mg/l), correlated significantly with tumour stage (p < 0.001), the risk of presenting nodal disease (2.1, 3.1, and 16.4%) and distant metastasis (2.9, 8.6, and 30.0%; p < 0.001). The Kaplan-Meier 5-year cancer specific survival (CSS) rates were 89.4, 77.9, and 49.5%, respectively (p < 0.001). Multivariate analysis identified CRP as an independent prognosticator for CSS as well as overall survival (p < 0.001). Patients with a CRP of 4--10 and >10 mg/l had a 1.67 and 2.48 fold higher risk of dying due to their RCC compared to those with a pre-operative CRP <=4 mg/l, respectively. CONCLUSIONS: A high preoperative serum CRP level is an independent predictor of poor survival in patients with RCC. Its routine use could allow better risk stratification and risk-adjusted follow-up of RCC patients.     

肾透明细胞癌组织Fibulin-3表达及其临床意义

目的 探讨Fibulin-3在肾透明细胞癌(clear cell renal cell carcinoma,CCRCC)中的表达及其临床意义.方法 收集中山大学附属第一医院2000-04-01-2007-04-01手术切除并经病理确诊的157例CCRCC患者的石蜡标本及相关临床病理资料.其中男10例,女56例,平均年龄51.7岁.制作组织芯片,应用免疫组织化学方法检测Fibulin-3蛋白的表达情况,根据评分结果将RCC患者分为Fibulin-3高表达和低表达两组,并分析其与患者多种临床参数的相关性.结果 Fibulin-3在157例CCRCC组织中的阳性表达率为100.0％,高表达58例,低表达99例.Fibulin-3蛋白表达与CCRCC患者的性别、年龄、肿瘤大小、Fuhrman分级和组织学类型等临床病理参数无相关性,P＞0.05.Kaplan-Meier生存分析显示,Fibulin-3高表达与肾癌患者的预后相关,P=0.003;多因素Cox回归分析表明,Fibulin-3是CCRCC患者生存时间的独立影响因素,HR=2.30,95％CI为1.278～4.140,P=0.005.结论 Fibulin-3高表达与CCRCC患者的不良预后相关,提示Fibulin-3是预测CCRCC患者预后的潜在分子标志.     

Cytoplasmic expression of the ELAV-like protein HuR as a potential prognostic marker in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the most frequent cancers and a leading cause of death from cancer in China. The human ELAV-like protein HuR has been found to contribute to cancer development and progression through stabilizing a group of cellular mRNAs of cancer-related genes. In this study, we investigated the expression of HuR in a cohort of ESCC patients using immunohistochemical staining. HuR detected in the cytoplasm of cancer cells was positive in 46.6 % of 58 ESCC specimens; 75.9 % of these specimens had nuclear immunoreactivity for HuR. Cytoplasmic HuR expression was higher in cancer tissues compared to 20 matched adjacent noncancerous tissues. A clinicopathological study showed that cytoplasmic HuR expression was positively associated with lymph node metastasis, depth of tumor invasion, and advanced stage, whereas nuclear HuR expression was not correlated with any clinicopathological factors. Patients positive for cytoplasmic HuR expression had a cumulative 5-year survival rate of 25.3 %, whereas it was 43.8 % for patients negative for cytoplasmic HuR expression. In a multivariate analysis, cytoplasmic HuR expression was an independent prognostic factor, whereas nuclear positivity for HuR was not. Our results indicate that high cytoplasmic HuR expression is associated with positive lymph node metastasis, deep tumor invasion, high stage, and poor survival in ESCC. Thus, HuR is the first mRNA stability protein whose expression is associated with poor survival in esophageal cancer.     

