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Background We attempted to elucidate whether p53 expression or TP53 mutation status was associated with cancer-specific survival in adjuvant FOLFOX-treated patients with stage III or high-risk stage II colorectal cancer (CRC). Methods We analysed CRCs (N = 621) for the presence of TP53 alterations and for p53 expression, using targeted resequencing and immunohistochemistry. CRCs were grouped into four subsets according to the p53 expression status, which included p53-no, mild, moderate and strong expression. Results The distributions of CRCs were 19.85, 11.05, 17.7% and 51.5% in the p53-no, mild, moderate and strong expression groups, respectively. Cases in the p53-mild to moderate expression group were associated with a more frequent proximal location, undifferentiated histology, lower N category, extraglandular mucin production, microsatellite instability, CIMP-P1, CK7 expression and decreased CDX2 expression compared with those of cases of the p53-no expression and p53-strong expression groups. According to survival analysis, the p53-mild expression group showed a poor 5-year relapse-free survival (hazard ratio (HR): 2.71, 95% confidence interval (CI) = 1.60–4.60, P

Summary Deletion of the HSP110 T 17 mononucleotide repeat has recently been identified as a prognostic marker that is correlated with wild-type HSP110 (HSP110wt) expression in microsatellite instability–high (MSI-H) colorectal cancers. The aim of this study was to assess the correlation between deletion of the HSP110 T 17 repeat and expression of HSP110wt using DNA testing and immunohistochemistry and to determine the prognostic implications of HSP110 T 17 deletion in MSI-H advanced gastric cancers (GCs). The status of HSP110wt expression was evaluated by immunohistochemistry using an HSP110wt-specific antibody in 142 MSI-H advanced GCs. The size of the HSP110 T 17 repeat deletion was analyzed in 96 MSI-H advanced GCs; deletions were divided into small (0-2base pairs) and large deletions (3-5base pairs). Low and high expressions of HSP110wt were detected in 38 (26.8%) and 104 (73.2%) of the 142 cases, respectively. The HSP110 T 17 deletion was observed in 45 (46.9%) of the 96 MSI-H GC samples. Tumors with high expression of HSP110wt showed a tendency to have small or no deletion of HSP110 T 17 . In Kaplan-Meier survival analysis, tumors with a large HSP110 T 17 deletion were associated with favorable overall survival and disease-free survival compared with those with small/no deletion of HSP110 T 17 . However, HSP110 T 17 deletion size was not an independent prognostic factor in multivariate analysis. In summary, deletion of the HSP110 T 17 repeat was frequently observed in MSI-H GCs, and HSP110 T 17 deletion size was inversely correlated with HSP110wt expression status. Large HSP110 T 17 was not a prognostic indicator in MSI-H GCs.

Objectives Nitrite as an alternative source of nitric oxide has been proposed, as it can mediate the protective response in the presence of ischemia or hypoxic conditions and inorganic nitrite can be reduced to nitric oxide by xanthine oxidoreductase. Here, we investigated whether pretreatment with sodium nitrite can attenuate liver damage in hepatic ischemia-reperfusion injury and identified the possible mechanism of nitrite reduction using 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide (C-PTIO), a nitric oxide scavenger, and allopurinol, a xanthine oxidoreductase inhibitor. Materials and methods In experiment 1, 30 male Sprague-Dawley rats were divided into 5 groups: (1) sham-operated; (2) hepatic ischemia-reperfusion injury; and (3-5) sodium nitrite administered intra-peritoneally 30 minutes before ischemia at 2.5, 25, and 250 μmol/kg, respectively. In experiment 2, 24 male Sprague-Dawley rats were divided into 4 groups: (1) hepatic ischemia-reperfusion injury; (2) sodium nitrite + hepatic ischemia-reperfusion injury; (3) C-PTIO + sodium nitrite + hepatic ischemia-reperfusion injury; and (4) allopurinol + sodium nitrite + hepatic ischemia-reperfusion injury. Sodium nitrite (25 μmol/kg) was then administered 30 minutes before hepatic ischemia, and C-PTIO or allopurinol was administered 5 minutes before sodium nitrite administration. Blood aspartate aminotransferase, alanine aminotransferase, hepatic tissue malondialdehyde, histologic changes, and expression of mitogen-activated protein kinase family members were evaluated. Results Sodium nitrite limited serum elevation of alanine aminotransferase and aspartate aminotransferase induced by hepatic ischemia-reperfusion with a peak effect occurring at 25 μmol/kg sodium nitrite. Pre-treatment with allopurinol abolished the protective effect of sodium nitrite, and C-PTIO treatment attenuated the hepatoprotection of sodium nitrite in rats with hepatic ischemia-reperfusion injury. Liver malondialdehyde activity after ischemia-reperfusion decreased in sodium nitrite-treated rats. Sodium nitrite also prevented hepatic ischemia-reperfusion-induced c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation. Conclusions Exogenous sodium nitrite had protective effects against hepatic ischemia-reperfusion injury. Catalytic reduction to nitric oxide and attenuation of hepatic ischemia-reperfusion is dependent on xanthine oxidoreductase.

