Sung-Im Do

Expression patterns of stromal MMP-2 and tumoural MMP-2 and -9 are significant prognostic factors in invasive ductal carcinoma of the breast.

Matrix metalloproteinases (MMPs) are matrix‐degrading enzymes that play a pivotal role in aggressive behaviours, such as rapid tumour growth, invasion, and metastasis, of several types of solid tumours. In particular, stromal MMP‐2 plays important roles in the progression of malignant tumours, but most clinical studies have focused on tumoural MMP‐2 and ‐9 expression, and not stromal MMP‐2 expression. One hundred and seventy‐seven cases diagnosed as invasive ductal carcinoma of the breast between 2000 and 2005 were included in this study. Expressions of tumoural MMP‐2 and ‐9 and stromal MMP‐2 were analysed by immunostaining on a tissue microarray. Subsequently, the associations between those results and various clinicopathological parameters were evaluated. Stromal MMP‐2 expression correlated significantly with clinicopathological parameters such as advanced T category, larger tumour size, high histological grade, tumour necrosis, ER‐ and PR‐negative, and HER‐2‐positive (all p < 0.05). In univariate and multivariate analyses, overall survival was linked with stromal MMP‐2 expression as well as dual expression of stromal MMP‐2 and tumoural MMP‐2 and ‐9 (all p < 0.05). Stromal MMP‐2 expression may play a crucial role in predicting aggressive clinical behaviour in breast cancer patients.

Activation of nuclear factor-κB contributes to growth and aggressiveness of papillary thyroid carcinoma.

Nuclear factor-κB (NF-κB) is involved in proliferation, angiogenesis, and metastasis in various malignancies; however, the role of NF-κB in papillary thyroid carcinoma (PTC) has not been fully elucidated. The purpose of this study was to elucidate the role and clinicopathological significance of the NF-κB signaling pathway in PTC. We investigated NF-κB RelA expression in 122 patients with conventional PTC by immunohistochemistry, and evaluated the correlation between RelA expression and clinicopathological parameters, including BRAF(V600E) mutation. Nuclear expression of NF-κB RelA, regardless of cytoplasmic expression, was identified in 91 of 122 PTCs (74.6%), and was more frequent in PTCs larger than 1cm (overt PTC) (P=0.001). There were significant differences in clinicopathological parameters, such as extrathyroidal extension (P=0.031), nodal metastasis (P=0.021) and BRAF(V600E) mutation (P=0.039), between NF-κB-positive and negative PTCs. Proliferation index was strongly associated with NF-κB activation (P=0.045) but not with BRAF(V600E) mutation (P=0.141). Taken together, our results suggest that NF-κB RelA activation contributes, at least in part, to tumor growth and aggressiveness of PTC after tumor transformation. The expression pattern of NF-κB may serve as a prognostic marker and a potential therapeutic target.

Diagnostic and Prognostic Relevance of MMP-11 Expression in the Stromal Fibroblast-Like Cells Adjacent to Invasive Ductal Carcinoma of the Breast

ABSTRACTBackgroundMatrix metalloproteinase 11 (MMP-11) is a matrix degrading enzyme known to be involved in the remodeling of extracellular matrix proteins. This enzyme recently has been reported to play a key role in tumor progression and results in poor clinical outcomes for several different types of tumors.MethodsA total of 192 patients diagnosed with invasive ductal carcinoma between 2000 and 2005 were included in this study. MMP-11 expression in tumors and stromal fibroblast-like cells was analyzed by immunohistochemical staining on a tissue microarray. Subsequently, evaluation of the associations between MMP-11 expression and clinicopathological characteristics was performed.ResultsMMP-11 expression of stromal fibroblast-like cells was correlated with prognostic factors, including tumor size, metastasis, histological grade, central tumor fibrosis, p53 expression, and luminal A subtype and was linked to therapeutic markers, such as ER and HER2 (all pxa0<xa00.05). There was a significant relationship between worse overall survival and MMP-11 expression in both tumors and stromal fibroblast-like cells (all pxa0<xa00.05). In multivariate analysis, MMP-11 expression of stromal fibroblast-like cells was still significantly associated with poor prognosis (pxa0=xa00.043).ConclusionsMMP-11 expression was significantly related to clinicopathological parameters, which may be essential to the prediction of disease outcome in patients with invasive ductal carcinoma of the breast.