Hepcidin as a prognostic biomarker in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is a common malignancy of urologic neoplasms. Hepcidin is a pivotal modulator of iron metabolism involved in human cancers; however, the biological significance of hepcidin in ccRCC remains to be fully understood. Therefore, in this study, we evaluated the expression profiles of hepcidin in ccRCC from several public databases and found that hepcidin expression was upregulated in ccRCC, which was further validated in ccRCC cell lines, clinical samples, and tissue microarray (TMA) quantitative real-time PCR and immunohistochemistry. In addition, we found that the expression level of hepcidin was correlated with the age, T stage and pathologic stage of patients. Furthermore, hepcidin promoter methylation was significantly associated with the worse poor clinical parameters of ccRCC patients, and hepcidin was an independent prognostic factor. Mechanistically, enrichment analysis revealed that hepcidin participated in the immune-related and metabolism-related pathways. Hepcidin was positively correlated with not only immune infiltration and immune checkpoints but also tumor mutation burden and cytotoxic T lymphocyte. Finally, we validated the positive correlation of hepcidin with the marker of macrophage (CD68) in the TMA. Our findings provide insights into understanding the function and its underlying mechanism of hepcidin in ccRCC and suggest that hepcidin might serve as a potential predictive biomarker of response to immunotherapy and the prognosis of patients with ccRCC.     

Cellular B-2 microglobulin expression as a prognostic indicator in renal cell carcinoma.

The expression of B-2 microglobulin (B-2M) on tumor cells and their normal cell counterparts in 39 patients with renal cell carcinoma was studied and correlated to tumor stage and survival. The median survival time of patients with localized disease (stage I) whose tumors expressed B-2M was 10.2 years while the median survival time for patients whose tumors did not express B-2M was only 3.6 years (p less than 0.001). For patients with more advanced disease (stages II, III, IV) whose tumors expressed B-2M, median survival time was 3.6 years compared to 2.0 years in patients whose tumors did not express B-2M, a non-significant difference. It is suggested that the tumor cell membrane expression of B-2M may serve as an indicator of good prognosis in early renal cell carcinoma.     

Tissue polypeptide specific antigen (TPS) as a tumor marker in renal cell carcinoma

Tissue polypeptide specific antigen (TPS) is a new tumor marker that indicates tumor proliferative rate rather than tumor burden. The purpose of this study was to assess the clinical value of TPS in patients with renal cell carcinoma (RCC). Serum levels of TPS were measured in 30 patients with locoregional and in 20 patients with advanced disease before and after therapy. The results showed that: (1) the detection sensitivity of TPS for RCC is 60.0%; (2) the detection sensitivity of TPS in advanced RCC (100.0%) was significantly higher than in locoregional RCC (33.3%); (3) the 10 locoregional RCC patients without recurrence had normal serum TPS levels during a follow-up period of 1 year; and (4) the 8 advanced RCC patients with good response during therapy had normal serum TPS levels, while 12 patients with poor disease had significantly elevated serum TPS levels during a follow-up period of 1 year. Our results suggest that TPS may have a potential clinical role as a valuable tumor marker for RCC, especially in advanced diseases and follow-up therapy response.     

Expression profile of N-cadherin differs from other classical cadherins as a prognostic marker in renal cell carcinoma

Renal cell carcinomas (RCCs) primarily express cadherin-6 and N-cadherin rather than E-cadherin, and the aberrant expression of cadherin-6 correlates with a poor prognosis in patients with E-cadherin-absent RCC. However, the role of N-cadherin in RCC has not yet been elucidated. In this study, we analyze the expression pattern of N-cadherin in surgical RCC specimens and discuss the function of N-cadherin in RCC together with a re-evaluation of our previous study. Forty-six surgically resected RCC specimens were used in this study. The expression and localization of E-cadherin and N-cadherin in surgical specimens were demonstrated by immunohistochemistry. Correlations between the expression pattern of each cadherin, pathological parameters and patient survival were analyzed. RCC specimens expressed N-cadherin as a normal pattern despite the elevation of tumor grade, and patients with N-cadherin-normal RCC had a poorer prognosis than those with N-cadherin-abnormal RCC. Since our previous study showed that N-cadherin only functioned in cell attachment when E-cadherin and cadherin-6 were impaired, N-cadherin plays a different role from E-cadherin or cadherin-6 in RCC and may be associated with the aggressiveness and malignant potential of RCC.     

