Ji-Shin Lee

Correlation between cyclooxygenase-2 and tumor angiogenesis in non-small cell lung cancer

The role of COX-2 expression and angiogenesis of lung cancer is yet to be delineated. Eighty four non-small cell lung cancer (NSCLC) specimens were evaluated for COX-2 expression, microvessel density (MVD), and vascular endothelial growth factor (VEGF) expression by immunohistochemical methods. The relationships between COX-2 expression and MVD, VEGF expression, and survival time were analyzed. COX-2 expression was observed in the cytoplasm and membrane of the carcinoma cells, and premalignant cells. COX-2 was positive in 67 cases (79.8%). There was a statistically significant correlation between COX-2 expression and tumor size, TNM stage, tumor type, VEGF expression, and vascular pattern with survival in univariate analysis. No significant correlation was seen between COX-2, VEGF expression and MVD. A lack of expression of either COX-2 or VEGF expression or both, however, was associated with lower MVD than the group with both expressed. The difference was statistically significant (P=0.005). Statistically significant differences were also observed according to TNM stage, vascular pattern, COX-2 expression, and VEGF expression. With multivariate analysis, only TNM stage and COX-2 expression retained their significance as independent predictors of survival. COX-2 expression takes part in tumor angiogenesis and is a significant poor prognostic factor in the surgically resected NSCLC. COX-2 inhibitor, either in combination therapy with other agents, or for chemoprevention, may be effective via suppression of angiogenesis in this fatal disease.

Genetic alterations of Wnt signaling pathway-associated genes in hepatocellular carcinoma.

Background and Aim:u2002 Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Recently, abnormal activation of the Wnt pathway has been found to be involved in the carcinogenesis of HCC. However, the relationship between genetic changes in the Wnt pathway–associated genes and its protein expression has not been studied in patients with HCC and cirrhotic nodules. The purpose of this study is to explore the contribution of inappropriate activation of the Wnt pathway in liver carcinogenesis.

Atypical teratoid/rhabdoid tumor of the central nervous system: clinico-pathological study.

Atypical teratoid/rhabdoid tumor (AT/RT) is a new entity among malignant pediatric brain tumors. This study was performed to investigate the clinicopathologic and cytogenetic features of the tumor. Five cases from a series of the brain tumors were studied. Clinical features of the patients were assessed with age, sex, location of the tumors, treatments and survival periods. Histopathologic features were analyzed by routine HE stain and immunohistochemical stains for epithelial membrane antigen, cytokeratin, vimentin, smooth muscle actin, desmin, GFAP, S‐100 protein, neurofilament protein, synaptophysin and α‐feto protein. Cytogenetic studies for karyotype analysis and fluorescent in situ hybridization were available in three cases. Mean age of patients was 5.6u2003years, and maximal survival periods were less than 13u2003months despite surgical and radiation therapy. The tumors were located in infratentorial and supratentorial areas. Histopathologically, the tumors were chiefly composed of rhabdoid cells, modified rhabdoid cells and undifferentiated small cells, mixed with epithelial, mesenchymal, and neural tumor‐like areas. These polyphenotypic features of the tumor cells were supported by diverse immunoreaction. Monosomy of chromosome 22 was demonstrated in two cases of the tumor. These results suggest that AT/RT may be a unique clinicopathologic entity, and histopathologic diagnosis of it should be made judiciously by differentiating other polymorphous tumors of the brain.

CDX-2 homeobox gene expression in human gastric carcinoma and precursor lesions.

Background:u2002 Recent studies have demonstrated that CDX‐2 is expressed in the intestinal metaplasia of the stomach and intestinal‐type gastric cancer. To address the role of CDX‐2 in carcinogenesis of gastric carcinomas of intestinal type, the expression of CDX‐2 in gastric carcinoma and precursor lesions were examined using immunohistochemistry.

