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Sample records for predict urothelial carcinoma

  1. Predictive models and prognostic factors for upper tract urothelial carcinoma: a comprehensive review of the literature

    PubMed Central

    Mbeutcha, Aurélie; Mathieu, Romain; Rouprêt, Morgan; Gust, Kilian M.; Briganti, Alberto; Karakiewicz, Pierre I.

    2016-01-01

    In the context of customized patient care for upper tract urothelial carcinoma (UTUC), decision-making could be facilitated by risk assessment and prediction tools. The aim of this study was to provide a critical overview of existing predictive models and to review emerging promising prognostic factors for UTUC. A literature search of articles published in English from January 2000 to June 2016 was performed using PubMed. Studies on risk group stratification models and predictive tools in UTUC were selected, together with studies on predictive factors and biomarkers associated with advanced-stage UTUC and oncological outcomes after surgery. Various predictive tools have been described for advanced-stage UTUC assessment, disease recurrence and cancer-specific survival (CSS). Most of these models are based on well-established prognostic factors such as tumor stage, grade and lymph node (LN) metastasis, but some also integrate newly described prognostic factors and biomarkers. These new prediction tools seem to reach a high level of accuracy, but they lack external validation and decision-making analysis. The combinations of patient-, pathology- and surgery-related factors together with novel biomarkers have led to promising predictive tools for oncological outcomes in UTUC. However, external validation of these predictive models is a prerequisite before their introduction into daily practice. New models predicting response to therapy are urgently needed to allow accurate and safe individualized management in this heterogeneous disease. PMID:27785429

  2. Prognostic Genetic Signatures in Upper Tract Urothelial Carcinoma.

    PubMed

    Li, Qiang; Bagrodia, Aditya; Cha, Eugene K; Coleman, Jonathan A

    2016-02-01

    Urothelial carcinoma is a highly heterogeneous disease that can arise throughout the entire urothelial lining from the renal pelvis to the proximal urethra. Upper tract urothelial carcinoma (UTUC) is rare, and while it shares many similarities with urothelial carcinoma of bladder (UCB), there are also significant differences between UTUC and UCB regarding clinical management and outcomes. No major advances have been made recently in the development of new systemic therapies for urothelial carcinoma, partly due to the lack of understanding of underlying molecular pathogenetic mechanisms. In the past decade, the emergence of next-generation sequencing has greatly enabled genomic characterization of tumor samples. Researchers are currently exploring a personalized approach to augment traditional clinical decision-making based on genetic alterations. In the present review, we summarize current genomic advances in UTUC and discuss the potential implications of these developments for developing prognostic and predictive biomarkers. PMID:26757906

  3. Persistent Uroplakin Expression in Advanced Urothelial Carcinomas: Implications in Urothelial Tumor Progression and Clinical Outcome

    PubMed Central

    Huang, Hong-Ying; Shariat, Shahrokh F.; Sun, Tung-Tien; Lepor, Herbert; Shapiro, Ellen; Hsieh, Jer-Tsong; Ashfaq, Raheela; Lotan, Yair; Wu, Xue-Ru

    2007-01-01

    As the terminal differentiation products of human urothelium, uroplakins (UPs) would be expected to diminish during urothelial tumorigenesis. Surprisingly, recent studies found UPs to be retained even by well-advanced urothelial carcinomas, suggesting that the loss of UPs does not strictly parallel urothelial transformation. Little is known, however, about whether the status of UPs is associated with a particular pathological parameter, tumor’s biological behavior or patient outcome. Here we assessed UP expression by immunohistochemistry on tissue arrays from 285 patients with bladder urothelial carcinomas or non-tumor conditions. UPs were expressed in all 9 normal urothelial specimens, 63/74 (85%) patients with non-muscle-invasive urothelial carcinomas on transurethral resection, 104/202 (51.5%) patients who underwent radical cystectomy for advanced urothelial carcinomas, and 33/50 (66%) lymph node metastases. Normally associated with urothelial apical surface, UPs were localized aberrantly in tumors, including micro-luminal, basal-laminal, cytoplasmic or uniform patterns. In non-muscle-invasive diseases, there was no association between UP expression and disease recurrence, progression or mortality. In contrast, in invasive diseases, absent UP expression was significantly associated with advanced pathologic stage, lymph node metastases, disease recurrence and bladder cancer-specific mortality (p=0.042, p=0.035, p=0.023 and p=0.022, respectively) in univariate analyses. Furthermore, UP status was independent of key cell-cycle regulators, including p53, pRb, p27 and cyclin D1, thus excluding a functional link between these two groups of proteins. Our data demonstrate for the first time that persistent UP expression is associated with a favorable clinical outcome and that UPs may be used as adjunct markers for predicting the prognoses of patients with invasive and metastatic bladder carcinomas. Our results also suggest that UP-positive and –negative carcinomas

  4. Does subdivision of the "atypical" urine cytology increase predictive accuracy for urothelial carcinoma?

    PubMed

    Bostwick, David G; Hossain, Deloar

    2014-12-01

    Urine cytology is routinely used for early diagnosis and monitoring of patients with hematuria or a history of urothelial carcinoma, but its clinical utility is greatly diminished by a high frequency of "atypical" specimens, reportedly around 20% in the literature. We compared our results with double-stained urine cytology specimens (papanicolaou and acid hematoxylin stains) with published results with only a single or double papanicolaou stain. The acid hematoxylin stain enhanced nuclear chromatin staining, eliminated significant background debris, and improved visibility of diagnostic cells in the presence of obscuring blood. Medical records of all urine cytologies received between 2005 and 2012 in our laboratories were reviewed. The study group consisted of all cases with bladder biopsy follow-up within one year of cytology. Of 43,131 urine cytologies diagnosed in our laboratories, biopsy follow-up results were available within one year in 10,473 cases, including 852 for symptoms and 1,461 for follow-up of bladder cancer. An additional 6,427 cases had cystoscopy results in which no biopsy was obtained. Cases were classified as negative (81.6%), atypical, favor reactive (2.9%), atypical, favor neoplastic (7.3%), suspicious (5.7%), and malignant (2.5%), with subsequent frequencies for urothelial cancer on biopsy of 13.3%, 31.1%, 37.6%, 53.6%, and 74.3%, respectively. No significant difference was found if atypical was subdivided into two categories: favor reactive and favor neoplastic. Subdivision of the atypical category did not improve diagnostic accuracy. Addition of the acid hematoxylin stain decreased the incidence of atypical urine cytologies from about 20% to 10.2%. PMID:24838797

  5. Ureterocele urothelial carcinoma: managing a rare presentation

    PubMed Central

    Astigueta, Juan Carlos; Abad-Licham, Milagros; Silva, Eloy; Alvarez, Víctor; Piccone, Francis; Cruz, Enrique; Redorta, Joan Palou

    2016-01-01

    It is very uncommon for urothelial carcinoma to develop in an ureterocele. It is generally discovered in an imaging study or in connection with haematuria. We found very few reports in the literature. Here, we report on the case of a 71-year-old male who initially presented with haematuria and low back pain and who then underwent transurethral resection for an intraureterocele tumour. Pathology confirmed urothelial carcinoma. PMID:26913072

  6. Immunohistochemical characterization of urothelial carcinoma.

    PubMed

    Rajcani, J; Kajo, K; Adamkov, M; Moravekova, E; Lauko, L; Felcanova, D; Bencat, M

    2013-01-01

    From the archive of BB Biocyt company, 32 urinary bladder carcinomas (urothelium carcinomas, UC) and 7 cases of chronic cystitis were selected and examined in semiserial sections for the following antigens: 1) cell proliferation marker Ki-67 (expressed in the nuclei), 2) cell cycle regulator p16/INK4a polypeptide (expressed in the cytoplasm and nuclei), 3) urothelium marker p63 (expressed in the nuclei), 4) cytokeratin 7 (CK7). 5) cytokeratin 20 (CK20) and 6) high molecular weight cytokeratin (HMWCK). Invasive urothelium carcinomas showing a high grade dysplasia (invasive HG UC) comprised over the half (20 out of 32) of the investigated tumours. Microinvasion to lamina propria (seen in three HG papillary carcinomas) was regarded as an early infiltration even when the position of muscular layer could not be determined. Classical invasion across the urinary bladder wall and/or to surrounding tissues was found in 17 cases of low-differentiated HG UCs. The rest (9 out of 32 neoplasms) were either non-invasive papillary carcinomas of high (non-invasive HG UC, 5 cases) or low malignant potential (noninvasive LG UC, 4 cases). Finally, 3 cases were papillary urothelium neoplasms of low malignant potential (PUNLMP). HMWCK was present in all invasive tumours, whereas the frequency of other urothelium markers ranged from 65 to 88 %. Nevertheless, at least two markers were expressed in each invasive tumour. Staining for Ki-67 antigen was positive in over 50 % of the nuclei of HG UCs, while in the LG UCs, the frequency of positive Ki-67 staining did not exceed 25 %. In PUNLMP, the positive rate of Ki-67 stained dysplastic cells was below 10 %. The staining for p16 antigen did not correlate with the degree of dysplasia within urothelium tumours. For routine diagnostic, we recommend to combine the Ki-67 staining with detection of HMWCK. In cases of chronic cystitis, which developed urothelial hyperplasia and/or squamous metaplasia, the presence of p63 antigen was a relevant

  7. A Novel Risk Stratification to Predict Local-Regional Failures in Urothelial Carcinoma of the Bladder After Radical Cystectomy

    SciTech Connect

    Baumann, Brian C.; Guzzo, Thomas J.; He Jiwei; Keefe, Stephen M.; Tucker, Kai; Bekelman, Justin E.; Hwang, Wei-Ting; Vaughn, David J.; Malkowicz, S. Bruce; Christodouleas, John P.

