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Background/aim: Autophagy is a cellular mechanism that recycles cellular components to maintain homeostasis. To investigate the clinical implication of autophagy in gastric cancer, the autophagy markers with autophagosome formation, LC3B and selective autophagy substrate p62/SQSTM1 (P62) were validated., Materials and Methods: LC3B and p62 expression was examined using immunohistochemistry, western blot assays, and reverse-transcription polymerase chain reaction (RT-PCR). The relationship of LC3B and p62 expression in gastric adenocarcinomas with clinicopathological parameters, including patient survival, were analyzed., Results: Normal gastric mucosae exhibit no LC3B and p62 expression, while tubular adenoma and gastric adenocarcinomas exhibit variable nuclear or cytoplasmic p62 expression. High LC3B, high cytoplasmic p62, and low nuclear p62 protein expression in gastric adenocarcinomas is positively correlated with poor prognostic factors including survival., Conclusion: Dynamic LC3B and p62 changes are suggested to be involved in gastric tumorigenesis and cancer progression. LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for gastric adenocarcinomas., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Prominin-1 (CD133) has been suggested as a potential marker of cancer stem cells (CSCs) in various cancer types. The aim of this study was to compare CD133 expression between adenoma cells, colorectal adenocarcinoma (CRAC) cells, and tumor microenvironment cells (TMEs) in terms of the adenoma-carcinoma sequence and to investigate the clinicopathological value of CD133 expression in CRACs as a prognostic marker., Materials and Methods: A total of 58 adenomas and 132 primary and 27 metastatic CRACs were examined for CD133 expression by immunohistochemistry. The cytoplasmic and nuclear expression levels of CD133 were scored by semi-quantitative methods., Results: Adenomas showed significantly lower cytoplasmic and nuclear CD133 expression than CRACs (p<0.001). Among the CRACs, primary CRACs demonstrated higher cytoplasmic and nuclear expression levels of CD133 than metastatic CRACs (p<0.001). Furthermore, decreased nuclear CD133 expression in CRACs was correlated with a poor outcome, including disease-free survival (DFS), by univariate and multivariate analyses (p=0.012 and p=0.039). For TMEs, adenomas showed a significantly higher CD133 expression than CRACs (p<0.001), and decreased expression of CD133 in CRACs was correlated with shorter DFS by univariate and multivariate analyses (p=0.004 and p=0.042)., Conclusion: Cytoplasmic and nuclear CD133 expression in CRAC cells and TMEs may play an important role in early CRAC carcinogenesis, while decreased CD133 nuclear expression in CRAC cells may contribute to CRAC metastasis. Further prognostic and therapeutic stratification may be performed according to CD133 localization., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: We sought to develop a matrix assisted laser desorption ionization-time of flight (MALDI-TOF)-based, ovarian cancer (OVC), low-mass-ion discriminant equation (LOME) and to evaluate a possible supportive role for triple-TOF mass analysis in identifying metabolic biomarkers., Materials and Methods: A total of 114 serum samples from patients with OVC and benign ovarian tumors were subjected to MALDI-TOF analysis and a total of 137 serum samples from healthy female individuals and patients with OVC, colorectal cancer, hepatobiliary cancer, and pancreatic cancer were subjected to triple-TOF analysis. An OVC LOME was constructed by reference to the peak intensity ratios of discriminatory low-mass ion (LMI) pairs. Triple-TOF analysiswas used to select and identify metabolic biomarkers for OVC screening., Results: Three OVC LOMEs were finally constructed using discriminatory LMI pairs (137.1690 and 84.4119 m/z; 496.5022 and 709.7642 m/z; and 524.5614 and 709.7642 m/z); all afforded accuracies of &gt; 90%. The LMIs at 496.5022 m/z and 524.5614 m/z were those of lysophosphatidylcholine (LPC) 16:0 and LPC 18:0. Triple-TOF analysis selected seven discriminative LMIs; each LMI had a specificity &gt; 90%. Of the seven LMIs, fourwith a 137.0455 m/z ion atretention times of 2.04-3.14 minuteswere upregulated in sera from OVC patients; the ion was identified as that derived from hypoxanthine., Conclusion: MALDI-TOF-based OVC LOMEs combined with triple-TOF-based OVC metabolic biomarkers allow reliable OVC screening; the techniques are mutually complementary both quantitatively and qualitatively.