Clinical features and epileptogenesis of dysembryoplastic neuroepithelial tumor

IntroductionDysembryoplastic neuroepithelial tumor (DNT) frequently causes medically intractable epilepsy.ObjectiveThe aim of this study was to investigate the basic mechanism of epileptogenecity of the tumor.Materials and methodsClinicopathological data in 13 cases of DNT and immunohistochemical changes of ionotropic glutamate receptor subunits in the tumor and peritumoral epileptogenic cortex were studied.ConclusionsMagnetic resonance imaging combined with electroencephalography (EEG), electrocorticography, and depth-electrode EEG was valuable to localize complicated epileptogenic zones of the patients with DNT. Neuropathological examinations of the peritumoral cerebral cortex presenting abnormal spikes showed different histopathological grades of neuronal migration disorder (NMD). The tumor cells in DNT disclosed increased immunopositivities of N-methyl-d-aspartate receptor 1 (NR1) and NR2A/B, and peritumoral epileptogenic NMD revealed increased immunopositivities of GluR2 and GluR3. The amplification of ionotropic glutamate receptor subunits in the tumor and peritumoral NMD may be the underlying cause of epileptic seizures in DNT patients.

Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence.

PurposeEpigenetic silencing of the DNA mismatch repair genes has been poorly described in colorectal carcinomas showing the classic adenoma–carcinoma pathway of carcinogenesis. The aim of this study was to investigate the methylation status of MutL homolog 1 (hMLH1), MutS homolog 2 (hMSH2), and O-6-methylguanine-DNA methyltransferase (MGMT) in a series of colorectal carcinomas that contain both adenomas and carcinomas.MethodsPromoter methylation of hMLH1, hMSH2, and MGMT was evaluated in normal mucosa, adenoma, and carcinoma samples from 112 colorectal cancer patients. Methylation was assessed by bisulfite modification and methylation-specific PCR. Expression of the gene products was also examined by immunohistochemistry.ResultsOf the 112 adenomas, methylation was detected for hMLH1 (2, 1.8%), hMSH2 (9, 8.0%), and MGMT (38, 33.9%). In the carcinoma samples, methylation was seen in hMLH1 (2, 1.8%), hMSH2 (15, 13.4%), and MGMT (53, 47.3%). In normal mucosa, hMSH2 (6, 5.4%) and MGMT (12, 10.7%) were methylated, whereas hMLH1 was not. Immunohistochemical analysis revealed abnormal hMLH1 (14, 12.5%), hMSH2 (11, 9.8%), and MGMT (53, 47.3%) expression with a significant correlation between aberrant MGMT methylation and a loss of MGMT expression.ConclusionsThese data suggest that CpG island methylation in hMSH2 and MGMT, but not hMLH1, is closely related to carcinogenesis in colorectal carcinomas presenting with a conventional adenoma–carcinoma sequence. Therefore, the detection of hMSH2 and MGMT methylation may have clinical significance in the evaluation of colon cancer patients and in tumor-specific management of the disease.

Utility of Napsin A and Thyroid Transcription Factor 1 in Differentiating Metastatic Pulmonary from Non-Pulmonary Adenocarcinoma in Pleural Effusion

Objective: It was our aim to evaluate the usefulness of napsin A and thyroid transcription factor 1 (TTF-1) in the differential diagnosis of metastatic pulmonary and non-pulmonary adenocarcinomas (ACs) in pleural effusion. Study Design: A total of 84 pleural effusion fluid cell blocks were collected from metastatic ACs. There were 53 pulmonary ACs and 31 non-pulmonary ACs. Immunohistochemical staining was performed with antibodies against napsin A and TTF-1. Results: Napsin A was positive in 44/53 (83%) cases of pulmonary ACs, and TTF-1 was positive in 30/53 (57%) cases of pulmonary ACs. All non-pulmonary ACs were negative for napsin A and TTF-1. Napsin A showed a reactivity in >75% of the tumor cells in 36 of the 44 positive cases (82%), whereas TTF-1 showed a reactivity in >75% of the tumor cells only in 6 of the 30 positive cases (20%; p < 0.01). Poorly differentiated pulmonary ACs expressed napsin A (73%) more frequently than TTF-1 (53%), but this was not statistically significant (p = 0.45). Conclusion: We conclude that napsin A is superior to TTF-1 with regard to distinguishing between metastatic pulmonary and non-pulmonary ACs in cell blocks prepared from malignant pleural effusions.

