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CD56 Expression Is Associated with Biological Behavior of Pancreatic Neuroendocrine Neoplasms
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The purpose of this study was to evaluate the clinicopathological features and immunohistochemical features of gastrointestinal stromal tumor (GIST), and specifically the expressions of platelet derived growth factor receptor A (PDGFRA), protein kinase C theta (PKC theta), discovered on GIST-1 (DOG-1), p16 and p27.
Total 118 patients who underwent surgical resection for GIST at our institution between Jan 1997 and Dec 2007 were retrospectively studied. Immunohistochemical staining for c-kit, PDGFRA, PKC-theta, DOG-1, p16 and p27 was performed on a tissue microarray of the 118 GIST. The clinicopathologic parameters, the disease-free survival (DFS) and the overall survival rate were analyzed along with immunohistochemistry.
The immunohistochemical stains for c-kit, CD34, PKC-theta, PDGFRA, DOG-1, p16 and p27 were positive in 89.8%, 72.0%, 56.8%, 94.9%, 90.7%, 69.5% and 44.1% of the tumor samples, respectively. The immunohistochemical expression of c-kit was strongly correlated with PKC-theta (p=0.000), DOG-1 (p=0.000) and CD34 (p=0.002). The DFS rate was significantly decreased for the patients with peritoneal GIST, high risk GIST, ≥10 cm-sized GIST, ≥10 mitoses/50 high power fields (HPFs) and p16 positivity (p=0.001, p=0.004, p=0.001, p=0.003 and p=0.028). GISTs ≥10 cm, epithelioid tumor cell type, and c-kit, and DOG-1 negativity were significantly associated with shorter period of overall survival (p=0.048, p=0.006, p=0.000 and p=0.000).
The expression of p16 and no expression of c-kit and DOG-1 in GISTs, as well as peritoneal tumor site, high risk group, large tumor size, epithelioid tumor cell type and numerous mitoses, may be potentially prognostic factors for predicting worse outcome for patients who suffer from GIST.
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A 25% rate of recurrence after performing complete resection in node-negative colon cancer patients suggests that their nodal staging is frequently suboptimal. Moreover, the value of occult cancer cells in tumor-free lymph nodes still remains uncertain. The authors evaluated the prognostic significance of the pathologic parameters, including the lymph node occult disease (micrometastases) detected by immunohistochemistry, in patients with node-negative colon cancer.
The study included 160 patients with curatively resected stage I or II colon cancer and they were without rectal cancer. 2852 lymph nodes were re-examined by re-do hematoxylin and eosin (H-E) staining and immunohistochemical staining. The detection rates were compared with the clinicopathologic characteristics and with the cancer-specific survival.
Occult metastases were detected in 8 patients (5%). However, no clinicopathologic parameter was found to be correlated with the presence of micrometastasis. Twenty patients developed recurrence at a median follow-up of 45.7 months: 14 died of colon cancer and 9 died from noncancer-related causes. Univariate analysis showed that lymphatic invasion and the number of retrieved lymph nodes significantly influenced survival, and multivariate analysis revealed that the stage, the number of retrieved lymph nodes and lymphatic invasion were independently related to the prognosis.
Inadequate lymph node retrieval and lymphatic invasion were found to be associated with a poorer outcome for node-negative colon cancer patients. The presence of immunostained tumors cells in pN0 lymph nodes was found to have no significant effect on survival, but these tumor were identified by re-do H-E staining. Maximal attention should be paid to the total number of lymph nodes that are retrieved during surgery for colon cancer patients.
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The aim of this study was to investigate the prognostic significance of the expression of p53 gene product in operable invasive breast cancer by performing immunohistochemical analysis.
Between January 1993 and December 2001, 440 operable invasive breast cancer patients underwent immunohistochemical staining for p53, and we retrospectively analyzed these results together with the clinical outcomes.
The overexpression of p53 was detected in 51.6% of the cases. The overexpression of p53 was inversely correlated with lymph node metastasis (p=0.005). The tumor size, tumor histology, histologic grade, hormonal receptor status and tumor stage were not related to the overexpression of p53. Multivariate Cox regression analysis indicate that lymph node metastasis, tumor size and the p53 expression were the significant prognostic factors for overall survival; lymph node metastasis, the estrogen receptor status and the p53 expression were the significant prognostic factors for relapse free survival. On the subgroup analysis, the p53 non-expressors showed better 7-year overall survival (92.7% vs. 76.7%, respectively, p=0.011) and relapse free survival (74.9% vs. 57.8%, respectively, p=0.032) than did the p53 overexpressors for the patients with lymph node metastasis. However, for the patients without lymph node metastasis, the survival rates were not different for both the p53 non-expressors and the p53 overexpressors.
Immunohistochemical staining of the p53 gene product was an independent prognostic factor for predicting survival of the lymph node positive invasive breast cancer patients.
