Clusterin Expression Inversely Correlates with Chemosensitivity and Predicts Poor Survival in Patients with Locally Advanced Cervical Cancer Treated with Cisplatin-Based Neoadjuvant Chemotherapy and Radical Hysterectomy

Overexpression of clusterin, an antiapoptotic molecule, has been reported to induce resistance to chemotherapy in a variety of cancer cell types. The aim of this study was to evaluate the significance of clusterin expression to predict response to platinum-based neoadjuvant chemotherapy and survival of patients with invasive cervical cancer who subsequently underwent radical hysterectomy. Biopsy specimens of invasive cervical cancer before neoadjuvant chemotherapy were obtained from 46 patients who subsequently underwent radical hysterectomy at Hokkaido University Hospital and Gunma University Hospital from 1994 to 2007. The expression of clusterin protein was analyzed by immunohistochemistry. Findings were evaluated in relation to several clinicopathological factors. Survival analyses were performed by the Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. Clusterin protein was mainly present in the cytoplasm of cervical cancer cells. The expression of clusterin protein in cervical cancer tissues before neoadjuvant chemotherapy was significantly related to poor response to chemotherapy among factors analyzed. Univariate analysis on prognostic factors showed that response to chemotherapy (p = 0.01), lymph node metastasis (p = 0.02), and clusterin expression (p = 0.02) were related to survival. Multivariate analysis revealed that lymph node metastasis (p = 0.03), and clusterin expression (p = 0.03) were independent prognostic factors for survival of cervical cancer patients. We conclude that clusterin expression could be a new molecular marker to predict response to platinum-based chemotherapy and survival of patients with cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy.     

Relationship among COX-2 protein expression,PGs levels and biologic behavior in ovarian carcinoma tissues

Recent epidemiological studies shows thatlong-term use of aspirin or other NSAIDs (non-steroidanti-inflammatory drugs, NSAIDs) reduces the risk ofcolon cancer development by 40% — 60%[1,2].Although the exact mechanisms of NSAIDs on cancerprevention have not been clarified, one of them maybe via the inhibition of COX-2 enzyme. In the presentstudy, we investigated the COX-2 protein,prostaglandin (PG)E2, 6-keto-PGF1α and thromboxane(TX)B2 by Western blot analysis and radio-immunoass…     

Prognostic Significance of Phosphatase of Regenerating Liver-3 Expression in Ovarian Cancer

Phosphatase of regenerating liver-3 (PRL-3) is overexpressed in several human cancers and associated with tumor progression, invasion and metastasis. However, the correlation between PRL-3 expression and clinical outcome in ovarian cancer has not been studied. In the present study, we investigated the expression of PRL-3 in 119 ovarian cancers and 30 normal ovarian tissues by immunohistochemistry with an anti-PRL-3 mouse monoclonal antibody 3B6, and analyzed its relationship with clinicopathologic factors and survival. The results demonstrated that PRL-3 expression was significantly higher in ovarian cancers compared to normal ovarian tissues (P < 0.001). PRL-3 expression is not correlated with patient age, menstruation, tumor size, histological type, residual tumor, or other clinical findings. The patients with PRL-3-positive tumors had a significant poor prognosis than those with PRL-3-negative tumors. Univariate analysis identified PRL-3 expression as a poor outcome predictor (HR 1.925, 95% CI, 1.046–3.544, P = 0.035). Multivariate analysis indicated that PRL-3 expression was an independent prognostic factor of borderline significance (HR 1.695, 95% CI, 0.914–3.145, P = 0.094). Our results suggest that PRL-3 may serve as a valuable marker for diagnosis of ovarian cancer and as a potential independent prognostic factor for ovarian cancer.     

Extracellular microRNA profiling for prognostic prediction in patients with high-grade serous ovarian carcinoma