CpG island methylator phenotype (CIMP)-high (CIMP-H) colorectal cancer (CRC) is defined when a tumor shows methylation at greater than or equal to 60% of CIMP panel markers. Although CRCs with methylation at 50% of panel markers are classified as CIMP-low/CIMP-0 tumors, little is known regarding the clinicopathological and molecular features of CRCs with methylation at 4/8 panel markers (4/8 methylated markers) and whether they are akin to CIMP-H or CIMP-low/CIMP-0 CRCs in terms of their clinicopathological or molecular features. A total of 1164 cases of surgically resected CRC were analyzed for their methylation status in 8 CIMP panel markers, and the frequencies of various clinicopathological and molecular features were compared between CRCs with 0/8, 1/8 to 3/8, 4/8, and 5/8 to 8/8 methylated markers. CRCs with 4/8 methylated markers were closer to CRCs with 5/8 to 8/8 methylated markers in terms of sex distribution, mucin production, serration, nodal metastasis, CK7 expression, CK20 loss, and CDX2 loss frequencies and overall survival rate. CRCs with methylation at 4/8 markers were closer to CRCs with 1/8 to 3/8 methylated markers in terms of less frequent right colon location and poor differentiation. CRCs with 4/8 methylated markers showed the shortest overall survival time compared with CRCs with 0/8, 1/8 to 3/8, 4/8, or 5/8 to 8/8 methylated markers. In terms of clinicopathological and molecular features, CRCs with 4/8 methylated markers appeared to be closer to CIMP-H than to CIMP-low/CIMP-0 and would thus be better classified as CIMP-H if the CRCs require classification into either CIMP-H or CIMP-low/CIMP-0.

PURPOSE Somatic mutations of the chromatin remodeling AT-rich interactive domain 1A (SWI-like) gene (ARID1A) have been identified in many human cancers, including breast cancer. The purpose of this study was to evaluate the nuclear expression of ARID1A in breast cancers by immunohistochemistry (IHC) and to correlate the findings to clinicopathologic variables including prognostic significance. METHODS IHC was performed on tissue microarrays of 476 cases of breast cancer. Associations between ARID1A expression and clinicopathologic characteristics and molecular subtype were retrospectively analyzed. RESULTS Low expression of ARID1A was found in 339 of 476 (71.2%) cases. Low expression of ARID1A significantly correlated with positive lymph node metastasis (p=0.027), advanced pathologic stage (p=0.001), low Ki-67 labeling index (p=0.003), and negative p53 expression (p=0.017). The ARID1A low expression group had significantly shorter disease-free and overall survival than the ARID1A high expression group (p

A glomus tumor in the mediastinum is very uncommon, and only five cases have been reported in the English literature. We recently encountered a 21-year-old woman with an asymptomatic mediastinal mass that measured 5.3 × 4.0 cm. Surgical excision was performed, and the tumor was finally diagnosed as mediastinal glomus tumor with an uncertain malignant potential. After reviewing this case and previous reports, we analyzed the clinicopathologic features associated with progression of such a tumor.

Deletion of the HSP110 T

// Kyung-Ju Kim 1, 2 , Han Kwang Yang 3 , Woo Ho Kim 4 and Gyeong Hoon Kang 1, 4 1 Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea 2 Department of Pathology, Yeungnam University College of Medicine, Daegu 42415, Republic of Korea 3 Department of General Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea 4 Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea Correspondence to: Gyeong Hoon Kang, email: ghkang@snu.ac.kr Keywords: gastric cancer, microsatellite instability, PD-L1, immunoscore, prognosis Received: February 13, 2017 Accepted: July 12, 2017 Published: July 22, 2017 ABSTRACT Background: The aim of this study was to evaluate how programmed death-ligand-1 (PD-L1) expression is linked to the immunoscore in the context of the tumor microenvironment and to assess the differential prognostic value of PD-L1 expression according to the immunoscore in 153 patients with microsatellite instability-high (MSI-H) advanced gastric cancer (GC). Results: We found that T-PD-L1 (+) and I-PD-L1 (+) were significantly associated with a high immunoscore. The integrated PD-L1 expression of tumor and immune cells was not significantly correlated with the overall survival (OS) of patients. However, a combined survival analysis of PD-L1 expression and immunoscore revealed four distinct subgroups with a statistically significant difference in OS. That is, the PD-L1 (+)/immunoscoreLow group showed the worst and the PD-L1 (+)/immunoscoreHigh group showed the best prognosis. Furthermore, a multivariate analysis revealed that the combined status of PD-L1 expression and immunoscore was an independent and significant prognostic factor for OS in patients with MSI-H GC. Materials and Methods: The immunoscore was quantified by the number of high-density areas of CD3+ and CD8+ tumor infiltrating lymphocytes both in the tumor regions and compartments (i.e., epithelial and stromal compartments of the tumor center and the invasive front), the scores of which range from I0 to I8. By using immunohistochemistry, the expression of PD-L1 was also analyzed in tumor cells (T-PD-L1) and immune cells (I-PD-L1) using four different cut-off values (1%, 5%, 10% and 50%). Conclusions: Our study revealed that PD-L1 expression is associated with the corresponding immunoscore and that the immunoscore can be a relevant marker for the determination of the prognostic role of PD-L1 expression in MSI-H GCs.