Expression of Cell Cycle-Related Proteins, p16, p53 and p63 as Important Prognostic Markers in Gallbladder Adenocarcinoma

Gallbladder cancer, the most common biliary tract malignancy, is a highly malignant neoplasm. In the present work, we have analyzed the significance of cell cycle-related proteins to predict prognosis and to provide guidance for optimal therapeutic decision-making in patients with gallbladder adenocarcinoma. The expressions of p16, p21, p27, p53, p63, cyclin D1, bcl-2 and bcl-6 were examined in a tissue microarray constructed from 96 cases of gallbladder adenocarcinoma by immunohistochemistry and correlated with clinicopathologic prognostic factors. Expression of p16 was correlated with a low pT stage, adenoma background and good prognosis. Cases with p63 expression showed a higher T stage, more frequent perineural invasion and poor prognosis when compared to cases without p63 expression. Over-expression of p53 or loss of p53 was associated with poor tumor differentiation, frequent distant metastasis and low disease-specific survival rate. The expressions of p21, p27, bcl-2, bcl-6 and cyclin D1 were not significant prognostic factors for gallbladder adenocarcinoma. These results indicate that p16, p63 and p53 can be used as prognostic markers in gallbladder adenocarcinoma; especially p53 and p63 as poor prognostic markers and p16 as a favorable prognostic marker.

Expression of TWIST1, Snail, Slug, and NF-κB and methylation of the TWIST1 promoter in mammary phyllodes tumor

TWIST1, Slug, Snail, SIP1, and NF-κB are overexpressed in various tumors and associated with metastasis and poor prognosis. In this study, we examined their potential roles in phyllodes tumor (PT). The expression of TWIST1, Snail, Slug, SIP1, and NF-κB in benign (nu2009=u2009103), borderline (nu2009=u200938), and malignant (nu2009=u200938) PTs was examined by immunostaining. The methylation status of the TWIST1 promoter was analyzed by methylation-specific PCR. We detected high expression levels of TWIST1 in 47.4xa0% of borderline/malignant PTs and 31.1xa0% of benign PTs, Slug in 64xa0% of borderline/malignant PTs and 62.1xa0% of benign PTs, epithelial SIP1 in 75.0xa0% of borderline/malignant PTs and 86.3xa0% of benign PTs, stromal SIP1 in 35.5xa0% of borderline/malignant PTs and 22.3xa0% of benign PTs, and NF-κB in 63.2xa0% of borderline/malignant PTs and 52.4xa0% of benign PTs. Snail expression was detected in all cases. A high expression of TWIST1 (pu2009=u20090.026) and TWIST1 promoter methylation (pu2009=u20090.000) were significantly more frequent in borderline/malignant PTs than in benign PTs. Moreover, a high expression of at least four of the five antibodies was more commonly observed in borderline/malignant PTs than in benign PTs (pu2009=u20090.026). However, no relationship was found between the expression of TWIST1 or the other proteins examined and the clinical outcome. Our results suggest that a high expression of TWIST1 and related proteins plays a pivotal role in the malignant progression of PT.

Extranodal Follicular Dendritic Cell Sarcoma with Rapid Growth in Parapharynx: A Case Report

Follicular dendritic cell sarcoma (FDCS) is a rare malignancy arising from the antigen-presenting cells in the lymph node and extranodal tissue. We describe a 31-year-old male patient who presented with a swelling of the left parapharynx. The radiologic findings showed a 4.7×4.5×1.9 cm-sized, ill-defined mass in the left parapharyngeal space. A fine-needle aspiration cytology was performed and it showed scattered, irregular, cohesive clusters of tumor cells with a spindle-to-ovoid shape with irregular contours in a background of lymphocytes. Based on these findings, a diagnosis of spindle cell neoplasm was made. The surgically resected tumor was composed of elongated, ovoid or polygonal cells showing positive immunohistochemistry for CD21, CD23, and CD35. Postoperatively, the residual tumor was observed to undergo a rapidly growth. There is an overlap in the cytologic and histologic findings between FDCS of the parapharynx and other tumors. Pathologists should therefore be aware of its characteristics not only to provide an accurate diagnosis but also to recommend the appropriate clinical management.

Diagnostic and prognostic relevance of Cullin1 expression in invasive ductal carcinoma of the breast

Background Cullin1 (Cul1) is a matrix degrading enzyme known to be involved in the remodelling of extracellular matrix proteins. This enzyme has recently been reported to play a key role in tumour progression and its presence is associated with poor clinical outcome for several different types of tumours. Methods 159 patients diagnosed with invasive ductal carcinoma between 2000 and 2005 were studied. Cul1 expression was analysed by immunohistochemical staining on a tissue microarray. The relationship between Cul1 expression and clinicopathological parameters was evaluated. Results Tumour expression of Cul1 was correlated with prognostic factors such as high histological grade and p53 expression, and was also linked to negative ER and positive HER2 as therapeutic markers (all p<0.05). There was a significant association between poor overall survival and high Cul1 expression in both univariate and multivariate analyses (all p<0.05). Conclusions Cul1 expression was significantly associated with high-grade tumours and poor prognosis, suggesting that it may play a role in breast tumour progression. Cul1 expression may therefore be crucial for the prediction of disease outcome in breast cancer patients.