    2013-01-01

    Purpose: Local-regional failures (LF) following radical cystectomy (RC) plus pelvic lymph node dissection (PLND) with or without chemotherapy for invasive urothelial bladder carcinoma are more common than previously reported. Adjuvant radiation therapy (RT) could reduce LF but currently has no defined role because of previously reported morbidity. Modern techniques with improved normal tissue sparing have rekindled interest in RT. We assessed the risk of LF and determined those factors that predict recurrence to facilitate patient selection for future adjuvant RT trials. Methods and Materials: From 1990-2008, 442 patients with urothelial bladder carcinoma at University of Pennsylvania were prospectively followed after RC plus PLND with or without chemotherapy with routine pelvic computed tomography (CT) or magnetic resonance imaging (MRI). One hundred thirty (29%) patients received chemotherapy. LF was any pelvic failure detected before or within 3 months of distant failure. Competing risk analyses identified factors predicting increased LF risk. Results: On univariate analysis, pathologic stage {>=}pT3, <10 nodes removed, positive margins, positive nodes, hydronephrosis, lymphovascular invasion, and mixed histology significantly predicted LF; node density was marginally predictive, but use of chemotherapy, number of positive nodes, type of surgical diversion, age, gender, race, smoking history, and body mass index were not. On multivariate analysis, only stage {>=}pT3 and <10 nodes removed were significant independent LF predictors with hazard ratios of 3.17 and 2.37, respectively (P<.01). Analysis identified 3 patient subgroups with significantly different LF risks: low-risk ({<=}pT2), intermediate-risk ({>=}pT3 and {>=}10 nodes removed), and high-risk ({>=}pT3 and <10 nodes) with 5-year LF rates of 8%, 23%, and 42%, respectively (P<.01). Conclusions: This series using routine CT and MRI surveillance to detect LF confirms that such failures are relatively common

  8. Metastatic brain tumor from urothelial carcinoma of the prostatic urethra

    PubMed Central

    Morita, Kohei; Oda, Masashi; Koyanagi, Masaomi; Saiki, Masaaki

    2016-01-01

    Background: Urothelial carcinoma occurs in the bladder, upper urinary tract, and lower urinary tract, including prostatic urethra. A majority of the reported cases of intracranial metastasis from urothelial carcinoma originates from the bladder and upper urinary tract. Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. Case Description: A 72-year-old male presented with a metastatic brain tumor and a 3-year history of urothelial carcinoma of the prostatic urethra treated with cystourethrectomy and chemotherapy with gemcitabine-cisplatin. Pathological diagnosis for tumor removal was compatible with metastatic brain tumor from urothelial carcinoma. Conclusion: Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. It is an extremely rare case, however, we should be careful of brain metastasis during follow-up for urothelial carcinoma in the lower urinary tract. PMID:27512612

  9. The Emerging Molecular Landscape of Urothelial Carcinoma.

    PubMed

    Solomon, James P; Hansel, Donna E

    2016-09-01

    Although there have been many recent discoveries in the molecular alterations associated with urothelial carcinoma, current understanding of this disease lags behind many other malignancies. Historically, a two-pathway model had been applied to distinguish low- and high-grade urothelial carcinoma, although significant overlap and increasing complexity of molecular alterations has been recently described. In many cases, mutations in HRAS and FGFR3 that affect the MAPK and PI3K pathways seem to be associated with noninvasive low-grade papillary tumors, whereas mutations in TP53 and RB that affect the G1-S transition of the cell cycle are associated with high-grade in situ and invasive carcinoma. However, recent large-scale analyses have identified overlap in these pathways relative to morphology, and in addition, many other variants in a wide variety of oncogenes and tumor-suppressor genes have been identified. New technologies including next-generation sequencing have enabled more detailed analysis of urothelial carcinoma, and several groups have proposed molecular classification systems based on these data, although consensus is elusive. This article reviews the current understanding of alterations affecting oncogenes and tumor-suppressor genes associated with urothelial carcinoma, and their application in the context of morphology and classification schema. PMID:27523968

  10. Targeting Hsp90 in urothelial carcinoma

    PubMed Central

    Skotnicki, Kamil; Landas, Steve; Bratslavsky, Gennady; Bourboulia, Dimitra

    2015-01-01

    Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review. PMID:25909217

  11. [Urothelial carcinoma in a pyelocaliceal cyst].

    PubMed

    Abate, Danilo; Vella, Marco; Alonge, Vincenza; Serretta, Vincenzo

    2014-01-01

    Renal complex cysts are lesions whose nature can be either benign or malignant. Depending on the presence of septa, solid components, enhancement or calcifications, they are distinguished according to the Bosniak classification based on CT findings, as well as MRI and ETG. We report a rare case of urothelial carcinoma, originating over a pyelocalyceal cyst in a 50-year-old man, and classified as Bosniak IIF by CT and MRI investigations.

  12. Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

    PubMed Central

    2014-01-01

    Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell cycle regulation, chromatin regulation, and kinase signaling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in miRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the PI3K/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date, suggesting the future possibility of targeted therapy for chromatin abnormalities. PMID:24476821

  13. Artificial intelligence for predicting recurrence-free probability of non-invasive high-grade urothelial bladder cell carcinoma.

    PubMed

    Cai, Tommaso; Conti, Gloria; Nesi, Gabriella; Lorenzini, Matteo; Mondaini, Nicola; Bartoletti, Riccardo

    2007-10-01

    The objective of our study was to define a neural network for predicting recurrence and progression-free probability in patients affected by recurrent pTaG3 urothelial bladder cancer to use in everyday clinical practice. Among all patients who had undergone transurethral resection for bladder tumors, 143 were finally selected and enrolled. Four follow-ups for recurrence, progression or survival were performed at 6, 9, 12 and 108 months. The data were analyzed by using the commercially available software program NeuralWorks Predict. These data were compared with univariate and multivariate analysis results. The use of Artificial Neural Networks (ANN) in recurrent pTaG3 patients showed a sensitivity of 81.67% and specificity of 95.87% in predicting recurrence-free status after transurethral resection of bladder tumor at 12 months follow-up. Statistical and ANN analyses allowed selection of the number of lesions (multiple, HR=3.31, p=0.008) and the previous recurrence rate (>or=2/year, HR=3.14, p=0.003) as the most influential variables affecting the output decision in predicting the natural history of recurrent pTaG3 urothelial bladder cancer. ANN applications also included selection of the previous adjuvant therapy. We demonstrated the feasibility and reliability of ANN applications in everyday clinical practice, reporting a good recurrence predicting performance. The study identified a single subgroup of pTaG3 patients with multiple lesions, >or=2/year recurrence rate and without any response to previous Bacille Calmette-Guérin adjuvant therapy, that seem to be at high risk of recurrence.

  14. Anabolic androgens affect the competitive interactions in cell migration and adhesion between normal mouse urothelial cells and urothelial carcinoma cells.

    PubMed

    Huang, Chi-Ping; Hsieh, Teng-Fu; Chen, Chi-Cheng; Hung, Xiao-Fan; Yu, Ai-Lin; Chang, Chawnshang; Shyr, Chih-Rong

    2014-09-26

    The urothelium is constantly rebuilt by normal urothelial cells to regenerate damaged tissues caused by stimuli in urine. However, the urothelial carcinoma cells expand the territory by aberrant growth of tumor cells, which migrate and occupy the damaged tissues to spread outside and disrupt the normal cells and organized tissues and form a tumor. Therefore, the interaction between normal urothelial cells and urothelial carcinoma cells affect the initiation and progression of urothelial tumors if normal urothelial cells fail to migrate and adhere to the damages sites to regenerate the tissues. Here, comparing normal murine urothelial cells with murine urothelial carcinoma cells (MBT-2), we found that normal cells had less migration ability than carcinoma cells. And in our co-culture system we found that carcinoma cells had propensity migrating toward normal urothelial cells and carcinoma cells had more advantages to adhere than normal cells. To reverse this condition, we used anabolic androgen, dihyrotestosterone (DHT) to treat normal cells and found that DHT treatment increased the migration ability of normal urothelial cells toward carcinoma cells and the adhesion capacity in competition with carcinoma cells. This study provides the base of a novel therapeutic approach by using anabolic hormone-enforced normal urothelial cells to regenerate the damage urothelium and defend against the occupancy of carcinoma cells to thwart cancer development and recurrence.

  15. Diagnosis of urothelial carcinoma from urine.

    PubMed

    Têtu, Bernard

    2009-06-01

    Urine cytology is the most widely used noninvasive test to detect urothelial tumors. However, it is limited by its low sensitivity. On the other hand, cystoscopy is the gold standard procedure to follow patients with a history of bladder cancer but this test is invasive and costly. Therefore, there is a real need to develop new tests that can be used in bladder cancer surveillance. Several soluble and cell-based markers have been developed and most of them improve the sensitivity of cytology but the specificity is invariably decreased. Of the cell-based tests, two obtained Food and Drug Administration approval. ImmunoCyt/uCyt is a fluorescent test that uses three monoclonal antibodies and UroVysion is an in situ hybridization test, which uses four different probes to different chromosomes. Both tests have a high sensitivity to detect cancer cells and can help to predict urothelial cancer recurrence. ImmunoCyt/uCyt is somewhat better at detecting low-grade tumors but UroVysion is not affected by prior BCG treatment. However, both tests use fluorescent dyes, are time-consuming and require trained personnel. Because of their high negative predictive value, both tests may help the urologist to postpone a number of cystoscopies, especially in patients with low-risk urothelial cancer. PMID:19494853

  16. [New WHO classification of urothelial carcinoma of the urinary bladder].

    PubMed

    Helpap, B

    2002-01-01

    The WHO classification of urothelial carcinomas of the urinary bladder (1999) presents the papillary urothelial neoplasia of low malignant potential (PUNLMP) as a new entity in between the papillomas and the papillary urothelial carcinomas. This neoplasia shows a typical basal palisading, a low mitotic rate, and a low MIB-1-proliferation index. The PUNLMP is said to have an increased risk of development of recurrent papillary lesions with the possibility of malignant transformation. At present, there is an intensive discussion on this new entity. The participants of a meeting on the consensus classification on urothelial tumors held in Ancona in 2000 have meanwhile split in two discussion groups. One favors the new WHO classification with the papillary urothelial carcinomas G I, G II, and G III, but without PUNLMP, whereas the other group favors the consensus classification of 1998 with papillomas, papillary urothelial neoplasia of low malignant potential, and non invasive as well as invasive low-grade and high grade papillary urothelial carcinomas. Future long term prospective studies will show the significance of PUNLMP compared to well differentiated non invasive papillary urothelial urinary bladder carcinoma G I (G Ia). Otherwise, there is no significant difference in the classification of carcinomas and non epithelial lesions compared with the previous classification of 1973. The new WHO does however discriminate the minimally invasive papillary urothelial carcinomas in those with infiltration of the lamina propria above the muscularis mucosae (pT1a), the infiltration of the lamina muscularis mucosae (pT1b), and the extension beyond the muscularis mucosae (pT1c). The recurrence rate increases from stage pT1b. This substaging may be of therapeutical relevance.

