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1.  Correlation between Histological Activity and Endoscopic, Clinical, and Serologic Activities in Patients with Ulcerative Colitis 
Objectives. Recent studies suggest that histological healing is a treatment goal in ulcerative colitis (UC). We aimed to evaluate the correlation between histological activity and clinical, endoscopic, and serologic activities in patients with UC. Methods. We retrospectively reviewed medical records from patients with UC who underwent colonoscopy or sigmoidoscopy with biopsies. The Mayo endoscopic subscore was used to assess endoscopic activity. Biopsy specimens were reviewed by two blinded pathologists and scored using the Geboes scoring system. Results. We analyzed 154 biopsy specimens from 82 patients with UC. Histological scores exhibited strong correlation with endoscopic subscores (Spearman's rank correlation coefficient r = 0.774, p < 0.001) and moderate correlation with C-reactive protein levels (r = 0.422, p < 0.001) and partial Mayo scores (r = 0.403, p < 0.001). Active histological inflammation (Geboes score ≥ 3.1) was observed in 6% (2 of 33) of the endoscopically normal mucosa samples, 66% (19 of 29) of mild disease samples, and 98% (90 of 92) of moderate-to-severe disease samples. Conclusions. Histological activity was closely correlated with the endoscopic, clinical, and serologic UC activities. However, several patients with mild or normal endoscopic findings exhibited histological evidence of inflammation. Therefore, histological assessment may be helpful in evaluating treatment outcomes and determining follow-up strategies.
doi:10.1155/2016/5832051
PMCID: PMC4709652  PMID: 26839541
2.  Predictive microRNAs for lymph node metastasis in endoscopically resectable submucosal colorectal cancer 
Oncotarget  2016;7(22):32902-32915.
Accurate prediction of regional lymph node metastasis (LNM) in endoscopically resected T1-stage colorectal cancers (CRCs) can reduce unnecessary surgeries. To identify miRNA markers that can predict LNM in T1-stage CRCs, the study was conducted in two phases; (I) miRNA classifier construction by miRNA-array and quantitative reverse transcription PCR (qRT-PCR) using 36 T1-stage CRC samples; (II) miRNA classifier validation in an independent set of 20 T1-stage CRC samples. The expression of potential downstream target genes of miRNAs was assessed by immunohistochemistry. In the discovery analysis by miRNA microarray, expression of 66 miRNAs were significantly different between LNM-positive and negative CRCs. After qRT-PCR validation, 11 miRNAs were consistently significant in the combined classifier construction set. Among them, miR-342-3p was the most significant one (P=4.3×10−4). Through logistic regression analysis, we developed a three-miRNA classifier (miR-342-3p, miR-361-3p, and miR-3621) for predicting LNM in T1-stage CRCs, yielding the area under the curve of 0.947 (94% sensitivity, 85% specificity and 89% accuracy). The discriminative ability of this system was consistently reliable in the independent validation set (83% sensitivity, 64% specificity and 70% of accuracy). Of the potential downstream targets of the three-miRNAs, expressions of E2F1, RAP2B, and AKT1 were significantly associated with LNM. In conclusion, this classifier can predict LNM more accurately than conventional pathologic criteria and our study results may be helpful to avoid unnecessary bowel surgery after endoscopic resection in early CRC.
doi:10.18632/oncotarget.8766
PMCID: PMC5078061  PMID: 27096956
endoscopically resectable colorectal cancer; microRNA; lymph node metastasis
3.  Role of autophagy-related protein expression in patients with rectal cancer treated with neoadjuvant chemoradiotherapy 
BMC Cancer  2016;16:207.
Background
Autophagy, a cellular degradation process, has complex roles in tumourigenesis and resistance to cancer treatment in humans. The aim of this study was to explore the expression levels of autophagy-related proteins in patients with rectal cancer and evaluate their clinical role in the neoadjuvant chemoradiotherapy setting.
Methods
All specimens evaluated were obtained from 101 patients with colorectal cancer who had undergone neoadjuvant chemoradiotherapy and curative surgery. The primary outcomes measured were the expression levels of two autophagy-related proteins (microtubule-associated protein 1 light chain 3 beta (LC3β) and beclin-1) by immunohistochemistry and their association with clinicopathological parameters and patient survival.
Results
Among the 101 patients, the frequency of high expression of beclin-1 was 31.7 % (32/101) and that of LC3β was 46.5 % (47/101). A pathologic complete response was inversely associated with LC3β expression (P = 0.003) and alterations in the expression of autophagy-related proteins (P = 0.046). In the multivariate analysis, however, autophagy-related protein expression did not show prognostic significance for relapse-free survival or overall survival.