As a continuous research for discovery of new COX-2 inhibitors, we present the simple chemical synthesis, in vitro biological screening, and molecular docking study of 1H-pyrrole-2,5-dione derivatives. New synthetic compounds were evaluated for the inhibitory activities on LPS-induced PGE2 production in RAW 264.7 macrophage cells as well as the COX-1 and COX-2 inhibitory potency. Among them, compound 9d (MPO-0029) was identified as more potent and selective COX-2 inhibitor [PGE2 IC50 = 8.7 nM, COX-2 IC50 = 6.0 nM; COX-2 selectivity index (SI) = >168] than celecoxib. Molecular docking experiments were further performed against COX-2 and COX-1 isozymes to determine their probable binding models. Results of molecular docking studies revealed that compound 9d (MPO-0029) has stronger binding interaction with COX-2 than with COX-1 isozyme, and provided successfully complementary theoretical support for the obtained experimental biological data.

It has been recently suggested that the expression levels of mutant HSP110 could be a prognostic marker in colorectal cancer with a high level of microsatellite instability (MSI-H). The aim of our study was to validate the prognostic significance of HSP110 mutation using immunohistochemistry and DNA testing in MSI-H colorectal cancer. Wild-type HSP110 (HSP110wt)-specific immunohistochemistry was performed in 168 MSI-H colorectal cancer tissues, and their expression levels were evaluated using a four-tier scoring system (0/1+/2+/3+). Of these tissues, 167 cases were analyzed for HSP110 T17 deletion. Associations with clinicopathological, molecular and survival parameters were statistically analyzed. The low-level expression of HSP110wt (0/1+) was observed in 40 MSI-H colorectal cancers (24%) and was significantly related to large HSP110 T17 deletions (≥ 4 bp, P

Pulmonary artery tumor embolism (PATE) is a rare disease without an established diagnostic method. In an autopsy series, however, the incidence of PATE was relatively high, between 3% and 26% in patients with a solid tumor. Here we report a case of a patient with a massive PATE from hepatocellular carcinoma diagnosed safely and promptly by endobronchial ultrasound-guided transbronchial needle aspiration.

We evaluated the association of cell adhesion molecule 4 (CADM4) expression with clinicopathologic parameters and overall survival (OS) in patients with small intestinal adenocarcinomas (SIAs) and determined its prognostic significance. CADM4 immunohistochemical staining was performed for 170 SIA samples. Loss of or low CADM4 expression was observed in 26 (15.3%) and 50 (29.4%) cases, respectively, and it was significantly associated with undifferentiated histology (p

Background: The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy. Methods: Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1–4), and negative (0). Results: A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22–80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (P

The synthetic procedures and reaction conditions for 3phenyl-4-(4-sulfonamido)-1H-pyrrole-2,5-dione 2l are shown in Scheme 1: 4-Chlorosulfonylphenylacetic acid (4) was prepared from the reaction of phenylacetic acid (3) with ClSO3H, and then treated with SOCl2 and subsequent NH3 gas in CH3CN to provide 4-chlorosulfonylphenylacetamide (5), which was condensed with ethyl benzoylformate (2) using NaH condition to yield 3-(4-sulfamoylphenyl)-4phenyl-1H-pyrrole-2,5-dione (2l). 8

PURPOSE Transducer-like enhancer of split 1 (TLE1) is a member of the Groucho/TLE family of transcriptional co-repressors that regulate the transcriptional activity of numerous genes. TLE1 is involved in the tumorigenesis of various tumors. We investigated the prognostic significance of TLE1 expression and its association with clinicopathological parameters in gastric cancer (GC) patients. MATERIALS AND METHODS Immunohistochemical analysis of six tissue microarrays was performed to examine TLE1 expression using 291 surgically resected GC specimens from the Soonchunhyang University Cheonan Hospital between July 2006 and December 2009. RESULTS In the non-neoplastic gastric mucosa, TLE1 expression was negative. In GC, 121 patients (41.6%) were positive for TLE1. The expression of TLE1 was significantly associated with male gender (P=0.021), less frequent lymphatic (P=0.017) or perineural invasion (P=0.029), intestinal type according to the Lauren classification (P=0.024), good histologic grade (P