  17. Upper urinary tract urothelial carcinoma with intratubular spread

    PubMed Central

    Sarungbam, Judy; Kurtis, Boaz; Phillips, John; Cai, Dongming; Zhang, David; Humayun, Islam; Yang, Ximing; Zhong, Minghao

    2014-01-01

    Upper urinary tract urothelial cell carcinomas (UUT-UCs) are uncommon and are defined as urothelial carcinoma involving the urinary tract from the renal calyces, renal pelvis to the distal ureter. One well-known an peculiar histopathological finding in UUT-UC is urothelial carcinoma with intratubular spread (retrograde spread within renal tubules). However, this special feature has not been systematically studied. We therefore collected a total of 53 consecutive cases of upper urinary tract urothelial carcinomas (UUT-UCs), and studied the clinical and pathological features of intratubular spread (IS). A cocktail stain comprised of antibodies PAX8 and p63 together with PAS was validated and employed to facilitate the study of intratubular spread. Seventeen cases (31.5%) showed intratubular spread demonstrated by either H&E stain and/or the cocktail stain. All of the 17 cases wit intratubular spread had tumor involvement of the renal calyx; the majority of these (14/17, 82.4%) were high grade urothelial carcinoma and the remainder (3/17, 17.6%) were low grade. 4 of 17cases (23.5%) were non-invasive. We classified intratubular spread into 4 different types, based on histopathological patterns: pagetoid, typical, florid, and secondary invasion from intratubular spread. In conclusion, study shows intratubular spread of urothelial carcinoma is fairly common phenomenon in UUT-UC and is associated with a variety of clinical-pathological features. High grade UUT-UC tends to have more extensive intratubular spread and secondary invasion into renal parenchyma. Distinct morphological characteristics as well as the staining pattern from a unique cocktail stain help to identify and evaluate intratubular spread of urothelial carcinoma. Recognizing these different types of intratubular spreading (IS) is crucial for accurate staging of some upper urinary tract urothelial carcinomas (UUT-UCs). PMID:25374911

  18. Differential Immunohistochemical Profiles for Distinguishing Prostate Carcinoma and Urothelial Carcinoma

    PubMed Central

    Oh, Woo Jin; Chung, Arthur Minwoo; Kim, Jee Soon; Han, Ji Heun; Hong, Sung Hoo; Lee, Ji Yeol; Choi, Yeong Jin

    2016-01-01

    Background The pathologic distinction between high-grade prostate adenocarcinoma (PAC) involving the urinary bladder and high-grade urothelial carcinoma (UC) infiltrating the prostate can be difficult. However, making this distinction is clinically important because of the different treatment modalities for these two entities. Methods A total of 249 patient cases (PAC, 111 cases; UC, 138 cases) collected between June 1995 and July 2009 at Seoul St. Mary’s Hospital were studied. An immunohistochemical evaluation of prostatic markers (prostate-specific antigen [PSA], prostate-specific membrane antigen [PSMA], prostate acid phosphatase [PAP], P501s, NKX3.1, and α-methylacyl coenzyme A racemase [AMACR]) and urothelial markers (CK34βE12, p63, thrombomodulin, S100P, and GATA binding protein 3 [GATA3]) was performed using tissue microarrays from each tumor. Results The sensitivities of prostatic markers in PAC were 100% for PSA, 83.8% for PSMA, 91.9% for PAP, 93.7% for P501s, 88.3% for NKX 3.1, and 66.7% for AMACR. However, the urothelial markers CK34βE12, p63, thrombomodulin, S100P, and GATA3 were also positive in 1.8%, 0%, 0%, 3.6%, and 0% of PAC, respectively. The sensitivities of urothelial markers in UC were 75.4% for CK34βE12, 73.9% for p63, 45.7% for thrombomodulin, 22.5% for S100P, and 84.8% for GATA3. Conversely, the prostatic markers PSA, PSMA, PAP, P501s, NKX3.1, and AMACR were also positive in 9.4%, 0.7%, 18.8%, 0.7%, 0%, and 8.7% of UCs, respectively. Conclusions Prostatic and urothelial markers, including PSA, NKX3.1, p63, thrombomodulin, and GATA3 are very useful for differentiating PAC from UC. The optimal combination of prostatic and urothelial markers could improve the ability to differentiate PAC from UC pathologically. PMID:27498545

  19. Role of Narrow Band Imaging in Management of Urothelial Carcinoma.

    PubMed

    Altobelli, Emanuela; Zlatev, Dimitar V; Liao, Joseph C

    2015-08-01

    Urothelial carcinoma of the bladder and upper tract is primarily diagnosed by white light endoscopy, which has well-known limitations that contribute to the increased risk of tumor recurrence and progression. Narrow band imaging (NBI) is an optical imaging technology that facilitates detection of tumor vasculature and differentiation of benign urothelium from neoplastic tissue. For urothelial carcinoma, NBI may be utilized in a variety of clinical settings, including office cystoscopy for initial identification and surveillance, transurethral resection for pathological diagnosis, and ureteroscopic management of upper tract lesions. Early evidence suggests that NBI increases the detection of urothelial carcinoma in the bladder and upper tract, including flat high-grade lesions such as carcinoma-in-situ that are a diagnostic challenge under white light. NBI also appears to improve the quality of transurethral resection and thereby reduce the frequency of tumor recurrence.

  20. Role of human papillomavirus in the development of urothelial carcinoma.

    PubMed

    Yavuzer, Dilek; Karadayi, Nimet; Salepci, Taflan; Baloglu, Huseyin; Bilici, Ahmet; Sakirahmet, Dilek

    2011-09-01

    It has been estimated that almost 10% of the worldwide cancer burden is linked to human papillomavirus (HPV) infection. Although the association between HPV and bladder carcinoma has been extensively investigated, data on the role of HPV in bladder carcinogenesis are controversial. The aim of the study was to assess the possible role of human papillomavirus in the development of urothelial bladder carcinomas. Formalin-fixed and paraffin-embedded archival tissue samples were used for DNA extraction. Seventy urothelial bladder carcinoma tissues were screened by nested-polymerase chain reaction (PCR) for HPV DNA with a control group of total 18 cervical tissues with invasive cervical carcinoma and cervical intraepithelial neoplasia III (CIN III). In the study group, we did not find HPV DNA positivity in any of the urothelial carcinomas. In the control group, 15 out of 18 (83.3%) samples were positive for the HPV DNA. These results indicated that there was no association between HPV infection and urothelial carcinomas. PMID:20428971

  1. Expression of Estrogen Receptor Beta Predicts Oncologic Outcome of pT3 Upper Urinary Tract Urothelial Carcinoma Better Than Aggressive Pathological Features

    PubMed Central

    Luo, Hao Lun; Sung, Ming Tse; Tsai, Eing Mei; Lin, Chang Shen; Lee, Nai Lun; Chung, Yueh-Hua; Chiang, Po Hui

    2016-01-01

    Upper urinary tract urothelial carcinoma (UT-UC) is rare and treatment options or prognostic markers are limited. There is increasing evidence indicating that urothelial carcinoma may be an endocrine-related cancer. The aim of this study was to analyze the prognostic effect of estrogen receptor beta (ERβ) on the outcome of UT-UC. From 2005 to 2012, this study included 105 patients with pT3 UT-UC. Perioperative factors, pathological features, and ERβ immunostaining were reviewed and prognostic effects were examined by multivariate analysis. This study divided patients into either the ERβ-high (n = 52) or ERβ-low (n = 53) group and analyzed their oncologic outcomes. All pathological features except infiltrating tumor architecture (significantly higher incidence in ERβ-low group, p = 0.004) are symmetric in both groups. Low ERβ expression was significantly correlated with local recurrence and distant metastasis in univariate analysis (p = 0.035 and 0.004, respectively) and multivariate analysis (p = 0.05 and 0.008, respectively). Cell line study also proved that knock down of ERβ cause less UTUC proliferation and migration. In addition, ERβ agonist also enhanced the cytotoxic and migration inhibition effect of cisplatin and ERβ antagonist cause the UTUC cell more resistant to cisplatin. This result may help identify patients in need of adjuvant therapy or develop potential targeted therapy. PMID:27052470

  2. Why are upper tract urothelial carcinoma two different diseases?

    PubMed Central

    Szarvas, Tibor; Módos, Orsolya; Horváth, András

    2016-01-01

    In the last few years growing evidence highlighted the differences between upper tract urothelial carcinoma (UTUC) and urothelial bladder carcinoma (UBC) which cannot be explained solely by their different anatomical location. The aim of this review was to summarize current progress in UTUC research and to underline the differences and similarities between UTUC and UBC by focusing on epidemiology, etiology, staging and risk factors as well as on surgical and medical management. UBC and UTUC sharing common risk factors such as smoking and aromatic amines, while aristolochic acid exposure or familiar Lynch syndrome are rather specific for UTUC. The grading of UBC and UTUC are identical, but inherent from their different anatomical locations, there are some differences between their stage classifications. As an example, in contrast to UBC where a clear recommendation for pT3 subclassification exists, in UTUC current research aims to define an adequate subclassification for pelvic pT3 cases aiming to provide a better risk stratification. The primary treatment for both UBC and UTUC is surgery. Similarly to UBC, UTUC patients at high risk of disease progression are treated by radical surgery. However, because of the inaccurate preoperative or transurethral staging of UTUC, many radical nephroureterectomies are performed unnecessarily. Preoperative prediction of pathological stage or patients’ prognosis may reduce this overtreatment by selecting patients for nephron-sparing surgery. To this end, predictive models combining histological and molecular features together with imaging data may be used. The antegrade or retrograde instillation of BCG or mitomycin C, as topical agents is feasible after conservative treatment of UTUC or for the treatment of CIS. However, the prognostic significance of lymph node positivity in UTUC seems to be similar to that of UBC, the therapeutic benefit of lymph node dissection (LND) in UTUC has not been firmly established yet. In addition

  3. Risk Prediction Models of Locoregional Failure After Radical Cystectomy for Urothelial Carcinoma: External Validation in a Cohort of Korean Patients

    SciTech Connect

    Ku, Ja Hyeon; Kim, Myong; Jeong, Chang Wook; Kwak, Cheol; Kim, Hyeon Hoe

    2014-08-01

    Purpose: To evaluate the predictive accuracy and general applicability of the locoregional failure model in a different cohort of patients treated with radical cystectomy. Methods and Materials: A total of 398 patients were included in the analysis. Death and isolated distant metastasis were considered competing events, and patients without any events were censored at the time of last follow-up. The model included the 3 variables pT classification, the number of lymph nodes identified, and margin status, as follows: low risk (≤pT2), intermediate risk (≥pT3 with ≥10 nodes removed and negative margins), and high risk (≥pT3 with <10 nodes removed or positive margins). Results: The bootstrap-corrected concordance index of the model 5 years after radical cystectomy was 66.2%. When the risk stratification was applied to the validation cohort, the 5-year locoregional failure estimates were 8.3%, 21.2%, and 46.3% for the low-risk, intermediate-risk, and high-risk groups, respectively. The risk of locoregional failure differed significantly between the low-risk and intermediate-risk groups (subhazard ratio [SHR], 2.63; 95% confidence interval [CI], 1.35-5.11; P<.001) and between the low-risk and high-risk groups (SHR, 4.28; 95% CI, 2.17-8.45; P<.001). Although decision curves were appropriately affected by the incidence of the competing risk, decisions about the value of the models are not likely to be affected because the model remains of value over a wide range of threshold probabilities. Conclusions: The model is not completely accurate, but it demonstrates a modest level of discrimination, adequate calibration, and meaningful net benefit gain for prediction of locoregional failure after radical cystectomy.