Conclusions
High expression of autophagy-related proteins shows a strong negative association with the efficacy of neoadjuvant chemoradiotherapy in patients with rectal cancer. Autophagy has clear implications as a therapeutic target with which to improve the efficacy of neoadjuvant chemoradiotherapy.
doi:10.1186/s12885-016-2250-0
PMCID: PMC4787053  PMID: 26965179
Rectal cancer; Neoadjuvant chemoradiotherapy; Autophagy; LC3β; Beclin-1; Prognosis
4.  Reduced Expression of TFF1 and Increased Expression of TFF3 in Gastric Cancer: Correlation with Clinicopathological Parameters and Prognosis 
Objectives: The trefoil factor family (TFF) is composed of three thermostable, and protease-resistant proteins, named TFF1, TFF2 and TFF3, and plays a role in gastrointestinal mucosal defence and repair. Recently, TFFs have been found to be related to the development of various types of cancer. This study assessed the relationship between the expression of TFF1 and TFF3 and the clinicopathological parameters in gastric carcinoma (GC). Materials and Methods: The expression of TFF1 and TFF3 was analyzed by immunohistochemistry in 292 GCs and 20 normal gastric tissues. Results: All normal gastric tissues expressed TFF1, but 53.8% of GCs showed reduced TFF1 expression. However, TFF3 was not detected in normal gastric tissues and 44.2% of GCs showed a high level of expression. Highly expressed TFF3 was significantly correlated with lymph node metastasis, lymphatic invasion, vein invasion, and advanced stage. The overall survival was shorter in patients with high expression of TFF3 than in those with low expression of TFF3 in 292 GCs and in 125 early GCs (EGCs). Moreover, in patients with EGCs, high expression of TFF3, associated with reduced expression of TFF1, was determined as an independent poor prognostic marker. Conclusions: Reduced expression of TFF1 and increased expression of TFF3 may play a role in the carcinogenesis of gastric cancer. Furthermore, high expression of TFF3 with reduced expression of TFF1 may be a marker of poor prognosis for patients with EGC.
doi:10.7150/ijms.5500
PMCID: PMC3547210  PMID: 23329884
TFF1; TFF3; gastric cancer
5.  Evaluation of treatment response and tissue necrosis as prognostic indicators following neoadjuvant chemoradiotherapy in rectal cancer patients 
Background/Aims:
The objective of this study was to assess the prognostic roles of treatment response and tissue necrosis after chemoradiotherapy (CRT) in locally advanced rectal cancer.
Methods:
A total of 243 patients with locally advanced rectal cancer who underwent neoadjuvant CRT were included. Three treatment response groups were classified by their pathological stage results: complete treatment response (CTR), intermediate treatment response (ITR), and poor treatment response (PTR). Three tissue necrosis groups were classified based on tissue pathological results: complete necrosis response (CNR), intermediate necrosis response (INR), and poor necrosis response (PNR).
Results:
Overall survival (OS) and recurrence-free survival (RFS) rate at three years were 74.5% and 61.3%, respectively. The 3-year OS rates of the CTR, ITR, and PTR groups were 83.7%, 75.9%, and 69.7%, respectively (p < 0.001); the 3-year RFS rates were 76.7%, 69.0%, and 52.1%, respectively (p < 0.001). The 3-year OS rates of the CNR, INR, and PNR groups were 83.7%, 80.6%, and 61.8%, respectively (p < 0.001); the 3-year RFS rates were 76.7%, 68.9%, and 44.3%, respectively (p < 0.001). When compared to CTR/CNR, PTR/PNR was strongly related to an increased risk of recurrence (hazard ratio [HR], 5.53; 95% confidence interval [CI], 2.01 to 15.23 vs. HR, 6.37; 95% CI, 2.29 to 17.74, respectively) in univariate Cox regression. Both PTR and PNR were strongly associated with shorter RFS and OS when compared with CTR and CNR in the multivariate Cox regression.
Conclusions:
Tissue necrosis is an equally important prognostic marker as treatment response for oncologic outcomes in locally advanced rectal cancer.
doi:10.3904/kjim.2016.31.1.134
PMCID: PMC4712417  PMID: 26767867
Rectal neoplasms; Chemoradiotherapy; Necrosis
6.  A possible complementary tool for diagnosing tuberculosis: a feasibility test of immunohistochemical markers 
Differentiation of tuberculous granuloma (TG) from non-tuberculous granuloma (NG) is histopathologically difficult. We evaluated the usefulness of selected immunohistochemical markers to differentiate tuberculous granuloma (TG) and non-tuberculous granuloma (NG). We selected six biomarkers (FoxP3, TNF-beta, E-selectin [ESEL], indoleamine 2,3-dioxygenase [IDO], lactoferrin [LACT], and tartrate-resistant acid phosphatase [TRAP]) and immunohistochemically analyzed their expression in the presence of two types of granulomatous tissue samples, TG (n = 36) and NG (n = 31), using a microarray format. Three of those six biomarkers (LACT, IDO, and TNF-beta) were moderately accurate in discriminating TG from NG, individually and in combination, according to ROC analysis (AUC = 0.7-0.89, sensitivity = 55.6-77.8%, specificity = 71.0-100%). Our data indicate that selected immunohistochemical markers (LACT, IDO, and TNF-beta) can be used in ancillary tests to differentiate TG from NG in tissue samples. Further large-scale studies are required to validate our results.
