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Galectin 1 is a 14-kd laminin-binding lectin involved in important biologic mechanisms of tumors, including neoplastic transformation, cell survival, angiogenesis, cell proliferation, and metastasis. In this study, we investigated the role of galectin 1 in cell survival and metastasis in cervical cancer. The expression of galectin 1 was determined in 73 formalin-fixed, paraffin-embedded cervical cancer tissues using an immunohistochemical method and compared with clinicopathologic risk factors for recurrence after surgery. To evaluate the role of galectin 1 in cell proliferation and invasion, we performed proliferation and invasion assays with galectin 1 small interfering RNA (siRNA) using cervical cancer cell lines, including HeLa and SiHa cells. Immunohistochemical analysis revealed that galectin 1 expression was found in most peritumoral stroma samples (72/73; 98.6%). Galectin 1 expression was significantly correlated with the depth of invasion in the cervix (P=.015) and lymph node metastasis (P=.045) on univariate analysis. When progression-free survival of all of the patients studied was analyzed based upon galectin 1 expression, galectin 1 expression was not correlated with progression-free survival (P=.32). Down-regulation of galectin 1 using small interfering RNA resulted in the inhibition of cell growth and proliferation of HeLa and SiHa cells. Moreover, the ability of cells to invade was significantly reduced by galectin 1 small interfering RNA. Our results revealed that high galectin 1 expression in peritumoral stroma was significantly correlated with depth of invasion in cervical lesions and lymph node metastasis of cervical cancer and that galectin 1 may be functionally involved in cell proliferation and invasion.

Gliomatosis peritonei (GP) is commonly associated with ovarian teratoma and is not thought to have an adverse prognostic effect. However, the prognostic impact and characteristics of GP remain to be clarified. In this study, we investigated the clinicopathologic features of ovarian teratoma associated with GP, and we further compared ovarian immature teratoma (IT) with GP to ovarian IT without GP. During the study period, there were a total of 16 ovarian teratomas associated with GP. Among them, 15 cases were ovarian ITs of various grades. When ovarian IT with GP (n = 15) was compared to ovarian IT without GP (n = 27), it was found that ovarian IT patients with GP had larger tumor size (median, 19 vs. 13 cm; P < 0.001), more frequent recurrence (40 %, 6/15 vs. 3.7 %, 1/27; P = 0.005), and frequently elevated preoperative CA-125 level (100 %, 12/12 vs. 50 %, 10/20; P = 0.004). All recurrences occurred within 2 years of the initial surgery. Survival curves indicated that ovarian IT patients with GP had significantly shorter recurrence-free survival compared to those without GP (P = 0.002). The 2-year recurrence-free survival rates were 59.3 and 96.3 % in IT with GP and IT without GP, respectively. However, all but one case of IT with GP are currently alive. In conclusion, GP is an adverse prognostic factor characterized by frequent recurrence in patients with ovarian IT.

We report the first case of isolated ovarian perivascular epithelioid cell tumor not otherwise specified in a 33-year-old woman with no history of tuberous sclerosis. A right ovary specimen revealed a well-circumscribed 2.5 × 2 cm solid mass. Microscopically, the mass was composed of nests of tumor cells that were separated by fibrous septa. The tumor cells were composed of pure epithelioid cells with abundant clear cytoplasm and dark brown pigments. Immunohistochemically, the tumor cells showed diffuse and strong cytoplasmic staining of HMB45; however, the tumor cells were not reactive for smooth muscle actin, desmin, inhibin-α, calretinin, and carcinoembryonic antigen. Strong nuclear expression of transcription factor E3 protein was observed in most tumor cells, and transcription factor E3 fluorescence in situ hybridization showed transcription factor E3 rearrangements associated with balanced Xp11 translocations.

Background Thymic neuroendocrine carcinomas (NECs) are uncommon, for which there is no established information available because of a limited number of epidemiological study in Asia. Methods We reviewed 21 cases of surgically resected thymic NECs, and evaluated their pathological and clinical features. Results It showed male predominance (male/female ratio, 15/6) with wide age range from 20 to 72 years (mean age, 49 years). All 21 cases were divided into two types according to the World Health Organization criteria: atypical carcinoid (n=18) and large cell NEC (n=3). Three cases of atypical carcinoid (AC) were associated with ectopic Cushing's syndrome. All the patients (3/3) with large cell NEC (3/3) and 16.7% (3/18) of those with AC died of tumor progression. Common sites of metastasis included lung, lymph node, brain, lumbar spine, mediastinum, bone, and liver. Conclusions In conclusion, thymic neuroendocrine tumors carry a poor prognosis. Regarding the tumor classification, our results showed that a vast majority of carcinoids in the thymus correspond to ACs. In addition, our results also indicate that typical carcinoid is a very rare entity. Some cases of AC exhibited a large size, solid pattern and they showed aggressive clinical behavior, which highlights the spectrum of histologic appearances of thymic NECs.

Background Mucinous gastric carcinoma (MGC) is a distinct histologic subtype of gastric cancer. However, the prognostic significances of the current TNM staging system and histology in MGC have not been studied. Methods 206 patients who underwent R0 resection for MGC were classified by tumor size (

AKT1 signaling pathway is important for the regulation of protein synthesis and cell survival with implications in carcinogenesis. In this study, we explored the prognostic significance of AKT1 pathway in intrahepatic cholangiocarcinomas. We investigated the status of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphorylated (p) AKT1 (p-AKT1), p-mammalian target of rapamycin (p-MTOR), p-p70 ribosomal protein S6 kinase (p-RPS6KB2) and p-eukaryotic initiation factor 4E-binding protein-1 (p-EIF4EBP1) in 101 intrahepatic cholangiocarcinomas by immunohistochemistry. Western blot analysis was performed to verify the expression levels of p-AKT1 and p-MTOR. The relationship of protein expression with clinicopathological data and the correlations of protein expression levels were explored. The overexpression of p-AKT1, p-MTOR, and PTEN was associated with a better survival in patients with intrahepatic cholangiocarcinoma (P=0.0137, 0.0194, and 0.0337, respectively). In a multivariate analysis, PTEN was an independent prognostic factor, and p-AKT1 showed tendency (P=0.032 and 0.051, respectively). The overexpression of p-MTOR was correlated with well-to-moderately differentiated tumors (P

Objective Higher level of circulating monocyte has been reported to be related with higher cancer incidence and mortality. We investigated the role of pre-treatment circulating monocyte count for cancer specific survival in cervical squamous cell carcinoma patients comparing with pre-treatment squamous cell carcinoma-related antigen (SCC-Ag) level. Methods We retrospectively enrolled patients with squamous cell carcinoma of the cervix (FIGO stage IB to IVA) who had complete blood cell counts with differential cell count and serum SCC-Ag level within 2weeks before starting initial treatment and were treated at Samsung Medical Center, Seoul, Korea, from 1996 to 2007. Results The 788 patients in our study group had a median follow-up of 53.4months and a five-year survival rate of 87.8%. The median value for pre-treatment circulating monocyte count was 349/μl (21–1463), and the median concentration of SCC-Ag was 1.6ng/ml (0.1–362.0). In multivariable analysis, the pre-treatment circulating monocyte count was an independent prognostic factor for progression-free survival and overall survival in locally advanced disease ( P =0.007 and P =0.038) but not in case of SCC-Ag for overall survival. The combined index of monocyte count and SCC-Ag level could enhance the prognostic value of SCC-Ag alone in patients with locally advanced cervical squamous cell carcinoma. Conclusions A higher pre-treatment circulating monocyte count is independently associated with poor prognosis in patients with locally advanced cervical squamous cell carcinoma. The pre-treatment circulating monocyte count may be considered as an adjunctive biomarker with SCC-Ag.