  4. Upper tract urothelial carcinoma: Paradigm shift towards nephron sparing management

    PubMed Central

    Fiuk, Julia V; Schwartz, Brad F

    2016-01-01

    Upper tract urothelial carcinoma (UTUC) is relatively rare compared to urothelial carcinoma of the lower tract, comprising only 5%-10% of all urothelial cancers. Although both entities share histologic properties, UTUC tends to be more invasive at diagnosis and portend a worse prognosis, with a 5 year overall mortality of 23%. To date, the gold standard management of UTUC has been radical nephroureterectomy (RNU), with nephron sparing techniques reserved for solitary kidneys or cases where the patient could not tolerate radical surgery. Limited data from these series, as well as select series where nephron-sparing endoscopic management has been offered to a broader patient base, suggest that minimally invasive, nephron sparing techniques can offer comparable oncologic and survival outcomes to RNU in appropriately selected patients. We review the current literature on the topic and discuss long term outcomes and sequelae of the gold standard treatment, RNU. We also discuss the oncologic outcomes of minimally invasive, endoscopic management of UTUC. Our goal is to provide the reader a comprehensive overview of the current state of the field in order to inform and guide their treatment decisions. PMID:26981440

  5. Upper tract urothelial carcinomas in patients with chronic kidney disease: relationship with diagnostic challenge.

    PubMed

    Wang, Li-Jen; Lee, Shen-Yang; Teh, Bin Tean; Chuang, Cheng-Keng; Nortier, Joëlle

    2014-01-01

    Chronic kidney disease and upper tract urothelial carcinomas display a bidirectional relationship. Review of the literature indicates that early diagnosis and correct localization of upper tract urothelial carcinomas in dialysis patients and kidney transplant recipients are important but problematic. Urine cytology and cystoscopy have limited sensitivity for the diagnosis of upper tract urothelial carcinomas in dialysis patients. Enhanced computed tomography and magnetic resonance imaging could prove useful for the detection and staging of upper tract urothelial carcinomas in dialysis patients. Renal ultrasound can detect hydronephrosis caused by upper tract urothelial carcinomas in kidney transplant recipients but cannot visualize the carcinomas themselves. High detection rates for upper tract urothelial carcinomas in kidney transplant recipients have recently been demonstrated using computed tomography urography, which appears to be a promising tool. To detect carcinomas in dialysis patients and kidney transplant recipients as early as possible, regular screening in asymptomatic patients and diagnostic work-up in symptomatic patients should be performed using a combination of urological and imaging methods. Careful assessment of subsequent recurrence within the contralateral upper urinary tract and the urinary bladder is necessary for dialysis patients and kidney transplant recipients with upper tract urothelial carcinomas.

  6. Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges

    PubMed Central

    Garg, Minal

    2016-01-01

    Urothelial carcinoma (UC) of the bladder is characterized by high recurrence rate where a subset of these cells undergoes transition to deadly muscle invasive disease and later metastasizes. Urothelial cancer stem cells (UroCSCs), a tumor subpopulation derived from transformation of urothelial stem cells, are responsible for heterogeneous tumor formation and resistance to systemic treatment in UC of the bladder. Although the precise reason for pathophysiologic spread of tumor is not clear, transcriptome analysis of microdissected cancer cells expressing multiple progenitor/stem cell markers validates the upregulation of genes that derive epithelial-to-mesenchymal transition. Experimental studies on human bladder cancer xenografts describe the mechanistic functions and regulation of epithelial plasticity for its cancer-restraining effects. It has been further examined to be associated with the recruitment of a pool of UroCSCs into cell division in response to damages induced by adjuvant therapies. This paper also discusses the various probable therapeutic approaches to attenuate the progressive manifestation of chemoresistance by co-administration of inhibitors of epithelial plasticity and chemotherapeutic drugs by abrogating the early tumor repopulation as well as killing differentiated cancer cells. PMID:27621760

  7. [Urothelial carcinoma. Does surgical pathology learn from molecular pathology?].

    PubMed

    Hofstädter, F

    2008-11-01

    The question is raised whether the new theories about initiation and progression of urothelial carcinoma gained by molecular techniques show effects on the classification and histopathological diagnosis. As fundamental new concepts are considered: two pathways of tumor progression, clonality of synchronous and metachronous tumors, tumor-analogous molecular findings in flat lesions, and stromal invasion as dominant principle of molecular tumor classification.The dual pathogenesis of molecular pathology is reflected by the WHO 2004 classification by the differentiation into low and high grade malignancy, but diluted by the use of PUNLMP (papillary urothelial neoplasia of low malignant potential). The new concept of frequent oligoclonality should induce investigations about the mechanism of propagation of these migrating or metastasizing cells and whether they possess stem cell characteristics. The role of flat urothelial lesions must be revised from a molecular pathological view point, but the histological diagnosis does not gain profit till now. The expression signatures of stromal invasive tumors compared with non-invasive ones points to the major importance of an exact histopathological diagnosis in this area.

  8. Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges

    PubMed Central

    Garg, Minal

    2016-01-01

    Urothelial carcinoma (UC) of the bladder is characterized by high recurrence rate where a subset of these cells undergoes transition to deadly muscle invasive disease and later metastasizes. Urothelial cancer stem cells (UroCSCs), a tumor subpopulation derived from transformation of urothelial stem cells, are responsible for heterogeneous tumor formation and resistance to systemic treatment in UC of the bladder. Although the precise reason for pathophysiologic spread of tumor is not clear, transcriptome analysis of microdissected cancer cells expressing multiple progenitor/stem cell markers validates the upregulation of genes that derive epithelial-to-mesenchymal transition. Experimental studies on human bladder cancer xenografts describe the mechanistic functions and regulation of epithelial plasticity for its cancer-restraining effects. It has been further examined to be associated with the recruitment of a pool of UroCSCs into cell division in response to damages induced by adjuvant therapies. This paper also discusses the various probable therapeutic approaches to attenuate the progressive manifestation of chemoresistance by co-administration of inhibitors of epithelial plasticity and chemotherapeutic drugs by abrogating the early tumor repopulation as well as killing differentiated cancer cells.

  9. Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges.

    PubMed

    Garg, Minal

    2016-08-26

    Urothelial carcinoma (UC) of the bladder is characterized by high recurrence rate where a subset of these cells undergoes transition to deadly muscle invasive disease and later metastasizes. Urothelial cancer stem cells (UroCSCs), a tumor subpopulation derived from transformation of urothelial stem cells, are responsible for heterogeneous tumor formation and resistance to systemic treatment in UC of the bladder. Although the precise reason for pathophysiologic spread of tumor is not clear, transcriptome analysis of microdissected cancer cells expressing multiple progenitor/stem cell markers validates the upregulation of genes that derive epithelial-to-mesenchymal transition. Experimental studies on human bladder cancer xenografts describe the mechanistic functions and regulation of epithelial plasticity for its cancer-restraining effects. It has been further examined to be associated with the recruitment of a pool of UroCSCs into cell division in response to damages induced by adjuvant therapies. This paper also discusses the various probable therapeutic approaches to attenuate the progressive manifestation of chemoresistance by co-administration of inhibitors of epithelial plasticity and chemotherapeutic drugs by abrogating the early tumor repopulation as well as killing differentiated cancer cells. PMID:27621760

  10. Upper tract urothelial carcinoma: epidemiology, high risk populations and detection.

    PubMed

    Redrow, Grant P; Matin, Surena F

    2016-08-01

    Upper tract urothelial carcinoma (UTUC) is a rare but highly morbid genitourinary malignancy. In 2014 approximately 15,000 new cases were diagnosed in the United States. It accounts for approximately 5-10% of all urothelial cell carcinomas, and 10% of renal tumors. Recent research has increased understanding of the epidemiology of this disease, including several high-risk populations. Environmental exposure to tobacco as well as aristolochic acid, and other carcinogens significantly increase the development of UTUC. Additionally, the genetic condition of hereditary nonpolyposis colorectal carcinoma (HNPCC), also known as Lynch Syndrome (LS) is linked to development of UTUC. Advances in imaging, ureteroscopy, cytological techniques and pathological recognition have allowed for improved detection of primary tumors and recurrent disease. Non-invasive imaging with computed tomography (CT) and magnetic resonance imaging (MRI) now represent the gold standard in imaging detection and surveillance, while technological advances in ureteroscopy allow for minimally invasive approaches to obtain pathologic diagnosis anywhere within the upper tracts. This review will highlight these recent improvements to allow better understanding of who is affected by this rare and morbid disease, as well as the latest developments in detection and surveillance. PMID:27008468

  11. Canine urothelial carcinoma: genomically aberrant and comparatively relevant

    PubMed Central

    Shapiro, S. G.; Raghunath, S.; Williams, C.; Motsinger-Reif, A. A.; Cullen, J. M.; Liu, T.; Albertson, D.; Ruvolo, M.; Lucas, A. Bergstrom; Jin, J.; Knapp, D. W.; Schiffman, J. D.

    2015-01-01

    Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97% and 84% of cases, respectively, and losses on CFA 19 were present in 77% of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to

  12. A case of urothelial carcinoma, lipid cell variant.

    PubMed

    Kojima, Yui; Takasawa, Akira; Murata, Masaki; Akagashi, Keigo; Inoue, Tomomi; Hara, Mamie; Tokunaga, Yuichi; Minase, Takashi; Hasegawa, Tadashi; Sawada, Norimasa

    2013-03-01

    The lipid cell variant of urothelial carcinoma is a rare variant of urinary bladder cancer, comprised of lipoblast-like cells. In this report, we describe a case of the lipid cell variant of aggressive urothelial carcinoma. A 78-year-old man was admitted to the hospital because of gross hematuria. On cystoscopy, an ulcerative lesion, non-papillary architecture, was observed in the lateral wall of the bladder. Transurethral resection was performed. Histopathological findings of the bladder tumor indicated neoplastic cells forming irregular solid nests and sheets. Lipoblast-like neoplastic cells that had eccentric nuclei and cytoplasmic vacuoles were observed, not only in the resected specimen, but also in urine samples. On mucin histochemistry, the tumor cell cytoplasm contained no neutral or acidic mucus. The lipoblast-like cells were positive for cytokeratins (AE1/AE3, CK7) and adipophilin, known as a protein associated with neutral lipid synthesis. In general, it is difficult to prove the existence of intracytoplasmic lipid in formalin-fixed paraffin-embedded materials. This is the first report in which the presence of lipid in vacuoles of the lipid cell variant has been verified by immunohistochemistry.

