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Supplementary Data from Homozygous Deletion of MTAP Gene as a Poor Prognosticator in Gastrointestinal Stromal Tumors

Purpose: Chromosome 9 is frequently deleted in high-risk gastrointestinal stromal tumors (GISTs), whereas its specific tumor suppressor genes (TSGs) are less understood. We did an integrative study of MTAP gene at 9p21 to analyze its implication in GISTs.Experimental Design: To search TSGs on chromosome 9, we used ultrahigh-resolution array comparative genomic hybridization to profile DNA copy number alterations of 22 GISTs, with special attention to MTAP gene. MTAP immunoexpression was assessable for 306 independent GISTs on tissue microarrays, with 146 cases analyzed for MTAP homozygous deletion, 181 for mutations of KIT and PDGFRA receptor tyrosine kinase genes, and 7 for MTAP hypermethylation.Results: Array comparative genomic hybridization identified 11 candidate TSGs on 9p and six on 9q. MTAP and/or CDKN2A/CDKN2B at 9p21.3 were deleted in one intermediate-risk (11) and seven high-risk (70) GISTs with two cases homozygously codeleted at both loci. MTAP homozygous deletion, present in 25 of 146 cases, was highly associated with larger size and higher mitotic rate, Ki-67 index, and risk level (all P < 0.01) but not with receptor tyrosine kinase genotypes. Whereas MTAP homozygous deletion correlated with MTAP protein loss (P < 0.001), 7 of 30 GISTs without MTAP expression did not show homozygous deletion, including three MTAP-hypermethylated cases. MTAP homozygous deletion was univariately predictive of decreased disease-free survival (P < 0.0001) and remained multivariately independent (P = 0.0369, hazard ratio = 2.166), together with high-risk category (P < 0.0001), Ki-67 index >5 (P = 0.0106), and nongastric location (P = 0.0416).Conclusions:MTAP homozygous deletion, the predominant mechanism to deplete protein expression, is present in 17 of GISTs. It correlates with important prognosticators and independently predicts worse outcomes, highlighting the role in disease progression. (Clin Cancer Res 2009;15(22):696372)

Introduction: Dysregulation of metal ion homeostasis is associated with urothelial carcinogenesis. From a published urinary bladder urothelial carcinoma (UBUC) transcriptome, we identified metallothionein 2A (MT2A) as the most significantly upregulated gene implicated in cancer progression among metal ion binding-related genes. Therefore, we analyzed the association between MT2A expression and clinical significance in our well-characterized cohort of patients with upper tract urothelial carcinoma (UTUC) and UBUC. Methods: We retrospectively reviewed the clinicopathological characteristics of 295 and 340 patients with UBUC and UTUC, respectively. MT2A expression was assessed using real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. We further correlated MT2A expression with clinicopathological factors, disease-specific survival (DSS) and metastasis-free survival (MFS) using the Pearson’s χ2 test, Kaplan-Meier analysis, and multivariate Cox proportional hazards model. Results: High MT2A expression was significantly associated with aggressive pathological features including high tumor stage, lymph node metastasis, high tumor grade, vascular invasion, and perineural invasion. In the Kaplan-Meier analysis, high MT2A expression was significantly correlated with poor DSS (p < 0.0001) and MFS (p < 0.0001); in the multivariate analysis, it was an independent predictor of CSS (p < 0.001) and MFS (p = 0.001). Gene coexpression analysis demonstrated that MT2A overexpression promotes UC progression through complement activation. Conclusion: High MT2A expression correlated with aggressive UC features and was an independent predictor of cancer metastasis and patient survival, suggesting its role in risk stratification and decision-making in patients with UTUC and UBUC.