Pathological detection of lymphovascular space invasion (LVSI) is a useful prognostic marker for patients with endometrial cancer. However, LVSI is criticized for its subjectivity and poor reproducibility. To improve the outcomes of patients with endometrial cancer, we evaluated objective parameters associated with LVSI to generate more accurate LVSI assessments and to identify patients with high-risk disease. We reviewed the medical records of 137 patients with endometrial cancer. Flow cytometry was used to determine DNA ploidy and S-phase fraction. Estrogen and progesterone receptor (ER and PR) levels and p53 and k-ras mutational status were tested. LVSI was found in 36 patients (26.3%). Patients with LVSI had significantly decreased recurrence-free survival and overall survival compared to those without LVSI. Aneuploid tumors were significantly more frequent in LVSI-positive patients compared with LVSI-negative patients (odds ratio = 5.208, P

Sung C O, Suh Y-L & Hong S-C (2011) Histopathology59, 308–317 CD34 and microtubule-associated protein 2 expression in dysembryoplastic neuroepithelial tumours with an emphasis on dual expression in non-specific types Aims: Three histological variants of dysembryoplastic neuroepithelial tumour (DNT) have been described, namely, simple, complex and non-specific. However, the concept of non-specific variants of DNT remains controversial, because they cannot be accurately distinguished by histological findings alone from ordinary gliomas. The aim was to characterize further the non-specific histological forms of DNT. Methods and results: Forty-one DNTs classified as three histological forms were investigated with CD34 and microtubule-associated protein 2 (MAP2) immunohistochemistry. CD34 immunoreactivity was more frequently observed in non-specific DNT types (16/18 cases; 88.9%) than in classic types (6/23 cases; 26.1%) (P

Galectin-3 (Gal-3) is a β-galactoside-binding lectin involved in regulating cell growth, angiogenesis, and tumor progression. We investigated the clinical significance of Gal-3 expression including its possible use as a prognostic marker or therapeutic target in epithelial ovarian carcinoma (EOC). Gal-3 expression was evaluated by immunohistochemistry in 71 patients with 54 serous, 13 endometrioid, and 4 mucinous ovarian carcinomas. We assessed the correlation of Gal-3 expression with clinical characteristics including histology, optimal debulking, chemosensitivity, and survival. In vitro, Gal-3 was inhibited using siRNA to evaluate its role in cell growth and sensitivity to chemotherapeutic agents in ovarian carcinoma cell lines. Gal-3 protein, which was mainly cytoplasmic in location, was observed in a majority (63/71, 88.7%) of the EOCs but not in normal ovarian tissues (P

Claudins are 22-27 kDa sized adhesion molecules that constitute tight junctions. Their expression levels are often tissue-specific, and their altered degrees of expression have been reported in a variety of cancers. In addition, the prognostic significance of claudin expression has been implicated in various human cancers. However, the prognostic significance of claudin-4 expression in esophageal squamous cell carcinoma (ESCC) remains to be clarified.We investigated the prognostic significance of claudin-4 expression in 164 cases of ESCC using immunohistochemisty. We also evaluated claudin-4 mRNA expression levels using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) and analyzed its specific promoter methylation status using quantitative methylation-specific PCR.According to clinicopathological parameters, low claudin-4 expression was found to be significantly associated with histological differentiation (P = 0.003), invasion depth (P = 0.002), and lymph node metastasis (P = 0.024). Low claudin-4 expression showed unfavorable influences on disease-free survival (P = 0.0115) and overall survival (OS) (P = 0.0009). In multivariate analysis, low claudin-4 expression was an independent predictor of poor OS (P = 0.007). Claudin-4 mRNA levels assessed using real-time RT-PCR were consistent with the protein levels determined using immunohistochemistry. Furthermore, this study demonstrates that loss of claudin-4 is associated with promoter hypermethylation.Our study indicates that claudin-4 expression is deregulated in ESCC, implying its potential use as a prognostic biomarker in ESCC.

Background/Aims Although gastric hyperplastic polyps are usually considered as benign lesions, a low risk of carcinomatous conversion is currently recognized. We aimed to identify the characteristics of hyperplastic polyps undergoing neoplastic transformation. Methods A total of 269 gastric hyperplastic polyps from 216 patients removed by endoscopic polypectomy (EP) or surgical resection were enrolled in this study, and their endoscopic pictures and pathology slides were reviewed. Results Neoplastic transformation was detected on forceps biopsy specimen in 11 cases. However, the pathology findings from the EP or surgical specimen revealed neoplastic transformation in 14 cases (5.2%; 4 with dysplasia and 10 with adenocarcinoma). No significant difference was found between hyperplastic polyps with and without neoplastic transformation in age, sex, location, number of polyps or gross appearance. However, neoplastic transformations were more frequently found in gastric hyperplastic polyps >1 cm than in polyps ≤1 cm (12 of 143; 8.4% vs. 2 of 126; 1.6%) (p=0.013). Conclusions Neoplastic transformations were more frequently found in gastric hyperplastic polyps >1 cm. Therefore, EP should be considered for gastric hyperplastic polyps >1 cm for the accurate diagnosis and definitive treatment.

Dysembryoplastic neuroepithelial tumors (DNTs) are benign glial-neuronal neoplasms with characteristic cliniopathologic features. Three histologic forms of DNTs have been described (simple, complex, and non-specific). The developmental origin of the tumors remains controversial. To determine the developmental origin and nature of the histologic forms of DNTs, immunohistochemical studies of nestin, TrkA, TrkB, p75, and NeuN were conducted in 40 cases of DNTs, including 11, 9, and 20 simple, complex, and non-specific forms, respectively. Nestin positivity of oligodendroglia-like cells (OLCs) was present in 50 and 27.3% of simple and complex forms, respectively. In the non-specific form of DNT, 94.7% of the cases were positive for nestin. Most DNTs exhibited diffuse, strong staining for TrkA and TrkB, irrespective of the histologic subtypes. Both p75 and NeuN positivity were found in about one-half of the simple, complex, and non-specific forms, respectively. Our study suggests that OLCs are a heterogeneous population of cells, and higher expression of nestin in the non-specific form of DNTs compared to the simple or complex forms suggests that the non-specific form has an earlier developmental origin than the simple or complex forms.