  13. Urothelial and Squamous Cell Carcinoma of Renal Pelvis – A Rare Case Report

    PubMed Central

    Hippargi, Surekha B.; Kumar, Mayank

    2016-01-01

    Primary malignant tumors of the renal pelvis are relatively rare. Urothelial carcinoma of renal pelvis accounts for 7% of all renal neoplasms, with Squamous Cell Carcinoma (SCC) forming a very small percentage of these cases. Urothelial and SCC of renal pelvis is still a rarer entity. This malignancy of the renal pelvis lacks the characteristic presentation of common renal cell carcinoma and usually presents at an advanced disease stage. We report a case of urothelial and SCC of renal pelvis in a 61-year-old male who presented with non-specific clinical complaints like dysuria and right flank pain. PMID:27790450

  14. Evaluation of fascin-1 expression as a marker of invasion in urothelial carcinomas

    PubMed Central

    Sharma, Arun; Badwal, Sonia; Dutta, Vibha; Basu, Atoshi

    2014-01-01

    Background Prognostication and therapeutic evaluation of urothelial carcinomas significantly depends on the depth of invasion. The assessment of invasion on routine histopathological sections may be difficult in some cases. Fascin is an actin-bundling protein involved in tumor cell migration with enhanced expression associated with invasive tumors. The data available on fascin-1 expression in urothelial carcinoma however is limited. To characterize fascin-1 expression in urothelial neoplasms and its correlation with invasiveness in urothelial carcinomas. Methods A descriptive study design wherein fascin-1 immunoreactivity was studied in 126 urothelial neoplasms using monoclonal antibody against fascin by immunohistochemistry. 52/126 (41.26%) were low grade carcinomas (48/52 stage pTa and 4/52 stage pT1), 46/126 (36.5%) high grade carcinomas (13/46 stage pTa, 8/46 stage pT1 and 25/46 stage pT2), 02/126 carcinoma-in-situ, 03/126 papilloma, 12/126 papillary urothelial neoplasm of uncertain malignant potential and 11/126 were other variants of urothelial carcinomas. Fascin-1 cytoplasmic immunoreactivity was assessed semiquantitatively in terms of extent, intensity and a combined immunoreactivity score. Correlation between immunoreactivity scores and invasiveness was evaluated using Pearson's chi-square (χ2) and Nonparametric Spearman rho (ρ) correlation coefficient two tailed. Results The scores for intensity, extent and combined immunoreactivity were significantly higher in invasive carcinomas. In addition, strong staining was observed exclusively in invasive carcinomas. None of the pTa tumors demonstrated intense staining, including those categorized as high grade carcinomas. Conclusion Fascin-1 overexpression may be used as a marker in urothelial carcinomas where it is morphologically difficult to determine the status of invasion. PMID:24843202

  15. Beyond conventional chemotherapy: Emerging molecular targeted and immunotherapy strategies in urothelial carcinoma.

    PubMed

    Ikeda, Sadakatsu; Hansel, Donna E; Kurzrock, Razelle

    2015-09-01

    Advanced urothelial carcinoma is frequently lethal, and improvements in cytotoxic chemotherapy have plateaued. Recent technological advances allows for a comprehensive analysis of genomic alterations in a timely manner. The Cancer Genome Atlas (TCGA) study revealed that there are numerous genomic aberrations in muscle-invasive urothelial carcinoma, such as TP53, ARID1A, PIK3CA, ERCC2, FGFR3, and HER2. Molecular targeted therapies against similar genetic alterations are currently available for other malignancies, but their efficacy in urothelial carcinoma has not been established. This review describes the genomic landscape of malignant urothelial carcinomas, with an emphasis on the potential to prosecute these tumours by deploying novel targeted agents and immunotherapy in appropriately selected patient populations. PMID:26138514

  16. Recurrence of Urothelial Bladder Carcinoma in the Colon Presenting as Hematochezia

    PubMed Central

    Krzyzak, Michael; Barakat, Iskandar; Deeb, Liliane

    2016-01-01

    Patients with superficial bladder cancers remain clinically indolent after treatment with even a modicum of urologic intervention. However, with more invasive disease, the majority of patients experience recurrence. The conventional route of metastasis and recurrence in primary urothelial cell carcinoma is through lymphatic system, with regional lymph nodes, lungs, liver, brain, and bone being the most common sites. Isolated intraluminal colonic recurrence in the absence of local invasion is extremely rare. We report a unique case of urothelial cell carcinoma presenting with an isolated colonic mass, which unexpectedly, on immunohistostaining, proved to be primarily of urothelial rather than colonic origin. PMID:27807561

  17. Role of surgical consolidation in metastatic urothelial carcinoma

    PubMed Central

    Abe, Takashige; Matsumoto, Ryuji; Shinohara, Nobuo

    2016-01-01

    Purpose of review Since the development of systemic combination chemotherapy, postchemotherapy extirpation has been performed in selected patients mainly with locally advanced and/or initially unresectable bladder cancer, and, in very selected patients, surgical consolidation for visceral metastases has also been performed. The purpose of this article was to review and summarize the current evidence for the role of surgical consolidation in metastatic urothelial carcinoma. Recent findings The role of metastasectomy has not yet been examined in a randomized setting. In terms of locally advanced and/or node-positive bladder cancer, studies further support the benefit of surgical consolidation, especially after a favorable response to systemic chemotherapy. Regarding metastasectomy for visceral metastasis, recent evidence suggested that lung metastases (ideally small solitary lesions) are a good indication. Summary Patients with a good response to chemotherapy, limited nodal/pulmonary disease, and a favorable performance status are good candidates for surgical consolidation. Careful patient selection is mandatory. PMID:27471992

  18. Autophagy and urothelial carcinoma of the bladder: A review

    PubMed Central

    Chandrasekar, Thenappan

    2016-01-01

    The incidence of urothelial carcinoma of the urinary bladder (bladder cancer) remains high. While other solid organ malignancies have seen significant improvement in morbidity and mortality, there has been little change in bladder cancer mortality in the past few decades. The mortality is mainly driven by muscle invasive bladder cancer, but the cancer burden remains high even in nonmuscle invasive bladder cancer due to high recurrence rates and risk of progression. While apoptosis deregulation has long been an established pathway for cancer progression, nonapoptotic pathways have gained prominence of late. Recent research in the role of autophagy in other malignancies, including its role in treatment resistance, has led to greater interest in the role of autophagy in bladder cancer. Herein, we summarize the literature regarding the role of autophagy in bladder cancer progression and treatment resistance. We address it by systematically reviewing treatment modalities for nonmuscle invasive and muscle invasive bladder cancer. PMID:27326411

  19. Clinicopathological prognostic factors for upper tract urothelial carcinoma

    PubMed Central

    Timev, Alexander; Dimitrov, Plamen; Vasilev, Vasil; Krastanov, Alexander; Georgiev, Marincho; Yanev, Krasimir; Simeonov, Peter; Panchev, Peter

    2016-01-01

    Introduction The aim of the present study was to evaluate the influence of clinicopathological factors including age, gender, tumor grade, tumor stage, lymphovascular invasion (LVI), tumor necrosis and previous history of non-muscle invasive bladder cancer on outcomes of patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). Material and methods A total of 60 patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma at our institute between 2005 to 2012 were included in our study. Univariate and multivariate analysis was performed using the Kaplan-Meier method, log rank statistics, the chi-square test and Cox regression models. Results The mean length of follow-up time was 33.3 months. There were 27 (45%) patients alive with the disease, whereas 33 (55%) were dead. In 19 cases (31.7%) the tumor grade was low, while in 41 cases (68.3%) it was high. Lymphovascular invasion was observed in 28 (46.7%) cases. Tumor necrosis was registered in 14 patients (23.3%). From the patients with LVI, 3 (9.6%) were alive, whereas from the patients negative for LVI, 75% were alive. Significant relationship was found between gender and grading and between positive LVI and low grading. Conclusions Day case Variables such as gender, grading, tumor stage, LVI and tumor necrosis were all demonstrated to be significant independent prognostic factors for the overall survival. On the multivariate analysis only LVI remained statistically significant, which may explain the different clinical course in patients and could be considered as a part of pathological reporting and treatment planning for the future. PMID:27123328

  20. Expression of MLH1 and MSH2 in urothelial carcinoma of the renal pelvis.

    PubMed

    Ehsani, Laleh; Osunkoya, Adeboye O

    2014-09-01

    In this study, we investigated microsatellite instability in urothelial carcinoma of the renal pelvis by lack of immunohistochemical staining for MLH1 and MSH2. The study included 44 cases of urothelial carcinoma of the renal pelvis obtained from radical nephroureterectomy specimens at our institution. We evaluated the loss of nuclear immunohistochemical staining of MLH1 and MSH2. Eight of 44 (18 %) patients had negative MLH1 expression and 25/44 (57 %) patients had negative MSH2 expression. Six of 8 (75 %) patients with negative MLH1 expression were male and 2/8 (25 %) patients were female. Nineteen of 25 (75 %) patients with negative MSH2 expression were male, and 6/25 (24 %) patients were female. Seven of 8 (88 %) cases with negative MLH1 expression were high-grade urothelial carcinoma, and 21/25 (84 %) cases with negative MSH2 expression were high-grade urothelial carcinoma. Twenty-one of 44 (48 %) cases had an inverted growth pattern, of which 3/21 (14 %) cases had negative MLH1 expression and 14/21 (67 %) cases had negative MSH2 expression. Our study showed that microsatellite instability based on negative expression of MLH1 and MSH2 was more common in male patients with high-grade urothelial carcinoma. There is a strong correlation between inverted growth pattern and negative MSH2 expression. Microsatellite instability testing should be performed in patients with upper urinary tract carcinoma and may have prognostic value. PMID:24874052

  1. Risk stratification for kidney sparing procedure in upper tract urothelial carcinoma

    PubMed Central

    Khene, Zine-Eddine; Mathieu, Romain; Kammerer-Jacquet, Solène-Florence; Seisen, Thomas; Roupret, Morgan; Shariat, Shahrokh F.; Peyronnet, Benoit

    2016-01-01

    Risk stratification for kidney sparing procedures (KSP) to treat upper tract urothelial carcinoma (UTUC) is a major issue. A non-systematic Medline/PubMed literature search was performed using the terms “upper tract urothelial carcinoma” with different combinations of keywords to review the current knowledge on this topic. Original articles, reviews and editorials in English language were selected based on their clinical relevance. Available techniques for KSP include segmental ureterectomy and endoscopic resection through a percutaneous or flexible ureteroscopic access. These approaches were traditionally restricted to patients with imperative indications. Current recommendations suggest that selected patients with normal contralateral kidney should also be candidates for such treatments. Modern imaging and endoscopy have improved to accurately stage and grade the tumor while various prognostic clinical factors and biomarkers have been proposed to identify tumor with aggressive features and worse outcomes. Several predictive models using different combinations of such baseline characteristics may help clinicians in clinical decision making. However, risk-adapted based approach that has been proposed in recent guidelines to identify patients who are more likely to benefit from KSP only relies on few clinical and pathological factors. Despite growing understanding of the disease, treatment of UTUC remains challenging. Further efforts and collaborative multicenter studies are mandatory to improve risk stratification to decide and promote optimal KSP in UTUC. These efforts should focus on the integration of promising biomarkers and predictive tools in clinical decision making. PMID:27785428

