Clinicopathological Parameters Of Patients Research Articles

Cyclin D1 expression in prostate carcinoma.

The purpose of this study was to investigate the relationship between cyclin D1 expression and clinicopathological parameters in patients with prostate carcinoma. We assessed cyclin D1 expression by conventional immunohistochemistry in 85 patients who underwent radical prostatectomy for prostate carcinoma and 10 normal prostate tissue samples retrieved from autopsies. We measured nuclear immunostaining in the entire tumor area and based the results on the percentage of positive tumor cells. The preoperative prostate-specific antigen (PSA) level was 8.68±5.16 ng/mL (mean±SD). Cyclin D1 staining was positive (cyclin D1 expression in >5% of tumor cells) in 64 cases (75.4%) and negative (cyclin D1 expression in ≤5% of tumor cells) in 21 cases (including 15 cases with no immunostaining). Normal prostate tissues were negative for cyclin D1. Among patients with a high-grade Gleason score (≥7), 86% of patients demonstrated cyclin D1 immunostaining of >5% (P<0.05). In the crude analysis of cyclin D1 expression, the high-grade Gleason score group showed a mean expression of 39.6%, compared to 26.9% in the low-grade Gleason score group (P<0.05). Perineural invasion tended to be associated with cyclin D1 expression (P=0.07), whereas cyclin D1 expression was not associated with PSA levels or other parameters. Our results suggest that high cyclin D1 expression could be a potential marker for tumor aggressiveness.

Role of serum carcinoembryonic antigen (CEA) as a tumor marker in breast cancer

Background: There is a need for biological prognostic indicators in breast cancer that would, alone or in combination with others, be sufficient to predict disease recurrence and, hence, be the basis for supplemental treatment after local therapy. Aims: To investigate the association between tumor marker serum carcinoembryonic antigen (CEA) and clinicopathological parameters in patients with breast cancer. Methods: A total of 134 patients with breast cancer treated in a single general surgery unit between January 2012 and November 2013 were included in the study, with age ranging between 28 and 73 years. Serum CEA values were compared before and after the treatment of breast cancer, between different histological types of breast cancer patients, between axillary lymphnode-positive and axillary lymphnode-negative patients, and between premenopausal and postmenopausal breast cancer patients. Data were analyzed using the statistical software SPSS version 19. Results: There was significant change in the values of serum CEA before (10.71 ± 2.79 ng/ml) and after the surgery for breast cancer (9.73 ± 3.00 ng/ml) (P < 0.006). There was further decline in the serum CEA level after a course of chemo-radiotherapy (7.30 ± 2.79 ng/ml) (P < 0.001). There was no significant difference between the different histological types of breast cancer (P value 0.55). The difference was significant in patients who were axillary lymphnode positive and negative (P < 0.001). There was no significant difference in premenopausal and postmenopausal breast cancer patients (P value 0.86). Conclusions: Serum CEA is a tumor marker of breast carcinoma. Its level decreased after treatment. This decrease is found more after chemo/radiotherapy following surgery. Serum CEA values are found to be elevated in patients with axillary lymphnode metastasis. There is no significant relation with the histologic type of breast cancer and menopausal status of the patient.

Correlation between the methylation of SULF2 and WRN promoter and the irinotecan chemosensitivity in gastric cancer

BackgroundAt present, no study has compared the correlation between SULF2, WRN promoter methylation and clinicopathological parameters of patients with gastric cancer and the sensitivity to irinotecan (CPT-11).MethodsWe collected 102 fresh tumor tissues from pathologically diagnosed gastric carcinoma patients. Methylation specific PCR was used to detect the promoter methylation of SULF2 and WRN. The chemosensitivity of irinotecan to gastric tomor was tested by MTT. Then we compared the chemosensitivity difference of the methylated group with unmethylated group.ResultsThe rates of SULF2, WRN methylation were 28.3% (29/102) and 23.6% (24/102), separately. Patients with SULF2 methylation were more sensitive to CPT-11 than those without SULF2 methylation (P < 0.01). Patients with both SULF2 and WRN methylation were also more sensitive to CPT-11 than others ( P < 0.05).ConclusionSULF2 and WRN promoter methylation detection indicates potential predictive biomarkers to identify and target the most sensitive gastric cancer subpopulation for personalized CPT-11 therapy.