The gene deleted in malignant brain tumor 1 (DMBT1) encoding a large scavenger receptor cysteine-rich protein was originally identified based on its deletion in a brain tumor cell line. The DMBT1 protein is involved in mucosal immune defense, epithelial differentiation and tumor suppression. In the present study, the clinicopathologic significance of DMBT1 protein expression in stool and tissue samples of colorectal cancer (CRC) patients was evaluated. Western blot analysis of fecal DMBT1 was performed for patients with CRC (n=177), colorectal adenoma (n=61), inflammatory bowel diseases (IBDs; n=54) and healthy individuals as the control group (n=151). Immunohistochemical analysis of tissue expression of DMBT1 was performed in 385 primary CRC tissues. Fecal DMBT1 expression was higher in CRC and IBD patients than in healthy controls or adenoma patients (P<0.0001), but not significantly different between IBD and CRC or between adenoma and healthy control groups. In CRC patients, fecal DMBT1 expression was not associated with the tumor stage or site. The sensitivity of fecal DMBT1 analysis for CRC was 50%, while the specificity and positive predictive value were 86.8 and 81.3%, respectively. Immunohistochemical expression patterns of DMBT1 in CRC tissues varied from loss to overexpression. Loss of expression was observed in 4.7% (18 out of 385 cases) and significantly associated with lymph node metastasis (P=0.016), distant metastasis (P=0.013), advanced stage (P=0.026), and higher histologic grade (P=0.033). In addition, DMBT1 loss was an independent poor prognostic factor for cancer-associated death (hazard ratio, 2.272; P=0.015) and disease recurrence (hazard ratio, 2.689; P=0.009). In conclusion, fecal DMBT1 has limited value as a diagnostic biomarker, while the tissue expression of DMBT1 may serve as an efficient prognostic marker for CRC. Furthermore, DMBT1 may have a role in the progression of CRC.

Aims: Gastrointestinal stromal tumours (GISTs) may arise anywhere in the gastrointestinal tract, but are rare in the oesophagus. We describe the clinical, pathological and molecular characteristics of 27 primary oesophageal GISTs, the largest series to date., Methods and Results: DNA was extracted and exons 9, 11, 13 and 17 of KIT, exons 12, 14 and 18 of PDGFRA and exon 15 of BRAF were amplified and sequenced. Oesophageal GISTs occurred in 14 men and 13 women aged between 22 and 80 years (mean: 56 years). All 27 cases were immunohistochemically positive for KIT, and 92 and 47% co-expressed CD34 or smooth muscle actin, respectively. Fifteen (71% of analysed cases) harboured KIT exon 11 mutations and one case each had a mutation in KIT exon 13 (K642E) or BRAF exon 15 (V600E). Long-term follow-up data (median, 96.5 months) were obtained for 20 cases; two patients had metastases at presentation and seven had developed local recurrence and/or metastasis after surgery. A large tumour size (≥ 10 cm), high mitotic rate (> 5/5 mm 2 ), presence of a deletion mutation in KIT exon 11 involving codons 557-558 and a positive microscopic margin were associated with recurrence and metastasis. The KIT mutations identified in oesophageal GISTs are similar to those observed in gastric GISTs., Conclusions: Complete surgical resection with clear margins is recommended, if technically feasible, and genotyping can help to improve diagnosis and further patient management in oesophageal GIST., (© 2017 John Wiley & Sons Ltd.)