One of the major challenges in bladder cancer management is in distinguishing aggressive from indolent tumors with similar clinicopathological factors, especially in cases of high-grade T1 stage tumors. To define a set of prognostic factors that can be easily assessed in clinical practice with a high cost-effectiveness, the expressions of 11 proteins were examined immunohistochemically in 403 cases of transurethral resection of bladder tumors, then correlated to clinical outcomes. Based on the protein immunoprofiles, urothelial carcinomas were divided into 4 intrinsic molecular subgroups with different clinical outcomes: subgroups 1 and 4 with the poorest survival, subgroup 2 with the best survival, and subgroup 3 with the intermediate survival outcome. The protein expression patterns of the 4 subgroups were mutually exclusive: overexpression of p53, EZH2, E2F1, and IMP3 and high Ki-67 proliferation index in subgroup 1; overexpression of cytoplasmic survivin in subgroup 4; overexpression of membranous TSP1 and cytoplasmic p27 in subgroup 2; and no representative protein overexpression in subgroup 3. Using these protein immunoprofiles, 3 risk groups were generated, which predicted disease-specific survival not only in total bladder carcinoma cases with 0.737 of predictive accuracy but also in high-grade stage T1 tumors with 0.658 of predictive accuracy. These results showed that urothelial carcinomas were composed of 4 clinically relevant molecular subgroups based on protein expression and that overall survival of those patients could be predicted using a set of a small number of protein expressions not only in total cases but also in high-grade stage T1 tumors.

The pathogenetic mechanism underlying the hydropic change in complete hydatidiform moles (CHMs) is poorly understood. A growing body of data suggests that pericytes play a role in vascular maturation. Since maturation of villous stromal vessels in CHMs is markedly impaired at early stages, we postulated that a defect in pericytes around stromal vessels in chorionic villi might cause vascular immaturity and subsequent hydropic change. To investigate this, we examined several markers of pericytes, namely, α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor-β (PDGFR-β), and desmin, in 61 normally developing placentas and 41 CHMs with gestational ages of 4–12 weeks. The ultrastructure of villous stromal vessels was also examined. Mature blood vessels from normal placentas show patent vascular lumens and formed hematopoietic components in the villous stroma. α-SMA and PDGFR-β expression in the villous stroma gradually increased and extended from the chorionic plate to peripheral villous branches. The labeled cells formed a reticular network in the villous stroma and, after week 7, encircled villous stromal vessels. In comparison, α-SMA and PDGFR-β expression in the villous stroma and stromal vessels of CHMs was significantly lower (p

Granulocytic sarcoma is a rare extramedullary tumor composed of myeloid progenitor cells. Primary involvement of the biliary tract without evidence of leukemia is exceedingly rare. Here, we report an isolated biliary granulocytic sarcoma in a 30-yr-old man who presented with jaundice, fever, and chill without any evidence of leukemia. However, five months after the diagnosis, he developed acute myelogenous leukemia with multilineage dysplasia and chromosomal abnormality. A rare possibility of biliary granulocytic sarcoma should be considered as a differential diagnosis in patients with obstructive jaundice. A histologic evaluation by aggressive diagnostic intervention is important and may improve prognosis.

We present a case of retroperitoneal arteriovenous malformation extending through the inferior vena cava into the heart, which was associated with dissection of the inferior vena cava in a 32-year-old female. Computed tomography and magnetic resonance imaging showed a double-lumen inferior vena cava and a rod-like solid component attached to a sac-like lesion in the right heart chambers. Digital subtraction angiography showed an arteriovenous malformation draining to the inner lumen of the inferior vena cava.

Acute phase reactants are a group of hepatic proteins that are synthesized and released into the circulation in response to certain stresses such as infection and physical injury [1]. C-reactive protein (CRP) is a well-known, major acute phase reactant that was originally found in the sera of patients infected with Streptococcus pneumoniae [2,3]. CRP mRNA transcription is primarily induced by pro-inflammatory cytokines interleukin (IL)-6 and IL- 1 [4-6]. The blood concentration of CRP is increased in inflammatory conditions of both infectious and non-infectious etiologies such as urinary tract infection and hyperlipidemic acute pancreatitis [7,8]. A growing body of evidence indicates a solid pathobiological relationship between chronic inflammation and carcinogenesis [9]. Innate immune components such as Toll-like receptors and NOD-like receptors play a role in the regulation of inflammation and development of cancer [10-12]. Serum CRP level has been shown to be a prognostic marker in various human cancers [13,14]. Likewise, high serum CRP level is a poor prognostic factor in hepatocellular carcinoma (HCC) in relation to early recurrence [15,16]. As hepatocytes are the primary origin of CRP synthesis, it is highly likely that neoplastic hepatocytes retain a functional capacity to synthesize CRP under the influence of pro-inflammatory stimuli. Not surprisingly, CRP expression has been rather extensively studied in hepatocellular adenomas [17,18], and CRP immunoreactivity is a critical parameter for molecular phenotyping and defining of the inflammatory subtype of hepatocel lular adenoma, which has a higher risk of malignant transformation [19-21]. Of note, based on the results of immunohistochemistry using a panel of antibodies and fluorescence in situ hybridization for gains of chromosomes 1, 8, and MYC in HCC arising in adenoma, Kakar et al.[22] recently proposed that a certain subset of hepatocellular adenomas may represent a well-differentiated version of HCCs. However, CRP expression in HCCs has not yet been studied. We postulated that the evaluation of CRP expression in HCC may provide valuable information regarding the unique biology of HCCs. This study was conducted to determine whether CRP is produced by HCC cells and to assess its clinicopathologic significance.

Carbonic anhydrase 9 (CA9), which regulates cellular proliferation and the acid-base balance, is known as prognostic factor in various types of cancer. The aim of this study is to investigate the clinical implications of CA9 expression in patients with hepatocellular carcinoma. Immunohistochemical staining for CA9 was performed on tissue microarrays of hepatocellular carcinoma and paired non-neoplastic liver tissue from a training cohort of 838 patients and a validation cohort of 225 patients. Membranous staining in more than 5 % of the tumor cells was considered to indicate CA9 positivity. The prognostic value of CA9 expression was statistically evaluated. In the training cohort, CA9 positivity (181 cases, 21.5 %) was significantly correlated with shorter overall survival (OS; p < 0.001) and recurrence-free survival (RFS; p = 0.004). In multivariate analysis, CA9 positivity was independently associated with reduced OS (p = 0.023), but not significantly associated with RFS (p = 0.384). These results were validated in an additional cohort (CA9 positivity in 35 cases, 15.6 %; OS, p = 0.015; RFS, p = 0.979). Pooled cohort analysis showed that this predictor was independently associated with higher mortality (OS; p < 0.001). These data indicate that CA9 expression is a poor prognostic factor in resectable hepatocellular carcinoma (HCC) patients.

Malignant transformation of mature cystic teratoma is uncommon, and occurs in approximately 2%–4% of cases [1]. The most common tumor is squamous cell carcinoma, followed by mucinous carcinoma, carcinoid tumor, thyroid carcinoma, etc.; however, any of the tissues in mature teratoma may undergo malignant transformation [1]. Goblet cell carcinoid (mucinous carcinoid) is a distinctive neoplasm with features of both carcinoid tumor and adenocarcinoma. Most cases described in the literature have occurred in the appendix and rarely, in the ovary. Although mature cystic teratomas occur in many extragonadal areas including the mesentery [2] and greater omentum, occurrence of goblet cell carcinoid arising in extragonadal teratoma has been rarely described, with only a single case in mediastinum being reported in the English literature [3]. Moreover, a combination of mucinous adenocarcinoma, goblet cell carcinoid, carcinoid tumor, and mature teratoma in an extragenital organ has not been reported. Herein, we present a rare case of combined mucinous adenocarcinoma and goblet cell and typical carcinoid tumor arising in mature cystic teratoma of the mesentery in a 48-year-old woman.