External validation of IMP3 expression as an independent prognostic marker for metastatic progression and death for patients with clear cell renal cell carcinoma

BACKGROUND: High-quality external validation studies have recently been highlighted to be of paramount importance for proper translation of prognostic markers into the clinical setting. To that end, the authors examined associations of the insulin-like growth factor-II mRNA binding protein, IMP3, with clinical and pathologic features of clear cell renal cell carcinoma (ccRCC) in an independent cohort of patients to validate recent work showing IMP3 as a prognostic marker for RCC progression and death. METHODS: The authors studied 716 consecutive tumor specimens from patients treated with surgery at the study institution for unilateral, sporadic, noncystic ccRCC between 1990 and 1999. Tissues were stained and scored for IMP3 expression and these expression levels were correlated with clinical and pathologic features as well as clinical outcomes including progression to distant metastases and death from RCC. RESULTS: It was observed that 213 ccRCC specimens (29.8%) expressed tumor cell IMP3. IMP3 expression was associated with advanced stage and grade of primary tumors as well as other adverse features including coagulative tumor necrosis and sarcomatoid differentiation. After multivariate adjustment for ccRCC prognostic features, positive IMP3 expression was still found to be associated with a 42% increase in the risk of death from RCC (hazards ratio [HR], 1.42; P= .024). Among the subset of patients with clinically localized disease, positive IMP3 expression was associated with a nearly 5-fold increased risk of distant metastases (HR, 4.71; P< .001). CONCLUSIONS: Using a large and independent cohort of ccRCC patients, the authors confirmed that tumor cell IMP3 expression represents an independent predictor of aggressive ccRCC tumor behavior.     

Serum cell-free DNA in renal cell carcinoma: a diagnostic and prognostic marker

BACKGROUND:

Currently, there are no established diagnostic and prognostic serum markers for renal cell carcinoma (RCC). The objective of this study was to evaluate the putative significance of serum cell‐free DNA.

METHODS:

Preoperative serum samples from 200 consecutive patients with sporadic, solid renal tumors were analyzed (157 patients with RCC and 43 patients with benign renal tumors). Quantitative real‐time polymerase chain reaction was used to assess total cell‐free DNA (ring finger protein 185 [RNF185]) and CpG island methylation of Ras association domain family member 1A (RASSF1A) von Hippel‐Lindau (VHL), prostaglandin‐endoperoxidase synthase 2 (PTGS2), and P16 (cyclin‐dependent kinase inhibitor 2A). Associations with RCC, pathologic variables, and disease‐specific survival were evaluated.

RESULTS:

Total cell‐free DNA levels and CpG island methylation of RASSF1A and VHL were highly diagnostic for RCC with an area under the receiver operating characteristic curve of 0.755, 0.705, and 0.694, respectively. VHL methylation was detected more frequently in patients with clear cell RCC than in those with other subtypes (P = .007). Total cell‐free DNA levels were higher in patients with metastatic RCC (P < .001) and necrotic RCC (P = .003) and were associated with poorer disease‐specific survival (P < .001). In multivariate analysis, the tumor stage, size, grade, and necrosis (SSIGN) score (P < .001) and categorized total cell‐free DNA levels (P = .028) were retained as independent prognostic factors.

CONCLUSIONS:

The current results indicated that cell‐free DNA represents a novel serum‐based diagnostic and prognostic biomarker for RCC. Total serum cell‐free DNA levels and CpG island methylation of RASSF1A and VHL may be useful diagnostic biomarkers for RCC. VHL methylation of cell‐free DNA is suggestive of clear cell RCC. Total serum cell‐free DNA may be a useful prognostic biomarker that may assist in tailoring postoperative surveillance and therapy. External prospective validation of these data will be required. Cancer 2012;. © 2011 American Cancer Society.     

Nin one binding protein expression as a prognostic marker in prostate carcinoma

Background

To investigate the prognostic value of expression levels of nin one binding protein (Nob1) in prostate carcinoma.

Methods

Nob1 protein levels were evaluated by Western blot in samples from 40 prostate carcinomas and matched adjacent non-neoplastic prostate tissues. Nob1 expression was also assessed by immunohistochemistry in samples from 300 prostate carcinoma and matched adjacent non-neoplastic prostate tissues, as well as 20 benign prostatic hyperplasia samples. The findings were compared with clinical and pathologic parameters and patient outcome.

Results

Nob1 protein analysis showed significant differences between the prostate carcinomas and control groups tested. Immunohistochemical analysis showed that Nob1 positivity was higher in prostate carcinoma than that in paired adjacent non-cancerous tissues (58 vs 7 %, P < 0.001). Nob1 positivity was significantly associated with high Gleason scores and metastasis in patients. Nob1 expression was significantly associated with shorter biochemical recurrence-free survival (BCRFS). Multivariate analysis revealed that Nob1 is an independent marker for BCRFS.