Programmed cell death 1 receptor (PD-1)/programmed death-1 ligand-1 (PD-L1) interaction has been linked to tumor immune evasion. PD-L1 expression has been indicated in identifying non-small cell lung carcinoma (NSCLC) patients for treatment with anti-PD-1 or anti-PD-L1 therapy. The goal of this study was to evaluate the clinicopathologic values of PD-L1 expression and single-nucleotide polymorphisms (SNPs) in the PD-L1 gene in lung adenocarcinoma (ADC) and squamous cell carcinoma (SqCC). The 147 NSCLC tissues consisted of 84 samples of ADC and 63 samples of SqCC. All tissue microarray paraffin blocks were used for PD-L1 immunohistochemical assays with 22C3, SP263, and SP142 clones. Three SNPs in the PD-L1 gene, rs4143815, rs822336, and rs822337, were genotyped using SNP pyrosequencing. The PD-L1 expression was significantly higher in SqCC than in ADC. Among ADCs, PD-L1 expression was significantly higher in papillary and solid types than in lepidic and acinar types. Statistical associations of the PD-L1 expression with a shorter disease-free survival outcome and lymph node metastasis in the ADCs were found but no associations in SqCCs. Among the three SNPs, the rs4143815 genotype CC was statistically associated with positive 22C3 PD-L1 labeling in NSCLCs. The rs4143815 genotype GG instead showed a trend of shorter survival outcomes but did not reach statistical significance in the ADCs. Our results showed a significantly higher prevalence of positive PD-L1 expression in lung SqCC than in ADC. However, the PD-L1 expression and rs4143815 genotype GG might be useful for the prediction of poor prognosis in lung ADC cases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Obstructive jaundice is frequently caused by bile duct strictures. Determination of malignant strictures is crucial for the initiation of appropriate treatment. Cytologic examination of bile drainage fluid is an easy and reproducible method of detecting malignant cells. This method, however, frequently yields indeterminate results, such as atypia or suspicious of malignancy, due to difficulties in differentiating malignancy from benign atypia. Immunocytochemical assessment of p53 expression by cells in bile drainage fluid may enhance the ability to detect malignancy., Methods: A total of 139 samples of bile drainage fluid were obtained from 80 patients. Following cytologic examination, the samples were incubated with antibody to p53. The performance of cytology with and without p53 immunocytochemistry was evaluated, with reference to surgical or clinical findings of benign and malignant biliary strictures., Results: Bile drainage cytology alone had a sensitivity of 31.6% and a specificity of 98.4% in the identification of malignant strictures, whereas the combination of p53 immunocytochemistry and bile drainage cytology had a sensitivity of 80.3% and a specificity of 92.1%. P53 immunocytochemistry alone had a sensitivity of 64.5% and a specificity of 92.7% for the identification of malignant strictures in bile drainage samples with atypical cytology, and a sensitivity of 85.0% and a specificity of 100.0% in samples with suspicious of malignancy., Conclusion: The addition of p53 immunocytochemistry to bile drainage cytology can be useful in identifying malignant strictures in samples showing indeterminate results on bile drainage cytology. Diagn. Cytopathol. 2017;45:592-597. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The prognostic role of detecting clonal immunoglobulin gene rearrangement (IgR) from bone marrow (BM) aspirates was evaluated by BIOMED-2 PCR in 97 patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-CHOP immunochemotherapy. Sixteen (16.5%) patients had BM involvement (BMI) defined by BM biopsy (MOR+) and 39 (40.2%) had positive IgR (PCR+). Patients with MOR + BMI showed inferior event-free survival (EFS) compared to those with MOR-/PCR- (p < 0.001) or those with MOR-/PCR + BMI (p = 0.002), while no significant difference in EFS was observed between patients with MOR-/PCR + and those with MOR-/PCR - BMI (p = 0.497). Use of the BIOMED-2 for PCR resulted in significant increase in detection of BMI. However, the increased sensitivity by PCR did not translate into improved prediction of prognosis, emphasizing the essential role of histopathological review of trephine biopsy for the detection of BMI.