Cell adhesion affects carcinogenesis, tumor progression, and metastasis. We datamined a published transcriptome (GSE12452) of nasopharyngeal carcinoma (NPC) and identified SSX2IP as a significantly upregulated gene in NPC carcinogenesis among genes associated with cell adhesion (GO:0007155). Consequently, we assessed SSX2IP protein expression and its prognostic significance in 124 patients with NPC using immunohistochemistry and the H-score method. The status of SSX2IP immunoexpression correlated with clinical and pathological characteristics, as well as oncological outcomes. High levels of SSX2IP expression were significantly associated with more advanced primary tumor and TNM stages. Kaplan-Meier and log-rank analyses revealed that high levels of SSX2IP expression, and advanced tumor stage and lymph node metastasis were significantly associated with lower rates of local recurrence-free survival (LRFS), distant metastasis-free survival (DMeFS), and disease-specific (DSS) survival. Multivariate analysis showed that high levels of SSX2IP expression significantly predicted DSS (hazard ratio [HR], 4.290; 95% confidence interval [CI], 2.271-8.102; p < 0.001), DMeFS (HR, 4.159' 95% CI, 2.072-8.345; p < 0.001), and LRFS (HR, 3.007' 95% CI,: 1.418-6.378; p = 0.004). We associated high levels of SSX2IP immunoexpression with aggressive pathological features and worse oncological outcomes, suggesting its potential therapeutic value for patients with NPC.

We investigated the association of receptor tyrosine kinase-like orphan receptor 2 (ROR2) expression with clinicopathological features and oncologic outcomes in large urothelial carcinoma (UC) of the upper tract (UTUC) and urinary bladder (UBUC) cohorts. Through transcriptomic profiling of a published dataset (GSE31684), ROR2 was discovered to be the most upregulated gene during UC progression, focusing on the JNK cascade (GO:0007254). Initially, the evaluation of ROR2 mRNA expression in 50 frozen UBUCs showed significantly upregulated levels in high-stage UC. Moreover, high ROR2 immunoexpression significantly correlated with high tumor stage, high tumor grade, lymph node metastasis, and vascular invasion (all p &lt, 0.05). In multivariate analysis, after adjusting for standard clinicopathological features, ROR2 expression status was an independent prognosticator of cancer-specific survival and metastasis-free survival in UTUC and UBUC (all p &lt, 0.01). In the subgroup analysis, it also significantly predicted bladder tumor recurrence in non-muscle invasive UBUC. Furthermore, the GO enrichment analysis showed that fatty acid, monocarboxylic acid, carboxylic acid metabolic processes, negative regulation of neutrophil migration, and negative regulation of granulocyte and neutrophil chemotaxis were significantly enriched by ROR2 dysregulation. In conclusion, high ROR2 immunoexpression was associated with aggressive pathological characteristics in UC and independently predicted worse prognosis, suggesting it could play roles in clinical risk stratification and therapy decisions.

Oral cancer (OC) is a serious health problem. Surgery is the best method to treat the disease but might reduce the quality of life of patients. Photodynamic therapy (PDT) may enhance quality of life but with some limitations. Therefore, the development of a new strategy to facilitate PDT effectiveness has become crucial. ATP-binding cassette G2 (ABCG2) is a membrane protein-associated drug resistance and stemness in cancers. Here, we examined whether ABCG2 plays an important role in regulating the treatment efficacy of PDT and whether ABCG2 inhibition by natural compounds can promote the effect of PDT in OC cells. Several head and neck cancer cells were utilized in this study. OECM1 and SAS cells were selected to investigate the relationship between ABCG2 expression and protoporphyrin IX (PpIX) accumulation. Western blot analysis, flow cytometry analysis, and survival probability were performed to determine PDT efficacy and cellular stemness upon treatment of different dietary compounds, including epigallocatechin gallate (EGCG) and curcumin. In this study, we found that ABCG2 expression varied in OC cells. Hypoglycemic culture for SAS cells enhanced ABCG2 expression as higher ABCG2 expression was associated with lower PpIX accumulation and cellular stemness in OC cells. In contrast, suppression of ABCG2 expression by curcumin and tea polyphenol EGCG led to greater PpIX accumulation and enhanced PDT treatment efficiency in OC cells. In conclusion, ABCG2 plays an important role in regulating the effect of PDT. Change in glucose concentration and treatment with natural compounds modulated ABCG2 expression, resulting in altered PDT efficacy for OC cells. These modulations raise a potential new treatment strategy for early-stage OCs.

