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AimsChronic inflammation and cancer stem cells are known risk factors for tumorigenesis. The aetiology of hepatocellular carcinoma (HCC) involves a multistep pathological process characterised by chronic inflammation and hepatocyte damage but the correlation between HCC, inflammation and cancer stem cell remains unclear. In this study, we examined the role of hepatic progenitor cells in a mouse model of chemical-induced hepatocarcinogenesis to elucidate the relationship between inflammation, malignant transformation and cancer stem cells.Methods and resultsWe used diethylnitrosamine (DEN) to induce liver tumour and scored for H&E and reticulin staining, and also immunohistochemistry staining for OV-6 expression and analysed the statistical correlation between each other. DEN progressively induced inflammation at 7 week 7 (40%, 2/5), week 27 (75%, 6/8), week 33 (62.5%, 5/8) and week 50 (100%, 12/12). DEN progressively induced malignant transformation at week 7 (0%, 0/5), week 27 (87.5%, 7/8), week 33 (100%, 8/8) and week 50 (100%, 12/12). Data obtained showed that DEN progressively induced high-levels of OV-6 expression at week 7 (20%, 1/5), week 27 (37.5%, 3/8), week 33 (50%, 4/8) and week 50 (100%, 12/12). DEN-induced inflammation, malignant transformation and high-level OV-6 expression in hamster liver as shown above and applying Spearman’s correlation to the data showed that expression of OV-6 was significantly correlated to inflammation (p = 0.001) and malignant transformation (p < 0.001)ConclusionsThere was a significant correlation between number of cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis in the hamster.

The concurrent occurrence of thymoma and diffuse large B-cell lymphoma in the thymus has not been previously reported. We describe a 74-year-old man who presented with general weakness, neck lymphadenopathy, night sweats, and body weight loss. A right anterior mediastinal mass was found on computed tomography of the chest. The immunohistochemical stains AE1/AE3, CD20, CD3, and MUM-1 confirmed the different components of the mediastinal tumor. A heavy-chain gene clonality assay and light-chain gene clonality assay confirmed the B-cell clonality of the mediastinal tumor and neck lymph node. The patient had received a complete course of chemotherapy, and the result of positron emission tomography–computed tomography showed complete remission. The pathologic report of this mass revealed composite type A thymoma and diffuse large B-cell lymphoma. If concurrent or composite thymoma and lymphoma are suspected, a thorough examination of the thymoma with a combination of ancillary studies is recommended to rule out the possibility of concurrent lymphoma.

Expressions of human p16 and p27 were tested for correlations with clinicopathologic features of urothelial carcinoma (UC). Tissue microarrays (TMA) constructed from paraffin-embedded specimens from 78 patients with UC were analyzed by immunohistochemical staining. In 49 of the 78 tumors (63%), high p16 expression was associated with absence of tumor invasiveness and low-grade carcinoma (p = 0.003 and p = 0.046, respectively). The p27 expression was high in 33 of the 78 tumors (42%) and showed a significant negative association with invasiveness, carcinoma grade, and tumor size (p = 0.016, p = 0.046, and p = 0.014, respectively). Kaplan–Meier analysis indicated that patients with high p27 levels had longer than average overall survival (p = 0.021). This study demonstrates that p16 and p27 are prognostic indicators of tumor stage and grade in UC and that they provide clinicians with the ancillary information needed for selecting suitable therapeutic strategies.

Cholesteatoma is a destructive and expanding growth of keratinizing squamous epithelium in the middle ear or petrous apex. The molecular and cellular processes of the pathogenesis of acquired middle ear cholesteatoma have not been fully understood. In this study, comparative proteomic analysis was conducted to investigate the roles of specific proteins in the pathways regarding keratinocyte proliferation in cholesteatoma. The differential proteins were detected by comparing the two-dimension electrophoresis (2-DE) maps of the epithelial tissues of 12 attic cholesteatomas with those of retroauricular skins. There were 14 upregulated proteins in the epithelial tissues of cholesteatoma in comparison with retroauricular skin. The modulation of five crucial proteins, HSP27, PRDX2, GRP75, GRP78 and GRP94, was further determined by RT-PCR, Western blot and immunohistochemistry. Phosphorylation of HSP27 at Ser-82 was identified by mass spectroscopy. The results of this study suggested that phosphorylated HSP27 is the end expression of two potential signal-transduction pathways, and together with PRDX2, they are very likely involved in the proliferation of keratinocytes in cholesteatoma. Upregulations of GRP75, GRP78 and GRP94 in keratinocytes may be able to counter endoplasmic reticulum stress, to inhibit cell apoptosis, to prevent protein unfolding and to promote cholesteatoma growth.

