Motility-related protein 1 (MRP-1/CD9) expression in urothelial bladder carcinoma and its relation to tumor recurrence and progression

BACKGROUND: CD9 has been implicated in cell adhesion, motility, and proliferation, and numerous studies have demonstrated its prognostic value in different solid tumors. The objective of this study was to determine the relation of CD9 expression to tumor grade and tumor stage of urothelial carcinoma of the bladder and to define the value of CD9 in predicting the behavior of superficial papillary tumors (SPTs) (pathologic Ta [pTa] and pT1). METHODS: Three hundred twenty patients (118 patients with pTa tumors, 111 patients with pT1 tumors, and 91 patients with pT2 tumors) were examined for CD9 expression using immunohistochemistry applied on formalin fixed, paraffin embedded tissue. Patients were stratified into 3 categories, depending on CD9 expression: positive (> 50% positive cells), reduced (5-50% positive cells), or negative (< 5% positive cells). RESULTS: Loss of CD9 expression was found to be associated significantly with high-grade and high-stage urothelial tumors (P < 0.0001). A reduced/negative (altered) CD9 expression was associated with SPT progression, but not with recurrence (P < 0.001). Patients who had pTa or pT1 tumors with altered CD9 expression had a relative risk of 5.59 (P = 0.005; 95% confidence interval [95% CI], 1.69-18.48) for progression compared with patients who had tumors with positive CD9 expression. Kaplan-Meier curves showed that a lack of CD9 expression was associated significantly with progression free survival (P < 0.001; log-rank test), but not with recurrence. In patients with SPTs, multivariate Cox proportional hazards regression analysis revealed that negative CD9 expression was an independent prognostic marker for the prediction of tumor progression (P = 0.007; 95% CI, 0.11-0.70). CONCLUSIONS: In patients with urothelial bladder carcinoma, CD9 expression was associated significantly with tumor stage and grade, and a loss of CD9 expression was an independent prognostic factor for predicting progression in patients with SPTs. Thus, CD9 immunoexpression is a potential new predictor of tumor behavior in patients with SPTs of the urinary bladder.     

Syndecan-1 expression has prognostic significance in head and neck carcinoma

The syndecans are a family of cell-surface heparan sulphate proteoglycans that regulate cell behaviour by binding extracellular matrix molecules such as growth factors. The syndecan family has four members, of which syndecan-1 is the most studied and best characterized. We have studied the prognostic significance of syndecan-1 expression in squamous cell carcinoma (SCC) of the head and neck treated with surgery and post-operative radiotherapy. Paraffin-embedded tissue samples taken from 175 patients with primary SCC, followed up from 2 to 15 years after surgery, were studied for expression of syndecan-1 by immunohistochemistry. A low number (< or =50%, the median value) of syndecan-1-positive tumour cells was associated with low histological grade of differentiation (P<0.0001), a large primary tumour size (T1-2 vs. T3-4, P = 0.02), positive nodal status (NO vs. N1-3, P = 0.0006), and high clinical stage (stage I or II vs. III or IV, P<0.0001). Low syndecan-1 expression was also associated with unfavourable overall survival in a univariate analysis (P = 0.001). In a multivariate survival analysis, the clinical stage and syndecan-1 expression were the only independent prognostic factors. We conclude that syndecan-1 is a novel prognostic factor in SCC of the head and neck treated with surgery and post-operative radiotherapy.     

Clinical outcome of adjuvant endocrine treatment according to PR and HER-2 status in early breast cancer.