Background CUL4A has been known for its oncogenic properties in various human cancers. However, its role in intrahepatic cholangiocarcinoma (iCCA) has not been explored. Methods We retrospectively investigated 105 iCCA cases from a single medical institution. Tissue microarrays were used for immunohistochemical analysis of CUL4A expression. CUL4A expression vectors were introduced in cell lines. Cell migration and invasion assays were used to compare the mobility potential of iCCA cells under basal conditions and after manipulation. Then we evaluated the effects of CUL4A on the cell growth by proliferation assay, and further checked the susceptibility to cisplatin in iCCA cells with or without CUL4A overexpression. Results CUL4A overexpression was detected in 34 cases (32.4%). Patients with CUL4A-overexpressing tumors exhibited shortened disease-free survival (mean, 27.7 versus 90.4 months; P = 0.011). In the multivariate analysis model, CUL4A overexpression was shown to be an independent unfavorable predictor for disease-free survival (P = 0.045). Moreover, stably transfected CUL4A-overexpressing iCCA cell lines displayed an increased mobility potential and enhanced cell growth without impact on susceptibility to cisplatin. Conclusions Our data demonstrate that overexpression of CUL4A plays an oncogenic role in iCCA and adversely affects disease-free survival. Thus, it may prove to be a powerful prognostic factor and a potential therapeutic target.

Objective: Neoadjuvant concurrent chemoradiotherapy (CCRT) is an increasingly common therapeutic strategy for locally advanced rectal cancer, but stratification of risk and final outcomes remain a major challenge. Transcobalamin 1 (TCN1), a vitamin B12 (cobalamin)-binding protein, regulates cobalamin homeostasis. High expression of TCN1 have been reported in neoplasms such as breast cancer and hepatocellular carcinoma. However, little is known about the relevance of TCN1 to rectal cancer receiving CCRT. This study examined the predictive and prognostic impact of TCN1 expression in patients with rectal cancer following neoadjuvant CCRT. Methods: Through data mining from a published transcriptome of rectal cancers (GSE35452), we identified upregulation of TCN1 gene as the most significantly predicted poor response to CCRT among ion transport-related genes (GO:0006811). We evaluated TCN1 immunohistochemistry and performed an H-score analysis on endoscopic biopsy specimens from 172 rectal cancer patients receiving neoadjuvant CCRT followed by curative surgery. Expression levels of TCN1 were further correlated with clinicopathologic features, therapeutic response, tumor regression grade (TRG) and survivals including metastasis-free survival (MeFS), disease-specific survival (DSS) and recurrent-free survival (LRFS). Results: TCN1 overexpression was significantly related to advanced post-treatment tumor (T3, T4; p