High-grade serous ovarian carcinoma is a leading cause of death in female patients worldwide. MicroRNAs (miRNAs) are stable noncoding RNAs in the peripheral blood that reflect a patient’s condition, and therefore, they have received substantial attention as noninvasive biomarkers in various diseases. We previously reported the usefulness of serum miRNAs as diagnostic biomarkers. Here, we investigated the prognostic impact of the serum miRNA profile. We used the GSE106817 dataset, which included preoperative miRNA profiles of patients with ovarian malignancies. Excluding patients with other malignancy or insufficient prognostic information, we included 175 patients with high-grade serous ovarian carcinoma. All patients except four underwent surgery and received chemotherapy as initial treatment. The median follow-up period was 54.6 months (range, 3.5-144.1 months). Univariate Cox regression analysis revealed that higher levels of miR-187-5p and miR-6870-5p were associated with both poorer progression-free survival (PFS) and overall survival (OS), and miR-1908-5p, miR-6727-5p, and miR-6850-5p were poor prognostic indicators of PFS. The OS and PFS prognostic indices were then calculated using the expression values of three prognostic miRNAs. Multivariate Cox regression analysis showed that both indices were significantly independent poor prognostic factors (hazard ratio for OS and PFS, 2.343 [P = .015] and 2.357 [P = .005], respectively). In conclusion, circulating miRNA profiles can potentially provide information to predict the prognosis of patients with high-grade serous ovarian carcinoma. Therefore, there is a strong demand for early clinical application of circulating miRNAs as noninvasive biomarkers.     

Endoglin (CD105) expression in ovarian serous carcinoma effusions is related to chemotherapy status

Endoglin (CD105), a cell surface co-receptor for transforming growth factor-β, is expressed in proliferating endothelial cells, as well as in cancer cells. We studied endoglin expression and its clinical relevance in effusions, primary tumors, and solid metastatic lesions from women with advanced-stage ovarian serous carcinoma. Endoglin expression was analyzed by immunohistochemistry in effusions (n = 211; 174 peritoneal, 37 pleural). Cellular endoglin staining was analyzed for association with the concentration of soluble endoglin (previously determined by ELISA) in 95 corresponding effusions and analyzed for correlation with clinicopathologic parameters, including survival. Endoglin expression was additionally studied in 34 patient-matched primary tumors and solid metastases. Carcinoma and mesothelial cells expressed endoglin in 95/211 (45%) and 133/211 (63%) effusions, respectively. Carcinoma cell endoglin expression was more frequent in effusions from patients aged ≤60 years (p = 0.048) and in post- compared to prechemotherapy effusions (p = 0.014), whereas mesothelial cell endoglin expression was higher in prechemotherapy effusions (p = 0.021). No association was found between cellular endoglin expression and its soluble effusion concentration. Endoglin was expressed in 17/34 (50%) primary tumors and 19/34 (56%) metastases, with significantly higher percentage of immunostained cells in solid metastases compared to effusions (p = 0.036). Endoglin expression did not correlate with survival. Tumor cell endoglin expression is higher in post- vs. prechemotherapy effusions, whereas the opposite is seen in mesothelial cells. Together with its upregulation in solid metastases, this suggests that the expression and biological role of endoglin may differ between cell populations and change along tumor progression in ovarian carcinoma.     

Prognostic and predictive values of pERK1/2 and pAkt-1 expression in non-small cell lung cancer patients treated with adjuvant chemotherapy

Ras/ERK and PI3K/Akt pathways are reported to play a prognostic role and contribute to drug resistance in many cancers. The objective of this study was to explore associations between the expression levels of several molecules in Ras/ERK and PI3K/Akt pathways and their clinical significance in predicting the effectiveness of postoperative adjuvant chemotherapy in patients with non-small cell lung cancer (NSCLC). The expressions of K-ras, Raf-1, ERK1/2, phosphorylated ERK1/2 (pERK1/2), Akt-1, phosphorylated Akt-1 (pAkt-1), and Bcl-2 were detected by immunohistochemistry in tumor specimens from 144 NSCLC patients. The correlations between the expression levels of these molecules and the clinicopathological characteristics were analyzed. Patient survival was analyzed by Kaplan–Meier method, log-rank test, and Cox regression. The positive expression rates of K-ras, Raf-1, ERK1/2, pERK1/2, Akt-1, pAkt-1, and Bcl-2 were 21.5%, 41.7%, 59.7%, 27.1%, 50.7%, 36.1%, and 30.6%, respectively. Univariate analysis showed that patients with pERK1/2-positive (P = 0.01), Bcl-2-positive (P = 0.023), or pAkt-1 negative (P = 0.021) had significantly better recurrence-free survival (RFS) than those with pERK1/2-negative, Bcl-2-negative, or pAkt-1-positive. Multivariate analysis showed that earlier stage (P ≤ 0.001), non-adenocarcinoma (P ≤ 0.001), pERK1/2-positive (P ≤ 0.001), and pAkt-1-negative (P = 0.016) were independent prognostic factors for a better RFS in NSCLC. pERK1/2-positive and pAkt-1-negative proved to contribute to a better RFS in postoperative NSCLC patients who received adjuvant chemotherapy after taking the stage and histological subtype into account. pERK1/2 and pAkt-1 could be considered as new independent prognostic biomarkers for predicting RFS and selecting patients who are more likely to benefit from postoperative adjuvant chemotherapy.     

