Excellent Accuracy of Glucose Level in Cystic Fluid for Diagnosis of Pancreatic Mucinous Cysts.

BACKGROUND: CEA in pancreatic cystic fluid (PCF) is standard for mucinous cysts diagnosis. Glucose is an alternative, but its accuracy remains poorly described. AIMS: To evaluate PCF glucose using a glucometer and compare its accuracy with CEA for mucinous cysts diagnosis. MATERIALS AND METHODS: In frozen PCF obtained by EUS-FNA, glucose was evaluated using a glucometer. CEA and cytology were available as standard of care. The accuracy of glucose and CEA was calculated using receiver operator (ROC) curves. Definitive diagnoses were surgical or clinicopathological. RESULTS: We evaluated 82 patients with a mean age of 61.3 ± 14.8 years (25-91), predominantly (59%) females. Diagnoses included 17 serous cystadenomas, five pseudocysts, 20 intraductal papillary mucinous neoplasms, three mucinous cystic neoplasms, five adenocarcinomas, four neuroendocrine tumors, two other types, 26 non-defined. The median glucose levels (interquartile range) were 19 mg/dL (19-19) in mucinous and 105 mg/dL (96-127) in non-mucinous cysts (p < 0.0001). The median CEA level was 741 ng/mL (165-28,567) in mucinous and 9 ng/mL (5-19) in non-mucinous cysts (p < 0.0001). For mucinous cyst diagnosis, a CEA > 192 ng/mL had a sensitivity of 72% (95% CI 51-88) and a specificity of 96% (95% CI 82-100), and ROC analysis showed an area under the curve (AUC) of 0.842 (95% CI 0.726-0.959), while glucose < 50 mg/dL had a sensitivity of 89% (95% CI 72-98), a specificity of 86% (95% CI 67-96), and an AUC of 0.86 (95% CI 0.748-0.973). Pseudocysts presented low glucose, identically to mucinous cysts, with CEA allowing differential diagnosis. CONCLUSION: Glucose measured by a glucometer is accurate for mucinous cyst diagnosis, with significantly higher levels in non-mucinous cysts, except pseudocysts.

Positive expression of insulin-like growth factor-1 receptor is associated with a positive hormone receptor status in ovarian cancer.

UNLABELLED: Summary PURPOSE: Ovarian cancer is the most deadly of all gynecologic malignancies, due in part to the diagnosis at an advanced stage caused by the deficiency of specific marks and symptoms, by the absence of reliable tests for screening, and by early detection. MATERIALS AND METHODS: Insulin-like growth factor-I (IGF-I) is known to be involved in the development and promotion of diverse examples of solid tumors including ovarian cancer. IGF-I levels in local tissue are subject to both endocrine and paracrine/autocrine regulation. RESULTS: Most patients will react initially to treatment, but almost 70% of them will have a recurrence. Consequently, new therapeutic modalities are urgently required to overcome chemoresistance observed in ovarian cancer patients. IGF-1R expression was evaluated immunohistochemically in tissue microarray blocks constructed from 1,200 ovarian cancer samples collected from three medical institutions. CONCLUSION: Evidence accumulates suggesting that the insulin/insulin growth factor (IGF) pathways could play a good therapeutic target in various cancers, including ovarian cancer.

Activated wnt signaling in stroma contributes to development of pancreatic mucinous cystic neoplasms.