Expression of p53 in imprint smears of endometrial carcinoma

The aims of this study were to determine the expression of p53 protein in endometrial adenocarcinomas (as a potential prognostic indicator before treatment) as well as normal endometrium in imprint smears and to correlate the results with clinicopathologic parameters of primary untreated endometrial cancer patients. Two hundred fifty five patients were evaluated with endometrial imprint cytology during a 29-month period. Endometrial samples freshly resected from women who underwent total abdominal hysterectomy were studied. One hundred twenty six patients had endometrial carcinoma and 129 cases were diagnosed as normal endometrium. The expression of p53 was assessed by immunocytochemistry. Positive staining was correlated with increased surgical-pathological stage, histological grade and lymph node metastases. High expression of p53 staining was significantly more frequent in histological type II than type I endometrial adenocarcinoma. High-grade endometrial carcinoma had higher proportions and stronger intensity compared with low-grade carcinoma. Negative immunostain for p53 protein was found in proliferative, secretory, and atrophic endometrium. Immunocytochemical findings from p53 stain, in addition to cytomorphologic features, appeared to be useful in the diagnosis and in the postoperative prognosis of endometrial carcinoma in endometrial cytology, especially if combined with other markers. High p53 expression correlates with morphologic features of aggressiveness and the expression pattern of p53 correspond to the expected cyclic/atrophic pattern in normal endometrium.

CD40 expression in pancreatic cancer.

CD40, a tumor necrosis factor receptor family member, is expressed in a variety of cell types. This widespread expression suggests that CD40 may play an important role in normal physiology and disease pathogenesis. The objective of the current study was to investigate the expression of CD40, and its association with clinicopathological features and survival in patients with pancreatic ductal adenocarcinoma. CD40 expression was assessed in 53 pancreatic ductal adenocarcinoma surgical specimens by immunohistochemistry, and expression was correlated with patient clinicopathological parameters and outcome. Among 53 pancreatic cancer specimens, CD40 expression was detected in 13 specimens (24.5%), and peritumoral lymphocytes were present in 45 specimens (84.9%). Patients with CD40-positive tumors exhibited prolonged median disease-free survival (DFS) compared with patients with CD40-negative tumors (15.60 +/- 3.87 versus 10.03 +/- 1.92); however, this was not significant (p = 0.845). Patients with peritumoral lymphocytic reaction exhibited prolonged median DFS compared with patients without peritumoral lymphocytes (10.96 +/- 1.40 vs. 7.60 +/- 0.47); however, this was not significant (p = 0.624). Patients with peritumoral lymphocytic reaction exhibited higher median overall survival compared with patients without peritumoral lymphocytes (15.20 +/- 1.78 vs. 10.13 +/- 1.39); however, again this was not significant (p = 0.100). These results suggest that CD40 expression on pancreatic cancer cells and peritumoral lymphocytic reaction may serve as prognostic markers.

Tissue microarray analysis reveals the expression and prognostic significance of phosphorylated AktThr308 in oral squamous cell carcinoma

We aimed to investigate the association between the expression of phosphorylated Akt(Thr308) (p-Akt(Thr308)) in oral squamous cell carcinoma (OSCC) tissues and clinicopathological parameters of OSCC patients and to verify the validity of p-Akt(Thr308) as a prognostic biomarker. One hundred and ninety-one patients with OSCC were recruited for the study. We tested the expression of p-Akt(Thr308) by immunohistochemistry (IHC) with tissue microarray (TMA) and analyzed with digital pathology analysis software. The clinicopathological parameters of all patients were collected from follow-up. P-Akt(Thr308) was detected in 95.2% of OSCC patients. The expression of p-Akt(Thr308) was significantly correlated with local recurrence and five-year survival rate. High expression of p-Akt(Thr308) in OSCC was associated with poor prognosis. P-Akt(Thr308) might be a candidate biomarker for the prediction of OSCC prognosis.