Preoperative chemoradiotherapy (CRT) is generally performed for locally advanced rectal cancer (LARC, cStage 2 or 3) to improve local disease control and patient survival. The pathological tumor response to CRT is a surrogate marker that is associated with oncological outcome. Thus, markers that predict the response to CRT would be valuable for individualizing treatment for LARC patients. The current study used metabolomics-based approaches to identify molecular markers that predict the response to CRT. Seventy-six patients with LARC who received pelvic radiotherapy and concurrent chemotherapy using tegafur-uracil and leucovorin were enrolled. Radical surgery was performed 6-8 weeks after the completion of CRT. The postsurgical pathological CRT response was evaluated using the ypStage or tumor regression grade. Profiling patterns of low-mass ions (LMIs) in the pretreatment sera were obtained from all patients using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Our previously developed two-step algorithms, which showed a powerful diagnostic capability during colorectal cancer screening, were then used to screen for meaningful LMIs with discriminatory power. One combination consisting of seven LMIs was identified, whose discriminatory score separated a good CRT response (ypStage 0-1) from a poor CRT response (ypStage 3-4) successfully. However, each individual LMI alone showed insignificant discriminatory power. This finding suggests that analysis of the LMIs in pretreatment serum could serve as a predictive marker of the CRT response in patients with LARC.

Ovarian cancer is recognized with high mortality due to asymptomatic nature of the disease and difficulties in diagnosing early stage of the cancer. The present study evaluates the use of differential scanning calorimetry (DSC) in differentiating the severity of ovarian cancer from healthy women. 47 diseased women were subdivided into four stages with respect to clinical relevance and severity. Stages I-II were regarded as early stages and stages III-IV were regarded as advanced stages. The two average transition temperatures (T m ) increased with disease severity from 64.84 and 70.32 °C (healthy) to 68.46 and 75.24 °C (stage IV), respectively. T m were increased depending on clinical groups. In addition, the change in heat capacity was also dependent on the disease severity. To further support and investigate the nature of the proposed interactions, matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis is employed. The results suggest the differences in peptide expression between early and advanced stage of ovarian cancer, affected abundant proteins in plasma. The combined DSC and MS approach was supportive in identifying a unique signature of ovarian cancer stages, and demonstrates the potential of DSC as a complementary diagnostic tool in the evaluation of early stage ovarian cancer.

Smad3 functions as an integrator of diverse signaling, including transforming growth factor β signaling and the function of Smad3 is complexly regulated by differential phosphorylation at various sites of Smad3. Despite the importance of Smad3 and its various phosphoisoforms, their prognostic significance has rarely been studied. In this study, we demonstrated the prognostic significance of Smad3, its phosphoisoforms, and Smad4 expression by immunohistochemistry in 126 esophageal squamous cell carcinomas. The phosphoisoforms of Smad3 studied in this article included phosphorylation at C-terminal (pSmad3C)(Ser(423/425)) and phosphorylation at the linker region (pSmad3L)(Ser(213)). High expression of Smad3 was associated with shorter overall survival. Co-existence of high expression of pSmad3L(S213) and low expression of pSmad3C(S423/425) were associated with advanced N stage and an independent prognostic factor for overall [hazard ratio (HR) 2.03, 95 % confidence interval (CI) (1.10-3.75), p = 0.023] and disease-free survival [HR 2.41, 95 % CI (1.32-4.39), p = 0.004]. In conclusion, co-existence of high pSmad3L(Ser(213)) expression and low pSmad3C(Ser(423/425)) expression can be considered as immunohistochemical biomarkers for predicting prognosis as well as future therapeutic targets. In addition, our results of combinatory effect of differential phosphorylation of Smad3 on prognosis suggest the mode of action of Smad3 might be logically determined by its phosphorylation pattern.