BACKGROUND & AIMS: Pancreatic mucinous cystic neoplasm (MCN), a cystic tumor of the pancreas that develops most frequently in women, is a potential precursor to pancreatic ductal adenocarcinoma. MCNs develop primarily in the body and tail of the pancreas and are characterized by the presence of a mucinous epithelium and ovarian-like subepithelial stroma. We investigated the involvement of Wnt signaling in KRAS-mediated pancreatic tumorigenesis and development of MCN in mice, and Wnt activation in human MCN samples. METHODS: LSL-Kras(G12D), Ptf1a-cre mice were crossed with elastase-tva mice to allow for introduction of genes encoded by the replication-competent avian sarcoma-leukosis virus long-terminal repeat with splice acceptor viruses to pancreatic acinar cells and acinar cell progenitors, postnatally and sporadically. Repeat with splice acceptor viruses that expressed Wnt1 were delivered to the pancreatic epithelium of these mice; pancreatic lesions were analyzed by histopathology and immunohistochemical analyses. We analyzed levels of factors in Wnt signaling pathways in 19 MCN samples from patients. RESULTS: Expression of Wnt1 in the pancreatic acinar cells and acinar cell progenitors of female mice led to development of unilocular or multilocular epithelial cysts in the pancreas body and tail, similar to MCN. The cystic lesions resembled the estrogen receptor- and progesterone receptor-positive ovarian-like stroma of MCN, but lacked the typical mucinous epithelium. Activated Wnt signaling, based on nuclear localization of ß-catenin, was detected in the stroma but not cyst epithelium. Wnt signaling to ß-catenin was found to be activated in MCN samples from patients, within the ovarian-like stroma, consistent with the findings in mice. CONCLUSIONS: Based on studies of mice and pancreatic MCN samples from patients, the canonical Wnt signaling pathway becomes activated and promotes development of the ovarian-like stroma to contribute to formation of MCNs.

Cyst Fluid Glucose is Rapidly Feasible and Accurate in Diagnosing Mucinous Pancreatic Cysts.

OBJECTIVES: Better diagnostic tools are needed to differentiate pancreatic cyst subtypes. A previous metabolomic study showed cyst fluid glucose as a potential marker to differentiate mucinous from non-mucinous pancreatic cysts. This study seeks to validate these earlier findings using a standard laboratory glucose assay, a glucometer, and a glucose reagent strip. METHODS: Using an IRB-approved prospectively collected bio-repository, 65 pancreatic cyst fluid samples (42 mucinous and 23 non-mucinous) with histological correlation were analyzed. RESULTS: Median laboratory glucose, glucometer glucose, and percent reagent strip positive were lower in mucinous vs. non-mucinous cysts (P<0.0001 for all comparisons). Laboratory glucose<50 mg/dl had a sensitivity of 95% and a specificity of 57% (LR+ 2.19, LR- 0.08). Glucometer glucose<50 mg/dl had a sensitivity of 88% and a specificity of 78% (LR+ 4.05, LR- 0.15). Reagent strip glucose had a sensitivity of 81% and a specificity of 74% (LR+ 3.10, LR- 0.26). CEA had a sensitivity of 77% and a specificity of 83% (LR+ 4.67, LR- 0.27). The combination of having either a glucometer glucose<50 mg/dl or a CEA level>192 had a sensitivity of 100% but a low specificity of 33% (LR+ 1.50, LR- 0.00). CONCLUSIONS: Glucose, whether measured by a laboratory assay, a glucometer, or a reagent strip, is significantly lower in mucinous cysts compared with non-mucinous pancreatic cysts.

Suboptimal accuracy of carcinoembryonic antigen in differentiation of mucinous and nonmucinous pancreatic cysts: results of a large multicenter study.

BACKGROUND AND AIMS: The exact cutoff value at which pancreatic cyst fluid carcinoembryonic antigen (CEA) level distinguishes pancreatic mucinous cystic neoplasms (MCNs) from pancreatic nonmucinous cystic neoplasms (NMCNs) is unclear. The aim of this multicenter retrospective study was to evaluate the diagnostic accuracy of cyst fluid CEA levels in differentiating between MCNs and NMCNs. METHODS: Consecutive patients who underwent EUS with FNA at 3 tertiary care centers were identified. Patients with histologic confirmation of cyst type based on surgical specimens served as the criterion standard for this analysis. Demographic characteristics, EUS morphology, FNA fluid, and cytology results were recorded. Multivariate logistic regression analysis to identify predictors of MCNs was performed. Receiver-operating characteristic (ROC) curves were generated for CEA levels. RESULTS: A total of 226 patients underwent surgery (mean age, 61 years, 96% white patients, 39% female patients) of whom 88% underwent Whipple's procedure or distal pancreatectomy. Based on surgical histopathology, there were 150 MCNs and 76 NMCNs cases. The median CEA level was 165 ng/mL. The area under the ROC curve for CEA levels in differentiating between MCNs and NMCNs was 0.77 (95% confidence interval, 0.71-0.84, P < .01) with a cutoff of 105 ng/mL, demonstrating a sensitivity and specificity of 70% and 63%, respectively. The cutoff value of 192 ng/mL yielded a sensitivity of 61% and a specificity of 77% and would misdiagnose 39% of MCN cases. CONCLUSIONS: Cyst fluid CEA levels have a clinically suboptimal accuracy level in differentiating MCNs from NMCNs. Future studies should focus on novel cyst fluid markers to improve risk stratification of pancreatic cystic neoplasms.