PMCID: PMC4713488  PMID: 26823702
Tuberculosis; extrapulmonary tuberculosis (EPTB); biomarkers; immunohistochemistry; granuloma; lactoferrin (LACT); FoxP3; indoleamine 2; 3-dioxygenase (IDO); TNF-beta; E-selectin (ESEL)
7.  GRP78 Protein Expression as Prognostic Values in Neoadjuvant Chemoradiotherapy and Laparoscopic Surgery for Locally Advanced Rectal Cancer 
Purpose
We investigated the relationships between biomarkers related to endoplasmic reticulum stress proteins (glucose-regulated protein of molecular mass 78 [GRP78] and Cripto-1 [teratocarcinoma-derived growth factor 1 protein]), pathologic response, and prognosis in locally advanced rectal cancer.
Materials and Methods
All clinical stage II and III rectal cancer patients received 50.4 Gy over 5.5 weeks, plus 5-fluorouracil (400 mg/m2/day) and leucovorin (20 mg/m2/day) bolus on days 1 to 5 and 29 to 33, and surgery was performed at 7 to 10 weeks after completion of all therapies. Expression of GRP78 and Cripto-1 proteins was determined by immunohistochemistry and was assessed in 101 patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT).
Results
High expression of GRP78 and Cripto-1 proteins was observed in 86 patients (85.1%) and 49 patients (48.5%), respectively. Low expression of GRP78 protein was associated with a significantly high rate of down staging (80.0% vs. 52.3%, respectively; p=0.046) and a significantly low rate of recurrence (0% vs. 33.7%, respectively; p=0.008) compared with high expression of GRP78 protein. Mean recurrence-free survival according to GRP78 expression could not be estimated because the low expression group did not develop recurrence events but showed a significant correlation with time to recurrence, based on the log rank method (p=0.007). GRP78 also showed correlation with overall survival, based on the log rank method (p=0.045).
Conclusion
GRP78 expression is a predictive and prognostic factor for down staging, recurrence, and survival in rectal cancer patients treated with 5-fluorouracil and leucovorin neoadjuvant CRT.
doi:10.4143/crt.2014.121
PMCID: PMC4614215  PMID: 25687871
Rectal neoplasms; Molecular chaperone GRP78; TDGF1 protein; Endoplasmic reticulum stress
8.  Expression of Matrix Metalloproteinase-9 Correlates with Poor Prognosis in Human Malignant Fibrous Histiocytoma 
Purpose
92 kDa matrix metalloproteinase-9 (MMP-9) is believed to play an important role in degrading the matrix and basement membrane, contributing to the invasion and metastasis of malignant solid tumors. However, little is known about its involvement in a malignant fibrous histiocytoma. The aim of this study was to investigate the expression of MMP-9 and to correlate its expression with clinicopathologic parameters in human malignant fibrous histiocytomas.
Materials and Methods
Archival tumor tissues from 20 patients with a malignant fibrous histiocytoma were analyzed by immunohistochemistry for the expression of MMP-9. Clinical information was obtained through the computerized retrospective database from the tumor registry.
Results
Seventeen of 20 (85%) tumors showed a positive reaction for MMP-9. MMP-9 activity was inversely correlated with patients' survival time (p=.011). There was no significant correlation between the activated MMP-9 expression and all the other clinicopathologic variables.
Conclusion
Our data demonstrate that MMP-9 activation is likely to occur in human malignant fibrous histiocytomas. It is also noteworthy that the expression of MMP-9 may aid in predicting patients' poor prognosis.
doi:10.4143/crt.2004.36.6.384
PMCID: PMC2843884  PMID: 20368833
MMP-9; Malignant histiocytic disorder
9.  Calcifying fibrous tumor presenting as rectal submucosal tumor: first case reported in rectum 
Calcifying fibrous tumor (CFT) is a recently recognized rare benign lesion characterized by dense hyalinized collagenous tissue with interspersed spindle cells and a lymphoplasmocytic infiltrate. Calcification is the hallmark of CFT and may present in the form of psammomatous bodies or dystrophic calcifications. CFT of the intestinal tract is uncommon and rectal CFT has never been reported. Recently, we experienced a case of CFT found in the rectum of a 36-year-old man. In this study, we described the characteristic histopathological findings with a review of the relevant literature. Although CFT of the intestinal tract as an intrinsic visceral lesion is unusual and clinically unexpected, CFT should be considered in the differential diagnosis of rectal submucosal tumor.
doi:10.1186/1477-7819-12-28
PMCID: PMC3913959  PMID: 24485017
Calcifying fibrous tumor; Submucosal tumor; Rectum
10.  Expression of Histone Deacetylases in Diffuse Large B-cell Lymphoma and Its Clinical Significance 
Background: Histone deacetylase inhibitors are a new class of drugs used in treatment of malignant tumors. Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma, and it accounts for more than 40% of all B-cell lymphomas. In this study, we aimed to determine the expression patterns of histone deacetylases (HDACs) in DLBCL, to examine whether HDAC expression patterns differ among cases, and to assess whether these findings have clinical significance.