The pretreatment platelet and plasma fibrinogen level correlate with tumor progression and metastasis in patients with pancreatic cancer

Cancer patients frequently present with activated coagulation pathways and thrombocytosis, which are potentially associated with tumor progression and prognosis. However, the prognostic value of abnormal plasma fibrinogen and platelet levels for the treatment of pancreatic cancer is unclear. The purpose of our study was to evaluate the prognostic value of plasma fibrinogen and platelet levels in pancreatic cancer, and to devise a prognostic model to identify the patients with greatest risk for a poor overall survival. One hundred and twenty-five patients diagnosed with pancreatic ductal adenocarcinoma in our hospital between May 2000 and June 2005 were included in this study. The plasma fibrinogen and platelet levels were examined before treatment and analyzed along with patient clinicopathological parameters and overall survival. The foundation of prognostic model was based on the risk factors according to the Cox proportional hazard model. The incidence of hyperfibrinogenemia and thrombocytosis was 24.8% (31/125) and 15.2% (19/125), respectively. The mean fibrinogen concentration differed significantly between the early (I/II) and late (III/IV) stage patients (3.19 ± 0.70 vs. 3.65 ± 0.90 g/l, p = 0.008). Patients with a higher concentration of plasma fibrinogen and platelets had a worse prognosis (p < 0.05). There also existed a significant correlation between higher fibrinogen/platelet levels and distant organ metastasis (p < 0.05, respectively). Bivariate correlation analysis showed that plasma fibrinogen levels correlated significantly with platelet levels (p = 0.000). Multivariate analysis revealed that pretreatment plasma fibrinogen levels (p = 0.027), tumor stage (p = 0.026) and distant metastasis (p = 0.027) were independent prognostic factors. The median survival time for the low-, intermediate-, and high-risk groups was 9.6 months (95% CI 6.2–13.0), 3.8 months (95% CI 2.3–5.3), and 2.3 months (95% CI 0.9–3.7), respectively (p = 0.000). Pretreatment plasma fibrinogen and platelet levels closely correlated with tumor progression, metastasis and overall survival in pancreatic cancer. The foundation of prognostic model may help us identify the greatest risk populations with pancreatic cancer.

Soluble e-cadherin as a diagnostic and prognostic marker in gastric carcinoma

Modifications in E-cadherin (E-Cad) expression are associated with dedifferentiation, progression, metastases and poor prognosis in many types of tumors. The aim of the present study was to identify a potential association of the pre- and post-operative soluble E-Cad levels (sE-Cad) with the clinicopathological parameters of patients with gastric cancer. Serum sE-Cad levels were determined in 99 gastric cancer patients and 78 healthy volunteers using ELISA. Levels of sE-Cad were significantly increased in gastric cancer patients compared with these levels in healthy controls (p < 0.001). For the evaluation of the diagnostic significance of sE-Cad the area under the receiver operating characteristic (ROC) curve (AUC) was 0.835, while the optimal cut-off point of 9.9 microg/mL was determined to classify gastric cancer patients, which yielded sensitivity of 72.7%, specificity of 80.8% and accuracy of 76.3%. Poor differentiation (p = 0.009) and the presence of distant metastases (p < 0.001) were the two significant independent prognostic determinants for high sE-Cad levels in multivariate linear regression analysis. The preoperative levels of sE-Cad also proved helpful in classifying patients according to the choice treatment (curative versus palliative) (AUC, 0.656); when the optimal cut-off point was set at 17.60 microg/mL, the sensitivity was 57%, the specificity was 83% and accuracy was 75%. Survival was shorter in patients with increased sE-Cad (median, 7 months vs 39 months, p = 0.0002), although multivariate Cox regression analysis demonstrated a marginal prognostic significance of sE-Cad for survival (adjusted HR = 1.68, 95% CI = 0.93 to 3.02, p = 0.072). Serum sE-Cad levels could be considered as a diagnostic and prognostic marker in gastric cancer patients as well as a tool to select a treatment approach. The prognostic value of sE-Cad on overall survival requires further study.