Claudin-18 overexpression in intestinal-type mucinous borderline tumour of the ovary.

AIMS: Mucinous borderline tumours of the ovary are subclassified as intestinal-type (IMBT) and endocervical-like (EMBT), which differ in their clinicopathological features. In this study, we attempted to elucidate characteristics of the mucinous epithelium in each subtype. METHODS AND RESULTS: The expression of claudin-18, a marker of gastric differentiation, MUCs, CDX2, CK7, CK20, oestrogen receptor (ER), progesterone receptor (PgR), CA-125 and vimentin in IMBTs (n = 54), EMBTs (n = 25) and serous borderline tumours (SBTs) (n = 22) were compared by immunohistochemistry. Claudin-18 positivity was identified in 98% of the IMBTs, whereas only 4% of the EMBTs were claudin-18-positive. Expression of intestinal markers such as CDX2 and MUC2 was relatively infrequent in IMBTs (48% and 33%, respectively). Müllerian-lineage markers such as ER, PgR and vimentin were expressed rarely in IMBTs, while most EMBTs and SBTs were positive for these markers. Hierarchial clustering revealed a close association between EMBTs and SBTs, while IMBTs were clearly separate. CONCLUSIONS: Claudin-18 positivity is a specific phenotype that is characteristic of IMBTs. Frequent and diffuse expression of gastric markers, along with less frequent and usually focal expression of intestinal markers, suggests that IMBTs are essentially composed of gastrointestinal-type mucinous epithelium (gastric-type epithelium with a variable degree of intestinal differentiation).

Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine.

BACKGROUND: Better pancreatic cyst fluid biomarkers are needed. OBJECTIVE: To determine whether metabolomic profiling of pancreatic cyst fluid would yield clinically useful cyst fluid biomarkers. DESIGN: Retrospective study. SETTING: Tertiary-care referral center. PATIENTS: Two independent cohorts of patients (n = 26 and n = 19) with histologically defined pancreatic cysts. INTERVENTION: Exploratory analysis for differentially expressed metabolites between (1) nonmucinous and mucinous cysts and (2) malignant and premalignant cysts was performed in the first cohort. With the second cohort, a validation analysis of promising identified metabolites was performed. MAIN OUTCOME MEASUREMENTS: Identification of differentially expressed metabolites between clinically relevant cyst categories and their diagnostic performance (receiver operating characteristic [ROC] curve). RESULTS: Two metabolites had diagnostic significance-glucose and kynurenine. Metabolomic abundances for both were significantly lower in mucinous cysts compared with nonmucinous cysts in both cohorts (glucose first cohort P = .002, validation P = .006; and kynurenine first cohort P = .002, validation P = .002). The ROC curve for glucose was 0.92 (95% confidence interval [CI], 0.81-1.00) and 0.88 (95% CI, 0.72-1.00) in the first and validation cohorts, respectively. The ROC for kynurenine was 0.94 (95% CI, 0.81-1.00) and 0.92 (95% CI, 0.76-1.00) in the first and validation cohorts, respectively. Neither could differentiate premalignant from malignant cysts. Glucose and kynurenine levels were significantly elevated for serous cystadenomas in both cohorts. LIMITATIONS: Small sample sizes. CONCLUSION: Metabolomic profiling identified glucose and kynurenine to have potential clinical utility for differentiating mucinous from nonmucinous pancreatic cysts. These markers also may diagnose serous cystadenomas.

Mucinous cystadenocarcinoma of the breast with a basal-like immunophenotype.