Patients with estrogen receptor (ER)+/progesterone receptor (PR)- and/or HER-2 overexpressing breast carcinomas may derive lower benefit from endocrine treatment. We examined retrospectively data from 972 breast cancer patients who received tamoxifen (725), tamoxifen + Gn-RH analogs (127) and aromatase inhibitors (120) as adjuvant treatments. ER+/PR- versus ER+/PR+ tumours were characterised by larger size (P = 0.001), higher tumour grade (P = 0.001), higher Ki-67 expression (P = 0.001) and lower mean ER (P = 0.000) and HER-2 expression (P = 0.000). At univariate analysis, tumour grading [hazard ratio (HR) = 4.0; 95% confidence interval (CI) = 1.4-11.1; P = 0.007], nodal status (HR = 3.4; 95% CI 1.2-5.7; P = 0.000), tumour diameter (HR = 2.9; 95% CI 1.7-4.7; P = 0.000) lack of PR expression (HR = 2.1; 95% CI 1.3-3.4; P = 0.002) and HER-2 overexpression (HR = 1.9; 95% CI 1.0-3.5; P = 0.03), as well as Ki 67 expression (HR = 1.7; 95% CI 1.0-2.7; P = 0.04) were associated with shorter disease-free survival (DFS). At the multivariate analysis, nodal status (HR = 3.6; 95% CI 1.9-6.8; P = 0.0001), lack of PR expression (HR = 2.3; 95% CI 1.3-4.0; P = 0.003) and tumour diameter (HR = 2.1; 95% CI 1.1-3.8; P = 0.018) retained their prognostic significance, whereas HER-2 overexpression was associated with a trend towards shorter DFS that was of borderline statistical significance (HR = 2.0; 95 % CI 1.0-3.9; P = 0.05). Our data suggest that lack of PR expression and HER-2 overexpression are both associated with aggressive tumour features, but the prognostic information of PR status on the risk of recurrence in endocrine-treated breast cancer patients is stronger.     

Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma

Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) have been considered as potential therapeutic targets in cholangiocarcinoma, but no studies have yet clarified the clinicopathological or prognostic significance of these molecules. Immunohistochemical expression of these molecules was assessed retrospectively in 236 cases of cholangiocarcinoma, as well as associations between the expression of these molecules and clinicopathological factors or clinical outcome. The proportions of positive cases for EGFR, VEGF, and HER2 overexpression were 27.4, 53.8, and 0.9% in intrahepatic cholangiocarcinoma (IHCC), and 19.2, 59.2, and 8.5% in extrahepatic cholangiocarcinoma (EHCC), respectively. Clinicopathologically, EGFR overexpression was associated with macroscopic type (P=0.0120), lymph node metastasis (P=0.0006), tumour stage (P=0.0424), lymphatic vessel invasion (P=0.0371), and perineural invasion (P=0.0459) in EHCC, and VEGF overexpression with intrahepatic metastasis (P=0.0224) in IHCC. Multivariate analysis showed that EGFR expression was a significant prognostic factor (hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.52-4.69; P=0.0006) and also a risk factor for tumour recurrence (HR, 1.89; 95% CI, 1.05-3.39, P=0.0335) in IHCC. These results suggest that EGFR expression is associated with tumour progression and VEGF expression may be involved in haematogenic metastasis in cholangiocarcinoma.     

Association between syndecan-1 expression and clinical outcome in squamous cell carcinoma of the head and neck.

Syndecans are a family of cell-surface heparan sulphate proteoglycans which are involved in cell-matrix interactions and growth factor binding. Syndecan-1 binds basic fibroblast growth factor (bFGF) and several components of the extracellular matrix. Syndecan-1 expression is induced during keratinocyte differentiation and reduced during the formation of squamous cell carcinomas (SCCs). The purpose of this study was to examine the association of syndecan-1 expression with prognostic factors and clinical outcome in SCC of the head and neck. Frozen sections of 29 primary SCCs were analysed for syndecan-1 expression using immunohistochemical methods. Intermediate or strong staining for syndecan-1 was associated with a smaller primary tumour size (P = 0.0005) and higher histological grade of differentiation (P = 0.006) than negative or weakly positive staining. In a univariate analysis, syndecan-1-positive tumours were associated with higher overall (P = 0.001) and recurrence-free survival (P = 0.003) than those tumours with no or little syndecan-1 expression. The results suggest that syndecan-1 could be an important prognostic factor of SCC of the head and neck. Further studies on the prognostic significance of syndecan-1 expression in SCCs are warranted.     

Prognostic and clinical significance of syndecan-1 expression in breast cancer: A systematic review and meta-analysis