This study explored the potential role of deleted in liver cancer-1 (DLC-1) as a prognostic indicator of cancer metastasis and survival in urothelial carcinoma (UC). Tissue microarrays were constructed from paraffin-embedded specimens from 88 UC patients, and immunohistochemical staining was performed to investigate the association of DLC-1 with clinicopathologic characteristics and clinical outcome. The DLC-1 expression showed a significant positive correlation with tumor location (p = 0.041) and a significant negative correlation with advanced histological grade (p = 0.013). In tumors with low DLC-1 expression, Bcl-2 positivity was observed in 24.4% of cases. The DLC-1 expression had significant negative associations with Bcl-2 expression (p = 0.032) and with highly metastatic UC (p = 0.032). Kaplan-Meier analysis showed that DLC-1 protein expression was negatively associated with both overall survival (OS) (p = 0.035) and with distant metastasis-free survival (DMFS) (p = 0.041), but not with disease-free survival. Multivariate analyses indicated that tumor size was the significant independent predictors of OS (p = 0.048); however, only DLC-1 expression was a significant independent predictor of DMFS (p = 0.019). In conclusion, reduced DLC-1 protein expression may be an important factor in tumor progression and a useful prognostic molecular marker in UC.

Objectives/Hypothesis: The mechanisms of cholesteatoma proliferation and growth remain unclear. The objective of this study is to discover the potential mechanisms of the proliferation and growth of cholesteatoma by direct experimental assessments on cholesteatoma tissues from patients. Study Design: Retrospective study by the comparisons between cholesteatoma tissues and retroauricular skin tissues from the patients. Methods: Two-dimensional gel electrophoresis, LC-MS/MS analysis and immunohistochemistry were performed to investigate specific protein expression in cholesteatoma tissues compared with retroauricular skin tissues collected from the patients. Western blotting analysis was conducted to verify the regulation of specific proteins found by 2-DE, and to determine the changes of associated potential modulators in cholesteatoma proliferation and growth. Results: Twelve serpin B3 isoforms were found by 2-DE and identified by LC-MS/MS analysis, which is coherent with the results exhibited by immunohistochemistry and western blot. Up-regulation of STAT3 and down-regulations of cathepsin K and cathepsin L were represented using western blot. Conclusions: The data in this study suggested serpin B3, STAT3, cathepsin K, and cathepsin L are associated with the proliferation and growth of cholesteatoma, and these proteins may be influential factors in cholesteatoma growth. Laryngoscope, 2012

Arsenic, a known human carcinogen, is found throughout the crust of the earth. Prolonged arsenic exposure is a known cause of urothelial carcinoma (UC) and blackfoot disease (BFD). The aim of this study was to determine the effect of sodium arsenite on Caveolin-1 and downstream signaling molecules (eNOS, IKKβ and COX-2) expression in human urothelial cells (SV-HUC-1). Immunohistochemical (IHC) staining of Caveolin-1, eNOS, IKKβ, and COX-2 was also compared between UC patients from endemic and non-endemic areas of BFD in Taiwan. Immunocytochemical staining and Western blotting results revealed increased expression of Caveolin-1, IKKβ, and COX-2 but decreased eNOS in SV-HUC-1 cells treated with low concentration of arsenite. Additionally, MEK inhibitor (U0126) significantly attenuated arsenite-induced expression of Caveolin-1, IKKβ and COX-2 while reducing eNOS expression. The IHC staining of UCs revealed that expressions of Caveolin-1, IKKβ, and COX-2 were significantly higher in patients from endemic areas of BFD compared to patients from non-endemic areas (p=0.011, p=0.002, p=0.0001) whereas eNOS was significantly lower (p=0.0001). The correlation observed between Caveolin-1 and downstream signaling molecule expression may be an important mechanism of arsenic-induced urothelial carcinogenesis.