One of the major challenges in prostate cancer research is to identify prognostic/predictive factors to distinguish aggressive disease from indolent one. To select prognostic/predictive markers of postoperative biochemical recurrence (BCR) that could be easily performed in daily pathology practice, the expression of 6 immunohistochemical markers including zinc-α-2-glycoprotein (AZGP-1), hCAP-D3, mucin 1, vimentin, E-cadherin, and ERG was assessed in a tissue microarray of 400 radical prostatectomy specimens. The expression levels were correlated with clinicopathologic factors and BCR. During the median follow-up period of 55 months, BCR occurred in 70 cases (17.5%). Low expression of AZGP-1 was noted in 76 cases (19.0%), whereas high expression of hCAP-D3, mucin 1, vimentin, and ERG was observed in 205 (51.3%), 81 (20.3%), 33 (8.3%), and 58 (14.5%) cases, respectively. Aberrant E-cadherin expression was noted in 29 cases (7.3%). By univariate analysis, BCR was associated with low expression of AZGP-1, high expression of hCAP-D3, and aberrant expression of E-cadherin. By multivariate analysis, only AZGP-1 remained an independent immunohistochemical factor, in addition to age, preoperative serum prostate-specific antigen level, Gleason score, tumor stage, and resection margin status. These results show that AZGP-1, hCAP-D3, and E-cadherin are potentially useful immunohistochemical markers to predict BCR, and that AZGP-1 can be used as an independent prognostic marker of aggressive prostate cancer.

CD10 expression was identified as a contributor to cancer progression in several cancers; however, the exact biological significance and mechanism of CD10 expression remains unclear. In addition, CD10 expression in esophageal squamous cell carcinoma (ESCC) has not been studied. We investigated the relationship between CD10 and Twist1. Furthermore, we examined the effect of CD10 on tumorigenicity using in vivo and in vitro systems as well as establishing the clinical significance of CD10 expression in ESCC using large clinical samples. CD10 expression was upregulated by Twist1 and there was a strong correlation between mRNA and protein expression. Twist1 can specifically upregulate CD10 at the transcriptional level via an interaction with the promoter region of CD10 and the proximal E-box CAGGTG in the CD10 promoter was identified as a binding site for Twist1. CD10 is frequently expressed in ESCC cell lines and silencing CD10 suppresses migration/invasion and anchorage-independent tumor growth of ESCC cells. Knockdown of CD10 inhibits the growth of ESCC xenograft in nude mice, suggesting that CD10 plays a role in enhancing the tumorigenesis of ESCC. From among 153 ESCC samples, 46 (30.0%) showed varying degrees of CD10 expression in cancer cells. In addition, stromal fibroblasts also showed varying amounts of CD10 expression in 92 (60.9%) tumor samples. CD10 overexpression in cancer cells as well as in stromal fibroblasts was an independent poor prognostic factor in both overall survival and disease-free survival. CD10 could be a promising target for the treatment of ESCC.

Intrahepatic cholangiocarcinomas occur mostly in the normal liver but they also arise in chronic advanced liver diseases. However, genetic differences between two groups have yet to be examined. High throughput mass spectrometry-based platform was used to interrogate mutations in intrahepatic cholangiocarcinomas and to compare the mutation profiles between 43 intrahepatic cholangiocarcinomas with normal liver and 38 with chronic advanced liver diseases. Forty seven mutations in 11 genes were identified in 38 of 81 cases (46.9%). The most commonly mutated gene was KRAS (11/81, 13.6%), followed by MLH1 (7/81, 8.6%), NRAS (7/81, 8.6%), GNAS (6/81, 7.4%), and EGFR (6/81, 7.4%). BRAF, APC, PIK3CA, CDKN2A, PTEN, and TP53 mutations were found with less than 5%. Overall mutation rate of intrahepatic cholangiocarcinomas with chronic advanced liver disease (15/38, 39.5%, 95% confidence interval: 23.9-55.0) was lower than that of intrahepatic cholangiocarcinomas with normal liver (23/43, 53.5%, 95% confidence interval: 38.5-68.3). Intrahepatic cholangiocarcinomas with chronic advanced liver disease showed higher EGFR mutation rate (5/38, 13.2% vs 1/43, 2.3%) and lower mutation rates of KRAS (3/38, 7.9% vs 8/43, 18.6%), MLH1 (2/38, 5.3% vs 5/43, 11.6%), and GNAS (1/38, 2.6% vs 5/43, 11.6%), compared with those in intrahepatic cholangiocarcinomas with normal liver. Mutations in PIK3CA, PTEN, CDKN2A, and TP53 were harbored only in intrahepatic cholangiocarcinomas with normal liver. KRAS (P=0.0075) or GNAS mutations (P=0.0256) were associated with poor overall survival in all patients with intrahepatic cholangiocarcinoma. Differential mutation patterns of intrahepatic cholangiocarcinomas with chronic advanced liver disease suggest different cholangiocarcinogenesis depending upon the predisposing factors, and support that different strategy for targeted therapy should be applied in intrahepatic cholangiocarcinoma subtypes.

Galectin-7 (GAL-7) has been highlighted as an important marker in many types of cancers by either inhibiting or promoting tumor growth. In this novel study, we assessed the association of GAL-7 with clinicopathological variables and survival outcomes in epithelial ovarian cancer (EOC) and investigated the role of GAL-7 in proliferation of ovarian cancer cell lines.The expression of GAL-7 was determined in 63 formalin-fixed, paraffin-embedded EOC tissues using an immunohistochemical method and we compared various associated clinicopathological factors. To evaluate the role of GAL-7 in cell proliferation, we performed proliferation assays with GAL-7 siRNA using ovarian cancer cell lines, including A2780-PAR cells.Immunohistochemical analysis revealed that GAL-7 expression was primarily detected in nuclei and occasionally in the nucleus and cytoplasm. High GAL-7 expression was associated with greater age (p=0.016), high mortality (p=0.025), and poor overall survival outcome (p=0.029). In addition, the residual tumor volume was larger in the high-expression group compared to the low-expression group, although the difference was not statistically significant (p=0.059). Down-regulation of GAL-7 using siRNA resulted in the inhibition of cell proliferation of A2780-PAR cells.We observed that high GAL-7 might be associated with poor survival outcome in patients with EOC, and may be functionally involved in cell proliferation.