Blood metabolites can be detected as low-mass ions (LMIs) by mass spectrometry (MS). These LMIs may reflect the pathological changes in metabolism that occur as part of a disease state, such as cancer. We constructed a LMI discriminant equation (LOME) to investigate whether systematic LMI profiling might be applied to cancer screening. LMI information including m/z and mass peak intensity was obtained by five independent MALDI-MS analyses, using 1,127 sera collected from healthy individuals and cancer patients with colorectal cancer (CRC), breast cancer (BRC), gastric cancer (GC) and other types of cancer. Using a two-stage principal component analysis to determine weighting factors for individual LMIs and a two-stage LMI selection procedure, we selected a total of 104 and 23 major LMIs by the LOME algorithms for separating CRC from control and rest of cancer samples, respectively. CRC LOME demonstrated excellent discriminating power in a validation set (sensitivity/specificity: 93.21%/96.47%). Furthermore, in a fecal occult blood test (FOBT) of available validation samples, the discriminating power of CRC LOME was much stronger (sensitivity/specificity: 94.79%/97.96%) than that of the FOBT (sensitivity/specificity: 50.00%/100.0%), which is the standard CRC screening tool. The robust discriminating power of the LOME scheme was reconfirmed in screens for BRC (sensitivity/specificity: 92.45%/96.57%) and GC (sensitivity/specificity: 93.18%/98.85%). Our study demonstrates that LOMEs might be powerful noninvasive diagnostic tools with high sensitivity/specificity in cancer screening. The use of LOMEs could potentially enable screening for multiple diseases (including different types of cancer) from a single sampling of LMI information., (© 2013 UICC.)

Serpin B5 is a candidate tumour suppressor, but its oncogenic activity has also been reported. Its function may be affected by protein interactions. The aim of this study was to assess the relationship between serpin B5 and carcinoembryonic antigen (CEA) expression in colorectal cancer (CRC). We also analysed the clinicopathological significance of serpin B5 expression in patients with CRC. Downregulation of serpin B5 was identified in a CEA-suppressed LoVo cell line using two-dimensional gel electrophoresis (2-DE) and matrix-associated laser desorption ionisation-mass spectrometry (MALDI-MS). The specific interaction and co-localisation of serpin B5 with CEA were confirmed by co-immunoprecipitation and confocal microscopy. Western blot analysis and ELISAs revealed significant positive correlations between levels of serpin B5 and CEA in human colon cancer cell lines and in the blood of patients with CRC. Tissue expression of serpin B5 in 377 patients with CRC was significantly associated with serum CEA, histological grade, stage, lymph node metastasis, lymphatic and perineural invasion, and infiltrative border. Strong expression of serpin B5 was also associated with a reduced DFS (p = 0.001) and OS (p = 0.017). Together, these findings describe a relationship between serpin B5 and CEA expression in CRC. Strong expression of serpin B5 was associated with a worse prognosis in patients with CRC and its expression may correlate with CEA levels in CRC., (© 2013 UICC.)

Purpose: The dipeptidyl peptidase IV (DPPIV) gene family exhibits multiple functions and is involved in the pathogenesis of various diseases. It has attracted pharmaceutical interest in the areas of metabolic disorders as well as cancer. However, clinicopathologic significance of DPPIV family in colorectal cancer is not fully understood., Materials and Methods: The clinical relevance of DPPIV and DPP10 expression was determined by immunohistochemical staining, and by assessing its clinicopathologic correlation in 383 colorectal cancer patients with known clinical outcomes., Results: DPPIV was not expressed in normal colon mucosa, but it showed luminal expression in 52 of the 383 colorectal cancers (13.5%). DPPIV expression in tumors was associated with right-sided location of the colon (p=0.010) and more advanced tumor stage (p=0.045). DPP10 was expressed in normal colonic mucosa, but its expression varied in primary colorectal cancer tissues. Loss of DPP10 expression was found in 11 colorectal cancers (CRCs) (2.9%), and multivariate analysis showed that loss of DPP10 expression was an independent factor for poor patient prognosis (p=0.008)., Conclusion: DPP10 may play a role in disease progression of colorectal cancer and loss of DPP10 expression in primary CRC is significantly associated with poor survival outcomes.