This study is to characterize the sequential change in CD133 expression after preoperative chemoradiotherapy (CRT) in rectal cancer and its impact on postoperative prognosis. Forty-one patients with rectal cancer who had received CRT before surgery were selected retrospectively. In each case, immunohistochemical analysis was performed to compare CD133 expression in biopsy specimens taken before and after CRT. After CRT, CD133 expression was significantly increased in 14 (34%) patients, mildly increased in 25 (61%), and decreased in 2 (5%). However, no mucin-rich tumors showed high CD133 expression before or after CRT (p < 0.001). Disease-free survival and overall survival were significantly poorer in patients with significantly increased CD133 (p = 0.049 and p = 0.038, respectively). Increased CD133 after CRT is a significant prognostic factor in rectal cancer patients treated with preoperative CRT and surgical resection. CD133 might be an essential cancer stem cell marker.

Breast cancer has become the second leading cancer among females in Taiwan. Even though the etiology of breast cancer is multifactorial, oxidative stress plays an important role in the carcinogenesis. The purpose of this study was to investigate the expression of manganese superoxide dismutase (MnSOD), one of the major antioxidant enzymes that is involved against oxidative stress, in adjacent cancer-free breast tissues and neoplasm tissues within the same patient. Sixty-five breast cancer patients’ formalin-fixed tissue blocks, including ductal carcinoma in situ (DCIS) tissues, invasive ductal carcinoma (IDC) tissues, and adjacent cancer-free tissues, were evaluated by immunohistochemical stain. Meanwhile, their demographic and clinical information was also collected. The combined scores of MnSOD-positive cell proportion and MnSOD staining intensity were compared for different tissues within the same patient. The results showed that the mean combined scores of MnSOD expression in adjacent cancer-free tissues (6.33), IDC (5.30), and DCIS (3.78) were significantly different when assessed by repeated-measurement analysis of variance (F=14.17, p

This study examines whether the expression of cyclooxgenase-2 (COX-2) in urothelial carcinoma (UC) is associated with macrophage infiltration, hypoxia-inducible factor-1alpha (HIF-1alpha) expression and angiogenesis. We investigated the expression of COX-2 associated with HIF-1alpha and performed double immunohistochemical analysis of 216 UCs for COX-2 expression and the correlation with tumor-associated-macrophage (TAM) density and microvessel density (MVD) in situ. A high expression of COX-2 was positively correlated with tumor invasiveness, histologic grade and HIF-1alpha expression in UC (p

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. Patients with HCC usually have poor prognosis and high mortality. It has been shown that carcinoembryonic antigen-related cell adhesion molecule 1 (CD66a) regulates cell signaling, proliferation, and tumor growth. The aim of this study is to analyze the expression and possible role of CD66a in HCC. Immunohistochemical staining of CD66a was performed on 86 HCC cases, and microvessel density was evaluated by CD34 immunostaining. The results were further correlated with clinicopathological parameters. For 47 of 86 HCC cases, the CD66a expression showed diffuse membrane or cytoplasmic staining. The other 39 HCC cases revealed loss of CD66a expression. Loss of CD66a expression was statistically significantly associated with large tumor size (p=0.016), fatty change (p=0.039), patients with transcatheter arterial embolization (p=0.007), and high microvessel density (p=0.036). CD34 expression had no significant association with tumor size, virus infection, histological grade, and capsular invasion. The diffuse and cytoplasmic expression of CD66a may involve the early stage of the HCC, and the loss of CD66a expression indicates tumor progression.

Recent molecular and pathological studies suggest that endometriosis may serve as a precursor of ovarian cancer (endometriosis-associated ovarian cancer, EAOC), especially of the endometrioid and clear cell subtypes. Accordingly, this study had two cardinal aims: first, to obtain mutation profiles of EAOC from Taiwanese patients; and second, to determine whether somatic mutations present in EAOC can be detected in preneoplastic lesions. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from ten endometriosis patients with malignant transformation. Macrodissection was performed to separate four different types of cells from FFPE sections in six patients. The four types of samples included normal endometrium, ectopic endometriotic lesion, atypical endometriosis, and carcinoma. Ultra-deep (1000×) targeted sequencing was performed on 409 cancer-related genes to identify pathogenic mutations associated with EAOC. The most frequently mutated genes were PIK3CA (6/10) and ARID1A (5/10). Other recurrently mutated genes included ETS1, MLH1, PRKDC (3/10 each), and AMER1, ARID2, BCL11A, CREBBP, ERBB2, EXT1, FANCD2, MSH6, NF1, NOTCH1, NUMA1, PDE4DIP, PPP2R1A, RNF213, and SYNE1 (2/10 each). Importantly, in five of the six patients, identical somatic mutations were detected in atypical endometriosis and tumor lesions. In two patients, genetic alterations were also detected in ectopic endometriotic lesions, indicating the presence of genetic alterations in preneoplastic lesion. Genetic analysis in preneoplastic lesions may help to identify high-risk patients at early stage of malignant transformation and also shed new light on fundamental aspects of the molecular pathogenesis of EAOC.Molecular characterization of endometriosis-associated ovarian cancer genes by targeted NGS. Candidate genes predictive of malignant transformation were identified. Chromatin remodeling, PI3K-AKT-mTOR, Notch signaling, and Wnt/β-catenin pathway may promote cell malignant transformation.