Conclusions

These findings provide evidence that Nob1 is an indicator of poor prognosis in prostate carcinoma.     

c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma

BackgroundActivation of the c-Met pathway occurs in a range of malignancies, including papillary renal cell carcinoma (RCC). Its activity in clear cell RCC is less clear. We investigated c-Met expression and inhibition in a large cohort of RCC tumors and cell lines.Methodsc-Met protein expression was determined by automated quantitative analysis (AQUA) on a tissue microarray (TMA) constructed from 330 RCC tumors paired with adjacent normal renal tissue. c-Met expression and selective inhibition with SU11274 and ARQ 197 were studied in clear cell RCC cell lines.ResultsHigher c-Met expression was detected in all RCC subtypes than in the adjacent normal renal tissue (P < 0.0001). Expression was highest in papillary and sarcomatoid subtypes, and high-grade and stage tumors. Higher c-Met expression correlated with worse disease-specific survival [risk ratio = 1.36; 95% confidence interval (CI) 1.08–1.74; P = 0.0091] and was an independent predictor of survival, maintained in clear cell subset analyses. c-Met protein was activated in all cell lines, and proliferation (and colony formation) was blocked by SU11274 and ARQ 197.Conclusionsc-Met is associated with poor pathologic features and prognosis in RCC. c-Met inhibition demonstrates in vitro activity against clear cell RCC. Further study of ARQ 197 with appropriate biomarker studies in RCC is warranted.     

Pituitary tumor-transforming gene expression is a prognostic marker for tumor recurrence in squamous cell carcinoma of the head and neck

Background  

The proto-oncogene pituitary tumor-transforming gene (PTTG) has been shown to be abundantly overexpressed in a large variety of neoplasms likely promoting neo-vascularization and tumor invasiveness. In this study, we investigated a potential role for PTTG mRNA expression as a marker to evaluate the future clinical outcome of patients diagnosed with primary cancer of the head and neck.     

HuR expression is a marker of poor prognosis in renal cell carcinoma

The HuR protein is a nucleocytoplasmic protein which plays an important role in the regulation of mRNA stability, and dysregulation of its expression has been linked to carcinogenesis. We studied 152 patients with primary renal cell carcinoma (RCC) who underwent surgery for the removal of kidney tumours between 1990 and 1999. The mean follow-up was 90 months. The expression of HuR and cyclooxygenase-2 (COX-2) was determined by immunohistochemistry using monoclonal antibodies. The immunostaining results were associated with patient age, clinical stage, Fuhrman grade and patient outcome. Cytoplasmic expression of HuR and COX-2 was positive in 37 (25%) and 22 (15%) of the tumours, respectively. The expression of HuR was associated with stage. The expression of COX-2 was associated with stage and nuclear grade. The RCC-specific survival was reduced in patients whose tumours expressed HuR or COX-2. The hazard ratio (HR) of patients with HuR-expressing tumours was 2.18 (95% confidence interval (CI), 1.16–4.09; p?=?0.015) and the HR of patients with COX-2-expressing tumours was 2.29 (95% CI, 1.15–4.54; p?=?0.018). In the Cox regression analysis the only independent prognostic factor was stage (p?<?0.001). Treatment of an RCC cell line (769-P) with HuR-targeted small interfering RNA resulted in the reduced expression of HuR and COX-2. We conclude that cytoplasmic HuR expression is associated with reduced RCC-specific survival. The HuR protein regulates the expression of COX-2 in RCC cells, which is one potential mechanism of action for the HuR-associated aggressive behaviour of RCC.     