// Wei-Ming Li 1, 2, 3, 4 , Chun-Nung Huang 2, 3 , Hung-Lung Ke 2, 3 , Ching-Chia Li 2, 3, 5 , Yu-Ching Wei 6 , Hsin-Chih Yeh 2, 3, 5 , Lin-Li Chang 1, 7 , Chun-Hsiung Huang 1, 2, 3 , Peir-In Liang 8 , Bi-Wen Yeh 2, 3 , Ti-Chun Chan 9 , Chien-Feng Li 9, 10, 11, 12, 13 , Wen-Jeng Wu 1, 2, 3, 5, 14, 15, 16 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 3 Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan 5 Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan 6 Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan 7 Department of Microbiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 8 Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 9 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 10 Departments of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan 11 National Cancer Research Institute, National Health Research Institutes, Tainan, Taiwan 12 Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 13 Department of Internal Medicine and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 14 Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan 15 Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan 16 Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan Correspondence to: Chien-Feng Li, email: angelo.p@yahoo.com.tw Wen-Jeng Wu, email: wejewu@kmu.edu.tw Keywords: urothelial carcinoma, transcriptome, MCM10, prognosis Received: July 20, 2016 Accepted: October 12, 2016 Published: October 21, 2016 ABSTRACT Urothelial carcinoma (UC) occurs in the upper urinary tract (UTUC) and the urinary bladder (UBUC). The molecular pathogenesis of UC has not been fully elucidated. Through data mining of a published transcriptome of UBUC (GSE31684), we identified Minichromosome Maintenance Complex Component 2 ( MCM2 ) and MCM10 as the two most significantly upregulated genes in UC progression among the MCM gene family, the key factors for the initiation of DNA replication. To validate the clinical significance of MCM2 and MCM10, immunohistochemistry, evaluated by H-score, was used in a pilot study of 50 UTUC and 50 UBUC samples. Only a high expression level of MCM10 predicted worse disease-specific survival (DSS) and inferior metastasis-free survival (MeFS) for both UTUC and UBUC. Correspondingly, evaluation of MCM10 mRNA expression in 36 UTUCs and 30 UBUCs showed significantly upregulated levels in high stage UC, suggesting its role in tumor progression. Evaluation of 340 UTUC and 296 UBUC tissue samples, respectively, demonstrated that high MCM10 immunoexpression was significantly associated with advanced primary tumors, nodal status, and the presence of vascular invasion in both groups of UCs. In multivariate Cox regression analyses, adjusted for standard clinicopathological features, MCM10 overexpression was independently associated with DSS (UTUC hazard ratio [HR]=2.401, P = 0.013; UBUC HR=4.323, P=0.001) and with MeFS (UTUC HR=3.294, P

Purpose Inflammatory responses affect each stage of carcinogenesis, from initiation, through invasion, to metastasis. Studies have shown that chronic inflammation induced by environmental and occupational exposures increase the risk of developing urothelial carcinoma (UC). Using a published UC transcriptome (GSE32894), we identified that among genes associated with inflammatory response (GO:0006954), TNFAIP6 was significantly upregulated during UC progression. Therefore, we investigated the association of TNFAIP6 with disease features, metastasis and survival in our well-characterized cohort of UC. Methods We determined TNFAIP6 expression in 340 upper urinary tract UCs (UTUC) and 295 urinary bladder UCs (UBUC) using immunohistochemistry and evaluated the results using H-score. TNFAIP6 expression correlated with clinicopathological features, disease-specific survival, and metastasis-free survival. Survival analysis was performed using Kaplan–Meier curves and Cox proportional hazards model. Results High TNFAIP6 expression was significantly associated with advanced pathological stage, lymph node metastasis, perineural invasion, vascular invasion, and high mitotic activity. Multivariate analysis identified high TNFAIP6 expression as an independent predictor of disease-specific survival (hazard ratio in UTUC: 2.891, P = 0.003; in UBUC: 2.175, P = 0.017) and metastasis-free survival (hazard ratio in UTUC: 3.803, P Conclusion High TNFAIP6 expression is associated with aggressive clinicopathological features and poor prognosis in UCs, suggesting it may serve as a novel prognosticator and treatment target. TNFAIP6 immunostaining may be used with current pathological examinations for better risk stratification for UCs.

Primary adrenal non-Hodgkin lymphoma is an extremely rare disease confined wholly or chiefly to extranodal involvement. We report the case of an old woman who presented with progressive malaise and was diagnosed with primary adrenal diffuse large B-cell lymphoma pathology using laparoscopic adrenalectomy. Enhanced computed tomography and positron emission tomography revealed bilateral adrenal involvement.