Hypoxia-regulated gene expression and prognosis in loco-regional gastroesophageal cancer

Gastroesophageal cancers are heterogeneous diseases with a poor outcome. Prognostic and predictive factors are needed to improve patient survival. Hypoxia is an adverse prognostic factor and is associated with resistance to chemo- and radiotherapy in various cancers. However, knowledge on the impact of hypoxia in gastroesophageal cancer is limited. The aim of this study was to evaluate potential prognostic factors in terms of a subset of hypoxia-responsive genes and clinicopathological parameters in patients with gastroesophageal cancer. Material and methods. Ninety-five patients with loco-regional gastroesophageal cancer treated with curative intent were retrospectively analyzed. Based on formalin-fixed paraffin-embedded diagnostic biopsies gene expressions of 15 hypoxia-induced and pH-independent genes from a previously described hypoxia gene expression classifier was quantified. The prognostic impact was evaluated for overall survival (OS) and disease-specific survival (DSS). Uni- and multivariate Cox proportional hazards model was used to identify hypoxia-responsive gene expression and clinicopathological parameters as prognostic markers. Results. An unsupervised hierarchical clustering of hypoxia regulated genes showed two well-differentiated patient clusters: One cluster of tumors with high gene expression and another with low gene expression, indicating a more hypoxic genotype versus a less hypoxic genotype respectively. As the group of esophageal squamous cell carcinomas (ESCC) alone showed intra-group heterogeneity this group was ranked according to the gene expression of the 15 genes. The most hypoxic third showed a trend towards a poorer outcome in terms of OS [HR = 0.48 (CI 0.21–1.07), p = 0.07] and DSS [HR = 0.48 (CI 0.18–1.24), p = 0.13]. Treatment response was identified as an independent prognostic factor for DSS in the group of ESCC [HR = 0.21 (CI 0.05–0.95), p = 0.04]. Conclusion. Gene expression analysis of 15 hypoxia-responsive genes was identified as a promising prognostic marker in patients with ESCC. Further studies confirming these results in larger patient cohorts are needed.

B7-H4 Expression is Associated with Cancer Progression and Predicts Patient Survival in Human Thyroid Cancer

This study aimed to investigate the expression of B7-H4 in human thyroid cancer and determine any association with patient clinicopathological parameters and survival. B7-H4 expression in 64 clinical thyroid cancer specimens was assessed with immunohistochemistry. Moreover, B7-H4 mRNA expression in 10 fresh resected specimens were evaluated by the reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical staining of CD3 was performed to assess the number of tumor infiltrating T lymphocytes (TILs) in thyroid cancers. Positive B7-H4 immunohistochemical staining was observed in 61 out of 64 (95.3%) specimens of thyroid cancer tissues. Significantly more B7-H4 mRNA copies were found in thyroid cancer tissue than that adjacent normal tissue. Moreover, B7-H4 expression in human thyroid cancer tissues was significantly correlated with patient TNM stages and extrathyroidal extension (P<0.05), being inversely correlated with the number of TILs (P<0.05). The overall survival rate of the patients with higher B7-H4 expression was significantly worse than that of the patients with lower B7-H4 expression. This present study suggests that high B7-H4 expression is associated with cancer progression, reduced tumor immunosurveillance and worse patient outcomes in human thyroid cancer.

Expression of a LINE-1 endonuclease variant in gastric cancer: its association with clinicopathological parameters