Finite element models of dynamic systems can be updated in two stages. In the first stage, mass and stiffness matrices are updated neglecting damping. In the second stage, a damping matrix is estimated with the mass and stiffness matrices fixed. Methods to estimate a damping matrix for this purpose are proposed in this paper. For a system with proportional damping, a damping matrix is estimated using the modal parameters extracted from the measured responses and the modal matrix calculated from the mass and stiffness matrices from the first stage. For a system with non-proportional damping, a damping matrix is estimated from the impedance matrix which is the inverse of the FRF matrix. Only one low or one column of the FRF matrix is measured, and the remaining FRFs are synthesized to obtain a full FRF matrix. This procedure to obtain a full FRF matrix saves time and effort to measure FRFs.

Purpose The AT-rich interactive domain 1A (ARID1A) gene encodes BRG1-associated factor 250a, a component of the SWItch/Sucrose NonFermentable chromatin remodeling complex, which is considered a tumor suppressor in many tumors. We aimed to investigate the prognostic significance of ARID1A expression in gastric cancers and explore its relationship with clinicopathologic parameters such as mismatch repair protein expression. Materials and Methods Four tissue microarrays were constructed from 191 resected specimens obtained at Soonchunhyang University Cheonan Hospital from 2006 to 2008. Nuclear expression of ARID1A was semiquantitatively assessed and binarized into retained and lost expression. Results Loss of ARID1A expression was observed in 62 cases (32.5%). This was associated with more frequent vascular invasion (P=0.019) and location in the upper third of the stomach (P=0.001), and trended toward more poorly differentiated subtypes (P=0.054). ARID1A loss was significantly associated with the mismatch repair-deficient phenotype (P=0.003). ARID1A loss showed a statistically significant correlation with loss of MLH1 (P=0.001) but not MSH2 expression (P=1.000). Kaplan-Meier survival analysis showed no statistically significant difference in overall survival; however, patients with retained ARID1A expression tended to have better overall survival than those with loss of ARID1A expression (P=0.053). In both mismatch repair-deficient and mismatch repair-proficient groups, survival analysis showed no differences related to ARID1A expression status. Conclusions Our results demonstrated that loss of ARID1A expression is closely associated with the mismatch repair-deficient phenotype, especially in sporadic microsatellite instability-high gastric cancers.

Tumor associated macrophages are major inflammatory cells that play an important role in the tumor microenvironment. In this study, we investigated the prognostic significance of tumor associated macrophages (TAMs) in MSI-high gastric cancers using immunohistochemistry. CD68 and CD163 were used as markers for total infiltrating macrophages and M2-polarized macrophages, respectively. The density of CD68+ or CD163+ TAMs in four different areas (epithelial and stromal compartments of both the tumor center and invasive front) were analyzed in 143 cases of MSI-high advanced gastric cancers using a computerized image analysis system. Gastric cancers were scored as "0" or "1" in each area when the density of CD68+ and CD163+ TAMs was below or above the median value. Low density of CD68+ or CD163+ macrophages in four combined areas was closely associated with more frequent low-grade histology and the intestinal type tumor of the Lauren classification. In survival analysis, the low density of CD163+ TAMs was significantly associated with poor disease-free survival. In multivariate survival analysis, CD163+ TAMs in four combined areas, stromal and epithelial compartments of both tumor center and invasive front were independent prognostic indicator in MSI-high gastric cancers. In addition, the density of CD163+ TAMs correlated with tumor infiltrating lymphocytes (TILs). Our results indicate that the high density of CD163+ TAMs is an independent prognostic marker heralding prolonged disease-free survival and that the prognostic implication of CD163+ TAMs might be determined by the proportional balance of TAMs and TILs in MSI-high gastric cancers.