  2. Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC)

    PubMed Central

    Pollard, Courtney; Smith, Steven C.; Theodorescu, Dan

    2010-01-01

    Urothelial carcinoma (UC) is the most common type of bladder cancer in Western nations. Most patients present with the non-muscle-invasive (NMIUC) form of the disease, while up to a third harbour the invasive form (MIUC). Specifically, the aetiology of NMIUC appears to be multifactorial and very different from that of MIUC. Loss of specific tumour suppressor genes as well as gain-of-function mutations in proteins within defined cellular signalling pathways have been implicated in NMIUC aetiology. The regions of chromosome 9 that harbour CDKN2A, CDKN2B, TSC1, PTCH1 and DBC1 are frequently mutated in NMIUC, resulting in functional loss; in addition, HRAS and FGFR3, which are both proto-oncogenes encoding components of the Ras–MAPK signalling pathway, have been found to harbour activating mutations in a large number of NMIUCs. Interestingly, some of these molecular events are mutually exclusive, suggesting functional equivalence. Since several of these driving changes are amenable to therapeutic targeting, understanding the signalling events in NMIUC may offer novel approaches to manage the recurrence and progression of this disease. PMID:20334706

  3. Primary multiple clear cell variant urothelial carcinomas of urinary bladder: a rare case report

    PubMed Central

    Zhang, Yutao; Huang, Jun; Feng, Hao; Tang, Yun

    2014-01-01

    Clear cell variant urothelial carcinoma of urinary bladder was very rare. There were only 6 report articles included by Pubmed and total 8 cases had been described till now. All of the past reports described single tumor of urinary bladder, but multiple carcinomas had not been reported. Here we reported a 65-years-old Chinese man who complained of intermittent gross hematuria and odynuria for more than 2 months in January 2013. Only one cauliflower-like tumor was detected approximately in the left wall of the urinary bladder with cystoscopy and the biopsy specimen was diagnosed as “urothelial carcinoma, high grade”. However, three tumors were found in anterior wall (×2) near neck of urinary bladder and posterior wall (×1) of the urinary bladder during transurethral resection of the bladder tumor. Typical urothelial carcinoma with partial clear cell appearance made it difficult to make a precise pathological diagnosis and immunohistochemical stain helped to diagnose the case as clear cell variant urothelial carcinoma, but not metastasis of the renal cell carcinoma. Finally, computerized tomographic scanning confirmed that there was no primary tumor in the kidney. The clinical and pathological characteristic had not been identified for the limited reports. More work should be done to know this kind of tumor well for guiding clinical therapy. PMID:25031765

  4. Association of urothelial carcinoma of the renal pelvis with papillary and medullary thyroid carcinomas. A new sporadic neoplastic syndrome?

    PubMed

    Albores-Saavedra, Jorge; Dorantes-Heredia, Rita; Chablé-Montero, Fredy; Córdova-Ramón, Juan Carlos; Henson, Donald E

    2014-10-01

    We describe 2 adult women (72 and 54 years), 1 with a low-grade noninvasive papillary urothelial carcinoma of the renal pelvis, who 14 years later developed a papillary carcinoma in 1 thyroid lobe and a medullary carcinoma in the contralateral lobe. Both neoplasms were similar in size and appeared symmetrical. Despite its small size, the medullary carcinoma metastasized in multiple cervical lymph nodes. The second patient had a high-grade invasive papillary urothelial carcinoma of the renal pelvis that infiltrated the renal parenchyma and metastasized in one of the lungs. Five months later, a papillary carcinoma was discovered in the thyroid gland. The 2 papillary thyroid carcinomas were of the follicular variant. Adjacent to 1 papillary carcinoma, there was a dominant nodule of a colloid and adenomatous goiter. The medullary carcinoma contained stromal amyloid and was immunoreactive for calcitonin and carcinoembryonic antigen. There was no C-cell hyperplasia (medullary carcinoma in situ). The 2 patients are alive, 1 is living with pulmonary metastasis from the high-grade urothelial carcinoma. Twelve cases of this neoplastic association were registered in the Survey, Epidemiology, and End Results Program from 1980 to 2009. We believe that the combination of these unusual neoplasms in the same patient may represent a new sporadic neoplastic syndrome.

  5. Hypercalcemia in Upper Urinary Tract Urothelial Carcinoma: A Case Report and Literature Review

    PubMed Central

    McHugh, Jonathan B.; Miller, David C.; Esfandiari, Nazanene H.

    2013-01-01

    Objective. We here report a patient with upper urinary tract urothelial carcinoma with hypercalcemia likely due to elevated 1,25-dihydroxyvitamin D. Methods. We present a clinical case and a summary of literature search. Results. A 57-year-old man, recently diagnosed with a left renal mass, for which a core biopsy showed renal cell carcinoma, was admitted for hypercalcemia of 11.0 mg/mL He also had five small right lung nodules with a negative bone scan. Both intact parathyroid hormone and parathyroid hormone-related peptide were appropriately low, and 1,25-dihydroxyvitamin D was elevated at 118 pg/dL. The patient's calcium was normalized after hydration, and he underwent radical nephrectomy. On the postoperative day 6, a repeat 1,25-dihydroxyvitamin D was 24 pg/mL with a calcium of 8.1 mg/dL. Pathology showed a 6 cm high-grade urothelial carcinoma with divergent differentiation. We identified a total of 27 previously reported cases with hypercalcemia and upper tract urothelial carcinoma in English. No cases have a documented elevated 1,25-dihydroxyvitamin D level. Conclusion. This clinical course suggests that hypercalcemia in this case is from the patient's tumor, which was likely producing 1,25-dihydroxyvitamin D. Considering the therapeutic implications, hypercalcemia in patients with upper urinary tract urothelial carcinoma should be evaluated with 1,25-dihydroxyvitamin D. PMID:23476827

  6. Urine and bladder washing cytology for detection of urothelial carcinoma: standard test with new possibilities

    PubMed Central

    Flezar, Margareta Strojan

    2010-01-01

    Background Light microscopic evaluation of cell morphology in preparations from urine or bladder washing containing exfoliated cells is a standard and primary method for the detection of bladder cancer and also malignancy from other parts of the urinary tract. The cytopathologic examination is a valuable method to detect an early recurrence of malignancy or new primary carcinoma during the follow-up of patients after the treatment of bladder cancer. Conclusions Characteristic cellular and nuclear signs of malignancy indicate invasive or in situ urothelial carcinoma or high-grade papillary urothelial carcinoma. However, low sensitivity of the method reflects the unreliable cytopathologic diagnosis of low-grade urothelial neoplasms as cellular and nuclear signs of malignancy in these neoplasms are poorly manifested. Many different markers were developed to improve the diagnosis of bladder carcinoma on urinary samples. UroVysion™ test is among the newest and most promising tests. By the method of in situ hybridization one can detect specific cytogenetic changes of urothelial carcinoma. PMID:22933917

  7. High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma.

    PubMed

    Nguyen, Doreen; Taheri, Diana; Springer, Simeon; Cowan, Morgan; Guner, Gunes; Mendoza Rodriguez, Maria Angelica; Wang, Yuxuan; Kinde, Isaac; VandenBussche, Christopher J; Olson, Matthew T; Ricardo, Bernardo F P; Cunha, Isabela; Fujita, Kazutoshi; Ertoy, Dilek; Kinzler, Kenneth W; Bivalacqua, Trinity J; Papadopoulos, Nickolas; Vogelstein, Bert; Netto, George J

    2016-10-01

    Somatic activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the most common genetic alterations in urothelial carcinoma (UC) of the bladder and upper urinary tract. Little is known, however, about TERT-mutation status in the relatively uncommon but clinically aggressive micropapillary (MPC) variant. We evaluated the presence of TERT promoter mutations in MPC of the bladder and upper urinary tract. A retrospective search of our archives for MPC and UC with micropapillary features (2005-2014) was performed. All slides were reviewed to confirm the histologic diagnosis. Thirty-three specimens from 31 patients had FFPE blocks available for DNA analysis and were included in the study. Intratumoral areas of non-micropapillary histology were also evaluated when present. Samples were analyzed with Safe-SeqS, a sequencing error reduction technology, and sequenced using the Illumina MiSeq platform. TERT promoter mutations were detected in all specimens with pure MPC (18 of 18) and UC with focal micropapillary features (15 of 15). Similar to conventional UC, the predominant mutations identified occurred at positions -124 (C228T) (85 %) and -146 (C250T) (12 %) bp upstream of the TERT ATG start site. In heterogeneous tumors with focal variant histology, intratumoral concordant mutations were found in variant (MPC and non-MPC) and corresponding conventional UC. We found TERT promoter mutations, commonly found in conventional UC, to be frequently present in MPC. Our finding of concordant intratumoral mutational alterations in cases with focal variant histology lends support to the common oncogenesis origin of UC and its variant histology. PMID:27520411

  8. Urothelial carcinoma of the allograft kidney developed in a renal transplant patient.

    PubMed

    Gökçe, Mehmet İlker; Kocaay, Akın Fırat; Aktürk, Serkan; Tüzüner, Acar

    2016-09-01

    Renal transplantation is the best option in the treatment of end-stage renal disease However these patients are under the risk of developing malignancies particularly due to effects of immune supression. These malignancies tend to be more agressive compared to the general population. Here, we present a case of urothelial carcinoma develoing in the ureter of allograft kidney. PMID:27635300

  9. Urothelial carcinoma of the allograft kidney developed in a renal transplant patient

    PubMed Central

    Gökçe, Mehmet İlker; Kocaay, Akın Fırat; Aktürk, Serkan; Tüzüner, Acar

    2016-01-01

    Renal transplantation is the best option in the treatment of end-stage renal disease However these patients are under the risk of developing malignancies particularly due to effects of immune supression. These malignancies tend to be more agressive compared to the general population. Here, we present a case of urothelial carcinoma develoing in the ureter of allograft kidney.