BackgroundThe prognostic value of syndecan-1 (SDC1, also called CD138) in breast cancer remains controversial. Therefore, we performed a meta-analysis to assess the clinical significance of SDC1 expression in breast cancer.Materials and methodsVarious databases were searched to evaluate possible correlations between SDC1 protein or mRNA expression and prognostic significance in breast cancer. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were applied to perform a quantitative meta-analysis.ResultsA total of 1305 breast cancer patients from 9 eligible studies were included in this meta-analysis. Significant associations between elevated SDC1 protein expression and poor disease-free survival (DFS) (HR = 1.55, 95% CI: 1.12–2.14; P = 0.007) and overall survival (OS) (HR = 2.08, 95% CI: 1.61–2.69; P < 0.001) were observed. In addition, enhanced SDC1 protein expression correlated with negative estrogen receptor (ER) expression (OR, 2.38; 95% CI, 1.64–3.44; P < 0.001) and positive human epidermal growth factor receptor 2 (HER2) expression (OR, 1.77; 95% CI, 1.14–2.76; P = 0.01). However, increased SDC1 protein expression did not correlate with relapse-free survival (RFS) (HR = 0.33, 95% CI: 0.03–3.13; P = 0.33). There were no additional significant correlations observed between SDC1 protein expression and other clinical factors, including tumor size, lymph node involvement, nuclear grade, and progesterone receptor (PR) expression.ConclusionThe results of this meta-analysis demonstrate that increased SDC1 protein expression in breast cancer is significantly associated with worse prognosis in terms of DFS and OS, and an aggressive phenotype is associated with negative ER expression and positive HER2 expression.     

Prolonged response to antisense cyclin D1 in a human squamous cancer xenograft model.

Local recurrence of squamous cell cancer (SCC) causes high morbidity and is often readily accessible, making such patients potential candidates for gene therapy. Cyclin D1 (CD1), critical in the G1-S transition in the cell cycle, is amplified in 20-50% and overexpressed in up to 80% of head and neck SCC. Our earlier studies indicated that CD1 expression increased with progression from low grade to high grade dysplasia, and that treatment of established tumors with antisense cyclin D1 (AS-cyclin D1) led to tumor regression during a one week evaluation period. We hypothesized that: 1) CD1 expression increases with disease progression to advanced SCC, and 2) AS-cyclin D1 therapy would lead to prolonged tumor regression in a xenograft model of human SCC. CD1 expression, evaluated by immunostain in 30 stage III/IV head and neck SCC, increased in the basal layer from normal-dysplasia (P = 0.06) and from dysplasia-carcinoma (P = 0.004). In the germinative layer CD1 expression increased from dysplasia-carcinoma (P = 0.002) but not from normal-dysplasia. Western blotting of eight SCC and two transformed keratinocyte cell lines demonstrated CD1 overexpression in 8/10 (80%) lines. An 11th cell line (A431) had previously been shown to overexpress cyclin D1. 8/9 (89%) cell lines overexpressing CD1 formed tumors in immunodeficient mice, whereas 0/2 cell lines without CD1 overexpression formed a tumor. Three established SCCs, one fast growing, one with moderate growth rate (with CD1 overexpression) and one slow growing (without increased CD1), shrank significantly for 2-4 weeks after AS-cyclin D1 treatment, while tumors transduced with control vector grew. Cyclin D1 expression increases in frequency with disease progression, and antisense cyclin D1 was effective in a xenograft model of human cancer, independent of tumor growth rate.     

Hypoxia-inducible factor-1alpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas

Hypoxia-inducible factor-1 (HIF-1)alpha expression was studied in the gastric carcinogenesis sequence and as a prognostic factor in surgically resected gastric and gastro-oesophageal junction tumours. Protein expression was examined using immunohistochemistry on formalin-fixed biopsies of normal mucosa (n=20), Helicobacter pylori associated gastritis (n=24), intestinal metaplasia (n=24), dysplasia (n=12) and intestinal (n=19) and diffuse (n=21) adenocarcinoma. The relationship between HIF-1alpha expression and prognosis was assessed in resection specimens from 177 patients with gastric and gastro-oesophageal junction adenocarcinoma. Hypoxia-inducible factor-1alpha expression was not observed in normal gastric mucosa but increased in density (P<0.01) and intensity (P<0.01) with progression from H. pylori-associated gastritis, intestinal metaplasia, dysplasia to adenocarcinoma. The pattern of staining in the resection specimens was focally positive in 49 (28%) and at the invasive tumour edge in 41 (23%). Invasive edge expression was associated with lymph node metastases (P=0.034), advanced TNM stage (P=0.001) and was an adverse prognostic factor for cancer-specific survival (P=0.019). In univariate analysis and in comparison with tumours not expressing HIF-1alpha, invasive edge staining was associated with a hazard ratio of 1.6 (95% CI 1.0-2.5) and focally positive staining a hazard ratio of 0.7 (95% CI 0.5-1.2). Hypoxia-inducible factor-1alpha lost prognostic significance in multivariate analysis. The results suggest HIF-1alpha is involved in gastric carcinogenesis and disease progression, but is only a weak prognostic factor for survival.     