Background and Objectives Urothelial carcinomas (UC) of urinary bladder (UB) and upper urinary tract (UT) are heterogeneous diseases with high morbidity and mortality. We looked for genes with metalloendopeptidase activity in a published UBUC transcriptomic database (GSE31684):MMP-11 was the most significant, showing stepwise up-regulation. We analyzed MMP-11 expression and association with clinicopathologic factors and survival in our well-characterized cohort of UCs. Methods We determined MMP-11 expression in 295 UBUCs and 340 UTUCs with immunohistochemistry, evaluated by H-score. In a retrospective study, MMP-11 expression was correlated with clinicopathologic features and with disease-specific survival (DSS) and metastasis-free survival (MeFS). The statistical significance was evaluated with univariate and multivariate analyses. Results High MMP-11 expression was significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular and perineural invasion, and frequent mitoses. In multivariate Cox regression analyses, which adjusted for standard clinicopathologic characteristics, MMP-11 expression was independently associated with cancer-specific mortality (hazard ratio [HR] in UTUC:3.027, P = 0.005; in UBUC: 2.631, P = 0.010) and with metastasis development (HR in UTUC:2.261, P = 0.018; in UBUC:1.801, P = 0.026). Conclusions MMP-11 overexpression is associated with aggressive tumor phenotype and unfavorable clinical outcome in UTUC and UBUC, suggesting it may serve as a novel prognostic and therapeutic target. J. Surg. Oncol. 2016;113:700–707. © 2016 Wiley Periodicals, Inc.

Yu-Ching Wei,1,2 Sheau-Fang Yang,2,3 Shih-Lun Chang,4,5 Tzu-Ju Chen,5,6 Sung-Wei Lee,7 Hung-Sung Chen,1 Li-Ching Lin,8 Chien-Feng Li6,9,10 1Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; 2Department of Pathology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 4Department of Otolaryngology, Chi Mei Medical Center, Tainan, Taiwan; 5Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan; 6Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan; 7Department of Radiation Oncology, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 8Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan; 9National Institute of Cancer Research, National Health Research Institute, Tainan, Taiwan; 10Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan Purpose: Nasopharyngeal carcinoma (NPC) is a heterogeneous disease. We searched for genes that function in cell adhesion in GSE12452, a published transcriptomic database. We found that POSTN, which encodes periostin (POSTN), was significantly upregulated in NPC tumorigenesis. Herein, we sought to analyze the expression of POSTN and its prognostic significances in patients with NPC. Materials and methods: In this single-institution retrospective study, we determined and analyzed POSTN expression by immunohistochemistry and H-score method, respectively, in 124 patients with NPC. The results indicated that POSTN expression was correlated with the clinicopathologic features, disease-specific survival (DSS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS) of NPC. We performed univariate and multivariate analyses to determinate the statistical significance. Results: High POSTN expression was significantly associated with lymph node metastasis (p=0.004) and advanced American Joint Committee on Cancer (AJCC) stage (p=0.006). In univariate analysis, high POSTN expression served as a significant prognostic factor for worse DSS (p=0.0002), DMFS (p=0.0138), and LRFS (p=0.0028). In multivariate Cox regression analyses, which was adjusted for AJCC stages, POSTN expression was independently associated with cancer-related death (HR: 2.311; 95% CI: 1.327–4.027; p=0.003) and local tumor recurrence (HR: 3.187; 95% CI: 1.108–4.408; p=0.024). Conclusion: High POSTN expression is associated with tumor aggressiveness and worse clinical outcomes in NPC, indicating that it may be a potential prognostic biomarker and a therapeutic target. Keywords: nasopharyngeal cancer, periostin, oncologic, outcomes

Insulin receptor substrate 2 (IRS2) is a candidate driver oncogene frequently amplified in cancer and is positively associated with IRS2 expression. The overexpression of IRS2 has been suggested to promote tumor metastasis. However, its function in intrahepatic cholangiocarcinoma (iCCA) has not been investigated extensively. The present study examined 86 cases of iCCA to analyze IRS2 expression and its correlation with clinicopathological characteristics using immunohistochemical assays. Three stable cell lines overexpressing IRS2 were established. The mobility potential of cells was compared in the basal condition and following manipulation using cell migration and invasion assays. Epithelial-mesenchymal transition (EMT)-associated proteins were assessed by western blotting. IRS2 was overexpressed in 29 iCCA cases (33.7%) and was significantly more frequent in cases with large tumor size (P=0.033), classified as an advanced stage by the American Joint Committee on Cancer (P=0.046). In comparison with the control cells, the three IRS2-overexpressing iCCA cell lines exhibited a statistically significant increase in mobility potential. Expression analysis of EMT markers demonstrated decreased epithelial marker levels and increased mesenchymal marker levels in IRS2-overexpressing cells compared with their corresponding control cells. The results of the present study indicate that IRS2 overexpression is characterized by a large tumor size and advanced tumor stage in iCCA, and that it may increase tumor mobility potential by regulating EMT pathways. Therefore, it is a valuable predictive indicator of metastasis and may provide a novel direction for targeted therapy in iCCA.