  10. Urothelial carcinoma of the allograft kidney developed in a renal transplant patient

    PubMed Central

    Gökçe, Mehmet İlker; Kocaay, Akın Fırat; Aktürk, Serkan; Tüzüner, Acar

    2016-01-01

    Renal transplantation is the best option in the treatment of end-stage renal disease However these patients are under the risk of developing malignancies particularly due to effects of immune supression. These malignancies tend to be more agressive compared to the general population. Here, we present a case of urothelial carcinoma develoing in the ureter of allograft kidney. PMID:27635300

  11. Uroplakin II Expression in Breast Carcinomas Showing Apocrine Differentiation: Putting Some Emphasis on Invasive Pleomorphic Lobular Carcinoma as a Potential Mimic of Urothelial Carcinoma at Metastatic Sites

    PubMed Central

    Tajima, Shogo; Koda, Kenji

    2016-01-01

    Uroplakin II antibody is exclusively specific for urothelial carcinoma. Nonurothelial carcinoma has not been reported to be immunoreactive for uroplakin II. In the present study, we hypothesized that breast carcinoma showing apocrine differentiation, such as invasive pleomorphic lobular carcinoma (IPLC) and apocrine carcinoma (AC), stains positive for uroplakin II. We identified 6 cases of IPLC between 2000 and 2014 by searching a computerized pathological database. We randomly selected 10 cases of each classic invasive lobular carcinoma (cILC) and AC and five cases of apocrine metaplasia (AM) that coexisted in a surgically resected breast carcinoma specimen. Immunohistochemistry was performed for uroplakin II, GATA3, CK7, CK20, and other representative markers positive for urothelial carcinoma. All cases of IPLC, AC, and AM, except those of cILC, showed immunoreactivity for uroplakin II. Poorly differentiated urothelial carcinoma sometimes shows similar morphology to IPLC with the following immunophenotype: CK7+, CK20−, GATA3+, and uroplakin II+. In the present study, this immunophenotype was observed in all the cases of IPLC and AC. Therefore, when studying metastatic, poorly differentiated carcinoma showing the aforementioned immunophenotype, we should consider the possibility of it being IPLC in addition to metastatic urothelial carcinoma.

  12. Pembrolizumab and Docetaxel or Gemcitabine Hydrochloride in Treating Patients Urothelial Cancer

    ClinicalTrials.gov

    2016-08-31

    Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter; Recurrent Bladder Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Regional Urothelial Carcinoma of the Renal Pelvis and Ureter; Stage III Bladder Urothelial Carcinoma; Stage III Urethral Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Urethral Cancer; Urethral Urothelial Carcinoma

  13. Incidental Lymphoma Discovered During Surveillance for Low-Grade Upper Tract Urothelial Carcinoma Treated Ureteroscopically: A Case Report Series.

    PubMed

    Hubosky, Scott G; Healy, Kelly A; Raval, Amar J; Lallas, Costas D; Filicko-O'Hara, Joanne; Bagley, Demetrius H

    2016-01-01

    Two cases of incidentally found follicular lymphoma during surveillance for ureteroscopically treated upper tract urothelial carcinoma with cross-sectional imaging are described. Multiple independent primary malignancies should be considered in this population. PMID:27579404

  14. Human epidermal growth factor receptor 2 expression in urothelial carcinoma of the renal pelvis: correlation with clinicopathologic parameters.

    PubMed

    Ehsani, Laleh; Osunkoya, Adeboye O

    2014-01-01

    The significance of human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is well established, and these patients are subsequently treated with Trastuzumab. Although HER2 expression in urothelial carcinoma of the urinary bladder has also been recently characterized, it has not been well studied in urothelial carcinoma of the renal pelvis. We investigated the relationship between HER2 overexpression in urothelial carcinoma of the renal pelvis and clinicopathologic parameters. Forty six cases were identified. HER2 overexpression was present in 34/46 (74%) cases. Mean patient age with HER2 overexpression was 68 years (range: 42-87 years). There was a male predominance with 28/34 (82%) patients. High grade urothelial carcinoma was present in 32/34 (94%) cases and 2/34 (6%) cases had low grade urothelial carcinoma. Pathologic staging was as follows; 9/34 (26%) cases were pTa, 10/34 (29%) cases were pT1, 2/34 (6%) cases were pT2, 12/34 (35%) cases were pT3, and 1/34 (3%) cases was pT4. An inverted growth pattern was present in 23/46 (50%) cases. HER2 overexpression was present in 15/23 (65%) cases of urothelial carcinoma with an inverted growth pattern. Our study showed that HER2 overexpression is more common in male patients with high grade urothelial carcinoma, especially those with an inverted growth pattern. It is highly conceivable that patients with urothelial carcinoma of the renal pelvis may be further stratified based on HER2 overexpression, and may also be potential candidates for Trastuzumab therapy in the neoadjuvant or adjuvant setting. PMID:24966967

  15. Immunohistochemical determination of ETS-1 oncoprotein expression in urothelial carcinomas of the urinary bladder.

    PubMed

    Sari, Aysegul; Calli, Aylin; Gorgel, Sacit Nuri; Altinboga, Aysegul Aksoy; Kara, Cengiz; Dincel, Cetin; Cakalagaoglu, Fulya

    2012-03-01

    ETS-1 protooncogene is an important transcription factor that plays a role in the regulation of physiological processes, such as cell proliferation and differentiation. ETS-1 is thought to be related to the growth of carcinoma cells by its regulation of the transcription of matrix metalloproteinases and urokinase-type plasminogen activator. In this study, we aimed to investigate the expression pattern of ETS-1 oncoprotein in urothelial carcinomas of the urinary bladder and determine its relationship with histopathologic parameters, including tumor grade and stage. One hundred six specimens of urothelial carcinoma and a total of 14 normal urothelium were analyzed immunohistochemically with anti-ETS-1 monoclonal antibody. The normal urothelium showed positive ETS-1 immunostaining. ETS-1 expression remained high in low-grade and noninvasive tumors, whereas it frequently decreased in high-grade or invasive carcinomas. Interestingly, ETS-1 was highly expressed in the basal cell layer of the noninvasive urothelial carcinomas. ETS-1 expression showed a strong negative correlation with the tumor grade (P<0.001; r, -0.67) and stage (P<0.001; r, -0.75). The nonmuscle-invasive tumors (pTa+pT1) and noninvasive tumors (pTa) had significantly higher ETS-1 expression than the muscle-invasive tumors (pT2; P<0.001) and invasive tumors (pT1+pT2; P<0.001), respectively. Results of our study show that decreased ETS-1 expression is significantly associated with high grade and advanced stage in urothelial carcinomas of the urinary bladder, and that the downregulation of ETS-1 expression may be a marker of the aggressiveness of such malignancies.

  16. Obesity and Outcomes in Patients with Metastatic Urothelial Carcinoma1

    PubMed Central

    Leiter, Amanda; Doucette, John; Krege, Susan; Lin, Chia-Chia; Hahn, Noah; Ecke, Thorsten; Sonpavde, Guru; Bamias, Aristotle; Oh, William K.; Galsky, Matthew D.

    2016-01-01

    Background: Obesity has been associated with worse outcomes in patients with clinically localized urothelial cancer. However, this impact has not been evaluated in metastatic disease. Objective: To assess the impact of obesity on outcomes of patients with metastatic urothelial cancer. Methods: Data from 537 patients were aggregated from eight phase II and phase III clinical trials investigating first-line cisplatin-based combination therapy in metastatic urothelial cancer. Chemotherapy regimen, adverse events, treatment response, and survival outcomes were compared across body mass index (BMI) and body surface area (BSA) categories. Results: BMI was classified according to WHO criteria (<18.5 underweight, 18.5–24.99 normal weight, 25–29.99 overweight, >30 obese). BSA was classified as either below or greater than or equal to (average for this cohort (1.87 m2 for males and 1.66 m2 for females). There was no significant difference in number of chemotherapy cycles, adverse events, and response rate or survival outcomes (overall and progression-free) across BMI and BSA categories. There was no significant difference in adverse events across BMI categories, but the incidences of embolic events and renal failure were higher in patients with an average or higher BSA than those with a lower than average BSA (6.6% vs. 3.1% for renal failure p = 0.06; 5.9% vs. 2.7% for renal failure, p = 0.07). There was no significant difference in response rate or survival outcomes (overall and progression-free) amongst BMI and BSA categories. Conclusions: Obese patients with metastatic urothelial cancer on cisplatin-based therapies have similar response rates, survival outcomes, and tolerability of cisplatin-based therapy to non-obese patients. PMID:27500201

  17. Study of mutated p53 protein by immunohistochemistry in urothelial neoplasm of urinary bladder.

    PubMed

    Roychowdhury, Anadi; Dey, Ranjan K; Bandyapadhyay, Anjali; Bhattacharya, Palash; Mitra, Rita Basu; Dutta, Riju

    2012-06-01

    It is difficult to predict which urothelial neoplasm would subsequently recur or progress to muscle invasive tumours or produce metastasis.The aim and objective of the study were to evaluate the scope of immunohistochemical expression of p53 in human urothelial neoplasms with regard to grade, stage and outcome of the patients. Eighteen consecutive patients were taken and urothelial tumour samples were obtained from transurethral resection or surgical excision. Histopathological examinations were performed and the grading was done according to the WHO/ISUP consensus classification of urothelial neoplasms. Immunohistochemical staining for p53 was performed on formalin fixed paraffin embedded tissue sections with appropriate positive and negative control. It was found 3 patients with papillary urothelial neoplasm of low malignant potential (PUNLMP), 5 cases of papillary low grade urothelial carcinoma, 10 patients with papillary high grade urothelial carcinoma including 2 cases of invasive urothelial carcinoma. All three PUNLMP cases showed negative results. Four out of 5 low grade papillary urothelial carcinoma had nuclear p53 accumulation, while all of the 10 papillary high grade carcinoma had high p53 index. The finding of negative p53 staining in PUNLMPs and high p53 index in high grade papillary urothelial carcinomas and invasive carcinomas support the notion that mutation of p53 gene might be unrelated to the development of urothelial neoplasms but definitely play a crucial role in progression of the malignancy.

  18. Coexistence of Malakoplakia and Papillary Urothelial Carcinoma of the Urinary Bladder.

    PubMed

    Lee, Song Liang Joshua; Teo, Jin Kiat; Lim, Sey Kiat Terence; Salkade, Hema Parag; Mancer, Kent

    2015-10-01

    Malakoplakia is a rare granulomatous disease that commonly involves the genitourinary tract, with the urinary bladder being the most frequently affected site. Grossly, malakoplakia can present as soft yellow plaques, nodules, bladder mass, or even without any visible lesion. In this article, we present a 74-year-old female with a background of hypertension, hyperlipidemia, and poorly controlled diabetes who presented with sepsis of unknown origin. During the course of the investigation of the source of her sepsis, an incidental bladder tumor was discovered. She subsequently underwent transurethral resection of the bladder tumor. Histology revealed ordinary low-grade papillary urothelial carcinoma that had small colonies of malakoplakia that appeared to have developed secondary to the tumor and presented concurrently. We seek to demonstrate the rare association of papillary urothelial carcinoma and malakoplakia.