BackgroundLong interspersed nuclear element-1 (LINE-1 or L1), the most abundant and only autonomously active family of non-LTR retrotransposons in the human genome, expressed not only in the germ lines but also in somatic tissues. It contributes to genetic instability, aging, and age-related diseases, such as cancer. Our previous study identified in human gastric adenocarcinoma an upregulated transcript GCRG213, which shared 88% homology with human L1 sequence and contained a putative conserved apurinic/apyrimidinic endonucleas1 domain.MethodsImmunohistochemistry was carried out by using a monoclonal mouse anti-human GCRG213 protein (GCRG213p) antibody produced in our laboratory, on tissue microarray constructed with specimens from 175 gastric adenocarcinoma patients. The correlation between GCRG213p expression and patient clinicopathological parameters was evaluated. GCRG213p expression in gastric cancer cell lines were studied using Western blotting analysis. L1 promoter methylation status of gastric cancer cells was tested using methylation-specific PCR. BLASTP was used at the NCBI Blast server to identify GCRG213p sequence to any alignments in the Protein Data Bank databases.ResultsMost primary gastric cancer, lymph node metastases and gastric intestinal metaplasia glands showed positive GCRG213p immunoreactivity. High GCRG213p immunostaining score in the primary gastric cancer was positively correlated with tumor differentiation (well differentiated, p = 0.001), Lauren’s classification (intestinal type, p < 0.05) and a late age onset of gastric adenocarcinoma (≥65 yrs; p < 0.05). GCRG213p expression has no association with other clinicopathological parameters, including survival. Western blotting analysis of GCRG213p expression in gastric cancer cells indicated that GCRG213p level was higher in gastric cancer cell lines than in human normal gastric epithelium immortalized cell line GES-1. Partial methylation of L1 in gastric cancer cells was confirmed by methylation-specific PCR. BLASTP program analysis revealed that GCRG213p peptide shared 83.0% alignment with the C-terminal region of L1 endonuclease (L1-EN). GCRG213p sequence possesses the important residues that compose the conserved features of L1-EN.ConclusionsGCRG213p could be a variant of L1-EN, a functional member of L1-EN family. Overexpression of GCRG213p is common in both primary gastric cancer and lymph node metastasis. These findings provide evidence of somatic L1 expression in gastric cancer, and its potential consequences in the form of tumor.

Immunohistochemical expression of core 2 β1,6‐N‐acetylglucosaminyl transferase 1 (C2GnT1) in endometrioid‐type endometrial carcinoma: a novel potential prognostic factor

It has been reported that the expression of core 2 β1,6-N-acetylglucosaminyl transferase 1 (C2GnT1), which synthesizes the core 2 branching structure on O-glycans, may be associated with the biological aggressiveness of tumour cells. Therefore, the aim of this study was to examine the relationship between the expression of C2GnT1 and clinicopathological parameters of patients with endometrial carcinoma. The immunohistochemical expression of C2GnT1 was examined in 84 cases of endometrioid-type endometrial carcinoma, 15 cases of endometrial hyperplasia, and 30 normal endometria. The staining intensity was reported according to a positivity index (PI, full score 100), calculated from the percentage of positive cells. The expression of C2GnT1 was significantly higher in endometrial carcinoma (PI = 8.31 ± 15.29) than in normal endometrium (PI = 0.52 ± 1.24) (P < 0.0005). In carcinomas, the PI was higher in high-grade or advanced-stage tumours, but not significantly. Topologically, C2GnT1 was strongly expressed at sites of deep myometrial invasion. In addition, patients with C2GnT1 overexpression (PI ≥ 10) had significantly shorter survival (P < 0.0005). Multivariable analysis also indicated that C2GnT1 overexpression was an independent prognostic factor (P = 0.017). C2GnT1 appears to be involved in the biological aggressiveness of endometrial carcinoma. C2GnT1 might become a novel prognostic factor for endometrial carcinoma.

Abstract 1759: Immunohistochemical detection of human telomerase reverse transcriptase in human cholangiocarcinoma and risk condition.