The standard procedure outlined by the United States Environmental Protection Agency (US EPA) in Method 1623 for analyzingGiardia lamblia cysts andCryptosporidium parvum oocysts in water samples consists of filtration, elution, centrifugal concentration, immunomagnetic separation (IMS), and immunofluorescence assay (IFA) followed by microscopic examination. In this study, the extent of (oo)cyst loss in each step of this procedure was evaluated by comparing recovery yields in segmented analyses: (i) IMS+IFA, (ii) concentration +IMS+IFA, and (iii) filtration/elution + concentration +IMS+IFA. The complete (oo)cyst recovery by the full procedure was 52–57%. The (oo)cyst loss in the IMS step was only 0–6%, implying that IMS is a fairly reliable method for (oo)cyst purification. Centrifugal concentration of the eluted sample and pellet collection before IMS resulted in a loss of 8–14% of the (oo)cysts. The largest (oo)cyst loss occurred in the elution step, with 68–71% of the total loss. The permeated loss of (oo)cysts was negligible during filtration of the water sample with a 1.0-μm pore polyethersulfone (PES) capsule. These results demonstrated that the largest fraction of (oo)cyst loss in this procedure occurred due to poor elution from the filter matrix. Improvements in the elution methodology are therefore required to enhance the overall recovery yield and the reliability of the detection of these parasitic protozoa.

It has been suggested that nuclear expression of maspin (mammary serine protease inhibitor; also known as SERPINB5) in colorectal cancer (CRC) is associated with proximal colonic tumor location, mucinous and poorly differentiated histology, microsatellite instability-high (MSI-H), and poor prognosis. Based on these findings, there may be a potential association between nuclear maspin expression and the CpG island methylator phenotype (CIMP) in CRC, but no study has elucidated this issue. Here, we evaluated maspin protein expression status by immunohistochemistry in 216 MSI-H CRCs. CIMP status was also determined by methylation-specific quantitative PCR method (MethyLight) using eight CIMP markers (MLH1, NEUROG1, CRABP1, CACNA1G, CDKN2A (p16), IGF2, SOCS1, and RUNX3) in 216 MSI-H CRCs. Associations between maspin expression status and various pathological, molecular, and survival data were statistically analyzed. Among the 216 MSI-H CRCs, 111 (51%) cases presented nuclear maspin-positive tumors. Nuclear maspin-positive MSI-H CRCs were significantly associated with proximal tumor location (P = 0.003), tumor budding (P < 0.001), lymphovascular invasion (P = 0.001), perineural invasion (P = 0.008), absence of peritumoral lymphoid reaction (P = 0.045), lymph node metastasis (P = 0.003), distant metastasis (P = 0.005), advanced AJCC/UICC stage (stage III/IV) (P = 0.001), and CIMP-high (CIMP-H) status (P < 0.001). Patients with nuclear maspin-positive tumors showed worse disease-free survival than patients with nuclear maspin-negative tumors (log-rank P = 0.025). In conclusion, nuclear maspin expression is molecularly associated with CIMP-H rather than MSI-H, and clinicopathologically correlates with tumor aggressiveness in CRC.

Accumulating evidence has indicated that serrated pathway-associated colorectal tumors may be associated with aberrant gastric-type differentiation. Here, we investigated the immunoexpression profiles of gastric-type markers and intestinal-type markers in colorectal tumors, focusing on their relation to serrated pathway-associated tumors. Immunohistochemistry for 7 gastric-type markers (ANXA10, VSIG1, CLDN18, CTSE, TFF2, MUC5AC, and MUC6) and 2 intestinal-type markers (CDX2 and CK20) was performed in 36 normal gastric/colorectal mucosa tissues, 163 colorectal polyps, and 175 microsatellite-unstable colorectal carcinomas (MSI-H CRCs). In normal tissues, all 7 candidate gastric-type markers showed expressional specificity for normal gastric mucosa. Among the colorectal polyps, sessile serrated adenoma/polyps demonstrated the highest positive rate of ANXA10, CLDN18, MUC5AC, and MUC6 expression (87%, 35%, 61%, and 52%, respectively). Microvesicular hyperplastic polyps showed the highest frequencies of ANXA10, VSIG1, and TFF2 positivity (87%, 87%, and 67%, respectively). ANXA10 and MUC6 expression was not detected in all conventional adenomas. In MSI-H CRCs, the expression of ANXA10, TFF2, and MUC5AC was significantly associated with sporadic tumors (P < .001, P = .01, and P < .001, respectively). Moreover, all of the 7 gastric-type markers were significantly related to preferential expression in proximal colon carcinomas among MSI-H CRCs. CDX2 and CK20 expression was retained in all colorectal polyps, whereas there were significantly high frequencies of CDX2 loss (28%) and CK20 loss (29%) in sporadic tumors among MSI-H CRCs. In conclusion, the early gain of gastric differentiation and late loss of intestinal differentiation are immunophenotypic features in the serrated pathway to colorectal carcinoma.