Cellular schwannoma is an uncommon variant of benign peripheral nerve sheath tumors, but is commonly misdiagnosed as malignant peripheral sheath tumor (MPNST). Conventional methods that are used to distinguish cellular schwannoma from MPNST include immunohistochemistry (IHC) staining. However, most markers cannot precisely differentiate these 2 tumor types, and thus identification of a better marker is needed to improve the accuracy of diagnosis. Here, we evaluate the use of chromodomain helicase DNA-binding protein 4 (CHD4) as a specific marker for cellular schwannoma by comparing CHD4 and S-100 IHC staining in 14 cellular schwannoma and 17 MPNST tissue samples. Our results indicated that nuclear CHD4 stains were in moderate-to-high in 94% MPNST (16 cases) and 93% cellular schwannoma (13 cases). However, cytoplasmic CHD4 stains were moderate-to-high in 93% cellular schwannoma (13 cases) but negative-to-weak in 100% MPNST (17 cases). In contrast, the S-100 stains were moderate-to-high in 86% of the cellular schwannoma (12 cases) and in 35% of the MPNST (6 cases). Taken together, the results indicated that different location of CHD4 staining is a potential biomarker to differentiate cellular schwannoma from MPNST.

Gemifloxacin is a common oral antibiotic for lower respiratory tract infection worldwide. We noticed an uncommon delayed onset skin rash in patients who received Gemifloxacin. Therefore, we retrospectively reviewed all patients who received Gemifloxacin from 1 January 2011 to 31 May 2016 in a university-affiliated hospital in Taiwan. A total of 1358 patients were enrolled, of whom 36 (2.65%) had skin eruptions. The female patients had a significantly higher odds ratio (OR) 2.24 (95% confidence interval (CI) 1.11&ndash, 4.53, p = 0.021) of having skin eruptions. A history of asthma was also a significant risk factor (OR 2.04, 95% CI = 1.01&ndash, 4.14, p = 0.043). Female asthmatic patients had the highest risk of skin eruptions (10/129, 7.2%) with an adjusted OR up to 4.45 (95% CI = 1.81&ndash, 10.93, p &lt, 0.001) compared to male and non-asthmatic patients. Of note, up to 58.3% (21/36) of the patients experienced a skin rash after they had completed and stopped Gemifloxacin. The median onset time was on the second day (ranging one to five days) after completing treatment. We reported that female asthmatic patients have the highest risk of Gemifloxacin-associated skin eruptions in Asia and that they highlighted a unique delayed onset skin rash.

Objectives To investigate the association of tumor location on oncological outcomes in patients treated with radical nephroureterectomy (RNU) for primary ureteral urothelial carcinoma (UC). Materials and methods From January 1990 to December 2007, 127 patients with primary solitary ureteral UC who underwent RNU at our institution were included. The patients were divided into 3 groups based on tumor location—proximal, middle, or distal ureter. Patients' medical records were reviewed retrospectively. The clinicopathologic data and oncologic outcomes were compared among the groups. Results Of the 127 patients, 40 (31.5%) had tumors in the proximal ureter, 40 (31.5%) in the middle ureter, and 47 (37.0%) in the distal ureter. Patients with distal ureteral UC were more likely to undergo open procedures to manage the bladder cuff (P = 0.005). Other clinical and histopathologic variables were not different among the 3 groups. Comparing the proximal, middle, or distal ureteral UC, bladder recurrence developed in, respectively, 25.0%, 25.0%, and 21.3% cases (P = 0.892); local retroperitoneal recurrence in 2.5%, 12.5%, and 4.3% (P = 0.141); contralateral recurrence in 0%, 0%, and 4.3%(P = 0.177); and distant metastasis in 17.5%, 10.0%, and 4.3% (P = 0.147). Recurrence-free and cancer-specific survival among the 3 groups were not different (P = 0.781 and 0.192, respectively). Conclusions Tumor location cannot be used to predict oncologic outcomes in patients treated with RNU for primary ureteral UC. Therefore, clinical decisions or follow-up protocol should not differ among patients with primary proximal, middle, or distal ureteral UC.