Mucinous cystadenocarcinoma (MCA) of the breast is extremely rare and was only recently described as a distinct variant of invasive ductal carcinoma of the breast. A case of MCA is reported in a 41-year-old woman. Mammographic and ultrasonographic examinations showed an irregularly shaped 10.0 × 8.0 × 5.5 cm lesion with patching calcification in the upper outer quadrant of the left breast. The gross examination revealed that the tumor has a well-circumscribed edge with a gelatinous cut surface and hemorrhage and necrosis were also noticed in the mass. Microscopically, the mass resembled mucinous cystic neoplasm of the ovary and pancreas closely, with cystic areas lined by columnar mucinous cells and associated with abundant extracellular and intracellular mucin, which is distinctively different from mucinous carcinoma with typically nests of low grade neoplastic cells floating in the mucin pool. The tumor cells were positive for CK7, CK20 and CDX2 were negative and displayed a typical immunophenotype of basal-like breast cancer (ER, PR, HER2 were negative, CK5/6 and EGFR were positive). Metastatic carcinoma was identified in three of 14 axillary lymph nodes. We describe here a very unusual case of breast MCA with basal-like immunophenotype.

[Expression and significance of neurogenic differentiation protein in pancreatic carcinoma].

OBJECTIVE: To investigate the expression and significance of neurogenic differentiation protein (NeuroD) in pancreatic carcinoma. METHODS: The expression of NeuroD, PCNA and p53 proteins in 127 specimens of pancreatic carcinoma was detected by tissue microarray and immunohistochemestry. The correlations were analyzed between NeuroD and PCNA, p53, neural invasion, sleeve-like lymphocytic infiltration around the nerve, pancreatitis adjacent to carcinoma, lymph node metastasis and age, gender, location of tumors, histological types and differentiation of pancreatic carcinomas. RESULTS: The positive rates of NeuroD, PCNA and p53 expression were higher in pancreatic carcinoma than those in non-tumor pancreatic tissues [64.6% (82/127) vs 10.5% (8/76), 57.5% (73/127) vs 9.2% (7/76), 59.1% (75/127) vs 9.2% (7/76), P < 0.01]. NeuroD expression in pancreatic carcinoma was related to that of PCNA and p53 and neural invasion (P < 0.05). No significant correlation was found between NeuroD and age, gender, tumor location, histological types and differentiation, sleeve-like lymphocytic infiltration, pancreatitis adjacent to the carcinoma and lymph node metastasis in pancreatic carcinomas. CONCLUSIONS: NeuroD overexpression in pancreatic carcinoma. The overexpression of NeuroD may contribute to the tumorogenesis and development of pancreatic carcinoma, and is closely correlated to the cancer cell proliferation, p53 signal pathway and neural invasion in pancreatic carcinoma.

[Expression and significance of p-AKT, p-GSK3ß and ß-catenin in epithelial carcinoma of ovary].

OBJECTIVE: To investigate the expressions of phosphorylated protein kinase B (p-AKT), phosphorylated glycogen synthase kinase 3ß (p-GSK3ß) and ß-catenin proteins and to evaluate their relationship with the clinical pathological characteristics in epithelial tumors of the ovary. METHODS: The expression of p-AKT, p-GSK3ß, and ß-catenin was detected with immunohistochemical staining (EnVision method) in 10 cases of benign epithelial neoplasia, 10 cases of borderline epithelial neoplasia and 70 cases of ovarian carcinoma. The relationship of the expression of p-AKT, p-GSK3ß and ß-catenin with the clinical pathological features was analyzed. RESULTS: The positive expression rates of p-AKT, p-GSK3ß and ß-catenin in epithelial ovarian carcinoma were 67.1% (47/70), 60.0% (42/70) and 71.4% (50/70), respectively. Compared to the results of benign and borderline epithelial neoplasia, the expression of the three proteins in carcinoma of the ovary was significantly different (all P < 0.05).Positive correlation was found between p-AKT and p-GSK3ß, p-GSK3ß and ß-catenin, and p-AKT and ß-catenin in epithelial ovarian carcinoma (r = 0.546, 0.581, 0.500, respectively; all P < 0.05). Compared to the results of benign and borderline epithelial neoplasia, the expression of p-AKT protein in epithelial ovarian carcinoma was significantly different (all P < 0.05). The expression of p-AKT was correlated with the differentiation of epithelial ovarian carcinoma (P < 0.05), but no relationship was found between its expression and histological classification and FIGO staging (P > 0.05). The expression of p-GSK3ß and ß-catenin in epithelial ovarian carcinoma were both higher than that in benign and borderline epithelial neoplasia (P < 0.05), and correlated with tumor differentiation and FIGO staging (P < 0.05), but no relationship were found between their expression with histological classification (P > 0.05). CONCLUSIONS: Positive correlations are found between p-AKT, p-GSK3ß and ß-catenin in epithelial ovarian carcinoma. The activation of ß-catenin is possibly correlated with inactivation of p-GSK3ß that binds to p-AKT.