Abstract Background/Aims: Telomerase activation plays a critical role in several human carcinogenesis through the maintenance of telomeres. The catalytic subunit of telomerase is human telomerase reverse transcriptase (hTERT), whose expression is the critical determinant of telomerase activity. Studies on hTERT in human cholangiocarcinoma (ChC) are rare, and there are no immunohistochemical studies on the correlations with its expressions and ChC patient's clinicopathological parameters. Methods : HTERT Immunoreactivity was measured in cancerous parenchyma of 28 archival cases of human cholangiocarcinoma (ChC) compared with hyperplastic small biliary ducts in surrounding non-neoplastic liver. And hTERT immunoreactivity was also assessed in both large and small hyperplastic biliary ducts (HBDs) in 9 archival cases of primary sclerosing cholangitis (PSC), which is risk condition for human cholangiocarcinogenesis. Measurements of intrahepatic biliary duct sizes and quantitative microdensitometry measurements of immunostaining intensities were determined using a color video image analysis system. Micro-optical density values related to a standard optical density curve were generated for each set of measurements, using arbitrary units of immunostaining intensity ranging from 0 (nondetectable) to 255 (highest intensity). Results : HTERT immunoreactivity was presented in nuclei of ChC and PSC cells. Mean micro-optical density values for hTERT in tumorous cells were almost 8-fold greater than that measured in small HBDs in surrounding non-tumorous liver within the same tissue sections. Although there was no significantly difference of tumor differentiation in hTERT expression, its expression was stronger in tubular type than in papillary type and in tubulopapillary type. In PSC cases, hTERT expression was significantly stronger in large HBDs (&amp;gt;500μm cross-sectional diameter) than in small HBDs (&amp;lt;500μm cross-sectional diameter). Conclusion : Our findings suggest that hTRET protein in human ChC may emerge at a early stage in the progression of the malignant process. The results also suggest hTERT as potentially important targets relevant to chemoprevention or adjunct therapy of ChC. Citation Format: Kanenori Endo, Shunichi Tsujitani, Miwa Yoshimoto, Jyoji Watanabe, Naruo Tokuyasu, Teruhisa Sakamoto, Takuji Naka, Yasuaki Hirooka, Masahide Ikeguchi. Immunohistochemical detection of human telomerase reverse transcriptase in human cholangiocarcinoma and risk condition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1759. doi:10.1158/1538-7445.AM2013-1759

Association of preoperative serum IGF- I concentration with clinicopathological parameters in patients with non-small cell lung cancer

Insulin-like growth factor-I (IGF-I) is a mitogenic and anti-apoptotic factor. Serum IGF-I concentration is related to some cancer risk and tumor progression. The aim of this research was to study the association of preoperative serum IGF-I concentration with clinicopathological parameters and prognosis of non-small cell lung cancer (NSCLC). Preoperative serum IGF-I concentration was measured in 80 consecutive patients with NSCLC who underwent radical lung cancer resection, and 45 patients with benign pulmonary lesion (BPL) by using enzyme linked immunosorbent assay (ELISA). The results showed that the serum IGF-I concentration was elevated and correlated with clinicopathological parameters and overall survival (OS) in NSCLC patients. Serum IGF-I concentration was significantly higher in patients with NSCLC than in those with BPL. The IGF-I concentrations were significantly higher in NSCLC patients with ≥T2, N1-3, and in IIIA-IV but not in those with <T2, N0, or IA-IIB. The increased serum IGF-I concentration was significantly correlated with poor prognosis. Our data show the positive correlation between IGF-I serum concentration and the tumor size for the first time. It seems that IGF-I related to the progression of lung cancer may depend on autocrine/paracrine function. In addition, our study reveals that higher serum IGF-I concentration is correlated with larger tumor size, advanced stages, local lymph node metastasis and worse prognosis, indicating that endocrine IGF-I is also important for the progression for NSCLC.

Alterations in K-ras, APC and p53-multiple genetic pathway in colorectal cancer among Indians

The incidence of colorectal cancer (CRC) is increasing rapidly in Asian countries during the past few decades, but no comprehensive analysis has been done to find out the exact cause of this disease. In this study, we investigated the frequencies of mutations and expression pattern of K-ras, APC (adenomatosis polyposis coli) and p53 in tumor, adjoining and distant normal mucosa and to correlate these alterations with patients clinicopathological parameters as well as with the survival. Polymerase chain reaction (PCR)-restriction digestion was used to detect mutations in K-ras and PCR-SSCP (Single Strand Conformation Polymorphism) followed by DNA sequencing was used to detect mutations in APC and p53 genes. Immunohistochemistry was used to detect the expression pattern of K-ras, APC and p53 proteins. The frequencies of mutations of K-ras, APC and p53 in 30 tumor tissues samples were 26.7 %, 46.7 % and 20 %, respectively. Only 3.3 % of tumors contained mutations in all the three genes. The most common combination of mutation was APC and p53 whereas mutation in both p53 and K-ras were extremely rare. There was no association between the mutations and expression pattern of K-ras, APC and p53 (p>0.05). In Indians, the frequency of alterations of K-ras and APC is similar as in Westerns, whereas the frequency of p53 mutation is slightly lower. The lack of multiple mutations in tumor specimens suggests that these genetic alterations might have independent influences on CRC development and there could be multiple alternative genetic pathways to CRC in our present study cohort.