High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer

Several epithelial tumours accumulate hyaluronan (HA) which promotes cancer cell invasion and metastasis. We analysed the expression of HA and its receptor CD44 and their prognostic value in 166 prostate cancer patients followed up for a mean of 13 years; standard deviation (S.D.) 2.7; range 8.7-21.4 years. HA was detected with a specific biotinylated probe prepared from cartilage aggrecan and link protein, and CD44 with an antibody recognising all forms of CD44. The peri- and intratumoral stroma from half of the patients strongly expressed immunohistochemically detectable HA in < or = 15% of the stromal area; the tumours in the remaining half expressed HA in > 15% of the area. The staining of cancer cells for HA was scored positive or negative, and for CD44 the median value of 80% of positive tumour cells was used as a cut-off point. The expression of HA in cancer cells was weakly associated with perineural infiltration of the tumour (P = 0.03) and high Gleason score (P = 0.002). There was also a significant inverse relationship between the expression of HA and CD44 in cancer cells (P < 0.001). The high level of HA in the peri-and intratumoral stroma was related to metastasis, high T-category, high Gleason score, perineural infiltration and high mitotic activity of the tumour (for all P < 0.001). There was a significant inverse relationship between the expression of CD44 in cancer cells and high level of strong expression of HA in the tumour stroma (P < 0.001). A low fraction of CD44-positive cells was related to a high TM-category, high Gleason score and rapid cell proliferation (for all P < 0.0001; M/V P value = 0.0013). In the univariate survival analysis, the high level of strong expression of HA in tumour stroma predicted an unfavourable outcome in the entire series (P = 0.003) and also in the M0 tumours (P = 0.07), while in T1-2 M0 tumours the prognostic value did not reach the level of statistical significance (P = 0.1). A low fraction of CD44-positive cells predicted a poor outcome in the entire series (P < 0.001) and also in M0 tumours (P = 0.003). Cancer cell-associated HA expression had no prognostic value in any tumour categories. In the multivariate analysis of prognostic factors, HA expression in the cancer cells or in the tumour stroma had no additional value to the standard prognostic factors TM-classification, Gleason score and CD44 expression. Our results show that stromal HA accumulation is related to several malignant features and adverse clinical outcome in prostate cancer. However, further studies based on uniformly treated patient cohorts are needed to establish the clinical significance of these findings in current clinical practice.     

Expression of CD44 Isoforms in Infiltrating Lobular Carcinoma of the Breast

Expression of CD44 has been shown to correlate with the progression and prognosis of some malignant tumors. The aim of this study was to evaluate the expression of CD44 isoforms in infiltrating lobular carcinomas and analyse their potential as prognostic indicators. A panel of 39 tumors were examined for their expression of membranous and cytoplasmic CD44s, v3, v5, v6, v7 and v3-10 in the infiltrating cells, by immunohistochemical staining. The protein positive tumors showed membranous and/or cytoplasmic staining with all antibodies used except for CD44v7, which only displayed cytoplasmic staining. Cytoplasmic expression of CD44v3 (P=0.014) and membranous expression of v6 (P=0.039) were significantly associated with alveolar, classical/alveolar carcinomas and mucinous/alveolar carcinomas. Furthermore, in alveolar, classical/alveolar and mucinous/alveolar carcinomas, cytoplasmic staining of CD44v5 was correlated with lymph node negative patients (P=0.048), whereas membranous v5 was correlated with lymph positive patients (P=0.048). In classical, classical/trabecular and trabecular carcinomas expression of membranous CD44s was significantly correlated with lymph node status (P=0.042).     

Cytoplasmic CD24 expression in colorectal cancer independently correlates with shortened patient survival.