BackgroundThe protein anillin (ANLN) has important roles in cell cytokinesis. Until now, no studies have evaluated the role of ANLN expression in a large cohort of patients with urothelial carcinoma of the upper urinary tract (UCUT).MethodsThis study analysed 156 cases of primary localised UCUT. Pathological slides were reviewed and clinical findings were collected. An immunohistochemical study was performed and the cytoplasmic and nuclear staining results of UCUT were recorded. Expressions of ANLN were analysed to identify correlations with various clinicopathological parameters, disease-specific survival (DSS) and metastasis-free survival (MeFS).ResultsOverexpression of ANLN in the nucleus had significant positive associations with tumour stage (p=0.017), histological grade (p=0.040), mitotic count (p=0.023), tumour necrosis (p=0.009), invasion patterns (pConclusionsSubcellular localisation of ANLN is correlated with different tumour phenotypes and probably confers different tumorigenicity. Since high nuclear expression of ANLN is also an independent predictor of poor DSS, it is a useful prognostic marker of UCUT.

The aim of our study was to analyze the expression and possible role of CD66a in colorectal adenoma and adenocarcinoma and the relationship between its expression and pre-operation serum carcinoembryonic antigen (CEA) level and tumor stage in patients with colorectal adenocarcinomas.Paraffin-embedded sections from 184 patients including 42 colorectal adenomas with low-grade dysplasia, 43 adenomas with high-grade dysplasia, and 99 adenocarcinomas were collected for this study. Immunohistochemical analysis was performed, and the expression and the location of CD66a were evaluated and were correlated with beta-catenin nuclear expression.The expression of CD66a was found not only in the apical membrane of neoplastic glands but also in secretion within the lumen of the neoplastic glands including adenomas and adenocarcinomas. Expressions of secreted CD66a were of higher level in adenocarcinoma than in adenoma with high-grade dysplasia and adenoma with low-grade dysplasia (p0.0001). High expression of secreted CD66a was also associated with tumor stage, invasion, and pre-operation serum CEA level of patients with colorectal adenocarcinoma.This study implied that CD66a can function both as an epithelial cell adhesion protein or alternatively as secreted CD66a. In addition, a high expression of CD66a was significantly correlated with tumor invasion, stage, and pre-operation serum CEA level.

Differential diagnosis of follicular adenoma (FA) and follicular carcinoma (FC) of the thyroid can be difficult in the routine practice of surgical pathology because the diagnosis of FC is strictly defined and determined by the presence of capsular and/or vascular invasion by the tumor. These features may be equivocal in the histologic sections. On the other hand, telomerase is expressed in many human cancers and is thought to contribute to their immortality. Human telomerase reverse transcriptase (hTERT) is the major determinant of human telomerase activity, and its expression is suggestive of capacity for unlimited replication. This case-control study examined the expression of hTERT using immunohistochemistry in 36 thyroid FC and 36 FA from patients who were matched by age and sex. The aim was to investigate the value of immunohistochemical staining for hTERT in the differential diagnosis of follicular neoplasms. The results revealed 23 cases of FC and 14 cases of FA that showed high expression of hTERT, with moderate to strong immunoreactivity. The remaining cases showed weak or negative staining. The difference between FA and FC was statistically significant (p < 0.05). In conclusion, immunohistochemical staining for hTERT can be considered an ancillary marker for differential diagnosis of FA and FC.