Although KRAS mutation has a predictive role in stage IV colorectal cancer (CRC) patients treated with anti-EGFR therapy, there have been controversies in the prognostic impact of KRAS mutation in stage II or III disease. The purpose of this study was to assess the prognostic impact of KRAS and BRAF mutation in patients treated with adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX). KRAS exon 2 and BRAF codon 600 were analyzed in patients with stage II and III CRC who underwent curative resection followed by adjuvant FOLFOX. Clinicopathologic features and disease-free survival (DFS) were compared. Among a total of 437 patients, mutational data of KRAS and BRAF were available in 388 and 433 patients, respectively. KRAS mutation (codon 12 and 13) and BRAF V600E mutation was found in 26.5 and 3.7 % of patients. DFS was significantly worse in the KRAS mutant patients compared to KRAS wild type patients (3-year DFS 79 and 92 %, p = 0.006). Multivariate analysis revealed KRAS mutation as an independent negative prognostic factor for DFS (adjusted hazard ratio 2.30, 95 % confidence interval 1.23–4.32). Among the various subtypes of KRAS mutation, G13D (3-year DFS 76 %, p = 0.008) was significantly associated with poor DFS, while G12D was not associated with prognosis (3-year DFS 86 %, p = 0.61). There was no association between BRAF mutation and DFS. KRAS mutation has an adverse prognostic impact on stage II or III CRC treated with adjuvant FOLFOX.

Annexin A10 (ANXA10) has recently been identified as a marker of sessile serrated adenomas/polyps of the colorectum. Although the serrated neoplasia pathway is thought to be involved in the majority of microsatellite instability-high (MSI-H) sporadic colorectal carcinomas (CRCs), the clinicopathological implications of ANXA10 expression in CRC are unknown. Here, we evaluated ANXA10 expression status in 168 MSI-H CRCs by immunohistochemistry. Among 168 MSI-H CRCs, nuclear staining for ANXA10 in tumor cells revealed 28 cases (17%) with ANXA10-positive (ANXA10+) tumors. Most of the ANXA10+ tumors were located in the proximal colon (96%, p < 0.001). The ANXA10+ phenotype in MSI-H CRC was significantly associated with female gender (68%, p = 0.016), CpG island methylator phenotype-high (CIMP-H) (68%, p < 0.001), MLH1 promoter hypermethylation (61%, p < 0.001), loss of MLH1 expression (82%, p = 0.019), and wild-type KRAS status (96%, p = 0.023). Survival analysis revealed no prognostic significance of ANXA10 expression in MSI-H CRC. In conclusion, ANXA10+ MSI-H colon carcinomas are characterized by serrated pathway features, including proximal location, female predominance, and high frequencies of CIMP-H status and MLH1 methylation.

Background Glioblastomas may develop de novo (primary glioblastomas, P-GBLs) or through progression from lower-grade astrocytomas (secondary glioblastomas, S-GBLs). The aim of this study was to compare the immunohistochemical classification of glioblastomas with clinically determined P-GBLs and S-GBLs to identify the best combination of antibodies for immunohistochemical classification. Methods We evaluated the immunohistochemical expression of epidermal growth factor receptor (EGFR), p53, and isocitrate dehydrogenase 1 (IDH-1) in 150 glioblastoma cases. Results According to clinical history, the glioblastomas analyzed in this study consisted of 146 P-GBLs and 4 S-GBLs. Immunohistochemical expression of EGFR, p53, and IDH-1 was observed in 62.6%, 49.3%, and 11.1%, respectively. Immunohistochemical profiles of EGFR(+)/p53(-), IDH-1(-)/EGFR(+)/p53(-), and EGFR(-)/p53(+) were noted in 41.3%, 40.2%, and 28.7%, respectively. Expression of IDH-1 and EGFR(-)/p53(+) was positively correlated with young age. The typical immunohistochemical features of S-GBLs comprised IDH-1(+)/EGFR(-)/p53(+), and were noted in 3.6% of clinically P-GBLs. The combination of IDH-1(-) or EGFR(+) was the best set of immunohistochemical stains for identifying P-GBLs, whereas the combination of IDH-1(+) and EGFR(-) was best for identifying S-GBLs. Conclusions We recommend a combination of IDH-1 and EGFR for immunohistochemical classification of glioblastomas. We expect our results to be useful for determining treatment strategies for glioblastoma patients.

Pulmonary artery tumor embolism (PATE) is a rare disease without an established diagnostic method. In an autopsy series, however, the incidence of PATE was relatively high, between 3% and 26% in patients with a solid tumor. Here we report a case of a patient with a massive PATE from hepatocellular carcinoma diagnosed safely and promptly by endobronchial ultrasound-guided transbronchial needle aspiration.