PURPOSE: CD24 is a cell adhesion molecule that has been implicated in metastatic tumor progression of various solid tumors. We aimed to clarify the expression patterns of CD24 in colorectal cancer and to correlate these to clinicopathologic variables including patient survival. EXPERIMENTAL DESIGN: 147 colorectal carcinomas and two colon carcinoma cell lines were immunostained for CD24. Cytoplasmic and membranous immunoreactivity were semiquantitatively scored. Fisher's exact test, chi(2) test for trends, Kaplan-Meier analysis, and Cox's regression were applied. RESULTS: The cell line CX-2 showed only a minimal membranous CD24 immunoreactivity, in contrast to HT29, which stained strongly in the cytoplasm. In colorectal cancer, 68.7% of the tumors showed membranous CD24 staining, whereas 84.4% showed cytoplasmic staining. In 10% of cases, an exceptionally strong cytoplasmic CD24 expression was observed. The latter significantly correlated to higher tumor stages (Dukes and pT), nodal or systemic metastasis, and higher tumor grade. In survival analysis, strong cytoplasmic CD24 expression correlated significantly (Cox's regression: P = 0.012, relative risk = 3.7) to shortened patient survival in the group of cases without distant metastases. CONCLUSIONS: CD24 is commonly up-regulated in colorectal cancer and is a new independent prognostic marker which corroborates the importance of CD24 in tumor progression of this disease.     

Prognostic significance of K-ras,p53, bcl-2, PCNA,CD34 in radically resected non-small cell lung cancers

The aim of this study was to investigate the prognostic significance of a panel of biological parameters in patients with radically resected non-small cell lung cancers (NSCLC). 269 cases with pathological stage I-IIIA NSCLC were retrospectively analysed. Immunohistochemistry was performed to detect protein expression of p53, bcl-2, proliferating cell nuclear antigen (PCNA) and CD34. Polymerase chain reaction (PCR)/direct nucleotide sequencing method was used to detect mutations in K-ras (codons 12, 13, 61, exons 1-2). The Kaplan-Meier estimates of survival were calculated for clinical and biological variables using the Cox model for multivariate analysis. Histological subtype and the pathologic tumour extension (pT) were the most powerful clinical-pathological prognostic factors for survival (P=0.030 and P=0.031, respectively), whereas among the biological parameters, p53 overexpression (P=0.032) and K-ras mutation (P=0.078) had a negative prognostic role, as demonstrated by multivariate analysis. Conversely, bcl-2, PCNA and CD34 expression were not correlated with survival. Statistically significant associations between p53 expression and the squamous cell carcinoma (SCC) subtype, bcl-2 expression and SCC subtype, K-ras mutation and p53 negative expression, p53 and bcl-2, bcl-2 and PCNA overexpression were observed. In conclusion, some biological characteristics such as the K-ras and p53 status may provide useful prognostic information in resected NSCLC patients, in addition to the classical clinico-pathological parameters. However, further studies are needed to clarify the value of adopting biological prognostic factor into clinical practice.     

Prognostic significance of CEA immunoreactivity patterns in large bowel carcinoma tissue

In order to determine the clinical value of CEA detection in large bowel cancer tissue the patterns rather than the intensity of immunoreactivity of CEA reactive antibodies were analyzed in 312 large bowel cancer patients especially in relation to patient survival. CEA immunoreactivity appeared to be distinguishable into a predominantly apical/cytoplasmic and a predominantly membranous pattern. Twenty-four (7.7%) tumours were found to be CEA negative or only focally positive. Two hundred and eighty-three (90.7%) of the carcinomas showed a predominantly apical/cytoplasmic immunoreactivity pattern, whereas 5 (1.6%) of the tumours revealed mostly membranous CEA immunoreactivity. CEA negative or focally positive carcinomas and CEA positive tumours with membranous immunoreactivity were significantly more often observed in the group of poorly differentiated carcinomas (P greater than 0.001), but showed no significant correlation with stage of tumour extension (P = 0.11). Also, these carcinomas demonstrated a more aggressive course in patients compared to CEA positive tumours with an apical/cytoplasmic CEA expression pattern. We, therefore, conclude that determination of the pattern of CEA immunoreactivity in large bowel cancer tissue may enable the detection of subgroups of patients with a poor prognosis.     