Background: The transforming growth factor-β/Smads signaling pathway plays an important role in tumorigenesis and progression in cancer, and may closely be related to the biological behaviors of some malignant tumors, such as gastric carcinoma. In this study, we investigated the roles of Smad3 and Smad3 phosphoisoforms in the prognosis of gastric carcinoma., Methods: We investigated the expressions of Smad3, pSmad3C(S423/425), pSmad3L(T179), pSmad3L(S204), and pSmad3L(S213) in tumor tissue microarrays of 442 gastric carcinoma patients who underwent curative surgery using immunohistochemistry and assessed their correlation with clinical outcome., Results: Positive Smad3 expression was observed in 33.5 % of gastric carcinoma. The rates of positive Smad3 phosphoisoforms expression varied according to the location of phosphorylation within Smad3: pSmad3C(S423/425) 28.5 %, pSmad3L(T179) 5.9 %, pSmad3L(S204) 1.8 %, and pSmad3L(S213) 20.8 %. Positive Smad3 expression was associated with diffuse type (p = 0.003), poorer histologic differentiation (p = 0.005), more frequent lymph node metastasis (p = 0.001), and higher AJCC stage (p = 0.006). Multivariate analyses revealed that Smad3 expression (p = 0.041), pSmad3L(T179) expression (p = 0.011), pSmad3L(S213) expression (p = 0.003), and American Joint Committee on Cancer (AJCC) stage were independent predictors of shorter disease-free survival. Smad3 expression (p = 0.033), pSmad3L(T179) expression (p = 0.012), pSmad3L(S213) expression (p = 0.005), and AJCC stage were also independent predictors of shorter overall survival. pSmad3C(S423/425) expression tended to show favorable influences on both disease-free survival (p = 0.134) and overall survival (p = 0.232)., Conclusions: Smad3, pSmad3L(T179), and pSmad3L(S213) expression might be independent predictors of both shorter disease-free survival and shorter overall survival in gastric carcinoma patients after curative surgery, and might help clinicians identify patients at high risk of recurrence.

Background: Caldesmon (CaD), a major actin-associated protein, is found in smooth muscle and non-muscle cells. Smooth muscle caldesmon, h-CaD, is a multifunctional protein, and non-muscle cell caldesmon, l-CaD, plays a role in cytoskeletal architecture and dynamics. h-CaD is thought to be an useful marker for smooth muscle tumors, but the role(s) of l-CaD has not been examined in tumors., Methods: Primary colon cancer and liver metastasis tissues were obtained from colon cancer patients. Prior to chemoradiotherapy (CRT), normal and cancerous tissues were obtained from rectal cancer patients. Whole-tissue protein extracts were analyzed by 2-DE-based proteomics. Expression and phosphorylation level of main cellular signaling proteins were determined by western blot analysis. Cell proliferation after CaD siRNA transfection was monitored by MTT assay., Results: The expression level of l-CaD was significantly increased in primary colon cancer and liver metastasis tissues compared to the level in the corresponding normal tissues. In cancerous tissues obtained from the patients showing poor response to CRT (Dworak grade 4), the expression of l-CaD was increased compared to that of good response group (Dworak grade 1). In line with, l-CaD positive human colon cancer cell lines were more resistant to 5-fluorouracil (5-FU) and radiation treatment compared to l-CaD negative cell lines. Artificial suppression of l-CaD increased susceptibility of colon cancer cells to 5-FU, and caused an increase of p21 and c-PARP, and a decrease of NF-kB and p-mTOR expression., Conclusion: Up-regulated expression of l-CaD may have a role for increasing metastatic property and decreasing CRT susceptibility in colorectal cancer cells.