[Expression and promotor methylation of p73 gene in ovarian epithelial tumors].

OBJECTIVE: To investigate the expression and promoter methylation status of p73 gene in ovarian epithelial tumors and their clinicopathological correlations. METHODS: Tissue microarrays (TMA) consisting of 68 ovarian cancers, 37 ovarian borderline tumors and 21 ovarian benign tumors were constructed. p73 expression was detected by immunohistochemistry (EnVision method). Fresh-frozen tissue samples from 13 cases of ovarian carcinomas and 5 cases of borderline tumors were evaluated for the presence of p73 promoter methylation using bisulfite sequencing. RESULTS: Overall, 92.6% (63/68) ovarian carcinomas expressed p73, with a mean value of 32% (percentage of p73 positive cells in the tumor). The mean value of p73 expression rate (40%) in serous carcinoma (26/26) was higher than those of other cancer types (P = 0.006). The mean value of p73 expression rate (40%) in type II ovarian carcinoma was significantly higher than that in type I ovarian carcinoma (24%, P = 0.010). The expression of p73 was not associated with FIGO stage and histological grade (both P > 0.05). The mean values of p73 expression in ovarian borderline tumor (30/37) and benign tumor (12/21) were 16% and 15%, respectively. Of the two groups, the mean value of p73 expression rate in serous type was higher than that in mucous type (P = 0.003, P = 0.026). Ovarian carcinomas had a higher level of p73 expression than borderline tumors and benign tumors (both P < 0.05), while that between ovarian borderline tumors and benign tumors had no statistical difference (P > 0.05). Among serous tumors (49/53), the mean value of p73 expression in the carcinoma group (26/26) was significantly higher than those in the borderline tumor group (12/14) and benign tumor group (11/13; P = 0.024 and P = 0.002, respectively), while that between borderline tumor group and benign tumor group had no statistical difference (P = 0.428). Among mucous tumors (15/27), the mean value of p73 expression in carcinoma group (6/7) was higher than that in benign tumor group (1/8; P = 0.032). No statistical difference of p73 expression was seen between the carcinoma group and ovarian borderline tumor group (8/12) and between the borderline tumor group and benign tumor group (P = 0.234, P = 0.201, respectively). p73 promotor methylation was found in 8 of 13 cases of carcinomas but at different methylation levels with a mean value of 8.0%. Two of 5 ovarian borderline tumors showed detectable p73 promotor methylation with a mean value of 9.0%. Compared with the borderline tumors, ovarian carcinomas showed a similar p73 methylation level (P > 0.05). The p73 methylation level in ovarian carcinomas was not associated with histological type, pathogenetic type, histological grade and FIGO stage (all P > 0.05). CONCLUSIONS: Most of ovarian epithelial tumors express p73 protein with mean values higher in ovarian carcinomas than those in the borderline and benign tumors. Ovarian serous carcinomas have the highest expression level of p73. A simple linear correlation does not exist between the promoter methylation and protein expression of p73.

Mucinous cystadenocarcinoma of the breast: a new entity with broad differentials-a case report.

BACKGROUND: Mucinous cystadenocarcinoma is a rare and recently described primary breast cancer with strikingly similar histomorphology to ovarian, pancreatic, and gastrointestinal counterparts. The diagnosis cannot be made until the metastatic lesion is ruled out. CASE PRESENTATION: We are reporting the case of a 65-year-old woman with primary mucinous cystadenocarcinoma of the breast while exploring clinicopathological features and approach to diagnosis. Though the immunohistochemistry panel of CK7, CK20, CDX2, SATB2, PAX8, mammoglobin, and GATA3 plays a crucial role in ruling out metastasis but aberrant CK20 positivity was seen in our case, the final diagnosis was made after a complete radiological workup. We also noted strong membranous HER2-protein expression and HER2-gene amplification by fluorescence in situ hybridization while in literature this tumor is reported to show mainly triple-negative basal type immunophenotype. CONCLUSION: A combined clinic-radio-immunohistochemical approach is essential to make a diagnosis of primary mucinous cystadenocarcinoma.