Combined hepatocellular carcinoma and cholangiocarcinoma (CHC) is a rare liver cancer which shares unequivocal features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). A greater awareness of genetic relationship between HCC and CC components is limited. To help characterize this rare liver neoplasm, we described clinicopathologic features and evaluated copy number (CN) changes in this study. A total of 13 cases of CHC were collected. Four paired HCC and CC components from four cases were first subject to genome-wide analysis. Nine target genes were subsequently selected for further analysis using quantitative polymerase chain reaction. The paired HCC and CC components in each case had a concordant trend of CN gain or loss in these nine genes. However, the magnitude of concordant CN gain or loss was different. There were significant differences of CN copies between HCC and CC in each case. We demonstrate genetic divergence between HCC and CC components in CHC.

Chen T-J, Huang S-C, Huang H-Y, Wei Y-C, Li C-F. Rsf-1/HBXAP overexpression is associated with disease-specific survival of patients with gallbladder carcinoma. APMIS 2011; 119: 808–14. Dysregulated chromatin remodeling often leads to abnormal gene expression or silencing in cells, thereby implicating tumor development and progression. As a subunit of remodeling and spacing factor (RSF) complex, Rsf-1, a novel nuclear protein with histone chaperon function, mediates ATPase-dependent chromatin remodeling and confer tumor aggressiveness in common carcinomas. We aimed, for the first time, to evaluate the Rsf-1 expression status and its associations with clinicopathological features and patient survival in a well characterized cohort of gallbladder carcinomas. Using tissue microarray-based immunohistochemistry, we assessed Rsf-1 expression in gallbladder carcinomas, yielding 88 cases undergoing surgical intervention with interpretable results. The Rsf-1 overexpression, present in 61 cases (69.3%), was significantly associated with higher histological grades (p = 0.002) and vascular invasion (p = 0.037) and marginally with non-papillary histotypes (p = 0.058). In univariate log-rank analysis, Rsf-1 overexpression was significantly predictive of disease-specific survival (p = 0.0015), which remained prognostically independent [p = 0.0191, risk ratio (RR) = 2.683], along with American Joint Committee on Cancer stages II–IV (p = 0.0265, RR = 2.102). Our findings indicate that Rsf-1 overexpression is common and associated with adverse prognosticators in gallbladder carcinomas. It may confer tumor aggressiveness through chromatin remodeling and represents a potential prognostic biomarker of gallbladder carcinomas.

Background There is a lack of consensus regarding the prognostic significance of different approaches to the bladder cuff at surgery for primary upper urinary tract urothelial carcinoma (UUT-UC). Objectives To compare the oncologic outcomes following radical nephroureterectomy using three different methods of managing the bladder cuff. Design, setting, and participants From January 1990 to December 2007, 414 patients with primary UUT-UC underwent radical nephroureterectomy at our institution. Of these, 301 were included in our study. Intervention Three methods of bladder cuff excision—intravesical incision, extravesical incision, and transurethral incision (TUI)—were performed. Measurements Patients' medical records were reviewed retrospectively. The clinicopathologic data and oncologic outcomes were compared among groups. Results and limitations Of the 301 patients, 81 (26.9%) underwent the intravesical method, 129 (42.9%) underwent the extravesical technique, and 91 (30.2%) underwent TUI. There were no differences in clinical and histopathologic data among the three groups. When comparing the intravesical, extravesical, and TUI techniques, bladder recurrence developed in, respectively, 23.5%, 24.0%, and 17.6% cases ( p =0.485); local retroperitoneal recurrence in 7.4%, 7.8%, and 5.5% ( p =0.798); contralateral recurrence in 4.9%, 3.9%, and 2.2% ( p =0.632); and distant metastasis in 7.4%, 10.4%, and 5.5% ( p =0.564). There were no differences in recurrence-free and cancer-specific survival among the three groups ( p =0.680 and 0.502, respectively). Conclusions The three techniques had comparable oncologic outcomes. Our data validate the TUI method of bladder cuff control in patients with primary UUT-UC without coexistent bladder tumors.

