Haeryoung Kim

Correlation of KIT and platelet-derived growth factor receptor |[alpha]| mutations with gene activation and expression profiles in gastrointestinal stromal tumors

Activating mutations of KIT and platelet-derived growth factor receptor α (PDGFRA) are known to be alternative and mutually exclusive genetic events in the development of gastrointestinal stromal tumors (GISTs). We examined the effect of the mutations of these two genes on the gene expression profile of 22 GISTs using the oligonucleotide microarray. Mutations of KIT and PDGFRA were found in 17 cases and three cases, respectively. The remaining two cases had no detectable mutations in either gene. The mutation status of KIT and PDGFRA was directly related to the expression levels of activated KIT and PDGFRA, and was also related to the different expression levels of activated proteins that play key roles in the downstream of the receptor tyrosine kinase III family. To evaluate the impact of mutation status and the importance of the type of mutation in gene expression and clinical features, microarray-derived data from 22 GISTs were interpreted using a principal component analysis (PCA). Three relevant principal component representing mutation of KIT, PDGFRA and chromosome 14q deletion were identified from the interpretation of the oligonucleotide microarray data with PCA. After supervised analysis, there was at least a two fold difference in expression between GISTs with KIT and PDGFRA mutation in 70 genes. Our findings demonstrate that mutations of KIT and PDGFRA affect differential activation and expression of some genes, and can be used for the molecular classification of GISTs.

Breast lesions with imaging-histologic discordance during US-guided 14G automated core biopsy: can the directional vacuum-assisted removal replace the surgical excision? Initial findings

The purpose of this study was to determine the frequency of carcinoma at percutaneous directional vacuum-assisted removal (DVAR) in women with imaging-histologic discordance during ultrasound (US)-guided automated core needle biopsy, and to determine the role of DVAR in breast lesions with imaging-histologic discordance. A US-guided 14-gauge automated core needle biopsy was performed on 837 consecutive lesions. Imaging-histologic discordance was prospectively considered in 33 of 634 benign biopsies. DVAR was recommended in those lesions. Among the 33 lesions, 26 lesions that underwent subsequent DVAR or surgical excision made up our study population. Medical records, imaging studies, and histologic findings were reviewed. Among the 26 lesions, 18 lesions underwent subsequent US–guided DVAR, with 8-gauge probes for 15 of the lesions, and 11-gauge for three of the lesions. Two lesions were diagnosed as having carcinoma (2/18, 11.1% of upgrade rate; 3.1–32.8% CI). The remaining eight lesions underwent subsequent surgical excision, and carcinoma was diagnosed in one case (12.5% of upgrade rate; 2.2–47.1% CI). A US-guided DVAR of the breast mass with imaging-histologic discordance during US-guided 14-gauge automated core needle biopsy is a valuable alternative to surgery as a means of obtaining a definitive histological diagnosis.

Hepatocellular carcinomas expressing 'stemness'-related markers: clinicopathological characteristics.

Hepatocellular carcinoma (HCC) is heterogeneous in histopathology, pathogenesis and biological behavior. There is accumulating evidence that the expression of ‘stemness-related markers such as K19, EpCAM and CD133 in HCC is associated with an aggressive biological behavior and poor clinical outcome compared to conventional HCCs that do not express stemness-related markers. Compared to conventional HCCs, these tumors more frequently demonstrate infiltrative growth patterns, vascular invasion and more intratumoral fibrous stroma, and there is a spectrum of morphological and immunophenotypic features between HCCs with stemness-related marker expression, scirrhous HCCs and combined hepatocellular-cholangiocarcinoma with stem cell features. Clinically, HCCs with stemness-related marker expression are associated with increased serum α-fetoprotein levels and a poor prognosis, and are also beginning to be noticed radiologically. These tumors have also been recognized as a specific subtype in recent molecular classifications, and increasing interest in the molecular pathogenesis of HCCs with stemness-related marker expression will shed light on the development of targeted therapy for these tumors. Therefore, it is important that pathologists identify HCCs expressing stemness-related markers such as K19 during routine pathological evaluation of surgically resected or biopsied HCC tissue, as it will help to identify a high-risk subgroup of HCCs characterized by increased chemoresistance, earlier recurrence after surgical and/or locoregional treatment, increased invasiveness/metastasis and poor overall survival. We will discuss the clinicopathological characteristics of a HCC subtype expressing stemness-related markers and its future perspectives.