Combination chemotherapy with paclitaxel and intraperitoneal cisplatin for ovarian cancer with disseminated lesions in the peritoneum and the diaphragm

Background: In ovarian cancer, the management of micrometastases disseminated in the peritoneal cavity is extremely important. We performed intravenous paclitaxel (PAC) infusion combined with cisplatin (CDDP) intraperitoneal infusion for progressive ovarian cancer. Methods: Twelve patients with progressive epithelial ovarian cancer (FIGO IIIc), which was resected using an optimal method at primary surgery, except for disseminated lesions in the peritoneum and the diaphragm, were studied. At primary surgery, a reservoir was placed in the peritoneal cavity. If metastases were identified in the diaphragm, then another reservoir was also placed in the subdiaphragm (double reservoirs). The basic regimen was set at 175 mg/m² with divided doses of PAC and 75 mg/m² CDDP by intraperitoneal injection. When a double reservoir was used, 30 mg/m² of subdiaphragmatic CDDP and 45 mg/m² of intraperitoneal CDDP were administered. The patients received five courses of this regimen. The response to the therapy was evaluated with tumor markers, and by using cytodiagnoses on the peritoneal washing fluid collected from the reservoirs. Results: After five courses of the chemotherapy, the tumor marker levels and cytodiagnoses of all patients became negative. With reference to adverse effects, grade 3–4 neutropenia was detected in 2 patients (16.6%), peripheral neuropathy was detected in 4 patients (33.3%), and alopecia was detected in 11 patients (91.6%). The median follow-up period was 29.2 months and median progression-free survival was 25.6 months. Conclusion: The combination chemotherapy with intravenous PAC and intraperitoneal CDDP was effective on ovarian cancer with disseminated lesions in the peritoneum and the diaphragm, having only mild adverse effects. Received: February 20, 2002 / Accepted: October 9, 2002 Correspondence to:F. Terauchi     

Association of Expression of Kruppel-Like Factor 4 and Kruppel-Like Factor 5 with the Clinical Manifestations of Breast Cancer

Kruppel-like factors (KLFs) are import modulators of cell proliferation, differentiation, and transformation and have recently been considered possible prognostic factors in breast cancer. In this study, we investigated the correlation between KLF4 and KLF5 expression and the clinical manifestations of breast cancer by immunohistochemical analysis. We observed increased KLF4 and KLF5 expression in tumor cells (invasive and in situ carcinomas), consistent KLF4 and KLF5 expression in in situ and invasive carcinomas, significant associations between KLF4 expression and tumor grade (p = 0.033), size (p = 0.035) and stage (p = 0.006), and an association between KLF5 expression and tumor grade (p = 0.033). Interestingly, we observed a relationship between increasing age and KLF4 expression (p = 0.007), with a tendency towards greater expression in tumor cells in patients over 50 years old. Moreover, KLF5 nuclear localization was restricted to non-tumor breast ducts and lobules; however, loss of nuclear expression of KLF5 in in situ and invasive carcinomas was observed. Although the mechanism of the loss of KLF5 nuclear expression is not clear, this phenomenon may imply a possible tumor-suppressor-like role for KLF5 in breast cancer tumorigenesis. The expression of KLF4 and KLF5 in breast cancer patients in Taiwan is similar to that in Western countries, except for the uncertainty surrounding its prognostic significance. Further clarification of the underlying mechanisms of KLF4 and KLF5 expression and their correlations with breast cancer outcomes is necessary.     