Materials and methods: We selected 91 cases of DLBCL diagnosed at St. Vincent Hospital, The Catholic University of Korea, from 2001-2012. We performed a pathology slide review and collected clinical data including age, sex, tumor site, survival time, and mortality. Immunohistochemical analysis was performed using primary antibodies for HDACs, including HDAC1 and 2 of class I, HDAC4 and 5 of class IIa, and HDAC6 of class IIb. Expression site was determined to be nuclear, cytoplasmic, or both. Staining intensities were graded as low and high. We assessed correlations between HDAC expression levels and clinical data and survival analysis.
Results: Of the 91 cases examined, 46 (50.5%) were men and 45 (49.5%) were women. Most of the patients were elderly, and 74 (81.3%) cases were older than 46 y. Forty-six (50.5%) cases showed lymph node involvement, and 45 (49.5%) cases showed lymphoma at extranodal sites. In nodal lymphoma, staining was strongly positive for HDAC2, whereas staining was weak or negative for HDAC4; however, there was no significant correlation with survival. But nodal lymphoma cases with high nuclear expression of HDAC2 and nodal lymphoma cases with high nuclear expression of HDAC2 and low nuclear expression of HDAC4 showed significantly shorter survival times compared with other cases.
Conclusions: High nuclear expression of HDAC2 may play an important role in survival of DLBCL patients, especially in those with nodal lymphoma, which is associated with a shorter survival time. Our results may have important implications for treatment of DLBCL by epigenetic regulation.
doi:10.7150/ijms.8522
PMCID: PMC4115238  PMID: 25076845
Diffuse large B-cell lymphoma; Histone deacetylase; Epigenetic; Nodal lymphoma; Survival
11.  Microtubule-Associated Protein Tau, α-Tubulin and βIII-Tubulin Expression in Breast Cancer 
Korean Journal of Pathology  2013;47(6):534-540.
Background
The microtubule-associated protein Tau binds to both inner and outer surfaces of microtubules, leading to tubulin assembly and microtubule stabilization. The aim of this study was to evaluate the significance of Tau, α-tubulin, and βIII-tubulin expression in breast carcinoma and to assess their relationships with disease progression in the context of taxane treatment.
Methods
Immunohistochemical expressions of Tau, α-tubulin, and βIII-tubulin were assessed in 183 breast cancer cases. Expression was correlated with clinicopathologic parameters, disease progression and overall survival.
Results
Tau expression was correlated with lymph node metastasis and estrogen receptor (ER) positivity (p=.003 and p<.001, respectively). Loss of α-tubulin was significantly correlated with distant metastasis (p=.034). Loss of βIII-tubulin was correlated with lymph node metastasis and ER positivity (p=.004 and p<.001, respectively). In taxane-treated cases, Tau expression and loss of α-tubulin and βIII-tubulin expression were related to disease progression (p=.001, p=.028, and p=.030, respectively). Tau expression was associated with a worse survival rate in taxane-treated patients (p=.049).
Conclusions
Tau expression and loss of α-tubulin and βIII-tubulin expression were correlated with aggressive behavior in taxane-treated breast cancer. Further evaluation of Tau, α-tubulin and βIII-tubulin may be useful in predicting clinical behavior and seeking therapeutic measures in taxane-based chemotherapy for breast cancer.
doi:10.4132/KoreanJPathol.2013.47.6.534
PMCID: PMC3887155  PMID: 24421846
Tau proteins; Tubulin; Taxoids; Breast neoplasms
12.  An Inverse Relationship between the Expression of the Gastric Tumor Suppressor RUNX3 and Infection with Helicobacter pylori in Gastric Epithelial Dysplasia 
Gut and Liver  2013;7(6):688-695.
Background/Aims
This study was performed to determine the association between RUNX3 expression and Helicobacter pylori infection in premalignant gastric lesions.
Methods
We examined 107 patients with gastric epithelial dysplasia who had undergone endoscopic mucosal resection or submucosal dissection. All tissue samples were evaluated by RUNX3 staining and subclassified by immunophenotype. H. pylori infection in dysplastic lesions and the normal surrounding tissue was examined by silver staining, and cagA status was assessed by polymerase chain reaction.
Results
The loss of RUNX3 expression was observed in 62 cases (57.9%), and an association with H. pylori infection was found in 54 cases (50.5%). The infection rate with the cagA-positive H. pylori strain was 63.0%. In RUNX3-negative lesions, the rate of H. pylori infection (p=0.03) and the frequency of category 4 lesions (according to the revised Vienna classification) were high (p=0.02). In addition, the gastric mucin phenotype was predominant. In RUNX3-negative category 4 lesions, the rate of cagA-positive H. pylori infection rate was high but not significantly increased (p=0.08).