A Feasibility Study of Adenosine Triphosphate-based Chemotherapy Response Assay (ATP-CRA) as a Chemosensitivity Test for Lung Cancer

PURPOSEnA chemosensitivity test can reflect the differences in responses of individual cancer patients to chemotherapeutic agents. The adenosine triphosphate-based chemotherapy response assay (ATP-CRA) is an accurate method, which does not require a large amount of tissue specimen. So far, no studies have evaluated the utility of the ATP-CRA in Korea. Therefore, we investigated the clinical usefulness of the ATP-CRA in 53 patients with lung cancer.nnnMATERIALS AND METHODSnTumor tissues were obtained from bronchoscopic biopsies or surgical resections. The validity of ATP-CRA was assessed focusing on the success rate, experimental error level (intraassay mean coefficient of variation [CV]) and reproducibility.nnnRESULTSnThe overall success rate of ATP-CRA was 90.6% (48/53). Normal cells were effectively eliminated from the tumor tissues with the use of ficoll gradient centrifugation and immunomagnetic separation, which was confirmed using loss of heterozygosity analysis of the 3p deletion. The mean CV of ATP assays was 10.5+/-4.6%. The reproducibility of ATP assays was 94+/-3.8%. The results of the ATP assays were reported to physicians within 7 days of specimen collection. More than 6 anticancer drugs were tested on the tumor specimens obtained from bronchoscopic biopsies.nnnCONCLUSIONnThe ATP-CRA is a stable, accurate and potentially practical chemosensitivity test in patients with lung cancer.

Columnar cell lesions of the breast: mammographic and US features

Objectives: Columnar cell lesions are being encountered with increasing frequency in breast biopsies performed. The purpose of our study was to determine whether columnar cell lesions of the breast have any distinctive imaging characteristics. Materials and methods: We retrospectively reviewed our institutional database for all records of breast pathology obtained in a 17-month period. Columnar cell lesion was diagnosed in 53 lesions and 12 of these 53 lesions contained columnar cell lesions as the sole histopathologic findings. These 12 lesions in nine patients made up our study population. They included columnar cell change (n = 4), columnar cell hyperplasia (n = 5), and columnar cell hyperplasia with atypia (n = 3). Results: All nine patients underwent mammography and sonography within 1 month of each other. Of the mammograms in nine patients, nine lesions (75%) appeared as clustered amorphous or indistinct (n = 5), fine pleomorphic (n = 3), or round (n = 1) microcalcifications. The tenth lesion showed a focal mass without microcalcifications and the remaining two lesions showed no abnormal findings. At sonography, not-circumscribed masses were depicted in six lesions and microcalcifications were visible in four lesions, of which three lesions were concurrent with masses. There were no sonographically focal lesions in the remaining five. Overall 11 lesions were classified as BI-RADS category 4 (92%) and one as category 3. Of the three lesions with atypia, two were classified as category 4a and one was classified as category 4c, and they showed no distinct imaging appearance from those without atypia. Conclusion: Columnar cell lesions usually present as nonpalpable, clustered indeterminate or suspicious microcalcifications on mammography. They are indistinguishable from other causes of suspicious microcalcifications such as atypical ductal hyperplasia or ductal carcinoma in situ and require needle biopsy or excisional biopsy for diagnosis.

CD24 and S100A4 expression in resectable pancreatic cancers with earlier disease recurrence and poor survival.

Objectives The objectives of this study were to study the expression status of markers associated with epithelial-to-mesenchymal transition (EMT) and metastasis in pancreatic ductal adenocarcinomas (PDACs) and to explore the prognostic value of these markers. Methods Immunohistochemical stains for CD24, CD44, E-cadherin, N-cadherin, Snail, S100A4, Vimentin, urokinase-type plasminogen activator receptor, Ezrin, and matrix metalloproteinase 2 were performed on 67 resected PDACs. Results Proteins associated with EMT and metastasis were more frequently expressed in PDACs with poor differentiation, higher tumor stage, and lymphatic and perineural invasion. CD24 expression was associated with frequent expression of EMT markers (CD44 [P = 0.004], S100A4 [P < 0.001], Vimentin [P = 0.022], urokinase-type plasminogen activator receptor [P = 0.002], and Ezrin [P = 0.010]). CD24 and S100A4 expressions in PDAC were significant prognostic factors for early tumor recurrence (hazard risk [HR], 5.185 and 2.490, P = 0.048 and 0.009, respectively) and poor survival (HR, 11.977 and 3.202, P = 0.006 and 0.004, respectively). In addition, the interaction between CD24 and S100A4 expression status was a significant prognostic factor for poor survival (HR, 18.518, P = 0.003). Conclusions The expression of markers of EMT and metastasis in PDACs was significantly associated with pathologic features of aggressiveness. CD24 and S100A4 expressions were significant predictors of poor survival; thus, immunohistochemistry for these markers in resected specimens may help to identify PDAC patients with a poor prognosis.