Prognostic factors of cutaneous melanoma and a new staging system proposed by the American Joint Committee on Cancer (AJCC): validation in a cohort of 1284 patients

This study, involving a cohort of 1284 evaluable patients, validates the American Joint Committee on Cancer (AJCC) proposal for the introduction of ulceration of primary cutaneous melanoma as an independent prognostic factor of survival. In univariate analyses, ulceration (Hazard Ratio (HR) 1.983; P<0.0001; 95% Confidence Intervals (CI) 1.692-2.325) was a predictor of worse overall survival. In multivariate analyses, ulceration (HR 1.302; P=0.022; (95% CI: 1.039-1.633) retained its prognostic significance for survival independent of tumour thickness (HR 1.101; P<0.0001; 95% CI: 1.055-1.150); mitotic activity (HR 1.039; P=0.005; 95% CI: 1.012-1.067); and age (HR 1.009; P=0.006; 95% CI: 1.003-1.016). Ulceration lost its significance in a subgroup analysis of 256 patients with clinically apparent regional lymph node metastases to the number of lymph nodes involved (HR 1.15; P=0.004; 95% CI:1.047-1.263). Ulceration is prognostically significant in the tumour but not the nodal classification of melanoma, with mitotic activity the second most important prognostic factor after tumour thickness.     

Hormonal factors and risks of esophageal squamous cell carcinoma and adenocarcinoma in postmenopausal women

The incidences of esophageal adenocarcinoma and squamous cell carcinoma (SCC) are higher in males than in females. We investigated whether female-related hormonal factors are associated with risks of these two types of esophageal cancer. We examined the association between use of hormone therapy (HT) and the risks of esophageal adenocarcinoma and SCC in postmenopausal women enrolled in the Women's Health Initiative (WHI) clinical trials and observational studies. Twenty-three esophageal adenocarcinoma and 34 esophageal SCC cases were confirmed among the 161,080 participants, after a median of 11.82 years of follow-up. Risk of esophageal SCC was lower among HT users (past users: HR = 0.25, 95% CI: 0.06-1.10 in 2 cases; current users: HR = 0.41, 95% CI: 0.18-0.94 in 9 cases). A decreased esophageal SCC risk was observed for current users of estrogen plus progestin (E+P) therapy (HR = 0.25, 95% CI: 0.07-0.86 in 3 cases) but not for current users of estrogen-only therapy (HR = 0.96, 95% CI: 0.28-3.29 in 6 cases). No association was observed between the use of HT and the risk of esophageal adenocarcinoma. No other reproductive or hormonal factors were significantly associated with the risk of either SCC or adenocarcinoma. Current use of E+P therapy was found to be associated with a decreased risk of esophageal SCC, but no association was observed with esophageal adenocarcinoma. To provide more definitive evidence, a pooled analysis of all available studies or a much larger study would be needed.     

Role of mammography screening as a predictor of survival in postmenopausal breast cancer patients

We examined the effect of population-based screening programme on tumour characteristics by comparing carcinomas diagnosed during the prescreening (N=341) and screening (N=552) periods. We identified screen detected (N=224), interval (N=99) and clinical cancer (N=229) cases. Median tumour size and proportion of axillary lymph node negative cases were 1.5 cm and 65% in the screen detected group, 2.0 cm and 44% in cases found outside the screening, and 3.2 cm and 41% in the cases from the prescreening period. Survival of the breast cancer patients was 66% (95% CI, 60-71%) in the prescreening era group and 73% (95% CI, 66-78%) in the screening era group after 10 years of follow-up. In the screening era group the survival of the screen detected cases was 86% (95% CI, 80-90%) and that of the clinical cancer cases 73% (95% CI, 66-78%) after 10 years. In multivariate analysis the risk of breast cancer death was not significantly different between the prescreening and screening periods (HR 0.82; 95% CI 0.59-1.12, P=0.21). Detection by screening was not an independent prognostic factor in multivariate analysis (HR 0.75; CI 95% 0.50-1.12; P=0.17).     

Motility-related protein (MRP-1/CD9) and KAI1/CD82 expression inversely correlate with lymph node metastasis in oesophageal squamous cell carcinoma