ALDH1-positive cancer stem-like cells are enriched in nodal metastases of oropharyngeal squamous cell carcinoma independent of HPV status

Oropharyngeal squamous cell carcinoma (OSCC) is caused by high-risk (HR) human papillomavirus (HPV) or alcohol and tobacco abuse. Aldehyde dehydrogenase 1 (ALDH1) is a confirmed marker for cancer stem-like cells (CSCs) of OSCC responsible for therapy resistance, recurrence and metastasis. Associations between HR-HPV/p16, CSC frequency and clinicopathological parameters in patients with metastatic OSCC were investigated. In the present study, HPV genotypes and expression of ALDH1 and p16 was analyzed in 40 paired OSCC and metastases. A significant correlation between ALDH1 positivity with lower primary tumor differentiation grade (P=0.009) and higher nodal status (P=0.015) was noted. Compared to primary tumors, the proportion of ALDH1-expressing cells was significantly increased in metastases (P=0.012), while significantly fewer ALDH1-expressing cells were found in HR-HPV-DNA⁺/p16⁺ primary tumors (P=0.038) compared to HR-HPV-DNA⁻/p16⁻ primary tumors. Metastases showed no difference. ALDH1⁺ CSCs are detectable in OSCC and metastases. ALDH1 high-grade OSCC exhibits a more aggressive phenotype characterized by higher nodal classification and lower differentiation. This suggests a subpopulation contained in the ALDH1-positive OSCC cell pool able to complete the metastatic cascade and subsequently enriching in metastasis independent of tumor etiology and ALDH1 content.

CpG island hypermethylation of corticotropin-releasing hormone-binding protein in kidney cancer and association with clinicopathological parameters.

414 Background: Significance of Urocortin (Ucn or UcnI), Ucn2, Ucn3, and their receptors, Corticotropin Releasing Factor Receptor 1 and 2 (CRFR1 and CRFR2), and the binding protein, Corticotropin-Releasing Hormone-Binding Protein (CRHBP) in oncology is growing rapidly. Recently we found that the UCN system may also be a relevant structure in renal cell cancer. Here we investigate whether CRHBP CGI methylation occurs in cc-RCC and whether its methylation is associated with clinicopathological parameters of patients. Methods: Tumoral tissues of 109 patients with renal cell cancer and their corresponding normal tissues have been used. Combined bisulfite restriction analysis (COBRA) for detection of relative degree of CpG island (CGI) methylation and pyrosequencing have been performed. Results: We found an approximately five-fold increase in mean methylation of the CRHBP CGI for tumor tissues (p &lt; 0.00005). Higher DNA methylation of the CRHBP CGI showed a positive correlation with advanced disease as well (p = 0.024). Conclusions: To our knowledge we report for the first time the CGI methylation of CRHBP in clear cell renal cell carcinoma indicating a contribution of epigenetic alteration of CRHBP to RCC tumorigenesis. Moreover, our results suggest CRHBP as a potential molecular marker for assessment of progression and aggressiveness of tumors.

Impact of Smoking Status on Bladder Tumor Recurrence After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

Although smoking status has a significant association with clinical features in patients with bladder cancer, there are few reports of the impact of smoking on the clinical outcome of upper tract urothelial cancer. We investigated the possible influence of smoking status on bladder tumor recurrence after radical nephroureterectomy. We identified a study population of 245 consecutive patients treated surgically for upper tract urothelial cancer at our 3 institutions between 1994 and 2010. We analyzed associations between subsequent bladder tumor recurrence and patient clinicopathological parameters, including smoking status. The 3-year bladder tumor recurrence-free survival rate was 32.6% in current smokers, 37.6% in former smokers and 61.7% in nonsmokers. Multivariate analysis revealed that male gender (HR 1.90, 95% CI 1.15-3.16, p = 0.013) and smoking status (former vs none HR 1.77, 95% CI 1.07-2.93, p = 0.027 and current vs none HR 1.58, 95% CI 1.03-2.42, p = 0.035) were independent risk factors for subsequent bladder tumor recurrence. Also, of patients with a positive smoking history those with 50 pack-years or greater showed a significantly higher incidence of bladder tumor recurrence after radical nephroureterectomy (HR 2.00, p = 0.003). Positive smoking history and male gender were independent risk factors for bladder tumor recurrence after radical nephroureterectomy. A larger number of cigarettes smoked may increase the incidence of bladder tumor recurrence in patients with upper tract urothelial cancer.