Preliminary observations and clinical value of N-acetyl resonances in ovarian tumours using in-vivo proton MR spectroscopy at 3T.

OBJECTIVE: To retrospectively evaluate the clinical significance of N-acetyl resonances at 2 ppm in in-vivo proton magnetic resonance (MR) spectroscopy for distinguishing mucinous and non-mucinous tumours in patients with ovarian masses. METHODS: MR spectroscopy was performed in patients with pathologically diagnosed ovarian tumours at 3T-MR imaging. Single-voxel MR spectroscopy data were collected from a single square volume of interest that encompassed the ovarian masses. The metabolite resonance peak areas at 2 ppm were quantified relative to unsuppressed water using a software package (LCModel). RESULTS: A total of 32 ovarian lesions in 32 patients were evaluated in this study. High metabolite peak at 2 ppm was observed in all nine mucinous tumours (9.71 +/- 7.46 mM), whereas low peak was observed in 14 of 23 non-mucinous tumours (3.12 +/- 1.42 mM) (p < 0.001). Using a cut off value of 4.45 mM for mucinous tumours had a sensitivity of 89%, specificity of 86%, PPV of 80%, and NPV of 92%. CONCLUSION: Proton MR spectroscopy with quantitative evaluation of the metabolite at 2 ppm concentration, which may suggest the presence of mucinous material containing N-acetyl mucinous compounds, can provide helpful information in distinguishing mucinous and non-mucinous ovarian tumours. Key Points • MR spectroscopy helps distinguish mucinous from non-mucinous ovarian tumours. • High N-acetyl resonance at 2 ppm is observed in ovarian mucinous tumours. • Thus MR spectroscopy could improve management of these patients.

Silencing of CXCR4 blocks progression of ovarian cancer and depresses canonical Wnt signaling pathway.

OBJECTIVE: CXC chemokine receptor 4 (CXCR4) was considered to be an important factor in cancer cell metastasis. This study was aimed to examine the expression of CXCR4 in ovarian cancer and determine the functions and the possible mechanisms of CXCR4 in the progression of ovarian cancer. METHODS: CXC chemokine receptor 4 messenger RNA expression in normal ovarian tissues, malignant epithelial ovarian tumors, and 3 ovarian cancer cell lines was analyzed. Immunohistochemical analysis was used to detect the protein expression of CXCR4 and ß-catenin in normal and malignant ovarian tissues. The effect of CXCR4 inhibition on cell proliferation and invasion was determined. RESULTS: CXC chemokine receptor 4 was highly expressed in malignant ovarian tumors and ovarian cancer cell lines, and the different expression of CXCR4 was observed between the ovarian cancers with lymph node metastasis and without lymph node metastasis. Furthermore, The CXCR4 expression was correlated with ß-catenin expression in ovarian tissues. Moreover, knockdown of CXCR4 could obviously reduce proliferation and invasion of ovarian cancer cell and inhibit Wnt target genes and mesenchymal markers such as vimentin and SLUG expression. CONCLUSIONS: CXC chemokine receptor 4 plays a critical role in the metastasis of human ovarian cancer possibly through modulating the Wnt/ß-catenin pathway. CXC chemokine receptor 4 is a potential therapeutic target for treatment of ovarian cancer.

[Expression of hSef and FGF-2 in epithelial ovarian tumor].

OBJECTIVE: To detect the expression of human similar expression to FGF gene(hSef) and fibroblast growth factor-2(FGF-2) and their correlation with epithelial ovarian tumor. METHODS: Immunohistochemical SP staining was used to detect the expression of hSef and FGF-2 proteins in 31 cases of epithelial ovarian carcinoma (EOC), 18 cases of benign epithelial tumor (BET), 10 cases of normal ovarian (NO) tissues collected from July 2007 to May 2008. The expression of hSef mRNA in 24 cases of EOC, BET and NO collected from July 2008 to May 2009 were analyzed by RT-PCR. RESULTS: The results of immunohistochemical study showed that the expression of hSef in the EOC tissues were significantly lower than that in the NO and BET (P < 0.001). However, the expression of FGF-2 was higher (P = 0.002). The expression of hSef had a negative correlation with FGF-2 (r(s) = -0.324, P = 0.012). The RT-PCR results showed that there was a gradually declined trend of expression of hSef in NO, BET to EOC (P < 0.001), but the expression of FGF-2 in NO, BET to EOC was gradually increased (P < 0.001), with a significant negative correlation (NO: r(s) = -0.910, P < 0.001; BET: r(s) = -0.859, P < 0.001; EOC: r(s) = -0.888, P < 0.001). CONCLUSIONS: The expression of hSef is decreased in epithelial ovarian carcinoma tissue, but the expression of FGF-2 is increased. It is likely that low hSef expression is related to the the carcinogenesis and development of epithelial ovarian carcinoma by suppressing the promoting effects of FGF-2 to cell proliferation.

Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma.

Recent evidence suggests that the chemokine axis of CXC chemokine ligand-12 and its receptor CXC chemokine receptor-4 (CXCL12/CXCR4) is highly expressed in gynecological tumors and the axis of CXC chemokine ligand-16 and CXC chemokine receptor-6 (CXCL16/CXCR6) is overexpressed in inflammation-associated tumors. This study aimed to determine the relationship between CXCL12/CXCR4, CXCL16/CXCR6 and ovarian carcinoma's clinicopathologic features and prognosis. Accordingly, the expression of these proteins in ovarian tissues was detected by tissue microarray and immunohistochemistry. The expressions of CXCL12/CXCR4 and CXCL16/CXCR6 were significantly higher in epithelial ovarian carcinomas than in normal epithelial ovarian tissues or benign epithelial ovarian tumors. The expression of chemokines CXCL12 and CXCL16 were positively correlated with their receptors CXCR4 and CXCR6 in ovarian carcinoma, respectively (r = 0.300, P < 0.05; r = 0.395, P < 0.05). Moreover, the expression of CXCL12 was related to the occurrence of ascites (Χ² = 4.76, P < 0.05), the expression of CXCR4 was significantly related to lymph node metastasis (Χ(2) = 4.37, P < 0.05), the expression of CXCR6 was significantly related to lymph node metastasis (Χ² = 7.43, P < 0.05) and histological type (Χ² = 33.48, P < 0.05). In univariate analysis, the expression of CXCR4 and CXCL16 significantly correlated with reduced median survival (Χ² = 4.67, P < 0.05; Χ² = 4.48, P < 0.05). Therefore, we conclude that the chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 may play important roles in the growth, proliferation, invasion, and metastasis of epithelial ovarian carcinoma.

Association of epidermal growth factor receptor and mitogen-activated protein kinase with cystic neoplasms of the pancreas.

The molecular pathobiology of pancreatic cystic neoplasms is poorly understood. The aim of this study was to know the involvement of epidermal growth factor receptor (EGFR) and its downstream targets in the serous cystic neoplasms and the mucinous cystic neoplasms of the pancreas. In a total of 72 pancreatic cystic neoplasms, including 39 serous cystic neoplasms and 33 mucinous cystic neoplasms, we examined the expression of native and phosphorylated EGFR, mitogen-activated protein kinase (MAPK), and AKT by immunohistochemistry and somatic mutations in EGFR, KRAS, BRAF, and PIK3CA, by direct sequencing. We also assessed the copy numbers of EGFR transcripts and the amplification of the EGFR gene in some of the samples. We found that EGFR, phosphorylated EGFR, MAPK, and phosphorylated MAPK were evidently expressed in 100, 54, 100, and 69% of the serous cystic neoplasms, and in 12%, none, 33, and 27% of the mucinous cystic neoplasms, respectively; the expression was significantly higher and more prevalent in the serous cystic neoplasms than in the mucinous cystic neoplasms. The expression of AKT and phosphorylated AKT was low in both the types of neoplasms. On average, EGFR transcripts in the serous cystic neoplasms and the mucinous cystic neoplasms increased 53.5- and 2.5-fold, respectively, as compared with that in normal tissues, with the increase in the former being significantly greater than that in the latter. Amplification of the EGFR gene was not detected in any of the examined serous cystic neoplasms. None of the tumors had mutations in any of the examined portions of the genes, except two mucinous cystic neoplasms with mutations in codon-12 of KRAS. These results indicate that EGFR and MAPK are actively involved in the pathobiology of serous cystic neoplasms and may therefore be potential diagnostic markers and therapeutic targets in patients with the above mentioned types of neoplasms.