Conclusions
Infection with H. pylori is associated with inactivation of RUNX3 in early gastric carcinogenesis. This mechanism was prominent in gastric cancer with a gastric mucin phenotype.
doi:10.5009/gnl.2013.7.6.688
PMCID: PMC3848534  PMID: 24312710
Helicobacter pylori; CagA protein; Core binding factor alpha 3 subunit
13.  Carcinoma Erysipeloides from Adenocarcinoma of the Lung 
Annals of Dermatology  2013;25(3):373-375.
doi:10.5021/ad.2013.25.3.373
PMCID: PMC3756208  PMID: 24003286
14.  Hedgehog Related Protein Expression in Breast Cancer: Gli-2 Is Associated with Poor Overall Survival 
Korean Journal of Pathology  2013;47(2):116-123.
Background
The hedgehog (Hh) signaling pathway is known to play a critical role in various malignancies, but its clinicopathologic role in breast cancer is yet to be established.
Methods
Tissue microarray blocks from 334 cases of breast cancer were prepared. The expression of six Hh signaling proteins including sonic hedgehog (Shh), patched (Ptch), smoothened (Smo), and the glioma-associated oncogene (Gli)-1, Gli-2, and Gli-3 were analyzed immunohistochemically.
Results
The expression of Hh signaling proteins was significantly correlated with some prognostic factors including the correlation of lymph node metastasis with the expression of Shh (p=0.001) and Ptch (p=0.064), the correlation of the stages with Shh and Gli-3 expression (p=0.007 and p=0.024, respectively), the correlation of the nuclear grade with the Smo (p=0.004) and Gli-3 (p=0.000), and the correlation of the histologic grade with the Ptch (p=0.016), Smo (p=0.007), and Gli-3 (p=0.000). The Shh, Ptch, Smo, Gli-1, and Gli-2 expression was significantly different between the phenotypes (p=0.000, p=0.001, p=0.004, p=0.039, and p=0.031, respectively). Gli-2 expression was correlated with a worse overall survival outcome (p=0.012).
Conclusions
Hh pathway activation is correlated with a more aggressive clinical behavior in breast carcinomas. The comparison of phenotypes suggested that the Hh pathway may be a useful therapeutic target for breast carcinoma. Patients with Gli-2 expression had a significantly lower overall survival rate and, therefore, it showed promise as a prognostic marker.
doi:10.4132/KoreanJPathol.2013.47.2.116
PMCID: PMC3647123  PMID: 23667370
Hedgehog proteins; Gli-2 protein; Gli protein; Breast neoplasms
15.  Fine Needle Aspiration Cytology of Thyroid Follicular Neoplasm: Cytohistologic Correlation and Accuracy 
Korean Journal of Pathology  2013;47(1):61-66.
Background
This study evaluated the accuracy of fine needle aspiration cytology (FNAC) in cases of follicular neoplasm (FN) on the basis of histologic diagnosis, and reviewed the cytologic findings of FN according to the FNAC.
Methods
Among the 66 cases diagnosed with thyroid FN by FNAC during the 7-year period from 2003 to 2009, 36 cases that had undergone thyroid surgery were available for review. Cytologic diagnosis was compared with the histologic diagnosis of each case.
Results
Among the 36 cases with a cytologic diagnosis of thyroid FN, histologic diagnosis was as follows: 20 follicular adenomas (55.6%), 3 Hurthle cell adenomas (8.3%), 2 follicular carcinomas (5.6%), 8 nodular goiters (22.2%), 2 papillary carcinomas (5.6%), and 1 Hashimoto's thyroiditis (2.8%), resulting in a diagnostic accuracy of FNAC for thyroid FN of 69.5%.
Conclusions
This study shows that FNAC for thyroid FN is a useful primary screening method because when FN is diagnosed by FNAC, the rate of FN histologic diagnosis is relatively high, however, adequate sampling and experience is a prerequisite for this procedure.