Cell-Free microRNA-214 From Urine as a Biomarker for Non-Muscle-Invasive Bladder Cancer

PurposeMicroRNAs are small noncoding RNAs and microRNA-214 (miR-214) has been associated with the inhibition of cancer cell growth, migration, and invasion. The aim of this study was to investigate whether cell-free miR-214 isolated from urine could be used as a biomarker for non-muscle-invasive bladder cancer (NMIBC).Materials and MethodsA total of 138 patients with primary NMIBC and 144 healthy normal controls were enrolled in this study. By use of quantitative polymerase chain reaction (PCR), the urinary levels of cell-free miR-214 were measured and the clinicopathological parameters of patients with NMIBC were compared with those of the controls.ResultsThe urinary levels of cell-free miR-214 were significantly higher in the NMIBC patients than in the controls (20.08±3.21 vs. 18.96±2.68, p=0.002). However, the urinary levels of cell-free miR-214 were neither graded nor staged for the NMIBC patients (p>0.05, each). When we compared the urinary levels of cell-free miR-214 according to clinical outcomes, patients with recurrence had lower levels of miR-214 than did those with no recurrence (19.24±2.67 vs. 20.41±3.41, p=0.023). By contrast, there were no significant differences in the urinary level of cell-free miR-214 between the NMIBC patients showing progression and those showing no progression (p=0.919). Multivariate Cox regression analysis revealed that urinary levels of cell-free miR-214 were an independent predictor of NMIBC recurrence (hazard ratio, 2.011; 95% confidence interval, 1.027 to 3.937; p=0.041).ConclusionsUrinary levels of cell-free miR-214 could be an independent prognostic parameter for NMIBC recurrence. Thus, urinary cell-free microRNA-214 might be a useful prognostic marker for NMI BC.

Upregulated Expression of ADAM17 Is a Prognostic Marker for Patients With Gastric Cancer

This study was designed to evaluate the expression and prognostic significance of A Disintegrin and Metalloproteinase17 (ADAM17) protein in patients with gastric cancer. Tumor invasion and metastasis are primary causes for treatment failure or death among cancer patients. ADAM17 is a multidomain transmembrane glycoprotein involved in the release of several ligands that were shown to promote tumor formation and progression. Elevated expression of ADAM17 was detected in a number of human cancers and was associated with poor progression and prognosis of the diseases. In gastric cancer, however, the expression and prognostic significance of ADAM17 has not been fully elucidated. The expressions of ADAM17 and extracellular matrix metalloproteinase inducer (EMMPRIN), a protein implicated in tumor invasion and metastasis, were detected using the tissue microarray technique and immunohistochemical EnVision method and compared with clinicopathological parameters of patients with gastric cancer. The expressions of ADAM17 and EMMPRIN were upregulated in gastric cancer lesions compared with their expressions in adjacent non-cancerous tissues (P < 0.01). High expression of ADAM17 was detected in 35.78% (156/436) of patients with gastric cancer and positively correlated with the expression of EMMPRIN (r = 0.738, P < 0.01). ADAM17 expression was associated with a number of clinicopathological parameters including depth of invasion and TNM stage of the tumor (P < 0.05). In each TNM stage, patients with high ADAM17 expression had a longer mean survival time than those with low expression (P < 0.05). Particularly, the mean survival time of stage II gastric cancer patients with low ADAM17 expression was longer than that of stage I patients with high ADAM17 expression (P < 0.01). Multivariate survival analysis suggested that, along with other parameters, ADAM17 and EMMPRIN expression were independent prognostic factors for patients with gastric cancer. ADAM17 was implicated in the progression of gastric cancer. On the basis of the TNM stage, detection of ADAM17 expression will be helpful for predicting prognosis of gastric cancer.