Purpose The enhancer of zeste homologue 2 (EZH2) is a catalytic subunit of the polycomb repressive complex 2, a highly conserved histone methyltransferase. EZH2 overexpression has been implicated in various malignancies, including breast cancer, where is associated with poor outcomes. This study aims to clarify nuclear EZH2 expression levels in breast cancers using immunohistochemistry (IHC) and correlate these findings with clinicopathologic variables, including prognostic significance. Methods IHC was performed on tissue microarrays of 432 invasive ductal carcinoma (IDC) tumors. Associations between EZH2 expression, clinicopathologic characteristics, and molecular subtype were retrospectively analyzed. The relationship between EZH2 protein expression in normal breast tissue and ductal carcinoma in situ (DCIS) was also assessed. Results High EZH2 expression was demonstrated in 215 of 432 tumors (49.8%). EZH2 was more frequently expressed in DCIS and IDC than in normal breast tissue (p=0.001). High EZH2 expression significantly correlated with high histologic grade (p

Purpose PIK3CA is often mutated in a variety of malignancies, including colon, gastric, ovary, breast, and brain tumors. We investigated PIK3CA expression in gastric cancer and explored the relationships between the PIK3CA expression level and clinicopathological features as well as survival of the patients. Materials and methods We examined PIK3CA expression in a tissue microarray of 178 gastric adenocarcinomas by immunohisto-chemistry and reviewed patients' medical records. Results In our study, 112 of the 178 gastric cancer patients displayed positive PIK3CA expression. Overexpression of PIK3CA was correlated with low grade differentiation (P=0.001), frequent lymphatic invasion (P=0.032), and high T stage (P=0.040). Patients with positive PIK3CA staining were more likely to display worse overall survival rate than those with negative PIK3CA staining, as determined by Kaplan-Meier survival analysis with log-rank test (P=0.047) and a univariate analysis using the Cox proportional hazard model (hazard ratio=1.832, P=0.051). Conclusions Elevated PIK3CA expression was significantly correlated with tumor invasiveness, tumor phenotypes, and poor patient survival.

Key clinicopathologic features of microsatellite instability-positive (MSI+) gastric cancers (GCs) are that they tend to be located in the antrum and have an intestinal phenotype and an expanding-type growth pattern. They are also associated with a better prognosis. Although MSI occurs mainly as a result of promoter CpG island hypermethylation in the mismatch repair gene MLH1, only a minority of MSI+ GCs develop from genetic mutations of mismatch repair enzymes, including MLH1 and MSH2. Furthermore, it is unknown whether there are differences in the clinicopathologic features of MSI+ GCs with and without MLH1 methylation. The methylation status of 17 genes (including MLH1) was assessed in 102 cases of MSI+ GC to determine whether there was a correlation between the clinicopathologic/molecular features of MSI+ GC and MLH1 methylation status. Compared with MSI+ GCs without MLH1 methylation (n = 22), MSI+ GCs with MLH1 methylation (n = 80) had an older age of onset (66.9 versus 60.9 years, P = .018), were more frequently located in the antrum (86.3% versus 50%, P = .001), exhibited an ulcerofungating gross type of tumor morphology (50.0% versus 9.1 %, P.001), and had a higher number of unstable microsatellite loci (4.7 versus 3.8, P.001) and a higher number of methylated genes (11.4 versus 6.2, P.001). In addition, MLH1-deficient tumors without MLH1 methylation were associated with a better clinical outcome than MLH1-deficient tumors with MLH1 methylation or tumors that retained expression of both MLH1 and MSH2 (P = .002). These findings suggest that MSI+ GCs with and without MLH1 methylation may have different clinicopathologic features. Furthermore, some of the known clinicopathologic features of MSI+ GC, including older age of onset, ulcerofungating gross morphology, and antral location, are not typical of MSI+ GC without MLH1 methylation.

To evaluate the feasibility and treatment outcomes of stereotactic radiosurgery (SRS) using a stereotactic body frame (Precision Therapy™), we prospectively reviewed 34 tumors of the 28 patients with primary or metastatic intrathoracic lung tumors. Eligible patients included were nine with primary lung cancer and 19 with metastatic tumors from the lung, liver, and many other organs. A single dose of 10 Gy to the clinical target volume (CTV) was delivered to a total dose of 30–40 Gy with three to four fractions. Four to eight coplanar or non-coplanar static fields were generated to adequately cover the planning target volume (PTV) as well as to exclude the critical structures as much as possible. More than 90% of the PTV was delivered the prescribed dose in the majority of cases (average; 96%, range; 74–100%). The mean PTV was 41.4 cm 3 ranging from 4.4 to 230 cm 3 . Set-up error was within 5 mm in all directions ( X , Y , Z axis). The response was evaluated by using a chest CT and/or 18 FDG-PET scans after SRS treatment, 11 patients (39%) showed complete response, 12 (43%) partial response (decrease of more than 50% of the tumor volume), and four patients showed minimally decreased tumor volume or stable disease, but one patient showed progression disease. With a median follow-up period of 18 months, a local disease progression free interval was ranging from 7 to 35 months. Although all patients developed grade one radiation pneumonitis within 3 months, none had symptomatic or serious late complications after completing SRS treatment. Given these observations, it is concluded that the stereotactic body frame based SRS is a safe and effective treatment modality for the local management of primary or metastatic lung tumors. However, the optimum total dose and fractionation schedule used should be determined after the longer follow-up of these results.