doi:10.4132/KoreanJPathol.2013.47.1.61
PMCID: PMC3589610  PMID: 23483732
Thyroid gland; Follicular neoplasm; Fine needle aspiration cytology
16.  Clinicopathological Implications of the Expression of Hypoxia-related Proteins in Gastric Cancer 
Objectives: Tumor hypoxia confers poor prognosis of a wide range of solid tumors due to increased malignancy, increased likelihood of metastasis and treatment resistance. The aim of this study was to assess the significance of the expression of HIF-1α and HIF-1α-inducible proteins in gastric cancer and their impact on prognosis. Materials and Methods: The expression of HIF-1α, GLUT-1, CA-9, and iNOS proteins was analyzed by immunohistochemistry in 193 gastric adenocarcinomas (GAs) and 20 normal gastric mucosa. Results: HIF-1α, GLUT-1, CA-9 and iNOS were expressed in 52.3%, 43.0%, 57.0%, and 43.0% of GAs, respectively, which are higher than the normal counterparts except for CA-9. HIF-1α expression was positively correlated with the expression of GLUT-1, CA-9 and iNOS. GLUT-1 expression was higher in the intestinal type (p = 0.012); however, iNOS expression was higher in the less-differentiated type and the diffuse type (p = 0.006, p = 0.032, respectively). The expression of HIF-1α and GLUT-1 was significantly correlated with lymph node metastasis (p = 0.009, p = 0.008, respectively), while the expression of GLUT-1 and iNOS was significantly correlated with the depth of invasion and advanced stage (p = 0.044, p = 0.004; p = 0.009, p = 0.008, respectively). Overall survival was shorter in patients with GLUT-1 expression than in those without GLUT-1 expression, which was statistically significant by univariate analysis (p = 0.042). On multivariate analysis, however, stage was determined as the only independent prognostic marker (p < 0.001). Conclusions: Our data suggest that overexpression of HIF-1α, GLUT-1, and iNOS may play an important role in gastric cancer progression. GLUT-1 is a potential candidate for predicting patient survival.
doi:10.7150/ijms.6054
PMCID: PMC3739021  PMID: 23935399
Gastric cancer; hypoxia; HIF-1α; GLUT-1; CA-9; iNOS
17.  Association between Genetic Instability and Helicobacter pylori Infection in Gastric Epithelial Dysplasia 
Background. In gastric carcinogenesis, changes of DNA methylation appear to be an early molecular event, and the genome-wide methylation state is closely correlated with the level of long interspersed nucleotide element-1 (LINE-1) methylation. In this study, we measured LINE-1 methylation level according to genetic instability and evaluated the effect of Helicobacter pylori infection on genetic instability in gastric epithelial dysplasia. Methods. Total 100 tissue samples of gastric epithelial dysplasia were analyzed. Seven loci that linked to tumor suppressor genes were used to identify significant structural chromosomal aberrations. Microsatellite status was investigated for two different microsatellite marker loci (BAT25 and BAT26). Also, we measured LINE-1 methylation level by combined bisulfite restriction analysis (COBRA-LINE-1) method. Results. There were no significant differences of LINE-1 methylation level according to chromosomal/microsatellite instability and H. pylori state. In the dysplastic lesions with H. pylori infection, LINE-1 methylation level of MSI lesion was significantly lower than that of microsatellite stable (MSS) lesion (40.23 ± 4.47 versus 43.90 ± 4.81%, P < 0.01). Conclusions. In gastric epithelial dysplasia with H. pylori infection, MSI is correlated with reduced LINE-1 methylation level. Coexistence of H. pylori infection and MSI might be a driving force of gastric carcinogenesis.
doi:10.1155/2012/360929
PMCID: PMC3546497  PMID: 23346103
18.  Tumor budding as a risk factor of lymph node metastasis in submucosal invasive T1 colorectal carcinoma: a retrospective study 
BMC Surgery  2012;12:16.
Background
This study was designed to identify risk factors for lymph node metastasis of early stage colorectal cancer, which was confirmed to a carcinoma that invaded the submucosa after radical resection.
Methods
In total, 55 patients revealing submucosal invasive colorectal carcinoma on pathology who underwent curative radical resection at the Department of Surgery, St. Vincent’s Hospital, The Catholic University of Korea from January 2007 to September 2010 were evaluated retrospectively. Tumor size, depth of submucosal invasion, histologic grade, lymphovascular invasion, tumor budding, and microacinar structure were reviewed by a single pathologist. Student t-test for continuous variables and Chi-square test for categorical variables were used for comparing the clinicopathological features between two groups (whether lymph node involvement existed or not). Continuous variables are expressed as the mean ± standard error while statistical significance is accepted at P < 0.05.
Results
The mean age of 55 patients (34 males and 21 females) was 61.2 ± 9.6 years (range, 43–83). Histologically, eight (14.5%) patients had metastatic lymph node. In the univariate analysis, tumor budding (P = 0.047) was the only factor that was significantly associated with lymph node metastasis. Also, the tumor budding had a sensitivity of 83.3%, a specificity of 60.5%, and a negative predictive value of 0.958 for lymph node metastasis in submucosal invasive T1 colorectal cancer.