Identification of increased NBS1 expression as a prognostic marker of squamous cell carcinoma of the oral cavity

Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide; however, accurate molecular markers to predict its prognosis are still limited. We previously demonstrated that overexpression of the DNA double‐strand break repair protein NBS1 is a prognostic marker of advanced head and neck squamous cell carcinoma (HNSCC). Therefore, we aimed to investigate the feasibility of using NBS1 as a biomarker in OSCC. In this study, we enrolled 148 OSCC for immunohistochemical (IHC) and clinical analysis. Data from 58 advanced non‐oral‐cavity HNSCC (NO‐HNSCC) cases were also included for comparison due to the biological and clinical discrepancy between OSCC and HNSCC originated from the other sites (e.g. pharynx or larynx). First, we validated the NBS1 IHC results by real‐time RT‐PCR analysis, and an excellent correlation between the results of these two assays confirmed the reliability and robustness of IHC procedures and interpretation. NBS1 overexpression was an independent prognostic marker in both OSCC and NO‐HNSCC cases. In OSCC, the prognostic significance of NBS1 was shown regardless of T stage and lymph node status. Increased NBS1 expression correlated with advanced T stage and recurrence/metastasis. NBS1 overexpression correlated with the phosphorylation levels of Akt and its downstream target mammalian target of rapamycin (mTOR). These results clearly illustrate the expression profile of NBS1 in OSCC and NO‐HNSCC, and highlight the role of NBS1 in HNSCC irrespective of the primary sites. It also indicates the practicability of application of NBS1 as a marker in OSCC. (Cancer Sci 2010; 101: 1029–1037)     

Homeobox gene expression profile indicates HOXA5 as a candidate prognostic marker in oral squamous cell carcinoma

The search for molecular markers to improve diagnosis, individualize treatment and predict behavior of tumors has been the focus of several studies. This study aimed to analyze homeobox gene expression profile in oral squamous cell carcinoma (OSCC) as well as to investigate whether some of these genes are relevant molecular markers of prognosis and/or tumor aggressiveness. Homeobox gene expression levels were assessed by microarrays and qRT-PCR in OSCC tissues and adjacent non-cancerous matched tissues (margin), as well as in OSCC cell lines. Analysis of microarray data revealed the expression of 147 homeobox genes, including one set of six at least 2-fold up-regulated, and another set of 34 at least 2-fold down-regulated homeobox genes in OSCC. After qRT-PCR assays, the three most up-regulated homeobox genes (HOXA5, HOXD10 and HOXD11) revealed higher and statistically significant expression levels in OSCC samples when compared to margins. Patients presenting lower expression of HOXA5 had poorer prognosis compared to those with higher expression (P=0.03). Additionally, the status of HOXA5, HOXD10 and HOXD11 expression levels in OSCC cell lines also showed a significant up-regulation when compared to normal oral keratinocytes. Results confirm the presence of three significantly upregulated (>4-fold) homeobox genes (HOXA5, HOXD10 and HOXD11) in OSCC that may play a significant role in the pathogenesis of these tumors. Moreover, since lower levels of HOXA5 predict poor prognosis, this gene may be a novel candidate for development of therapeutic strategies in OSCC.     

CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma

CD47 inhibits phagocytosis and its overexpression is correlated with poor prognosis in patients with several types of cancer. It has also been reported that CD47 expression in multiple sclerosis is regulated by microRNAs. However, the regulatory mechanism of CD47 in cancer tissues has not been yet clarified. Re-analysis of a public microarray database revealed that miR-133a is downregulated in esophageal squamous cell carcinoma (ESCC). Moreover, in?silico algorithms predicted that miR-133a is a regulator of CD47. The purpose of this study was to clarify the clinical significance of CD47 and its regulatory mechanism by miR-133a in ESCC. Quantitative real-time RT-PCR was used to evaluate CD47 and miR-133a expression in 102 cases of curative resected ESCC and adjacent non-cancerous tissue. The regulation of CD47 by miR-133a was examined with precursor miR-133a-transfected cells. A mouse xenograft model was used to investigate the ability of miR-133a to suppress tumor progression. High expression levels of CD47 were associated with lymph node metastasis (P=0.049). Multivariate analysis showed that CD47 expression was an independent prognostic factor (P=0.045). miR-133a expression was significantly lower in cancer tissues compared to adjacent non-cancerous tissues (P<0.001). In?vitro assays showed that miR-133a is a direct regulator of CD47. miR?133a significantly inhibited tumorigenesis and growth in?vivo. CD47 expression is a novel prognostic marker in ESCC that is directly inhibited by the miR-133a tumor suppressor. This correlation could provide new insight into the mechanism of cancer progression and a promising candidate for target therapy in ESCC.