Background: Tuberculosis presenting as an isolated liver tumour, without active pulmonary or miliary tuberculosis, or other clinical evidence of tuberculosis, is distinctly rare. A greater awareness of this rare clinical entity may prevent needless surgical intervention. Aims: To help characterise this distinctly rare presentation of tuberculosis, five new cases are presented, together with a review of the world literature. The clinical, laboratory, radiological, and pathological features of these patients are described. Methods: Polymerase chain reaction (PCR) assay of the liver tissue was carried out in all cases to confirm an aetiological diagnosis of Mycobacterium tuberculosis infection. Results: All five patients (44–71 years old; two women, three men) underwent surgery, and had a preoperative diagnosis of malignant hepatic neoplasm and a postoperative histological diagnosis of chronic granulomatous inflammation, suggestive of tuberculosis. None of them had a known previous history of tuberculosis. All of them were positive for M tuberculosis by PCR analysis of the liver tissue. Conclusions: This report illustrates the difficulty in reaching a correct preoperative diagnosis. It is usually unsuspected and confused with primary or metastatic carcinoma of the liver, especially when it coexists with other malignancies. A high index of suspicion is required for diagnosis, which can be made only by histological and bacteriological studies, and PCR analysis.

Background Type 2 diabetes mellitus (DM), characterized by peripheral insulin resistance, is the most common form of diabetes. Probiotics are live micro-organisms that, when administered in adequate amounts, confer delaying effect on DM development. In this study, the effects Lactobacillus reuteri GMNL-263 (Lr263), a new probiotic strain developed by our laboratory, on insulin resistance and the development of hepatic steatosis in high-fructose fed rats were explored. Furthermore, the relevant regulatory pathways involved were also investigated. Method Male Sprague–Dawley rats were fed a high-fructose diet with or without Lr263 administration for 14 weeks. The composition of fecal microbiota, oral glucose tolerance, glycated haemoglobin, insulin, leptin, C-peptide, and incretins were measured. The markers of liver injury, serum and hepatic lipids profile, activity of hepatic antioxidant enzyme, and proinflammatory cytokines in adipose tissue were investigated. Additionally, the expression of hepatic lipogenic genes and insulin signaling related genes in adipose tissue were also studied. Liver sections were examined for hepatic steatosis using hematoxylin-eosin staining. Results The levels of serum glucose, insulin, leptin, C-peptide, glycated hemoglobin, GLP-1, liver injury markers, lipid profile in serum and liver were significantly increased in high-fructose-fed rats. However, after Lr263 administration, the elevation of these parameters was significantly suppressed. Feeding of Lr263 reversed the decreased number of bifidobacterium species and lactobacillus species and increased number of clostridium species induced by high fructose treatment. The decreased activities of hepatic antioxidant enzymes in HFD rats were dramatically reversed by Lr263 treatment. Concentrations of IL-6 and TNF-α in adipose tissue which were elevated in high fructose treatment were markedly decreased after Lr263 feeding. Decreased levels of PPAR-γ and GLUT4 mRNA after high fructose treatment were significantly enhanced by Lr263 administration. Lr263 consumption normalized the increased lipogenic gene (Srebp-1c, FAS, and Elvol6) expressions stimulated by high fructose. Administration of Lr263 significantly ameliorated hepatic steatosis observed in high fructose treated rats. Conclusion Our study provided evidences clarifying the effectiveness of Lr263 on reducing insulin resistance as well as hepatic steatosis formation in high-fructose-fed rats and suggested that Lr263 may be a promising therapeutic agent in treating type 2 diabetes.

Polymorphous low-grade adenocarcinoma (PLGA) is a rare tumour that mostly affects oral minor salivary glands. Our review of the literature found that there are only two reported cases of PLGA originating in the nasopharynx. Another nasopharyngeal PLGA in a 14-year-old boy is reported, focusing on the histopathological features and ultrastructural findings.

Alteration of the suppressor of cytokine signalling-3 (SOCS-3) has been observed in certain human cancers. However, the clinical role of this short-lived protein in hepatocellular carcinoma (HCC) is not well established. Therefore, we aimed to explore the potential role of SOCS-3 proteins in HCC.Paraffin embedded sections from 87 HCC patients were included in this study. The expression patterns of SOCS-3 proteins were analysed using immunohistochemistry and the results were correlated with clinicopathological characteristics and overall survival of the HCC patients.The SOCS-3 expression of HCC lesions and the adjacent non-tumourous liver tissues was significantly correlated (p = 0.035), while the SOCS-3 expression in HCC lesions was significantly and positively correlated with vascular invasion and histological grading (p = 0.034 and 0.032, respectively). The Kaplan-Meier survival curve showed that the HCC patients with high SOCS-3 expression were associated with a poor overall survival rate in the HCC subgroup with positive vascular invasion (p = 0.014). Furthermore, a multivariate Cox regression model showed that SOCS-3 expression was also a significant determinant of the overall survival for HCC (p = 0.006).Our results indicate that altered SOCS-3 expression is associated with the overall survival in a subset of HCC patients with positive vascular invasion. Constitutive and altered SOCS-3 expression may have potential roles in a subset of HCC patients.