Conclusions
The tumor budding seems to have a high sensitivity (83.3%), acceptable specificity (60.5%), and a high negative predictive value (0.958). A close examination of pathologic finding including tumor budding should be performed in order to manage early CRC properly.
doi:10.1186/1471-2482-12-16
PMCID: PMC3469500  PMID: 22866826
Lymph node metastasis; T1 colorectal cancer; Tumor budding
19.  Primary gastric Hodgkin's lymphoma 
Gastric Hodgkin's lymphoma is extremely rare. We present a case of primary Hodgkin's lymphoma arising in the stomach of a 65-year-old woman. The patient complained of epigastric discomfort and reflux for one month. Endoscopic examination revealed a protruding lesion characterized by a smooth surface at the antrum. An abdominal computed tomography uncovered a 2.5 × 2.0 cm, exophytic submucosal mass. After the tentative preoperative diagnosis of a gastrointestinal stromal tumor, a gastric wedge resection was performed. Microscopic examination of the mass demonstrated a diffuse proliferation of large atypical lymphoid cells with mono- and binucleated pleomorphic nuclei and prominent nucleoli. Immunohistochemically, the tumor cells were positive for CD30, CD20, and CD79a, whereas they were negative for cytokeratin, carcinoembryonic antigen, CD3, CD15, epithelial membrane antigen, and anaplastic lymphoma kinase-1. Based on the morphological features and immunohistochemical results, in addition to the clinical findings, a diagnosis of primary gastric Hodgkin's lymphoma was established.
doi:10.4174/jkss.2012.83.2.111
PMCID: PMC3412183  PMID: 22880187
Stomach; Hodgkin's lymphoma; CD30 antigens
20.  Immunohistochemical Expression of DCUN1D1 in Non-small Cell Lung Carcinoma: Its Relation to Brain Metastasis 
Purpose
Non-small cell lung carcinoma (NSCLC) comprises 75-85% of all lung cancers, and approximately 25% of all NSCLC patients develop brain metastasis. There are no reliable markers for predicting in which patients this metastasis will occur. DCUN1D1, also known as squamous cell carcinoma-related oncogene, is associated with tumor progression and poor outcomes in NSCLC. The objective of this study was to investigate the role of DCUN1D1 expression in cases of brain metastasis due to NSCLC.
Materials and Methods
Primary tumor samples from a total of 71 cases of NSCLC, either with (n=40) or without (n=31) brain metastasis, were evaluated for DCUN1D1 expression by immunohistochemistry analysis.
Results
DCUN1D1 expression was detected in 16 patients (23%) and tended to correlate with T classification (15% of T1-2 tumors vs. 30% of T3-4 tumors, p=0.083). DCUN1D1 expression was significantly associated with tumor stage. It was observed in none of the patients with stage I disease, 10% of those with stage II disease, and 29% with stage III disease (p=0.009). In addition, 14 of 16 DCUN1D1-positive patients resulted in brain metastasis (p=0.01). The odds ratio of brain metastasis for patients with DCUN1D1 expression was 3.112 (p=0.009).
Conclusion
DCUN1D1 expression may play a role in tumor progression and development of brain metastasis in patients with NSCLC. Evaluation of DCUN1D1 expression may provide assistance in identifying those patients who are at higher risk for brain metastasis.
doi:10.4143/crt.2012.44.1.57
PMCID: PMC3322202  PMID: 22500162
Non-small cell lung carcinoma; DCUN1D1 protein; Neoplasm metastasis
21.  Review of atypical cytology of thyroid nodule according to the Bethesda system and its beneficial effect in the surgical treatment of papillary carcinoma 
Purpose
For the atypical cases of fine needle aspiration (FNA) cytology of thyroid nodules, ultrasonographic findings are a primary guideline for the surgical treatment. However, they have the intrinsic risk of overtreatment, as well. In this study we examined whether the Bethesda system could provide a real effect on the diagnostic rate of atypical cytology, and thereby reduce the number of cases diagnosed as atypical from FNA cytology.
Methods
We reviewed 166 cases diagnosed as atypical by FNA cytology at this institute between the years 2005 to 2010. We classified these cases on the basis of ultrasonographic and cytological findings and compared them with the histological results.
Results
Ultrasonographically, findings suspicious for malignancy and indeterminate were associated with 83.7% and 47.2% of malignancy rates, respectively. Cytopathologically, the malignancy rates varied according to the main cytological features and the highest malignancy rate was 77.3%. Based on the Bethesda system, 39.2% of the cases diagnosed as atypical could be grouped into the category of suspicious for malignancy and yielded a malignancy rate of 76.9%.
Conclusion
Although ultrasonography provides an excellent guideline for the surgical treatment of atypical cases, it also showed considerable risk of overtreatment. The Bethesda system did not offer definitive effects on the rate of atypical cytology, but this system seemed to provide stricter boundaries for the atypical cytology and to aid in reducing the rates thereof. This in turn may permit that more limited cases are allotted to ultrasonographic decision making.
doi:10.4174/jkss.2011.81.2.75
PMCID: PMC3204571  PMID: 22066105
Thyroid nodule; Cytology; Atypical; The Bethesda system; Ultrasonography
22.  Differential LINE-1 Hypomethylation of Gastric Low-Grade Dysplasia from High Grade Dysplasia and Intramucosal Cancer 
Gut and Liver  2011;5(2):149-153.
Background/Aims
Gastric epithelial dysplasia is considered a precancerous lesion with a variable clinical course. There is disagreement, however, regarding histology-based diagnoses, which has led to confusion in choosing a therapeutic plan. New objective markers are needed to determine which lesions progress to true malignancy. We measured LINE-1 methylation levels, which have been reported to strongly correlate with the global methylation level in gastric epithelial dysplasia and intramucosal cancer.