Tonsillar squamous cell carcinomas (TSCC) frequently present with locally advanced diseases and cervical metastases, which are associated with poor prognoses. Epithelial-mesenchymal transition (EMT) is critical for tumor invasiveness and metastatic potential. Recent studies have shown that TWIST1-inducing EMT is overexpressed and hypermethylated in several cancers, indicating disease progression. The aim of the present study was to determine the clinical and prognostic significance of TWIST1 hypermethylation and EMT-related protein expression in TSCC. Methylation levels of TWIST1 promoter were analyzed by quantitative real-time methylation-specific polymerase chain reaction. Immunohistochemical analyses of TWIST1, Snail, and SMAD nuclear interacting protein-1 (SNIP1) were performed in 65 formalin-fixed, paraffin-embedded blocks of surgically resected specimens. TWIST1 promoter hypermethylation was found in 27.7% (18/65) of TSCCs. TWIST1 promoter hypermethylation was associated with poor differentiation (P = .012). Contralateral cervical lymph node metastasis was more frequently observed in TWIST1-methylated tumors (P = .029). High protein expressions of TWIST1, Snail, and SNIP1 were observed in 14 TSCC specimens (21.5%), 21 TSCC specimens (32.3%), and 38 TSCC specimens (58.5%), respectively. SNIP1 expression correlated significantly with TWIST1 methylation (P = .001), whereas TWIST1 protein expression did not. Contralateral cervical lymph node metastasis was an independent risk factor of the decreased overall survival rate (P = .002). TWIST1 methylation (P = .031) and pN stage (P = .037) were independent factors of poor prognoses affecting disease-free survival. TWIST1 promoter hypermethylation may be a useful molecular marker for predicting prognoses and contralateral cervical lymph node metastases in patients with TSCC.

PURPOSE: Cervical cytology and human papillomavirus (HPV) DNA co-testing is recommended as a screening method for detecting cervical lesions. However, for women who are HPV-positive but cytology-negative, the appropriate management and significance of HPV-58 infection remain unknown. METHODS: This study of prevalent HPV detected at baseline with a median follow-up of 3.2 years evaluated the risk factors associated with cervical abnormalities and assessed the significance of HPV-58 infection. A total of 265 women were enrolled. All high-grade squamous intraepithelial lesions (HSIL) that were detected by cytology were confirmed by histology. Histological diagnoses of cervical intraepithelial neoplasia 2/3 were classified as HSIL. Women were classified into four groups according to the HPV genotype that was detected at their first visit: HPV-58 (n = 27), HPV-16 (n = 52; 3 women had HPV-58 co-infection), ten other high risk (HR) types (n = 79), or low/undetermined risk types (n = 107). RESULTS: Of 265 women, 20 (7.5%) had HSIL on their follow-up examinations. There were significant differences in the cumulative incidence of HSIL between the four groups (p

PURPOSE: Inactivation of TP53, which occurs predominantly by missense mutations in exons 4-9, is a major genetic alteration in a subset of human cancer. In spite of growing evidence that gain-of-function (GOF) mutations of p53 also have oncogenic activity, little is known about the clinical relevance of these mutations. METHODS: The clinicopathological features of high-grade serous ovarian carcinoma (HGS-OvCa) patients with GOF p53 mutations were evaluated according to a comprehensive somatic mutation profile comprised of whole exome sequencing, mRNA expression, and protein expression profiles obtained from the Cancer Genome Atlas (TCGA). RESULTS: Patients with a mutant p53 protein (mutp53) with a GOF mutation showed higher p53 mRNA and protein expression levels than patients with p53 mutation with no evidence of GOF (NE-GOF). GOF mutations were more likely to occur within mutational hotspots, and at CpG sites, and resulted in mutp53 with higher functional severity (FS) scores. Clinically, patients with GOF mutations showed a higher frequency of platinum resistance (22/58, 37.9%) than patients with NE-GOF mutations (12/56, 21.4%) (p=0.054). Furthermore, patients with GOF mutations were more likely to develop distant metastasis (36/55, 65.5%) than local recurrence (19/55, 34.5%), whereas patients with NE-GOF mutations showed a higher frequency of locoregional recurrence (26/47, 55.3%) than distant metastasis (21/47, 44.7%) (p=0.035). There were no differences in overall or progression-free survival between patients with GOF or NE-GOF mutp53. CONCLUSION: This study demonstrates that patient with GOF mutp53 is characterized by a greater likelihood of platinum treatment resistance and distant metastatic properties in HGS-OvCa.

Difference in prognosis between grade 3 endometrioid carcinoma (G3EC) of the endometrium and uterine serous carcinoma (USC) is controversial. In this study, we further evaluated the difference in prognosis, if any, between G3EC (n = 61) and USC (n = 47) on a total of 565 patients with endometrial cancer. In addition, meta-analysis was performed using data from seven previous publications (n = 8,637) and from the Asan Medical Center (n = 108). Regarding the cases from our institution, USC tended to occur in older patients (≥65 years) than G3EC (P = 0.011). Deep myometrial invasion (more than or equal to half) was more frequently identified in G3EC (36/61, 59.0 %) than in USC (17/47, 36.2 %) (P = 0.021). Between patients with early stage G3EC and USC (stages I and II), there were no significant differences in any clinicopathological parameter, but there was a significant difference in overall survival (P = 0.017) that was not found in advanced stage (P = 0.588). USC was an independent prognostic factor for poor overall survival (hazard ratio, 6.125; P = 0.030) in early stage patients. In the meta-analysis on 5-year survival in patients with early stage cancers, which also included our study results, a higher relative risk (1.92, 95 % CI 1.62–2.27) was demonstrated in USC than in G3EC (P

Trastuzumab in association with systemic cytotoxic chemotherapy is the standard of care for patients with advanced HER2-positive gastric carcinoma (GC). However, HER2 as a prognostic factor in GC remains controversial. HER2 overexpression and amplification was evaluated by immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 2,798 GCs obtained from 2,727 gastrectomy and 71 open/laparoscopic biopsy specimens from patients with peritoneal seeding. Regional heterogeneity was defined as the proportion of tumor cells showing membranous staining in 10–70 % of tumor cells. Genetic heterogeneity was determined by the existence of HER2/CEP17 ratio higher than 2.0 in >5 to

PURPOSE: Recent high-throughput sequencing technology has identified numerous somatic mutations across the whole exome in a variety of cancers. In this study, we generate a predictive model employing the whole exome somatic mutational profile of ovarian high-grade serous carcinomas (Ov-HGSCs) obtained from The Cancer Genome Atlas data portal. METHODS: A total of 311 patients were included for modeling overall survival (OS) and 259 patients were included for modeling progression free survival (PFS) in an analysis of 509 genes. The model was validated with complete leave-one-out cross-validation involving re-selecting genes for each iteration of the cross-validation procedure. Cross-validated Kaplan-Meier curves were generated. Cross-validated time dependent receiver operating characteristic (ROC) curves were computed and the area under the curve (AUC) values were calculated from the ROC curves to estimate the predictive accuracy of the survival risk models. RESULTS: There was a significant difference in OS between the high-risk group (median, 28.1 months) and the low-risk group (median, 61.5 months) (permutated p-value

Sodium alginate is currently used in medical products, including drugs and cosmetic materials. It can also be used as a submucosal injection material due to its excellent water retention ability. Alginate with a high water retention ability is called alginate hydrogel (AH). The aim of this study was to investigate the usefulness of AH as a submucosal injection material. To investigate the optimal viscosity of AH as a submucosal injection material, we observed the changes in submucosal height from the initial submucosal height in the stomachs of six miniature pigs for each injection material tested (0.3 % AH, 0.5 % hyaluronic acid, glycerol). All submucosal heights were compared serially over time (3, 5, 10, 20, and 30 min). Both immediate and 1-week delayed tissue reactions were investigated endoscopically in the same living pigs. Histological analyses were performed after the animals had been sacrificed. In a preliminary study, we determined that 0.3 % sodium alginate mixed with BaCl2 (400 μl) was the optimal viscosity of AH as an injection material. Our comparison of submucosal height changes over time showed that there was a significant decrease in submucosal height just 3 min following the injection of hyaluronic acid and glycerol, but that following the injection of AH a significant decrease in submucosal height was observed only after 10 min (p