Unlabelled: We evaluated EGFR and KRAS mutations between 37 paired primary tumors and corresponding metastases in lung adenocarcinoma. A substantial discordance was found in EGFR mutation status between primary tumors and corresponding metastases including pleural metastases. Moreover, the responsiveness to EGFR tyrosine kinase inhibitors tend to be correlated with EGFR mutation status in metastatic lesions than in primary tumors., Introduction: The aim of this study was to compare epidermal growth factor receptor (EGFR) and KRAS mutations between primary tumors and corresponding metastases including pleural metastases in lung adenocarcinoma., Methods: Thirty-seven paired primary lung adenocarcinomas and corresponding metastatic tumors were analyzed for EGFR and KRAS mutations. In addition, 21 pleural metastases including malignant pleural effusion or pleural biopsy were used in performing these mutation analyses., Results: EGFR mutations were detected in 18 primary lung adenocarcinomas (48.6%) and in 16 corresponding metastases (43.2%). EGFR mutations showed a discordance rate of 16.2% (6 of 37 patients) between primary lung adenocarcinomas and corresponding metastases. Among 21 pleural metastases, 3 patients (14.3%) showed that the EGFR mutation was discordant. KRAS mutations were detected in one primary tumor and in two metastatic tumors. Eighteen patients were treated with EGFR tyrosine kinase inhibitors. One of seven patients who experienced partial response had EGFR mutations only in the metastasis, and two of seven patients who experienced progressive disease carried wild-type EGFR only in the metastasis., Conclusions: EGFR mutations were discordant between primary tumors and corresponding metastases in a significant portion of lung adenocarcinomas. Furthermore, these discordance was also observed in metastases to the pleura, the nearest metastatic site., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The aim of the present study was to determine the expression profile of the hedgehog (Hh) signaling molecules in normal, hyperplastic, and carcinomatous uterine endometrium. For this purpose, 271 endometrial tissue samples, (62 of normal endometrium, 127 of endometrial hyperplasias, and 82 endometrial adenocarcinomas) were studied using antibodies recognizing Hh-related signaling proteins, such as, sonic hedgehog (Shh), Patched (PTCH), Smoothened (Smo), Suppressor of fused [Su(Fu)], Gli-1, Gli-2, and Gli-3 by immunohistochemistry. The mRNA expression of these molecules was also assessed on reverse transcription-polymerase chain reaction. In the normal endometrium, the expression of Hh signaling molecules was generally downregulated except for Su(Fu), Gli-2, and Shh. In particular, the expression of both PTCH and Smo was very low or almost absent. Overall expression of Hh signaling molecules increased in hyperplastic endometrium; in particular, PTCH and Smo were significantly highly expressed in complex and atypical hyperplasia. In carcinoma samples extensive alterations were observed in the expression pattern of the signaling molecules. Nuclear Gli-2, cytoplasmic Gli-3, and Su(Fu) were overexpressed, whereas Shh, PTCH, and Smo expression were significantly reduced compared with the hyperplastic endometrium. The results suggest that the alteration of Hh signaling may be implicated in tumorigenesis of the endometrium.

To evaluate the expressions of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in thyroid neoplasms in a Korean population, we studied a total of 154 cases: papillary carcinoma of classical type (PTC), 86; follicular adenoma (FA), 21; follicular carcinoma (FC), 35; medullary carcinoma (MC), 3; undifferentiated carcinoma (UC), 5; and Hurthle cell neoplasm (HN), 4. Using immunohistochemical staining, COX-2 expression was detected in 62 (72.1%) PTC specimens, 5 (23.8%) FA specimens, 10 (28.6%) FC specimens, 0 (0.0%) MC specimens, 1 (20.0%) UC specimen, and 3 (75%) HN specimens. iNOS expression was detected in 66 (76.7%) PTC specimens, 4 (19.0%) FA specimens, 13 (37.1%) FC specimens, 0 (0.0%) MC specimens, 3 (60.0%) UC specimens, and 4 (100%) HN specimens. The results showed that COX-2 and iNOS were frequently expressed in the PTC and HN specimens, and iNOS was more frequently overexpressed in the FC specimens than in the FA specimens. In PTC, COX-2 and iNOS were significantly overexpressed in patients over 45 yr of age (p=0.029, p=0.041), and iNOS expression was increased in patients with a large primary tumor (p=0.028). These results suggest that the upregulation of COX-2 and iNOS may contribute to the tumor progression of thyroid gland, particularly in PTC and HN, and iNOS may play an adjuvant role during the tumor progression of FC.