Down-regulation of osteoprotegerin expression as a novel biomarker for colorectal carcinoma

A better understanding of tumor biology is important in the identification of molecules that are down-regulated in malignancy and in determining their role in tumor suppression. The aim of this study was to analyze osteoprotegerin (OPG) expression in colorectal carcinoma (CRC) and to investigate the underlying mechanism for changes in the expression of OPG. OPG expression was assessed in CRC tissue samples and cell lines. The methylation status of the OPG promoter region was determined, and the effects of demethylation on OPG expression were analyzed. The effects of recombinant OPG (rOPG) administration on cellular functions were also investigated. Clinical and prognostic implications of OPG protein expression in CRC patients were analyzed. The CRC tissues and cells showed significantly lower OPG expression. Pyrosequencing of OPG-silenced CRC cells revealed that the OPG gene promoter was highly methylated. Treatment with demethylating agent significantly elevated OPG mRNA and protein expression. rOPG significantly decreased cell viability and MMP-2 and VEGF-A production in CRC cells. Reduced OPG immunoreactivity was associated with aggressive oncogenic behavior in CRC. Also, OPG expression was found to be an independent predictor of recurrent hepatic metastasis and independent prognostic factor for worse survival rates. We demonstrated that OPG silencing in CRC occurs through epigenetic repression, and is involved in the development and progression of CRC. Our data suggest that OPG is a novel prognostic biomarker and a new therapeutic target for the treatment of patients with CRC.

Hyperoxia accelerates progression of hepatic fibrosis by up-regulation of transforming growth factor-β expression

AIMnTo investigate the effect of hypoxia or hyperoxia on the progression of hepatic fibrosis and to examine the role of transforming growth factor-β (TGF-β) in the livers of rats exposed to hypoxic or hyperoxic conditions.nnnMETHODSnMale Sprague-Dawley rats were injected intraperitoneally with thioacetamide to induce hepatic fibrosis and were randomly divided into a hypoxia group, a hyperoxia group and an untreated control group. Ten rats in the hypoxia group were exposed to an altitude of 20000 ft for 1 h/d during 7 wk. Ten rats in the hyperoxia group were exposed to a water depth of 20 m with 100% oxygen supply for 1 h/d during 7 wk. We evaluated the degree of hepatic fibrosis using Masson trichrome stain and examined the expression level of hepatic TGF-β mRNA using quantitative real-time reverse transcriptase-polymerase chain reaction analysis.nnnRESULTSnEight of 10 rats exposed to hypoxia showed diffuse and confluent fibrosis with the formation of structurally abnormal parenchymal nodules involving the entire liver, consistent with hepatic cirrhosis. Nine of 10 rats exposed to hyperoxia also demonstrated obvious histological findings of hepatic cirrhosis identical to those in hypoxic rat livers. In contrast, 8 of 10 untreated rats had periportal or septal fibrosis only. The frequency of hepatic cirrhosis in hypoxic rats (P = 0.009) and hyperoxic rats (P = 0.003) was significantly higher than that in untreated rats. In addition, hepatic TGF-β mRNA levels in hyperoxic rats were significantly higher than those in untreated rats. The mean value of the normalized TGF-β mRNA/β-actin expression ratio in the hyperoxic rats was 1.9-fold higher than that in the untreated rats (P = 0.027).nnnCONCLUSIONnWe demonstrated that both hypoxia and hyperoxia accelerated the progression of hepatic fibrosis in rats. Significant up-regulation of hepatic TGF-β in hyperoxic rats suggests that TGF-β is involved in the acceleration of hepatic fibrosis under hyperoxic conditions.

Feasibility of Preoperative Axillary Lymph Node Marking with a Clip in Breast Cancer Patients Before Neoadjuvant Chemotherapy: A Preliminary Study

BackgroundThe aim of this study was to determine the feasibility of image-guided marker-clip placement in axillary lymph nodes (ALNs) for breast cancer upon initial presentation and to assess the reliability of this method with sentinel lymph node biopsy (SLNB) for axillary restaging after neoadjuvant chemotherapy (NAC).MethodsBetween June 2015 and August 2016, a marker clip was placed at a clinically positive ALN under ultrasonography (US) guidance before initiation of NAC in 20 patients. Preoperative localization of marker-clipped LNs was performed, and the localized LNs were removed by SLNB. We compared the postoperative results of the marker-clipped LNs, SLNs and ALNs.ResultsImage-guided marker-clip placements and localization of marker-clipped LNs were performed successfully in 20 patients. A total of 24 marker clips were inserted, and 23 marker-clipped LNs were successfully retrieved during surgery (identification rate, 23/24, 95.8%). In the 11 patients with pathologically confirmed metastatic marker-clipped LNs, four became negative after NAC, and seven maintained metastatic residues on the marker-clipped LNs. Three of the seven patients had metastatic residues on the ALNs, and two of the three patients also had negative SLNs. Marker-clipped nodes accurately predicted the axillary nodal status in these two patients compared with SLNs alone.ConclusionImage-guided marker-clip placement on positive ALNs before NAC and removal with SLNB is technically feasible. This technique can improve the accuracy of the residual disease evaluation on the axilla, especially in patients with negative SLNB results, and can identify candidates for limited axillary surgery after NAC.