Prognostic Value of Raf Kinase Inhibitor Protein in Esophageal Squamous Cell Carcinoma

Raf kinase inhibitory protein (RKIP, also PEBP1) is involved in regulation of multiple cellular signaling processes and suppressing metastasis in animal models. Downregulation of RKIP expression has been shown to promote tumor progression in a variety of human cancers. However, its role and clinical significance in resectable esophageal squamous cell carcinoma (ESCC) is still scanty. The purpose of this study was to investigate the prognostic significance of RKIP expression by immunohistochemistry in a group of patients with ESCC treated with surgical resection. RKIP expression in 233 surgically resected ESCC specimens and 49 cases of adjacent normal tissues was detected by using immunohistochemical staining. The clinical and prognostic significance of RKIP expression was statistically analyzed. Kaplan-Meier analysis was used to compare the postoperative survival between groups. Significant downregulation was noted for RKIP protein in ESCCs, compared to adjacent normal tissues (p < 0.001). A lower disease-free survival and overall survival of ESCC was found in patients whose tissues had low RKIP expression (both P < 0.001). In addition, RKIP expression could stratify the patient survival (disease-free survival/overall survival) in stage II (P = 0.01 and 0.02, repectively). The Cox proportionate hazard regression model also established that low expression of RKIP was significantly correlated with increased risk (RR = 3.572) of recurrence compared with high RKIP expression (P < 0.001). Furthermore, the results of multivariate analysis suggested that RKIP expression (P < 0.001) was an independent factor that affected overall survival. These findings suggest that the low expression of RKIP be associated with poor survival in resectable ESCC patients.     

Prognostic impact of vascular endothelial growth factor-A expression in resected gallbladder carcinoma

The purpose of this study was to evaluate the value of vascular endothelial growth factor-A (VEGF-A) expression and other confirmed prognostic factors in predicting clinical outcomes after the resection of gallbladder carcinoma (GBC). Between January 1999 and January 2006, a total of 84 consecutive and non-selected patients who underwent resection for GBC were retrospectively reviewed. Of the 84 patients studied, 45 cases (53.6%) exhibited high expression of VEGF-A and were placed into the high expression group. The 14 cases (16.7%) that showed no VEGF expression and the 25 cases (29.7%) that had lower VEGF-A levels were pooled into the low expression group (46.4%). There was a relationship between VEGF-A status and pM stage (P = 0.027) as well as histologic differentiation (P < 0.001). In univariate analysis by log-rank test, ECOG performance status, CA 19-9, pN stage, pM stage, histologic differentiation, and VEGF-A expression were significant prognostic factors (P = 0.015, 0.001, 0.020, <0.001, 0.040, and <0.001, respectively). Multivariate analysis revealed that pN status and VEGF-A expression maintained independent prognostic influence on overall survival (P < 0.001 and P = 0.013, respectively). VEGF-A expression has a positive correlation with pM stage and histologic differentiation. pN status and VEGF-A expression were independent prognostic factors of overall survival in patients with resected GBC.     

Weapons Ovarian Epithelial Tumors May Use in Immune Escape: An Immunohistochemical Correlational Study

Investigate FasL and survivin expression in a series of primary ovarian surface epithelial tumors, correlate their expression with each other, and characterize the presence of CD3+ T-lymphocytes in studied tumors and determine whether their presence correlates with FasL or survivin expression in malignant cases. FasL and survivin expression was assessed in 54 ovarian epithelial tumors. The results were compared between different tumor types and grades. Correlation between both markers’ expression in all studied tumors was done. Either marker’s expression was compared to the mean CD3+ T-lymphocytes per HPF in the studied malignant tumors. Either FasL or survivin expression was significantly higher in malignant versus benign ovarian epithelial tumors (p < 0.001 for both) and both markers were strongly correlated to each other (r = 0.877 & p < 0.001). Malignant tumors show significantly higher mean CD3+ T-lymphocytes than benign and borderline tumors. The mean CD3+ T-lymphocytes decrease significantly on increasing malignant tumor grade (p = 0.019) and expression of both FasL and survivin (r = −0.729, -0.582, respectively & p < 0.001 for both). The higher expression of FasL and survivin in malignant as compared to benign ovarian tumors suggest that they have a significant role in pathogenesis of ovarian carcinoma. Both markers are strongly correlated to each other and may contribute to immune escape of ovarian carcinoma as their higher expression is associated with decreased number of CD3 + T-lymphocytes.     