Expression of androgen receptors and inhibin/activin α and βA subunits in breast apocrine lesions†

The importance of androgens and their receptors inhibin and activin remains unknown for mammary epithelial cells. We investigated the role of these hormones in breast apocrine lesions (BAL) using immunohistochemistry to study androgen receptors (AR) and the inhibin/activin α and βA subunits. Forty‐two cases of BAL were evaluated, including 22 cases of fibrocystic disease (FCD) showing prominent apocrine changes, 10 intraductal papillomas with extensive apocrine metaplasia, 5 cases of apocrine carcinoma in situ (CIS), and 5 cases of apocrine carcinoma. Fifty non‐apocrine lesions were included as controls: 20 cases of FCD, 5 cases of DCIS, and 25 cases of invasive ductal carcinoma. AR was more frequently expressed in BAL than in non‐apocrine lesions (p=0.001). AR expression was not related to tumor progression. AR showed a significant positive correlation with βA subunits (r=0.832, p<0.001), and an inverse correlation with α subunits (r=−0.233). The α and βA subunits demonstrated a significant inverse correlation with each other (r=−0.271, p=0.0048). As the expression of the α and βA subunits reflects inhibin and activin A, respectively, AR and activin A may be implicated in apocrine morphogenesis, but not in tumor progression.

High Expression of MicroRNA-196a Indicates Poor Prognosis in Resected Pancreatic Neuroendocrine Tumor.

AbstractThere is limited data on miRNA expression in pancreatic neuroendocrine tumors (PanNETs). In this study, we aimed to identify miRNAs that could be potential prognostic biomarkers of PanNETs in patients who underwent curative surgery.For miRNA target screening, 2 primary PanNETs and corresponding liver metastases were screened for miRNA expression by the NanoString nCounter analysis. Candidate miRNAs were selected by ≥2-fold difference of expression between metastatic versus primary tumor. For miRNA target validation, quantitative real-time PCR was performed for candidate miRNAs on 37 PanNETs and matched nonneoplastic pancreata, and the miRNA levels were correlated with the clinicopathological features and patient survival data.Eight miRNAs (miRNA-27b, -122, -142–5p, -196a, -223, -590–5p, -630, and -944) were selected as candidate miRNAs. Only miR-196a level was significantly associated with stage, and mitotic count. When PanNETs were stratified into high (nu200a=u200a10) and low (nu200a=u200a27) miRNA-196a expression groups, miRNA-196a-high PanNETs were significantly associated with advanced pathologic T stage (50.0% vs 7.4%), N stage (50.0% vs 3.7%), higher mitotic counts (60.0% vs 3.7%), and higher Ki-67-labeling indices (60.0% vs 22.2%). In addition, high miRNA-196a expression was significantly associated with decreased overall survival (Pu200a=u200a0.046) and disease-free survival (Pu200a<u200a0.001) during a median follow-up of 37.9 months with the hazard ratio for recurrence of 16.267 (95% confidence intervalu200a=u200a1.732–153.789; Pu200a=u200a0.015).MiRNA-196a level may be a promising prognostic marker of recurrence in resected PanNETs, although further experimental investigation would be required.

Induction of cell apoptosis in non-small cell lung cancer cells by cyclin A1 small interfering RNA

Cyclin A1 and cyclin B1 are overexpressed in various tumors but are present at low levels in normal tissues. Cyclin A1 is restricted to germ cells undergoing meiosis. In order to explore the possibility of using cyclin A1 and cyclin B1 as anticancer targets, we knocked them down in two lung cancer cell lines, H157 and H596, using siRNA. As with cyclin A1 siRNA in lung cancer cell lines, cyclin B1, Cdc2 and CDK2 were all significantly downregulated. The S phase fraction increased significantly, and they eventually underwent apoptosis by way of downregulated intrinsic apoptotic pathways and modulators with upregulated extrinsic apoptotic pathways. Our study suggests that cyclin A1 might be a promising anticancer target specific to lung cancer. (Cancer Sci 2006; 97: 1082–1092)

Obstructive Colitis Proximal to Obstructive Colorectal Carcinoma

The term obstructive colitis refers to ulceroinflammatory lesions occurring in the colon proximal to a completely or partially obstructing lesion. It has been referred to by various terms in the literature. This entity differs from the carcinoma of the colon that complicates true ulcerative colitis where there is involvement distal to the neoplasm as well as proximal to it. Although it has appeared in the literature over several decades, it remains an uncommon and troublesome disease. In Yonsei University Medical Center, for 11 years from January 1996 to December 2006 we encountered seven patients with obstructing colorectal carcinoma complicated by obstructive colitis. Here we report our cases to share our experience and to review the literature to facilitate the recognition and proper management of this rare disease entity.