Background Previous reports regarding the rates at which various internal tumors metastasize to the skin have been limited and have only included the Caucasian population. Moreover, the mechanisms that predispose certain internal malignancies to metastasize to the skin have rarely been discussed in the scientific literature. Objectives We determined the frequencies with which various internal malignancies metastasize to the skin in patients from a Taiwanese medical center. We also evaluated whether expressions of chemokine receptors CCR10 and CXCR4 by tumor cells correlate with cutaneous metastatic ability. Methods Clinical records from Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, during 20 years (1986-2006) were reviewed and cases of biopsy-proven primary internal malignancies and cutaneous metastases were identified. Immunohistochemical staining with antibodies to CCR10 and CXCR4 was performed on a selected number of internal malignancies with and without skin metastases. Results From 12,146 patients with internal malignancies, we found 124 cases (1.02%) with cutaneous metastases. The highest rates of skin metastases were found to occur from carcinoma of the breast, followed by the lung, oral mucosa, colon and rectum, stomach, and esophagus. However, the rate of cutaneous metastasis from breast cancer was much lower compared with previous studies involving Caucasians. In general, adenocarcinomas gave rise to cutaneous metastases at a higher frequency compared with other histologic subtypes. In addition, the expressions of CCR10 and CXCR4 by tumor cells did not correlate well with the presence or absence of skin metastases. Limitation This study is retrospective in nature. Conclusions Different internal malignancies metastasize to the skin with different frequencies, and the rates at which different malignancies metastasize to cutaneous sites differ between the Taiwanese and Caucasian populations. The mechanisms responsible for the cutaneous metastatic ability of certain malignancies likely involve factors other than chemokine receptors CCR10 and CXCR4, because their expressions by tumor cells are neither necessary nor sufficient for the formation of skin metastases.

Background Although eccrine poroma (EP) occurs preferentially in palmoplantar areas, pigmented variants of EP have not been documented on the palms and soles. Objectives We seek to confirm the notion regarding lack of pigmented EP on palmoplantar areas and determine whether the absence of pigmentation in palmoplantar EPs is due to lack of expression of melanocyte-stimulating cytokines by tumour cells. Methods We searched the PubMed and Web of Science databases (1966–2006) for reports of pigmented EPs. In addition, a total of 17 EPs were collected from our pathology department. The presence of melanin was examined with haematoxylin-eosin sections, and melanocyte colonization was shown by immunohistochemical stains for tyrosinase. In addition, immunohistochemical staining with antibodies to melanocyte-stimulating cytokines, including endothelin-1, stem cell factor, and nerve growth factor, was done on these tumours. Results A review of the literature revealed 15 pigmented EP reports, none of which were located in palmoplantar areas. Among 17 EPs collected from our pathology department, 7 occurred in palmoplantar areas and 10 in non-palmoplantar areas. Three of the palmoplantar EPs and three of the non-palmoplantar EPs showed positive staining with melanocyte-stimulating cytokines. However, none of the palmoplantar EPs contained melanocytes or melanin pigment, wheras the three non-palmoplantar EPs that stained positively with melanocyte-stimulating cytokines were colonized with melanocytes and showed pigmentation clinically. Conclusions The expression of melanocyte-stimulating factors by tumour cells is associated with melanocyte colonization in non-palmoplantar EPs but not palmoplantar EPs. Therefore, the presence of melanocyte-stimulating cytokines per se is not sufficient by itself to induce melanocyte colonization. Certain characteristics of palmoplantar skin, such as the dermal components of these anatomical sites, may play a role in inhibiting melanocyte colonization of EPs.