Background: The purpose of this study was to identify genes that are differentially expressed in chemosensitive serous papillary ovarian carcinomas relative to those expressed in chemoresistant tumours. Methods: To identify novel candidate biomarkers, differences in gene expression were analysed in 26 stage IIIC/IV serous ovarian adenocarcinomas (12 chemosensitive tumours and 14 chemoresistant tumours). We subsequently investigated the immunohistochemical expression of GRIA2 in 48 independent sets of advanced ovarian serous carcinomas. Results: Microarray analysis revealed a total of 57 genes that were differentially expressed in chemoresistant and chemosensitive tumours. Of the 57 genes, 39 genes were upregulated and 18 genes were downregulated in chemosensitive tumours. Five differentially expressed genes (CD36, LIFR, CHL1, GRIA2, and FCGBP) were validated by quantitative real-time PCR. The expression of GRIA2 was validated at the protein level by immunohistochemistry, and patients with GRIA2 expression showed a longer progression-free and overall survival (P=0.051 and P=0.031 respectively). Conclusions: We found 57 differentially expressed genes to distinguish between chemosensitive and chemoresistant tumours. We also demonstrated that the expression of GRIA2 among the differentially expressed genes provides better prognosis of patients with advanced serous papillary ovarian adenocarcinoma.

PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare group of tumors with a wide spectrum of clinical behavior. However, there are no known clinically relevant biomarkers to predict metastasis. EXPERIMENTAL DESIGN: To investigate differential gene expression signatures of metastatic vs non-metastatic NETs, we studied cell cycle regulatory genes in 19 metastatic and 22 non-metastatic colorectal NETs by PCR arrays. Immunohistochemistry (IHC) and quantitative real-time RT-PCR were performed to verify the results and another set of 38 GEP-NETs were further studied for validation. RESULTS: We first delineated six candidate genes for metastasis including ATM, CCND2, RBL2, CDKN3, CCNB1, and GTSE1. ATM was negatively correlated with metastatic NETs (p

Secretory, clear cell, and rhabdoid meningiomas are rare variants of meningiomas characterized by unique histologies and behaviors. Extracellular matrix proteins provide a morphologic structure and influence the biologic behavior of tumors. However, the effects of extracellular matrix proteins on morphologies and biologic behaviors of secretory meningioma, clear cell meningioma, and rhabdoid meningioma have not been established. We evaluated the expression of matrix metalloproteinase 2, matrix metalloproteinase 9, galectin-3, fibronectin, and collagen IV in a series of those rare variants of meningioma and verified their clinicopathologic significance. A total 51 cases included 12 secretory meningiomas, 9 clear cell meningiomas, and 30 rhabdoid meningiomas. Extracellular matrix proteins showed different expression patterns according to the histologic subtypes, and messenger RNA levels were well correlated with immunoexpressions. Secretory meningiomas showed high expressions of fibronectin and galectin-3. Clear cell meningiomas showed high expression of matrix metalloproteinase 2, matrix metalloproteinase 9, and collagen IV. Rhabdoid meningiomas showed high expressions of matrix metalloproteinase 9, galectin-3, and fibronectin. Clinically, high expression of matrix metalloproteinase 9 was associated with tumor recurrence (P.001) and local invasion at the time of diagnosis (P = .018) among the extracellular matrix-related proteins, and was also associated with shorter recurrence-free survival (P = .025) in the patients with rhabdoid meningioma. In conclusion, the differential expressions of extracellular matrix-related genes according to the histologic subtypes appear to be involved in biologic behavior and clinical outcome, and high matrix metalloproteinase 9 expression is associated with recurrences in rhabdoid meningiomas.

Objective Immune competence is an important prognostic factor in cancer patients. Surgical management of cancer can cause a variety of immunological disturbances, the clinical consequences of which are still unclear. Materials and methods Patients with clinically staged cervical carcinoma (IB to IIA) who were treated at Samsung Medical Center, Seoul, Korea from 1994 to 2007 were retrospectively enrolled. We compared peri-operative peripheral lymphocyte counts, tumor-infiltrating lymphocyte scores, and survival in patients with early cervical cancer treated by abdominal type III radical hysterectomy. Results The sample included 756 patients. The median follow-up was 58months with a range of 3–181months. There was a positive correlation between pre-operative peripheral lymphocyte counts and tumor infiltrating lymphocyte score. Pre-operative peripheral lymphocyte counts decreased significantly after surgery. In multivariate analyses for recurrence, higher pre-operative peripheral lymphocyte counts and recovery of lymphocyte counts (more than 100/μL from the pre-operative level) on post-operative day 3 were independent positive prognostic factors and LN metastasis was negatively associated with post-operative recovery of peripheral lymphocyte counts. Conclusion Peripheral lymphocyte counts after cervical cancer surgery are important prognostic factors, and management aimed at minimizing immune disturbances after surgery should be assessed, especially in patients with LN metastasis.

The standard treatment for high grade ovarian serous cancer (HG-OSC) is aggressive cytoreductive surgery followed by platinum based chemotherapy. However, approximately 30% of patients exhibit platinum resistance, and those patients show aggressive clinical courses. Currently, it is difficult to predict which HG-OSC patients will respond to platinum-based chemotherapy.We analyzed whole exome sequences for 174 HG-SOC patients using data obtained from The Cancer Genome Atlas (TCGA) data portal regarding platinum response. Patients were categorized as having either hypermutation or hypomutation according to the number of mutations in their sample.HG-SOC showed multiple somatic mutations in individual patients with an average mutated gene number of 61.9. The mean mutation number per patient significantly differed between the platinum sensitive and resistant groups (P0.001). Patients who were platinum sensitive were more likely to have somatic hypermutation in their cancer cells and multivariate logistic regression analysis revealed that somatic hypermutation was an independent factor for risk estimation of platinum sensitivity (odds ratio [OR]=3.616; P=0.002). In multivariate Cox hazard analysis, we identified that somatic hypermutation, as well as platinum response and surgical outcome, were independent prognostic factors in HG-OSC (overall survival, P=0.012; progression free survival, P=0.036).Somatic hypermutation was significantly associated with platinum sensitivity and was an independent prognostic factor in HG-OSC patients treated with platinum based chemotherapy.

Mucinous gastric carcinoma (MGC) is a distinct histologic subtype of gastric cancer. However, the prognostic significances of the current TNM staging system and histology in MGC have not been studied.206 patients who underwent R0 resection for MGC were classified by tumor size (3 cm as T1; ≥ 3-5 cm as T2; ≥ 5-9 cm as T3; and ≥ 9 cm as T4). Immunohistochemistry for EGFR and HER2 was also performed.Tumor sizes ranged from 1.2 to 21.0 cm (median 6.2 cm). Large tumor size (≥ 5 cm) was significantly associated with older patient age, deeper invasion depth, and more frequent lymph node metastasis (P0.05). Tumor size was a significant prognostic factor in both univariate (P0.001) and multivariate (P0.04) analyses. However, depth of invasion was not significant in multivariate analyses. A modified staging system based on tumor size predicted survival more accurately than did the conventional TNM staging system. We verified our results in an independent validation cohort of 123 MGC patients. Overexpression of either EGFR or HER2 was rare.In MGCs, tumor size is an independent prognostic factor and a modified TNM system based on tumor size predicted survival accurately.