OBJECTIVE To examine the hypothesis that nuclear factor-κB (NF-κB), a transcription factor involved in anti-apoptosis, invasion, and angiogenesis, plays a role in the carcinogenesis of upper urinary tract urothelial carcinoma (UUT-UC) and has prognostic value for survival. PATIENTS AND METHODS In all, 90 patients with UUT-UC [mean (range) age, 64.5 (24–84) years] who underwent surgery at our institution from January 1991 to December 2005 were included. Clinicopathological data were collected retrospectively. We performed immunohistochemical staining for NF-κB (p65) on paraffin-embedded sections of the tumour and corresponding normal tissues. The association between survival and potential prognostic factors was examined. RESULTS The median follow-up was 40 months. In all, 55 patients (61.1%) with UUT-UC overexpressed cytoplasmic NF-κB, and nuclear immunoreactivity for NF-κB was detected in 24 patients (26.7%). On univariate analysis, significant prognostic factors for survival were tumour location, stage, grade, lymph node involvement, and nuclear NF-κB expression. On multivariate analysis, nuclear NF-κB positivity was an independent predictor for disease-specific survival [Cox regression hazard ratio (HR) 2.87; P= 0.025] and overall survival (HR 2.24; P= 0.037). CONCLUSION These results imply a role for nuclear NF-κB expression in the tumorigenesis of UUT-UC. Nuclear NF-κB may serve as a useful independent molecular marker to predict outcome and may represent a promising therapeutic target for patients with UUT-UC.

Purpose: Chromosome 9 is frequently deleted in high-risk gastrointestinal stromal tumors (GISTs), whereas its specific tumor suppressor genes (TSGs) are less understood. We did an integrative study of MTAP gene at 9p21 to analyze its implication in GISTs. Experimental Design: To search TSGs on chromosome 9, we used ultrahigh-resolution array comparative genomic hybridization to profile DNA copy number alterations of 22 GISTs, with special attention to MTAP gene. MTAP immunoexpression was assessable for 306 independent GISTs on tissue microarrays, with 146 cases analyzed for MTAP homozygous deletion, 181 for mutations of KIT and PDGFRA receptor tyrosine kinase genes, and 7 for MTAP hypermethylation. Results: Array comparative genomic hybridization identified 11 candidate TSGs on 9p and six on 9q. MTAP and/or CDKN2A/CDKN2B at 9p21.3 were deleted in one intermediate-risk (11) and seven high-risk (70) GISTs with two cases homozygously codeleted at both loci. MTAP homozygous deletion, present in 25 of 146 cases, was highly associated with larger size and higher mitotic rate, Ki-67 index, and risk level (all P < 0.01) but not with receptor tyrosine kinase genotypes. Whereas MTAP homozygous deletion correlated with MTAP protein loss (P < 0.001), 7 of 30 GISTs without MTAP expression did not show homozygous deletion, including three MTAP-hypermethylated cases. MTAP homozygous deletion was univariately predictive of decreased disease-free survival (P < 0.0001) and remained multivariately independent (P = 0.0369, hazard ratio = 2.166), together with high-risk category (P < 0.0001), Ki-67 index >5 (P = 0.0106), and nongastric location (P = 0.0416). Conclusions: MTAP homozygous deletion, the predominant mechanism to deplete protein expression, is present in 17 of GISTs. It correlates with important prognosticators and independently predicts worse outcomes, highlighting the role in disease progression. (Clin Cancer Res 2009;15(22):696372)