Lynch syndrome (formerly called hereditary nonpolyposis colorectal cancer) is an autosomal dominant disorder caused by a germline defect in the DNA mismatch repair (MMR) system. It is characterized by early development of malignancies, particularly colorectal carcinoma (CRC) and endometrial carcinoma.1 Defective MMR systems typically induce microsatellite instability (MSI), which results in frequent mutations in cancer-related genes, ultimately contributing to carcinogenesis.2 MSI is defined as an alteration in the length of DNA microsatellite repeat sequences and is accepted as one of the major molecular phenotypes in CRCs, including sporadic tumors as well as Lynch syndrome tumors. Sporadic CRCs that are microsatellite instability-high (MSI-H) account for approximately 10% to 15% of CRCs, and hereditary MSI-H CRCs (Lynch syndrome-associated CRCs) account for approximately 3% to 5% of CRCs in Western countries.3,4 It is well known that the major cause of a defective MMR system in Lynch syndrome is a germline mutation in one of the MMR genes, including MLH1, MSH2, PMS2, or MSH6, whereas nearly all sporadic MSI-H CRCs are thought to be caused by CpG island hypermethylation in the promoter region of MLH1.2,4 Although most Lynch syndrome-associated tumors have a molecular basis of an MMR deficiency caused by germline mutations in MMR genes, Ligtenberg et al.5 recently identified another mechanism of defective MMR in a small subset of Lynch syndrome families, characterized by MSH2 promoter methylation due to germline deletions in the 3' exons of the epithelial cell adhesion molecule (EPCAM; also known as TACSTD1) gene. This molecular alteration is also referred to as MSH2 "epimutation" on the basis of its unique heritable feature of epigenetic silencing.6 Various deletions in the 3' end of the EPCAM gene have been identified in Lynch syndrome tumors, and the molecular mechanism of the MSH2 epimutation has been successfully elucidated.7,8 Interestingly, recent investigations have suggested that the loss of EPCAM protein expression could be a supportive diagnostic marker in cases of Lynch syndrome because EPCAM loss is specifically found in Lynch syndrome patients carrying EPCAM germline deletions.9,10,11 Although these findings indicate that immunohistochemistry (IHC) for EPCAM could be a simple and useful method for the screening of germline EPCAM deletion-associated Lynch syndrome patients, the studies have some limitations in that only small sample sizes originating from a few Western races (Germans and Spaniards) were investigated by only two research groups. Additional studies using larger samples from diverse ethnic groups are necessary for the validation of the relationship between a loss of EPCAM expression and MSH2-deficient Lynch syndrome CRCs. In the present study, we investigated the expression statuses of EPCAM and MMR proteins using IHC in 168 MSI-H CRC tissues obtained from Korean patients. Promoter CpG island methylation status of the MLH1 gene was also determined for each sample. Association of alterations in EPCAM expression with various clinicopathological and molecular factors was analyzed.

For image-guided radiation therapy (IGRT) of prostate cancer, gold markers called fiducials can be inserted into the prostate in advance. Here we examined the short-term results of IGRT for prostate cancer. We obtained the clinical data of 10 patients who underwent IGRT at the Department of Radiation Oncology in Kangnam Sacred Heart Hospital of Hallym University during March 2006 and July 2007. Three gold markers were implanted in the prostate before the radiotherapy. Exact focusing of the image was obtained by 3 gold markers on simple X-ray film or cone beam computed tomography during radiation therapy. The errors induced by setting up the patients during IGRT were examined. The setup errors, averaged over all patients, were 󰠏0.88 mm, 1.85 mm, and −0.40 mm in the left-right, cranial-caudal, and anterior-posterior directions, respectively. The motion of the prostate was greatest in the cranial-caudal (6.5 mm) direction. The post-radiation therapy prostate-specific antigen (PSA) level was decreased dramatically in all 10 patients. Two of three patients who had received hormonal therapy with IGRT showed a PSA nadir 12 months later without hormonal therapy. There were no peri-radiotherapy complications. Through the use of IGRT with gold markers, we could correct the setup errors that occur in conventional radiation therapy. Post-IGRT PSA was decreased dramatically. Even though our data are limited, we suggest that IGRT may be an effective radiation therapy modality for decreasing peri-radiotherapy complications and improving radiotherapy results in prostate cancer through exact focusing of the radiation.