Objective: Patient age is one important factor used to evaluate the risk in women with ASC-H (atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion). This finding may be associated with atrophic changes reflecting a hypoestrogenic status and suggests that body mass index (BMI) can affect the outcome of ASC-H smears in postmenopausal women. Study Design: We investigated the outcome of 154 postmenopausal women with an ASC-H smear and assessed relationships with BMI categories and serum estradiol levels. Results: In patients with higher BMI, an underlying squamous intraepithelial lesion (SIL) was more frequent than in patients with lower BMI, and a higher BMI was also associated with increased serum estradiol levels. When samples were classified by preparation method, these findings were more pronounced in liquid-based smears than in conventional smears. Principal component analysis using three factors (BMI, age and human papilloma virus status) revealed two distinct groups: those with a negative cervical smear and those with a smear result indicating SIL+. Conclusion: Hormonal alterations can affect the outcome of ASC-H smears, and BMI is one factor that should be considered when evaluating the risk associated with ASC-H smears in postmenopausal women.

Objective 67-kDa laminin receptor (67LR) has been identified as a prognostic biomarker for a variety of human cancers. We investigated the clinical significance of 67LR expression and its functional role in epithelial ovarian cancer (EOC). Methods 67LR expression was evaluated by immunohistochemistry in 62 patients with EOC. We assessed the correlation of 67LR expression with clinical characteristics. In vitro experiment was performed for 67LR with inhibition using siRNA to evaluate its role in cell survival, apoptosis, and invasion in EOC cells. Results 67LR was predominantly expressed on the cell membrane in the majority of EOC samples (45/62, 73%). 67LR expression was significantly correlated with advanced stage ( P =0.001). Patients with 67LR expression had shorter progression-free survival among all the patients ( P =0.010) and in particular among patients with advanced stages ( P =0.046). When 67LR expression was inhibited by siRNA in EOC cells (HeyA8 and A2780), there was a significant decrease of cell proliferation and invasion as well as increase of apoptosis. Conclusion These findings suggest that 67LR expression may play an important role in tumor progression into advanced stage with poor prognosis in EOC and down-regulation of 67LR on tumor cells may be a therapeutic target in those patients.

Three histological variants of dysembryoplastic neuroepithelial tumour (DNT) have been described, namely, simple, complex and non-specific. However, the concept of non-specific variants of DNT remains controversial, because they cannot be accurately distinguished by histological findings alone from ordinary gliomas. The aim was to characterize further the non-specific histological forms of DNT.Forty-one DNTs classified as three histological forms were investigated with CD34 and microtubule-associated protein 2 (MAP2) immunohistochemistry. CD34 immunoreactivity was more frequently observed in non-specific DNT types (16/18 cases; 88.9%) than in classic types (6/23 cases; 26.1%) (P 0.001). Peritumoral CD34 expression of non-neoplastic cells was significantly associated with CD34-positive tumours (20/22 cases; 90.9%) than with CD34-negative tumours (3/19 cases; 15.8%) (P 0.001). MAP2 positivity in oligodendroglia-like cells or glial elements was significantly different between classic types and non-specific types (P = 0.025). CD34 and MAP2 immunoreactivities were significantly more frequent in non-specific types (83.3%) than in simple (10%) and complex forms (30.8%) (P 0.001).Non-specific DNTs are glioneuronal tumours that have a heterogeneous population of cells with more immature neuronal and glial phenotypes. Furthermore, with regard to practical implications, combined analysis of CD34 and MAP2 is useful in distinguishing DNTs from particularly diagnostically challenging mimics.

Epithelial–mesenchymal transition is characterized by a loss of cell adhesion and increased cell mobility due to cells gaining a mesenchymal phenotype. During the epithelial–mesenchymal transition process, tumor cells are expected to lose their epithelial phenotype and gradually and sequentially acquire a mesenchymal phenotype. Epithelial–mesenchymal transition is a dynamic and reversible process, which has been observed in patient tissues to display a wide spectrum of phenotypes. However, very little is known about the clinical significance of the different phenotypes of the epithelial–mesenchymal transition. Based on the expression pattern of various epithelial–mesenchymal transition-related proteins, we divided 168 esophageal squamous cell carcinomas into different phenotypes, including complete type; incomplete type, including hybrid type and null type; and a wild type. The clinical significance of each phenotype was investigated. Of the 168 cases, 31 were categorized as complete type, 53 as incomplete type (hybrid type, 26 cases; null type, 27 cases), and 84 as wild type. Epithelial–mesenchymal transition phenotype was significantly associated with tumor size (P=0.021), differentiation (P=0.001), and invasion depth (P

Of the genetic changes in primary central nervous system lymphoma (PCNSL), little is known. To detect copy number alterations and differentially expressed genes in PCNSL, we analyzed a total of 12 PCNSL samples with high-resolution array-based comparative genomic hybridization and performed expression profiling in 7 of the 12 samples. The most frequent deletion found in 8 patients (66.7%) occurred in 9p21.3 containing CDKN2A. We compiled the top 96 genes (family-wise error rate, P < .05) showing the greatest differential expression between PCNSL and normal lymph node tissues. From these, we selected 8 candidate genes (NPFFR2, C4orf7, OSMR, EMCN, TPO, FNDC1, COL12A1, and MSC) in which expression changes were associated with copy number aberrations. All 8 genes showed both down-regulation in expression microarray and deletion in array-based comparative genomic hybridization analyses. These genes participate in cell signaling or cell adhesion. In addition, low mRNA expression of C4orf7 was significantly associated with poor survival (P = .0425). Using gene set enrichment analysis, we identified several signal transduction pathways, such as Janus kinase-signal transducers and activators of transcription pathway and adhesion-related pathways, which may be involved in pathogenesis of PCNSL. In conclusion, this study identified novel tumor suppressor genes that may serve as therapeutic targets of PCNSL.

Stromal fibroblasts perform important roles in cancer development and progression. Overexpression of Twist1, a basic helix-loop-helix transcription factor, is often associated with aggressive behavior in many tumors. In this study, we investigated Twist1 expression patterns in gastric stromal fibroblasts and cancer cells using a monoclonal Twist1 antibody after validating the effectiveness of four commercial Twist1-specific antibodies. Twist1 expression was more frequently observed in gastric cancer-associated fibroblasts (CAFs) than in other cancer cells but was otherwise rarely expressed in noncancerous tissue. In laser capture microdissection of stromal fibroblasts, Twist1 immunopositive fibroblasts exhibited significantly increased Twist1, fibroblast-specific protein 1, and CXCL14 mRNA expression. Furthermore, Twist1 mRNA expression showed a significant linear correlation with that of platelet-derived growth factor receptors β and α. We found that conditioned media from Twist1-expressing skin and lung fibroblasts significantly promote invasion of gastric cancer cells in vitro. In 195 gastric cancer samples, CAF Twist1 expression was associated with tumor size, invasion depth, and lymph node metastasis. Twist1 was also associated with poor prognosis in patients with gastric cancer, particularly in those with the diffuse type. In conclusion, CAFs in gastric cancer frequently have altered Twist1 expression, and increased Twist1 expression in fibroblasts contributes to the progression of cancer cells and poor patient survival.