Jab1 is a coactivator of AP-1 transcription factor and the fifth subunit of the COP9 signalosome. This protein is a potential oncogene and is involved in the mediation of nuclear exportation and degradation of the tumor suppressor p27(Kip1). However, control of Jab1 gene expression and its de-regulation in cancer cells are largely unknown. In this study, we demonstrated that Jab1 is overexpressed in 53 (80.3%) of a series of 66 human breast tumor tissues. In addition, its expression is significantly correlated with HER-2/neu overexpression (P=0.0318). HER-2/neu-overexpressing MDA-MB-453 human breast cancer cells exhibited higher expression of Jab1 than that of MCF-7 breast cancer cells. Promoter activity assay suggested that HER-2/neu oncogene upregulated Jab1 via transcriptional activation. Inhibition of HER-2/neu activity by Herceptin or AG825 significantly attenuated Jab1 expression in HER-2/neu-overexpressing MDA-MB-453 cells. On the contrary, ectopic expression of HER-2/neu stimulated Jab1 expression in MCF-7 cells. Knockdown of Jab1 expression by siRNA resulted in p27(Kip1) upregulation and G1 growth arrest in Jab1-overexpressing MDA-MB-453 cells. Taken together, our results suggest that Jab1 is a downstream target for HER-2/neu and its overexpression is linked with HER-2/neu expression in breast cancer.

Aims: The mechanisms of urothelial carcinogenesis in areas highly contaminated with arsenic remain unclear. The aim was to determine whether hypermethylation of death-associated protein kinase (DAPK) gene is associated with chronic arsenic exposure. Methods and results: The frequency of aberrant promoter methylation of DAPK in 17 urothelial carcinomas from an arsenic-contaminated area and 21 urothelial carcinomas from a non-arsenic-contaminated area was determined by methylation-specific polymerase chain reaction. DAPK hypermethylation status was significantly higher in urothelial cancers arising in arsenic-contaminated areas when compared with tumours from patients from non-contaminated areas (P = 0.018). In the subset of patients from living environments which were contaminated with arsenic, there was a statistically significant association between DAPK hypermethylation and patient’s age, tumour invasiveness, histological grade and recurrence. This was not seen for urothelial carcinoma from patients from non-contaminated areas. A close correlation was also found between DAPK promoter methylation and low-intensity DAPK expression, as detected by immunohistochemistry (P = 0.037). Conclusion: Exposure to arsenic may induce DAPK promoter hypermethylation and inactivate the function of DAPK in urothelial carcinoma. This could prove to be a key molecular event contributing to the malignant phenotype of tumour arising in patients from arsenic-contaminated environments.

The clinical pathologic criteria for nuclear features of papillary thyroid carcinoma are subjective and sometimes cannot distinguish carcinoma from adenomatous goiter and follicular neoplasms. No single antibody has demonstrated high sensitivity or specificity in making these distinctions. Using quantitative analysis of immunohistochemical staining with D2-40, a recently available monoclonal antibody used as a lymphatic endothelial marker, we examined 72 cases of papillary carcinoma. Controls included 36 follicular adenomas, 36 follicular carcinomas, and 20 adenomatous goiters with papillary hyperplasia. Cytoplasmic D2-40 immunoreactivity was present in 60 of 72 papillary carcinomas, 2 cases of follicular adenoma and 2 cases of follicular carcinoma, whereas no adenomatous goiter or normal thyroid glands contained positive epithelial cells. Overexpression of D2-40 in papillary thyroid carcinomas thus has potential diagnostic utility in differentiating these tumors from their potential histologic mimics.

Prurigo nodularis is an intensely pruritic dermatosis characterized by lichenified and excoriated papules and nodules. The course of prurigo nodularis is often chronic, and some patients respond very poorly to the standard therapeutic modalities. Because the pathogenesis of this disease remains obscure, the treatment of prurigo nodularis can be disappointing and frustrating for both the patients and physicians. Thalidomide, a tumor necrosis factor-alpha antagonist, has been suggested as an alternative treatment option for recalcitrant prurigo nodularis. In the past, the regimen for treatment of prurigo nodularis often required thalidomide at 200 mg/day. We recruited patients with intractable prurigo nodularis and treated them with low-dose thalidomide. Six patients with idiopathic prurigo nodularis were successfully treated with low-dose thalidomide (50-100 mg/day) without clinical development of peripheral neuropathy. In summary, our preliminary results suggest that low-dose thalidomide may be a safe and effective treatment option for patients with recalcitrant idiopathic prurigo nodularis.