Bcl-2 as a predictor of chemosensitivity and prognosis in primary epithelial ovarian cancer

This retrospective study of ovarian cancer aimed to elucidate whether expression of apoptosis-related proteins, bcl-2, p53 or MDM-2, is associated with resistance to chemotherapy, especially cisplatin (CDDP) based chemotherapy. Expression of bcl-2, p53 and MDM-2 was assessed by immunohistochemical staining of tumour tissues collected at initial surgery prior to treatment with CDDP-based chemotherapy. Among 66 patients with advanced ovarian cancer with measurable tumour following surgery and evaluable for response to chemotherapy, 42, 45 and 56% were positive for bcl-2, p53 and MDM-2, respectively. Significantly fewer tumours of patients who had a complete response to chemotherapy (CR) showed positivity for bcl-2 (2/20) than for p53 (6/20) and MDM-2 (8/20, P < 0.001). There was an inverse correlation between bcl-2 staining and initial response to chemotherapy, especially in serous and endometrial adenocarcinomas. In patients with stage III-IV, serous or endometrioid adenocarcinomas, significantly poorer survival was seen for those with bcl-2 positive tumours than those with negative bcl-2 staining (P = 0.0064). p53 and MDM-2 were not correlated with initial response to chemotherapy. Multivariate analysis revealed that bcl-2, residual tumour size and histology were significant independent prognostic factors. These results suggest that bcl-2 can be a possible predictor of response to chemotherapy and prognosis in patients with advanced ovarian carcinoma.     

Is nuclear expression of Y box-binding protein-1 a new prognostic factor in ovarian serous adenocarcinoma?

BACKGROUND: Nuclear expression of Y box-binding protein (YB-1), a member of the DNA binding protein family, has been reported to be much more highly concentrated in cisplatin-resistant cell lines than in their parental counterparts, suggesting an ability to limit cisplatin sensitivity. Moreover, YB-1 plays a key role in P-glycoprotein expression. Because ovarian carcinoma traditionally has been treated with cisplatin-based chemotherapy, the sensitivity of the tumors to chemotherapy could reflect a particular prognosis in patients with ovarian carcinoma. The aim of the current study was to determine whether YB-1 expression correlated with prognosis in ovarian serous adenocarcinoma patients. METHODS: The expression of YB-1 in the nucleus was examined immunohistochemically in 42 paraffin embedded primary Stage III (International Federation of Gynecology and Obstetrics) serous ovarian carcinoma tumors extirpated by primary surgery at Kyushu University Hospital between 1985-1995. RESULTS: Of the 40 primary ovarian tumors examined, 12 (30%) were positive for YB-1 expression in the nucleus. There was no significant difference in intraperitoneal stage, histologic grade, or residual tumor size after primary surgery between patients with tumors with positive and those with negative nuclear expression of YB-1 protein. The disease free survival curve for patients whose tumors were positive for nuclear expression of YB-1 protein was significantly worse than that for patients whose tumors were negative (P = 0.0025). P-glycoprotein was overexpressed in 4 of 12 tumors with nuclear YB-1 expression (33%) but there was no statistical significance between the expression of nuclear YB-1 and P-glycoprotein. CONCLUSIONS: The expression of YB- 1 protein in the nucleus may be considered a useful prognostic marker and also may reflect the sensitivity of ovarian serous adenocarcinoma to chemotherapy.     

CD10 Expression in Epithelial and Stromal Cells of Non-small Cell Lung Carcinoma (NSCLC): A Clinic and Pathologic Correlation

CD10 is a zinc dependent metallopeptidase, and its expression in stromal and/or epithelial cells of many carcinomas has been suggested to have prognostic value. This study investigates CD10 expression in epithelial and stromal cells of non small cell lung carcinoma (NSCLC), and evaluates its prognostic value for this tumor and its histologic subtypes. Sixty-six cases of NSCLC [35 cases of nonsquamous cell carcinoma (NSCC) and 31 cases of squamous cell carcinoma (SCC)] were analyzed immuno-histochemically for CD10 antibody. Fisher’s exact test and univariate survival analyses were performed. Comparison of clinicopathologic characteristics for NSCLC showed that only stromal CD10 expression had worse prognostic impact, associated with the presence of recurrence (p = 0.001), death (p = 0.006) and disease positivity (p = 0.001). For SCC, CD10 was found to be expressed mainly in the stromal cells, and was associated with a decreased survival (p = 0.000) and disease free survival (p = 0.000). CD10 expression was restricted to the epithelial cells in NSCC and associated with an increased disease free survival (p = 0.036). Stromal CD10 expression apppears to be a worse prognostic factor in NSCLCs. CD10 which is expressed in different cell components of SCC and NSCC appears to have opposing effects on the behaviour of these histologic types.     