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Recent research in molecular biology has identified a significant number of novel markers, which may have diagnostic, prognostic and therapeutic significance. High-throughput tissue array method facilitates the validation of novel markers by enabling the simultaneous analysis of hundreds or thousands of tissue specimens. Tissue array slides can be analyzed using techniques such as immunohistochemistry and in situ hybridization. In this review, we give a brief overview of tissue array method and its application to high throughput clinicopathologic research.
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The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes. MMPs are known to be involved in tumor invasion, and several have been implicated in tumor prognosis. The aim of this study was to evaluate the prognostic significances of the expressions of MMP-7 and -9 in rectal cancer.
The tumor tissues of 87 patients with stage II or III rectal carcinoma that underwent potentially curative resection followed by postoperative adjuvant chemoradiation and 5-fluorouracil based chemotherapy, were investigated immunohistochemically using monoclonal antibodies against MMP-7 and MMP-9. Clinical information, including tumor grades, carcinoembryonic antigen (CEA) levels, and disease-free survival and overall survival were evaluated with respect to the expressions of MMP-7 and -9.
Median follow-up duration was 53.2 months, and median patient age was 55±11 years (range 32~75). MMP-7 expression in tumor tissue was found to be significantly correlated with the presence of nodal metastasis (p=0.029), whilst MMP-9 expression correlated with depth of tumor invasion (p=0.019). No relationships were found between the expressions of MMP-7 or -9 and age, sex, tumor size, tumor grade, or CEA level. Univariate analysis showed that MMP-7 expression was associated with poor 5-year overall survival (12.8 months vs. 65.3 months, p=0.0405). Multivariate analysis confirmed that MMP-7 was independently associated with an adverse outcome (Relative risk: 1.415, p=0.027). However, MMP-9 expression was not found to be related to clinical outcome.
MMP-7 expression in tumor tissue is associated with lymph node metastasis and a poor 5-year overall survival in rectal cancer patients.
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Maspin is known as a tumor suppressor gene, but its significance has been questioned in various human cancers. The aim of this study was to investigate the expression pattern of Maspin in human gastric adenocarcinomas and its possible correlation with clinicopathological findings.
The expression of Maspin mRNA was measured by nested RT-PCR using 60 frozen adenocarcinomas of the stomach and 31 noncancerous tissues from the proximal resection margin. Immunohistochemical study for Maspin protein expression was carried out using 62 paraffin-embedded tissues, composed of both cancer and noncancerous tissues.
Maspin mRNA expression was detected in 80.0% (48 of 60) of the gastric adenocarcinomas, but in only 22.6% (7 of 31) of the normal gastric mucosa (p<0.001). The positive rate of Maspin protein expression was higher in the adenocarcinomas than the normal tissues (62.9% vs. 27.4%, p<0.05). In addition, the intestinal type of tumors showed significantly higher expression levels compared to the diffuse type of tumors (81.5% vs. 48.6%, p<0.05).
Our results suggest that Maspin is frequently expressed in human gastric cancers, and its expression might be associated with tumorigenesis of the intestinal type of gastric cancer.
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Gallbladder cancer is a malignancy with poor prognosis, predominantly resulting from invasion and metastasis. Our previous studies have demonstrated that prostaglandin E2 (PGE2), generated by cyclooxygenase 2 (Cox-2), transactivates epidermal growth factor receptor (EGFR), c-Met and β-catenin; thus, enhancing colon cancer cell growth and invasiveness
Thirty-five specimens of invasive gallbladder cancer, 8
Cox-2, c-Met, β-catenin, c-erbB2 and EGFR were over-expressed in 80, 74, 71, 62 and 11% of invasive gallbladder cancers, respectively. β-catenin was expressed in 80% of non-malignant specimens, exclusively in the cell membrane, while the cancer specimens showed cytoplasmic and/or nuclear staining. Significantly higher Cox-2, c-Met and β-catenin expressions were present in cancer cells of the invasive front than in the tumor central areas (p<0.001), and these expressions were significantly (p=0.01) associated with the invasion depth. Co-expressions of Cox-2, c-Met, β-catenin and c-erbB2 were present in 42% of the specimens in cancer cells forming the invasive front.
The overexpressions, and often co-localizations, of Cox-2, c-Met and β-catenin in cancer cells forming the invasive front indicate their local interactions and important roles in invasion.
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DNA-PKcs is one of the DNA repair genes. It was recently found that hyperplasia and dysplasia of the intestinal mucosa and the production of aberrant crypt foci were developed in DNA-PKcs-null mice, and this suggests a suppressive role for DNA-PKcs in tumorigenesis.
To investigate the possible relationship between the clinico-pathologic characteristics and the survival of gastric cancer patients, the expression status of DNA-PKcs was determined in 279 consecutive gastric cancers. Immunohistochemical analysis was performed to evaluate the expression levels of DNA-PKcs protein by using the tissue array method.