Background: Obesity is associated with several human malignancies, including hepatocellular carcinoma (HCC). This association may result from the deregulated expression of adipokines. Aims: To explore the potential role and the prognostic value of leptin receptor (Ob-R) in HCC. Methods: 66 patients with pathologically confirmed HCC were included in this study. Immunohistochemistry was used to evaluate the expression of Ob-R, microvessel density (MVD) and Ki-67 index in these patients. Eventually, the profiles of Ob-R expression, obtained by a semiquantitative scoring system, were further correlated with Ki-67 expression, intratumour MVD, clinicopathological characteristics and overall survival. Results: High Ob-R expression was seen in 53% of patients with HCC and was significantly correlated with intratumour MVD (high v low; 59.4 ?3.2) v 44.7 ?3.7); p = 0.004), but not with Ki-67 expression. In addition, Ob-R expression was inversely correlated with vascular invasion (p = 0.037), but not with other known clinicopathological characteristics. The Kaplan–Meier survival curve showed that high Ob-R expression was associated with a better overall survival (p = 0.027). Meanwhile, multivariate analysis showed that Ob-R expression was a significant determinant for HCC (odds ratio 0.02, 95% confidence interval 0.01 to 0.85; p = 0.041). Conclusion: Ob-R expression may have a potential role in the carcinogenesis of HCC. The positive association of Ob-R expression in the cancerous lesions of HCC with the survival outcome can be explained by its inverse correlation with vascular invasion, and may have prognostic value in HCC.

Background: The objective of this study was to evaluate the relationship of HIF-1a expression and tumor angiogenesis, recurrence/distant metastasis, and its value in the prediction of aggressive behavior of gastrointestinal stromal tumor (GIST). Methods: Paraffin-embedded specimens from 62 patients with GIST were divided into two groups, low risk (n = 31) and high risk (n = 31) according to the tumor size, mitotic count and proliferating cell nuclear antigen (PCNA) index. We investigated the expression of the HIF-1a and analyzed correlation with tumor angiogenesis monitored by expression of vascular endothelial growth factor (VEGF) and tumor microvessel density using immunohistochemical staining. The data were analyzed with c 2 test or Fisher’s exact test and multivariate test. Results: There were statistically significant differences between high risk (29/31; 93.5%) and low risk (8/31; 25.8%) of GIST in high expression of HIF-1a (P < 0.0001). In addition, the incidence of recurrence/distant metastasis was significantly higher in cases of high HIF-1a expression (12/35; 34.3%) than in cases of low HIF-1a expression (1/24; 4.2%)(P = 0.009). Moreover, high VEGF expression (37/43; 86.0%) and microvessel density (30/32; 93.8%) were significantly higher in high HIF-1a expression tumors than in low-expression tumors (P < 0.0001). Conclusions: Our findings suggest that HIF-1a may play an important role in aggressive behavior and tumor angiogenesis in GIST. In addition, high expression of HIF-1a was significantly correlated with tumor recurrence/distant metastasis, so it may provide an ancillary prognostic factor for GIST.

Aims The sinonasal region is a frequent site for Epstein-Barr virus (EBV) related tumours, including nasopharyngeal carcinoma, sinonasal undifferentiated carcinoma and malignant lymphoma. Olfactory neuroblastoma is a rare neoplasm, arises from olfactory epithelium, is found in the upper nasal cavity, and may be confused morphologically with the above tumours. Our aim was to determine whether EBV is associated with olfactory neuroblastoma. Methods We collected tissue samples for 16 olfactory neuroblastomas over an 11-year period at Kaohsiung Medical University Hospital. Diagnoses were confirmed from pathological review and immunohistochemistry. We used in situ hybridisation for EBV encoded small RNAs in those tumours. Results None of the epithelial cells in the 16 cases of olfactory neuroblastoma was positive for EBV. Conclusions EBV does not play a major role in the aetiology of olfactory neuroblastoma.

Dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) are the spindle cell mesenchymal neoplasms of the dermis and subcutis. Their histogenesis still remains uncertain and controversial. Traditionally, CD34 and factor XIIIa or other markers have been widely used to distinguish these two diseases. However, the results of these markers reveal overlapping and they lack specificity. Formalin-fixed, paraffin-embedded blocks were collected from the biopsied cases in Kaohsiung Medical University Hospital in Taiwan between 2004 and 2006. This study included 19 cases of DF and 17 cases of DFSP. Immunohistochemical analysis using antibodies CD34, matrix metalloproteinases (MMP)-2, MMP-9, and MMP-11 was performed. We found that the expression of CD34, MMP-2 and MMP-11 shows significant statistical differences in Immunohistochemistry (IHC) study positive or negative reactivity (positive of CD34 in DFSP and positive of MMP-2 and MMP-11 in DF; p=0.03, p