Clinicopathologic and Prognostic Significance of CD24 in Gallbladder Carcinoma

CD24, a small cell surface protein, has emerged as a novel oncogene and prognostic factor for poor outcomes in many human cancers. However, the association of CD24 expression pattern in gallbladder carcinoma with patients’ survival has not been reported. To shed light on this problem, we performed an analysis on the relationship between CD24 expression and prognostic parameters in gallbladder carcinoma. CD24 expression was examined immunohistochemically on paraffin-embedded tissue specimens from 207 patients who underwent surgical treatment for gallbladder carcinoma in the period between January 2004 and May 2009. CD24 positive expression was found in 78.7% (163/207) of the tumor samples. It tended to be associated positively with tumor histological grades and pT stages. Kaplan-Meier curves showed that CD24 positive expression was significantly related to decreased overall survival (p < 0.01). Multivariate analysis, including CD24 expression, pT stage, tumor grade, and resection margin involvement, showed that CD24 positive expression was an independent prognostic marker in gallbladder carcinoma (p = 0.02; relative risk = 1.6). Our data demonstrate for the first time that CD24 is an important marker of malignancy and poor prognosis in gallbladder carcinoma. Its detection combined with cancerous staging may increase the ability of investigators to predict the prognosis of patients with gallbladder carcinoma. Furthermore, the CD24 antigen represents an attractive target for specific therapies with monoclonal antibodies in patients with CD24-overexpressing gallbladder carcinoma, so the detection of CD24 may help clinicians select patients likely to benefit from novel molecular therapies.     

Maspin,VEGF and p53 Expression in Small Biopsies of Primary Advanced Lung Cancer and Relationship with Clinicopathologic Parameters

Maspin, one of the serine protease inhibitors, has been shown to inhibit tumor progression and metastasis. We aimed to investigate maspin, p53 and VEGF expression in patients with squamous cell carcinoma (SCC), adenocarcinoma (AC) and small cell lung carcinoma (SCLC). The study included 28 SCC, 18AC, 17 SCLC biopsy samples. We used the streptavidin biotin immunoperoxidase method to test for maspin, p53 and VEGF antibodies. Medical records of these patients were reviewed from archival files. Cytoplasmic maspin expression was detected in 89.3%, 77.8%, 52.9% of SCC, AC and SCLC, respectively. The rate was significantly higher in non-small cell lung cancer (NSCLC) and SCC than SCLC (p = 0.013, p = 0.021, respectively). The mean percentages of maspin expression were significantly higher in NSCLC, SCC and AC than in SCLC (p = 0.0001, p = 0.0001, p = 0.038, respectively). In ACs, maspin and p53 expressions were correlated, although this was not statistically significant (p = 0.053, r = 0.464), and maspin positive cases had a significantly higher T status compared to negative cases (p = 0.036). In SCC, the stage of disease was positively correlated with p53 (p = 0.007, r = 0.536) and negatively correlated with VEGF expression (p = 0.013, r = −0.498). Multivariate analysis demonstrated that stage of disease was a significant independent prognostic parameter in NSCLC (95% confidence interval: 1.067–3.969; p = 0.031). Although maspin expression is higher in SCC and AC, and is related with higher T status in AC, our data did not indicate its prognostic significance. Larger scale studies are needed to reveal the exact role of maspin in lung cancer pathogenesis.     

Expression and Prognostic Value of PRL-3 in Human Intrahepatic Cholangiocarcinoma