Although the mechanisms of action of the transmembrane superfamilies, motility-related protein-1 (MRP-1/CD9) and KAI1/CD82, are not well known, they are reported to suppress the metastasis of several kinds of cancers. The suppression of cell motility by MRP-1/CD9 may cause suppression of the metastasis. As we could not find any reports concerning the expression of MRP-1/CD9 and KAI1/CD82 in oesophageal cancers we investigated their expression in oesophageal specimens. We conducted immunohistochemical staining for MRP1/CD9 against 108 cases of oesophageal squamous cell carcinoma using anti-MRP-1/CD9 monoclonal antibody M31-15, and for KAI1/CD82 against 104 cases using anti-KAI1/CD82 monoclonal antibody C33. To investigate the gradual expression of MRP-1/CD9 and KAI1/CD82, 24 oesophageal dysplasias were immunohistochemically stained using the same method and then investigated. The expression of both MRP-1/CD9 and KAI1/CD82 were positive on the cell membranes of normal oesophageal epithelial cells, but reduced or negative in the cancer cells. Reduced MRP-1/CD9 expressions significantly correlated to tumour depth (P = 0.0009). We found a significantly greater number of reduced or negative expression of MRP-1/CD9 and KAI1/CD82 in lymph node metastatic cases (P = 0.0003 and P= 0.0129, respectively), but not in distant metastatic cases. The 5-year survival rate of MRP-1/CD9-negative and reduced patients was significantly worse than those of positive patients (n = 108, curative cases, RO). Few cases remained KAI1/CD82-positive (9.6%; 10/104) in oesophageal cancer. Twenty (83.3%) and twenty-two (91.7%) cases out of 24 dysplasias were defined as KAI1/CD82-positive and MRP1/CD9-positive, respectively. The decrease in MRP-1/CD9 and KAI1/CD82 expression may facilitate lymph node metastasis in oesophageal squamous cell carcinomas. Knowing the status of the expression of MRP-1/CD9 appears helpful in predicting the prognosis for each patient.     

Prognostic Impact of Cyclin D1, Cyclin E and P53 on Gastroenteropancreatic Neuroendocrine Tumours

Conventional classifications of gastroenteropancreatic neuroendocrine tumours (GEP- NETs) are ratherunsatisfactory because of the variation in survival within each subgroup. Molecular markers are being foundable to predict patient outcome in more and more tumours. The aim of this study was to characterize theexpression of the proteins cyclin D1, cyclin E and P53 in GEP- NETs and assess any prognostic impact. Tumorspecimens from 68 patients with a complete follow-up were studied immunohistochemically for cyclin D1, cyclinE and P53 expression. High cyclin D1 and cyclin E immunostaining (≥ 5% positive nuclei) was found in 48(71%) and 24 (35%) cases, and high P53 staining (≥ 10% positive nuclei) in 33 (49%) . High expression of P53was more common in gastric neuroendocrine tumors and related to malignant behavior, being associate with aworse prognosis on univariate analysis (RR=1.9, 95%CI=1.1-3.2). High expression of cyclin E was significantlyassociated with shorter survival in the univariate analysis (RR=2.0, 95%CI=1.2-3.6) and multivariate analysis(RR=2.1, 95%CI=1.1-4.0). We found no significant correlation between the expression of cyclin D1 and anyclinicopathological variables. Our study indicated a prognostic relevance for cyclin E and P53 immunoreactivity.Cyclin E may be an independent prognostic factor from the 2010 WHO Classification which should be evaluatedin further studies.     

Insulin-like growth factor binding protein-3, in association with IGF-1 receptor, can predict prognosis in squamous cell carcinoma of the head and neck

The aim of this study was to investigate the prognostic role of insulin-like growth factor-1 receptor (IGF-1R) and IGF binding protein-3 (IGFBP-3) in patients with squamous cell carcinoma of the head and neck (SCCHN). The clinical data of 131 SCCHN patients who had undergone surgical resection were retrospectively reviewed, and their intratumoral expression of IGF-1R and IGFBP-3 was evaluated by immunohistochemistry. Thirty-six cases (27.5%) experienced tumor recurrence during the median follow-up period of 53.7months (95% CI, 19.0-90.7months). IGF-1R-positivity and IGFBP-3-positivity were observed in 96 (73.3%) and 70 cases (53.4%), respectively. IGFBP-3-positivity was associated with shorter time to progression (TTP) by univariate (P=0.03) and multivariate analyses (95% CI, 0.23-0.91), whereas IGF-1R itself failed to show its prognostic relevance. However, it was revealed that the prognostic role of IGFBP-3 expression was dependent on IGF-1R expression in the analysis of four subgroups classified according to IGF-1R and IGFBP-3 expression: the IGF-1R-positive/IGFBP-3-positive subgroup was the best prognostic group, while the IGF-1R-negative/IGFBP-3-positive subgroup was the worst in terms of TTP (P=0.017). In conclusion, it is suggested that IGFBP-3 expression, in a state of co-expression with IGF-1R, can predict poor prognosis in SCCHN patients.