Mucinous colorectal adenocarcinoma with signet-ring cells: immunohistochemical and ultrastructural study.

A primary mucinous colorectal adenocarcinoma tissue with signet-ring cells, as revealed after histological evaluation, was examined ultrastructurally. The authors also analyzed the immunohistochemical data of the tissue for serotonin, vasoactive intestinal polypeptide (VIP), bombesin, somatostatin, and glucagon, using the peroxidase anti-peroxidase (PAP) method and the immunogold labeling method for light and electron microscope, respectively. Electron microscopically mucinous adenocarcinoma was characterized by the formation of small lumen. Adenocarcinoma cells were full of mucous granules of varying electron density, providing a good environment for the tumor cells to grow. They also exhibited a significant loss of microvilli and intracytoplasmic junctions, which could allow the cells to disseminate. Signet-ring cells were located in the basal site of the ducts or in the lamina propria and appeared neoplastic, with mucin accumulation intracellularly and an eccentric crescent-shaped nucleus. The cytoplasmic organelles were decreased and at the periphery of the cell. The PAP method demonstrated that these cells were strongly positive for bombesin and also positive for vasointestinal polypeptide (VIP). The immunogold method detected bombesin immunoreactivity in the vacuoles as well as in other cytoplasmic membranes, whereas VIP was localized mainly in the plasma membrane. The location of signet-ring cells combined with the immunoreactivity for bombesin and VIP indicated that signet-ring cells were of neuroendocrine origin and probably dedifferentiated enterochromaffin-like endocrine cells. These findings have implications for understanding the biological behavior of these composite malignant tumors and could help in the knowledge of the origin of signet-ring cells.

Immunohistochemical expression of epidermal growth factor receptor, E-cadherin, and matrix metalloproteinase-9 in ovarian epithelial cancer and relation to patient deaths.

Ovarian cancer is the most frequent cause of death from gynecologic cancer in the world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR), E-cadherin, and matrix metalloproteinase (MMP)-9 are frequently studied in cancer; but their prognostic value in ovarian carcinoma remains unclear. In this study, we investigated the immunohistochemical expression of EGFR, E-cadherin, and MMP-9 in 120 cases of ovarian epithelial carcinoma; their relation to each other; their relation to histologic type, grade, and stage; and their relation to death rates after 3years of follow-up. Our results show that EGFR and MMP-9 were overexpressed extensively in high grades and advanced stages especially in nonserous carcinomas. E-cadherin was gradually lost in advanced cancers. There was a positive relation between the 3 antibodies and between them and the death rates. There is a strong relationship between EGFR and MMP-9, and this relation may occur by affecting E-cadherin. The present study provides a rationale for evaluating drugs that target these new pathways that may be promising in ovarian cancer treatment.

[Expression and clinical significance of TLR9 in ovarian cancer].

OBJECTIVE: To detect the expression of Toll-like receptor 9 (TLR9) in ovarian cancer, and to explore their clinical significance. METHODS: Western blot method and immunohistochemical staining were used to examine the expression of TLR9 in the ovarian cancer, paracancerous tissues and normal ovarian tissues, obtained during operation from 30 ovarian carcinoma patients and 30 normal non-tumor patients. The relationships of TLR9 with pathological grade, clinical stage, and metastasis of ovarian cancer were statistically analyzed. RESULTS: The percentage of positive cells expressing TLR9 protein in human ovarian cancer tissues, paracancerous tissues and normal ovarian tissues were 80.0%, 36.7% and 20.0%, respectively. The protein expression level of TLR9 was gradually descending (P < 0.01). The highly expressed TLR9 significantly correlated with the degree of tumor differentiation, an advanced FIGO stage and lymph node metastasis. The Western blot results showed that TLR9 protein expression in ovarian cancer, paracancerous tissues and normal ovarian tissues were 0.803 ± 0.072, 0.411 ± 0.087 and 0.113 ± 0.065, respectively. The expression of TLR9 in ovarian cancer was significantly higher than that in normal tissue and paracancerous tissues (P < 0.01). CONCLUSIONS: TLR9 has a higher expression in ovarian cancer tissues. TLR9 expression has a close relationship with pathological grades of ovarian cancer, suggesting that TLR9 plays an important role in the development and progression of ovarian cancer through immunologic mechanisms.