Methods
A total of 145 tissue samples were analyzed by two histopathologists. All tissues were excised by therapeutic endoscopic mucosal resection and paired with adjacent normal tissue samples. A modified long interspersed nucleotide elements-combined bisulfite restriction analysis (COBRA-LINE-1) method was used.
Results
Gastric epithelial dysplasia and intramucosal cancer tissues had significantly lower levels of LINE-1 methylation than adjacent normal gastric tissues. High-grade dysplasia and intramucosal cancer were distinguishable from low-grade dysplasia based on LINE-1 methylation levels. Furthermore, the distinction could be determined with high sensitivity and specificity, as shown by the receiver operating characteristic (ROC) curve (AUC, 0.82; 95% confidence interval, 0.74 to 0.88).
Conclusions
LINE-1 methylation levels may provide a diagnostic tool for identifying high-grade dysplasia and intramucosal cancer.
doi:10.5009/gnl.2011.5.2.149
PMCID: PMC3140658  PMID: 21814593
LINE-1 methylation; Gastric epithelial dysplasia; Intramucosal cancer
23.  Colon Ischemia Associated with Buerger's Disease: Case Report and Review of the Literature 
Gut and Liver  2010;4(2):287-291.
Buerger's disease, or thromboangiitis obliterans, is a nonatherosclerotic inflammatory disease affecting the small- and medium-sized arteries and veins of the extremities (arms, hands, legs, and feet). It is most common in the Orient, Southeast Asia, India, and the Middle East, and usually affects men aged between 20 and 40 years, although it is becoming more common in women. It is well established that most such patients smoke heavily and experience an improvement in symptoms following smoking cessation. Mesenteric involvement in Buerger's disease is extremely rare; however, we describe herein two cases of colon ischemia in patients who were previously diagnosed with lower-extremity Buerger's disease. In one case, the patient developed colonic obstruction, and surgical resection was performed. Histopathologic findings were compatible with the chronic stage of Buerger's disease. In the other case, angiography revealed abrupt occlusion of the inferior mesenteric artery with numerous collateral vessels, just like the corkscrew appearance found in the extremities. If patients with established Buerger's disease of the extremities complain of gastrointestinal symptoms, early interventional diagnosis should be performed to prevent intestinal obstruction and gangrene.
doi:10.5009/gnl.2010.4.2.287
PMCID: PMC2886923  PMID: 20559539
Thromboangiitis obliterans; Mesenteric involvement; Colon ischemia
24.  Genetic Instability in Gastric Epithelial Neoplasias Categorized by the Revised Vienna Classification 
Gut and Liver  2010;4(2):179-185.
Background/Aims
The aim of this study was to determine the structural chromosomal aberrations, such as loss of heterozygosity (LOH) and microsatellite instability (MSI), at multiple tumor suppressor gene loci in gastric epithelial neoplasia categorized by the revised Vienna classification.
Methods
All tissue samples were excised by endoscopic mucosal resection. Sixty category 3 (low-grade adenoma) tissue samples and 51 category 4 samples (high-grade adenoma and intramucosal carcinoma with adenoma) were examined at the 7 sets of microsatellite loci linked to the tumor suppressor gene locus.
Results
For category 3 and 4 tissue samples, there were no differences in the frequencies of LOH-positive chromosomes or the extent of chromosomal loss. The Helicobacter-pylori (H. pylori)-positive rate was significantly higher in MSI-positive category 4 samples than in category 3 samples (p=0.04). The frequency of MSI positivity was significantly higher in category 4 samples than in category 3 samples (p=0.003).
Conclusions
H. pylori infection is associated with genetic instability of the premalignant lesion. MSI occurs in the early stages of gastric carcinogenesis and its occurrence increases during malignant transformation. Detection of MSI in premalignant gastric lesions may be a surveillant of risk of malignant transformation.
doi:10.5009/gnl.2010.4.2.179
PMCID: PMC2886946  PMID: 20559519
Genetic instability; Gastric epithelial neoplasia; Vienna classification
25.  Acute Thermal Injury of the Esophagus from Solid Food: Clinical Course and Endoscopic Findings 
Journal of Korean Medical Science  2010;25(3):489-491.
A 53-yr-old man presented with a two-day history of odynophagia and a foreign body sensation. Two days before admission, the patient began to experience odynophagia and a foreign body sensation in the chest after swallowing several extremely hot pieces of solid food (prawn) in haste. Endoscopy revealed a huge longitudinal ulcer, typical of friable hyperemic mucosa with necrotic debris along the full length of the esophagus in the posterolateral region. Here we present the clinical course of serial endoscopy of an acute thermal injury of the esophagus caused by solid food.
doi:10.3346/jkms.2010.25.3.489
PMCID: PMC2826729  PMID: 20191054
Acute Thermal Injury; Esophagus; Solid Food

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