Pathophysiologic characteristics of balloon cells in cortical dysplasia

ObjectsBalloon cells are histopathological hallmarks of cortical malformations, i.e., focal cortical dysplasia (FCD) of the Taylor type or the cortical tubers of tuberous sclerosis, and they are believed to be the epileptogenic substrate and cause therapeutic drug resistant epilepsy in man. This study was carried out to investigate the developmental histogenesis and epileptogenesis of balloon cells in FCD.Materials and methodsWe used an immunohistochemical approach to examine the expressions of primitive neuroepithelial cell antigens (CD34, nestin, and vimentin), ionotrophic glutamate receptor subunits (NR1, NR2A/B, GluR1, GluR2, GluR3, GluR4, and GluR5/6/7), and P-glycoprotein in balloon cells from FCD and normal cerebral cortex epileptogenic lesions.ConclusionBalloon cells presented in clusters or as scattered cells throughout FCD lesions involving the gray and white matter. We found the balloon cells to be classifiable into three subtypes based on glial fibrillary acidic protein (GFAP) and neurofilament protein (NF-L) immunohistochemistry, i.e., as neuronal, astrocytic, and uncommitted. Immunopositivity for nestin, CD34, and vimentin in balloon cells of FCD suggests that they may be derived from the abnormal development and differentiation of neural stem cells. Moreover, it appears that epileptogenesis in cortical dysplasia is partly caused by the upregulations of some glutamate receptor subunit proteins (NR1, NR2A/B, GluR1, and GluR3) in balloon cells and dysplastic neurons. We speculate that the presence of the drug resistance protein P-glycoprotein in balloon cells might explain medically refractory epilepsy in FCD.

VEGF as a Predictor for Response to Definitive Chemoradiotherapy and COX-2 as a Prognosticator for Survival in Esophageal Squamous Cell Carcinoma

We investigated the patterns of pretreatment expression of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) by immunohistochemical staining and determined their correlation with treatment response and survival in 44 patients with esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). The definitive CCRT consisted of a median dose of 54 Gy (range: 40.0-68.4 Gy) and two cycles of concurrent administration of mostly 5-fluorouracil + cisplatinum. High expression of EGFR, VEGF, and COX-2 was found in 79.5%, 31.8%, and 38.6%, respectively. The Cox regression analysis for overall survival (OS) showed that both the treatment response and COX-2 expression were significant. The 3-yr OS rates of patients that achieved a complete response and those that did not were 46.7% and 5.3%, respectively (P = 0.006). The logistic regression analysis for treatment response with various parameters showed that only a high expression of VEGF was significantly associated with a complete response. Unlike other well-known studies, higher expression of VEGF was significantly correlated with a complete response to CCRT in this study. However, higher expression of COX-2 was significantly associated with shorter survival. These results suggest that VEGF might be a predictive factor for treatment response and COX-2 a prognostic factor for OS in patients with ESCC after definitive CCRT.

VE1 immunohistochemical detection of the BRAF V600E mutation in thyroid carcinoma: a review of its usefulness and limitations

The BRAF V600E mutation is a valuable prognostic factor in thyroid carcinoma despite lingering debate. Successful immunohistochemical (IHC) detection of the BRAF V600E mutation using a VE1 antibody was introduced recently. The objective of this study was to verify the usefulness of IHC detection of the BRAF V600E mutation in thyroid carcinoma using the VE1 antibody. IHC detection of BRAF V600E was performed on various thyroid carcinoma subtypes. IHC results were compared with those obtained from real-time polymerase chain reaction (PCR) detection. Discordant cases were re-examined using a direct sequencing method following nested PCR amplification. The BRAF V600E mutation was detected in 68xa0% (71/104) of papillary carcinoma cases and 78xa0% (7/9) of anaplastic carcinoma cases. The mutation was not detected in patients with follicular carcinoma (0/18) or in medullary carcinoma (0/21). The overall sensitivity and specificity of IHC using the VE1 antibody were 100 and 94xa0%, respectively, suggesting that molecular-based results were indeterminable in four VE1-positive cases. IHC using the VE1 antibody is a highly sensitive and specific method for BRAF V600E mutation detection and may represent a future replacement for DNA-based molecular tests.