Phosphatase of regenerating liver (PRL)-3 is involved in the metastasis of various tumors, but the expression of PRL-3 and its possible role in primary intrahepatic cholangiocarcinoma (ICC) has not been reported yet. In this study, we assessed the expression levels of PRL-3 by immunohistochemistry in 102 primary ICC samples, 62 matched lymph node metastases (LNM) and 102 adjacent normal liver tissues. Then we investigated the relationship between PRL-3 expression and clinicopathologic factors. Survival analysis was performed to determine the prognostic significance of PRL-3 expression in ICC. Immunochemistry results suggested PRL-3 expression was negative or weak in non-neoplastic intrahepatic bile ducts of adjacent liver tissue. In primary lesion and LNM high PRL-3 expression was frequently detected. Furthermore, the rate of high PRL-3 expression in LNM was higher than that in primary lesion (80.6% vs. 47.1%, P < 0.05). High expression of PRL-3 in primary tumors was significantly associated with TNM (P < 0.001), T stage (P < 0.001), vascular invasion (P = 0.002), and LNM (P < 0.001). Survival analysis results with Kaplan-Meier method and Cox proportional hazard model indicated high expression of PRL-3 was correlated with decreased overall survival and was an independent prognostic marker of overall survival. Thus, our results suggested high expression of PRL-3 was correlated with progression and metastasis of ICC and indicated negative prognostic impact. PRL-3 might serve as a novel prognostic marker for patients with ICC.     

Clinical and Prognostic Value of the Presence of Irregular Giant Nuclear Cells in pT1 Ovarian Clear Cell Carcinoma

In the early stages of epithelial ovarian cancer, histopathological grading is important. However, the grading of ovarian clear cell carcinoma (OCCC) remains controversial. We aimed to identify irregular giant nuclear cells (IGNCs) by a simple method in clinical practice, and to evaluate the prognostic value of IGNCs in pT1 OCCC. Eighty-seven pT1 OCCC patients who underwent initial surgery at Jikei University Kashiwa Hospital, Chiba, Japan, were retrospectively assessed. Paraffin-embedded tissue sections (PTSs) stained with hematoxylin and eosin were reviewed. Giant nuclear cells (GNCs) were defined as cells with a nuclear length of more than twice the median nuclear length. GNCs with irregular nuclear circumferences were defined as IGNCs. Cases where one or more GNCs existed and where IGNCs accounted for >10% of the GNCs were classified as IGNC-positive. We also attempted to identify IGNCs on touch imprint cytology smears (TICSs). Among the 87 cases, 68 were IGNC-negative and 19 were IGNC-positive. The 5-year disease-free and overall survival rates were 88.9% and 90.3% in the total patients, 98.3% and 100% in the IGNC-negative group, and 59.7% and 62.0% in the IGNC-positive group, respectively. These survival rates were significantly lower in the IGNC-positive group than in the IGNC-negative group (adjusted hazard ratio = 14, 95% confidence interval = 2.7–124 and adjusted hazard ratio = 25, 95% confidence interval = 2.9–768, respectively). Prognostic differences were not identified for other factors. IGNC identification on 28 available TICSs predicted IGNC identification on PTSs (sensitivity = 50.0%, specificity = 100%, P = 0.007). The presence of IGNCs has clinical and prognostic value for pT1 OCCC.     

Expression of C-reactive protein and cyclooxygenase enzyme-2 in clear cell renal cell carcinoma: correlation with pathological parameters in 110 patients

C-reactive protein is produced in response to cytokines such as interleukin (IL)-6. It is known that increased plasma IL-6 levels induce increased hepatic and intratumoral production of C-reactive protein. Cyclooxygenase enzyme-2 is induced by various stimuli, including inflammation and various growth factors. Expression of these two markers has not been well studied in clear cell renal cell carcinoma. The objective of this study is to correlate the expression of C-reactive protein and cyclooxygenase enzyme-2 in clear cell renal cell carcinoma with pathologic parameters. A search of the surgical pathology and consultation files at our institution was performed for nephrectomy specimens with clear cell renal cell carcinoma from 2007 to 2008. Immunohistochemical stains for C-reactive protein and cyclooxygenase enzyme-2 were performed. Staining intensity was graded as 0, 1+, 2+, and 3+. The staining intensity was then correlated with pathologic stage and Fuhrman nuclear grade for each case. A total of 110 cases were identified. Strong expression of C-reactive protein was associated with higher Fuhrman nuclear grade and pathologic stage, and the strength of correlation was statistically significant (p = 0.01 and p = 0.001), respectively. However, cyclooxygenase enzyme-2 expression did not show statistically significant correlation with both pathologic stage and Fuhrman nuclear grade (p = 0.1 and p = 0.15), respectively. To our knowledge, this is the largest study to date correlating the expression of both C-reactive protein and cyclooxygenase enzyme-2 in tissue with pathologic parameters in patients with clear cell renal cell carcinoma, which could have significant prognostic and therapeutic implications.