Out of 279 consecutive gastric cancers, 63 cases (22.6%) showed the loss of DNA-PKcs expression. The loss of DNA-PKcs expression was significantly associated with advanced cancer (p<0.001), lymphatic invasion (p=0.001), lymph node metastasis (p=0.009), and advanced pTNM stage (p=0.009). Univariate survival analysis revealed that patients with the loss of DNA-PKcs expression had significantly poorer survival than those patients with intact DNA-PKcs expression (p=0.004). Moreover, the loss of DNA-PKcs expression was identified to correlate with a lower survival in the subgroup of stage I gastric cancer patients (p=0.037).
The loss of DNA-PKcs expression was found in 23% of human gastric cancers and this was identified to significantly correlate with poor patient survival, especially for stage I gastric cancer patients.
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The human CD24 antigen is a small heavily glycosylated cell surface protein, which is expressed in hematological malignancies, as well as in a large variety of solid tumors. Its expression is now known to be related to the prognosis of several kinds of tumors. This study is designed to examine the prognostic significance of CD24 in Korean gastric cancer patients.
In the present study, we examined CD24 expression in 300 consecutive cases of gastric carcinoma by immunohistochemical staining using the tissue-array method. We also investigated the clinicopathological profiles related to CD24 expression.
One hundred and three cases out of 300 (34.3%) showed the positive expression of CD24. The altered expression of CD24 was significantly associated with differentiated cancer (p=0.003), the intestinal subtype according to the Lauren classification (p<0.001), the advanced stage cancer (p=0.027), with lymphatic invasion (p=0.038) and with vascular invasion (p=0.006). The survival analysis revealed that the patients with CD24 positive expression showed significantly poorer survival than those without CD24 expression. Moreover, a combined evaluation revealed that PTEN+/CD24- cases showed the best survival compared to other groups (p=0.01).
Positive CD24 expression occurs in a subset of gastric carcinomas and it correlates significantly with lymphatic invasion, blood vessel invasion and poor survival.
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The purpose of this study was to investigate the prognostic significance of the expression of EGFR and C-erbB-2 gene products by immunohistochemical analysis for curatively resected gastric adenocarcinoma.
Between January 1996 and December 2001, 739 patients with curatively resected gastric cancer patients underwent immunohistochemical staining for EGFR and C-erbB-2 proteins, and we retrospectively analyzed their correlation with the clinical outcome.
The overexpressions of EGFR and C-erbB-2 were 25.4% and 26.2%, respectively. The overexpressions of EGFR was associated with the more poorly differentiated tumor (p=0.000) and with neuronal invasion (p=0.03). Overexpression of C-erbB-2 was associated with less vascular invasion (p=0.001). Tumor depth or node metastasis was not related to the overexpression of EGFR or C-erbB-2. The seven-year overall survival and relapse-free survival rates were 87.2% and 75.8%, respectively. Upon multivariate Cox regression analysis, the tumor stage, tumor size and patient age were important prognostic factors for overall survival, and tumor stage was the important factor for relapse-free survival. Overexpressions of EGFR or c-erbB-2 were not significant prognostic factors.
Immunohistochemical staining of EGFR and C-erbB-2 gene products were not independent prognostic factors for predicting the overall survival and the relapse-free survival in curatively resected gastric cancer.
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Increasing experimental evidence indicates that abnormal expression of c-kit may be implicated in the pathogenesis of a variety of solid tumors. It has been reported that over 70% of small cell lung cancer (SCLC) contain the c-kit receptor. In the present study, a c-kit analysis has been extended to non-small cell lung cancer (NSCLC). The expressions of p53, vascular endothelial growth factor (VEGF) and cd34, in addition to c-kit, were evaluated to investigate the correlations between these proteins and to determine their potential relationships with the clinicopathological data.
Paraffin-embedded tumor sections, obtained from 147 patients with NSCLC, were immunohistochemically investigated using anti-c-kit, anti-p53, anti-VEGF and anti-cd34 antibodies.
c-kit was expressed in 40 (27%) of the tumors examined: 27% of the adenocarcinomas, 27% of the squamous cell carcinomas and 29% of the undifferentiated carcinomas. p53 and VEG F immunoreactivities were present in 107 (73%) and 110 (75%) carcinomas, respectively. Anti-cd34 was negative in all samples. No associations were established among these proteins. The c-kit, however, showed a strong correlation with the T factor: T1 (n=11), 0%; T2 (n=49), 16% and T3 (n=87), 37% (p=.006).
It is suggested that in NSCLC c-kit is expressed relatively frequently and may become a therapeutic target for the patients with inoperable or recurrent c-kit positive tumors. The alterations in p53 probably constitute an early event, whereas the activated c-kit may contribute to tumor progression.
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