A 46-year-old woman presented with whole abdominal discomfort, and imaging revealed a 3-cm-sized ill-defined ovarian mass with extensive peritoneal carcinomatosis. Histologic examination showed malignant fibrous histiocytoma of ovary with predominant myxoid stroma. Microscopic examination showed a highly cellular neoplasm composed of fibroblast-like cells with a predominant myxoid stroma and high pleomorphism and mitotic activity. Immunohistochemically, the tumor was negative for smooth muscle actin, desmin, S-100, pancytokeratin, c-kit, epithelial membrane antigen, and calretinin. Malignant fibrous histiocytoma of ovary is extremely rare, with only six previously reported cases. To the best of our knowledge, the myxoid type of malignant fibrous histiocytoma of ovary has not been previously reported in the English literature except for a case arising in a dermoid cyst of ovary. We present the case and briefly discuss the differential diagnosis.

Twist1 is known to be involved in epithelial-mesenchymal transition (EMT) and tumor progression. However, its specific role is different depending on the type of cancer. The functional role and clinical significance of Twist1 in esophageal squamous cell carcinoma (ESCC) have been rarely studied.We examined Twist1 expression in a total of 199 samples using immunohistochemistry and real-time reverse-transcription polymerase chain reaction (RT-PCR). We also studied the association of Twist1 with EMT of ESCC using tissue samples and in vitro models. In addition, we examined the changes in the whole-genome expression profiles of two ESCC cell lines after inducing upregulation of Twist1.Twist1 expression was increased in ESCC compared with that of normal esophagus (P 0.01). We found that expression of Twist1 was strongly associated with poor prognosis on both univariate analysis [relative risk (RR) = 3.019, P = 0.000] and multivariate analysis (RR = 3.131, P = 0.000). In addition, we found that Twist1 expression was strongly correlated with EMT in ESCC tissues. Upregulation of Twist1 induced other EMT inducers in all three esophageal cancer cell lines investigated (TE1, TE8, and TE10). Twist1 also enhanced the migratory and invasive abilities of all three cell lines. Finally, microarray analysis of gene expression in the three ESCC cell lines revealed that Twist1 upregulation affected the expression of mainly cytoskeleton and extracellular matrix-related genes, which are directly related to cell morphology and movement.Our study indicates that Twist1 is associated with EMT of esophageal squamous cell carcinoma and may be used as a diagnostic and prognostic biomarker in ESCC.

Claudin-7 (CLDN-7) is a tight junction protein that has been shown overexpressed in several human cancers. We investigated prognostic significance of CLDN-7 overexpression in patients with epithelial ovarian carcinoma (EOC) and its functional role on cell proliferation in ovarian carcinoma cell lines.CLDN-7 expression was evaluated by real-time RT-PCR and immunohistochemical analysis in 71 patients with EOC. We assessed the association of CLDN-7 expressions with prognosis of the patients including sensitivity to platinum-based chemotherapy. In vitro experiment was performed with and without inhibition of CLDN-7 by its siRNA to evaluate the sensitivity of the human ovarian cancer cells to cisplatin chemotherapy.CLDN-7 transcripts in EOCs were significantly up-regulated compared with normal ovarian tissues (P0.001). The expression of CLDN-7 protein was observed in majority (69/71, 97.1%) of the EOCs but not in normal ovarian tissues (P0.001). High CLDN-7 expression in primary tumour correlated with shorter progression-free survival (PFS) of the patients (P=0.005) and poor sensitivity to platinum-based chemotherapy (P=0.024). Moreover, CLDN-7 was highly expressed in 2774 and HeyA8 human ovarian cancer cells and inhibition of CLDN-7 by its siRNA significantly enhanced the sensitivity of 2774 and HeyA8 cells to cisplatin treatment.These findings suggest CLDN-7 expression is an independent prognostic factor for PFS and it may play a role in regulating response to platinum-based chemotherapy in the treatment of EOC.

Objective Hypoxia has been established as a key factor influencing the pathophysiology of malignant growth. Hypoxia-induced changes in gene expression are coordinated primarily by hypoxia inducible factor-1 alpha (HIF-1α) and HIF-2α. The purpose of this study was to determine whether or not HIF-2α expression is associated with survival and response to radiation in patients with cervical cancer. Methods After reviewing the medical records of 119 patients treated in our institution by primary therapy for stage IIB-IVA cervical cancer, we performed a case-control study. Cases (n=12) were selected from patients with local recurrence or radiation failure after primary radiation therapy with or without concurrent chemoradiation. For each case, we selected two controls from patients who had no evidence of local recurrence. Using pre-treatment paraffin-embedded tissues, we evaluated the expression of HIF-2α by immunohistochemistry. Staining was scored based on intensity (intensity score [IS], 0-3) and proportion (proportion score [PS], 0-100). The results were analyzed by the Student t-test, Mann-Whitney U test, Fisher's exact test, and Cox proportional hazards regression model. Results Cytoplasmic expression of HIF-2α, representing the degree of hypoxia, had a relationship with poor response to radiotherapy. The hazard ratio of recurrence was 1.71 for the HIF-2α IS (p=0.110) and 1.04 for the HIF-2α PS (p

Despite the usefulness of Pap tests for cancer screening, outcomes can be difficult to predict when atypical squamous cells (ASCs) are identified. According to the 2001 Bethesda system, ASCs can be subdivided into two groups: ASCs of undetermined significance (ASC-US); and ASCs, cannot exclude high-grade squamous intra-epithelial lesion (ASC-H). ASC-H interpretations are uncommon, and studies involving this type of lesion are based on small numbers of cases.Cross-sectional, retrospective study of 392 ASC-H cases. The follow-up outcomes of ASC-H cases that were diagnosed during routine primary screening between 2002 and 2008 were investigated, and relationships between clinicopathological parameters were assessed, particularly positive test for high-risk HPV (HPV) DNA, patient age at diagnosis and previous abnormal cytology.Of the 392 cases, high-grade squamous intra-epithelial lesion (HSIL) was detected in 111 (28.3%) cases, squamous cell carcinoma was detected in 15 (3.8%) cases, low-grade squamous intra-epithelial lesion was detected in 37 (9.4%) cases, reactive change was detected in 178 (45.4%) cases, atrophy was detected in 47 (12.0%) cases, and adenocarcinoma was detected in four (1.0%) cases. The prevalence of HSIL or greater was 27.8% for women aged ≥ 40 years, and 52.3% for women aged40 years (p0.001). HPV positivity in ASC-H smears was significantly associated with HSIL or greater, irrespective of age (40 years, p=0.003; ≥ 40 years, p0.001). ASC-H with previous abnormal cytology greater than ASC-US showed a significantly higher detection rate for HSIL or greater at follow-up (p0.001).Patient age, positive HPV DNA test and previous abnormal cytology are useful predictors of underlying HSIL or greater in women with ASC-H.