  19. A Rare Metastatic Myositis Ossificans of Obturator Muscle Secondary to Urothelial Carcinoma

    PubMed Central

    Dell’Atti, Lucio

    2015-01-01

    The most frequent metastatic sites of the urothelial bladder cancers (UBCs) are bones, lungs, lymph nodes, liver, pleura, and brain. In the literature, skeletal muscle metastases from UBC have been rarely reported. We report a case of a 65-year-old male with metastatic myositis ossificans to obturator muscle 14 months after radical cystectomy performed for a muscle invasive transitional cell carcinoma. An abdomen computed tomography scan showed a lesion of about 8 cm in diameter in the left obturator muscle with myositis ossificans aspect. Ultrasound guided biopsy specimen of the left obturator muscle revealed poorly differentiated metastatic urothelial carcinoma with malignant myositis ossificans aspects. The patient refused additional surgery and received systemic chemotherapy and radiotherapy at the site of the lesion. The patient more than 6 months after treatment has a good performance status with a partial reduction of the mass and negative imaging for metastases in the follow-up. PMID:26500729

  20. TERT promoter mutations in renal cell carcinomas and upper tract urothelial carcinomas.

    PubMed

    Wang, Kun; Liu, Tiantian; Liu, Li; Liu, Jikai; Liu, Cheng; Wang, Chang; Ge, Nan; Ren, Hongbo; Yan, Keqiang; Hu, Sanyuan; Björkholm, Magnus; Fan, Yidong; Xu, Dawei

    2014-04-15

    TERT promoter mutations are identified in many malignancies including bladder cancer (BC) and upper tract urothelial carcinoma (UTUC). In contrast, no mutations were found in renal cell carcinoma (RCC) as reported in a recent study. Because the mutant TERT promoter in urine DNA was recently tested as a marker for BC, it is important to ascertain whether these mutations are truly absent in RCCs. Here we determined TERT promoter mutations in 109 patients with RCC and 14 patients with UTUC. The mutations were found in 9/96 (9.3%) clear cell RCC (ccRCC) tumors and 1/8 (13%) chromophobe RCC tumors. Among ccRCC patients, the mutation was correlated with the advanced stages and metastasis, and higher TERT expression. Among UTUCs, the mutation was detected in tumors from 3/5 (60%) patients with renal pelvic cancer and 1/9 (11%) patients with ureter cancer. The mutation was also detected in 1 of 4 urine samples from patients with mutation+ UTUC. Collectively, TERT promoter mutations do occur in RCCs and are associated with aggressive disease. The mutation is more frequent in renal pelvic cancer. Thus, the mutant TERT promoter found in urine may come from not only BC, but also RCC or UTUC. PMID:24742867

  1. TERT promoter mutations in renal cell carcinomas and upper tract urothelial carcinomas

    PubMed Central

    Liu, Jikai; Liu, Cheng; Wang, Chang; Ge, Nan; Ren, Hongbo; Yan, Keqiang; Hu, Sanyuan; Björkholm, Magnus; Fan, Yidong; Xu, Dawei

    2014-01-01

    TERT promoter mutations are identified in many malignancies including bladder cancer (BC) and upper tract urothelial carcinoma (UTUC). In contrast, no mutations were found in renal cell carcinoma (RCC) as reported in a recent study. Because the mutant TERT promoter in urine DNA was recently tested as a marker for BC, it is important to ascertain whether these mutations are truly absent in RCCs. Here we determined TERT promoter mutations in 109 patients with RCC and 14 patients with UTUC. The mutations were found in 9/96 (9.3%) clear cell RCC (ccRCC) tumors and 1/8 (13%) chromophobe RCC tumors. Among ccRCC patients, the mutation was correlated with the advanced stages and metastasis, and higher TERT expression. Among UTUCs, the mutation was detected in tumors from 3/5 (60%) patients with renal pelvic cancer and 1/9 (11%) patients with ureter cancer. The mutation was also detected in 1 of 4 urine samples from patients with mutation+ UTUC. Collectively, TERT promoter mutations do occur in RCCs and are associated with aggressive disease. The mutation is more frequent in renal pelvic cancer. Thus, the mutant TERT promoter found in urine may come from not only BC, but also RCC or UTUC. PMID:24742867

  2. Expression of Fibroblast Growth Factor Receptor 3 in the Recurrence of Non-Muscle-Invasive Urothelial Carcinoma of the Bladder

    PubMed Central

    Maeng, Young-Hee; Eun, Su-Yong

    2010-01-01

    Purpose The fibroblast growth factor receptor 3 (FGFR3) gene is known to be frequently mutated in noninvasive urothelial carcinomas of the bladder. In this study, we investigated the expression of FGFR3, Ki-67, and p53 in bladder cancers and the effects of expression on tumor recurrence. Materials and Methods Fifty-five cases of primary bladder cancer were examined by immunohistochemistry. The relationship of these markers with various clinicopathological factors, including recurrence, was assessed. Results Positivity for cytoplasmic FGFR3 (FGFR3-c) was associated with a lower cancer grade (p=0.022) and stage (p=0.011). Recurrence was more frequent in patients with a higher stage, negative FGFR3-c, and high Ki-67 expression. According to univariate analysis, predictors of recurrence-free survival included the following: age, stage, FGFR-c, Ki-67, and p53. However, none of these was independent from the other parameters in multivariate studies. Conclusions The immunohistochemical expression of FGFR3 is not only one of the characteristic features of lower-grade and lower-stage urothelial carcinoma but also a possible marker in predicting disease recurrence. PMID:20414420

  3. Lifetime risk of urothelial carcinoma and lung cancer in the arseniasis-endemic area of Northeastern Taiwan

    NASA Astrophysics Data System (ADS)

    Yang, Tse-Yen; Hsu, Ling-I.; Chen, Hui-Chi; Chiou, Hung-Yi; Hsueh, Yu-Mei; Wu, Meei-Maan; Chen, Chi-Ling; Wang, Yuan-Hung; Liao, Ya-Tang; Chen, Chien-Jen

    2013-11-01

    Arsenic in drinking water has been shown to increase the risk of urothelial carcinoma and lung cancer. However, the lifetime risk of developing urothelial carcinoma and lung cancer caused by exposure to arsenic in drinking water has not been reported. This study aimed to assess the lifetime risk of urothelial carcinoma and lung cancer caused by arsenic exposure from drinking water and cigarette smoking habit for residents living in the arseniasis-endemic area in Northeastern Taiwan. We recruited 8086 residents in 1991-1994 and monitored them for their newly developed types of cancers, identified by computerized linkage with the national cancer registry profile. There were 37 newly diagnosed urothelial carcinoma cases and 223 new lung cancer cases during the follow-up period (until 2007). The lifetime (35-85 years old) cumulative risk of developing urothelial carcinoma from an arsenic concentration in the drinking water of <10, 10-99, and 100+ μg/L was 0.29%, 1.07% and 3.43%, respectively. The corresponding probabilities were 7.42%, 8.99% and 17.09% for the lifetime risk of developing lung cancer. Cigarette smoking was associated with an increased risk of urothelial carcinoma and lung cancer, showing the hazard ratio (95% confidence interval) of 2.48 (1.27-4.82) and 3.44 (2.00-5.90) after adjusting for the arsenic concentration in drinking water. After adjusting for cigarette smoking, the hazard ratio (95% confidence interval) of developing urothelial carcinoma caused by the arsenic concentration in drinking water of <10, 10-99 and 100+ μg/L was 1.0 (the reference group), 2.18 (0.59-8.01), and 8.71 (2.49-30.48), respectively. The corresponding figures were 1.0 (the reference group), 1.14 (0.80-1.61), 1.84 (1.28-2.65) for lung cancer. Synergistic effects on the development of urothelial carcinoma and lung cancer existed between the arsenic exposure level and cigarette smoking. It is suggested that people who have had a high exposure to arsenic in drinking water

  4. MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy

    PubMed Central

    Popovska-Jankovic, Katerina; Noveski, Predrag; Jankovic-Velickovic, Ljubinka; Stojnev, Slavica; Cukuranovic, Rade; Stefanovic, Vladisav; Toncheva, Draga; Staneva, Rada; Polenakovic, Momir; Plaseska-Karanfilska, Dijana

    2016-01-01

    Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups. PMID:27218105

  5. MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy.

    PubMed

    Popovska-Jankovic, Katerina; Noveski, Predrag; Jankovic-Velickovic, Ljubinka; Stojnev, Slavica; Cukuranovic, Rade; Stefanovic, Vladisav; Toncheva, Draga; Staneva, Rada; Polenakovic, Momir; Plaseska-Karanfilska, Dijana

    2016-01-01

    Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups. PMID:27218105

  6. Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas.

    PubMed

    Malouf, Gabriel G; Compérat, Eva; Yao, Hui; Mouawad, Roger; Lindner, Veronique; Rioux-Leclercq, Nathalie; Verkarre, Virginie; Leroy, Xavier; Dainese, Linda; Classe, Marion; Descotes, Jean-Luc; Barthelemy, Philippe; Yacoub, Mokrane; Rouprêt, Morgan; Bernhard, Jean-Christophe; Creighton, Chad J; Spano, Jean-Philippe; Su, Xiaoping; Khayat, David

    2016-01-01

    Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients. PMID:27484008

  7. Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas

    PubMed Central

    Malouf, Gabriel G.; Compérat, Eva; Yao, Hui; Mouawad, Roger; Lindner, Veronique; Rioux-leclercq, Nathalie; Verkarre, Virginie; Leroy, Xavier; Dainese, Linda; Classe, Marion; Descotes, Jean-Luc; Barthelemy, Philippe; Yacoub, Mokrane; Rouprêt, Morgan; Bernhard, Jean-Christophe; Creighton, Chad J.; Spano, Jean-Philippe; Su, Xiaoping; Khayat, David

    2016-01-01

    Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients. PMID:27484008

  8. Immunotherapy in urothelial carcinoma: fade or future standard?

    PubMed Central

    Breyer, Johannes; Burger, Maximilian

    2016-01-01

    Immunotherapy of non-muscle-invasive bladder carcinoma by Bacillus-Calmette-Guérin (BCG) instillation is a well-established treatment option since decades. Despite this fact, the immunocellular basis was first studied in recent years. New aspects of immunotherapy, also for progressed bladder carcinoma, might follow promising research on immunological targets. PMID:27785423

  9. Prospective evaluation of FISH for detecting upper tract urothelial carcinoma in voided urine specimens

    PubMed Central

    YU, QIUBO; LI, YANAN; LI, GANG; LI, TINGHONG; ZENG, HAN; YANG, ZHU; WANG, DELING

    2016-01-01

    The aim of the present study was to estimate the diagnostic value of fluorescence in situ hybridization (FISH) analysis of tumor cells in voided urine specimens for detecting upper tract urothelial carcinoma (UTUC). Cytology and FISH analyses were conducted on voided urine collected in the morning from 125 patients with suspected UTUC. During follow-up, ureteroscopy with biopsy and histopathology were used to confirm the presence of tumors. The average follow-up time was 23.8 months (range, 6–36 months). A total of 8 patients who could not be contacted until the last follow-up were excluded from the study. Of the remaining 117 patients, 19 were histologically demonstrated to have UTUC, of whom, 3 patients had stage pTis disease, 6 had stage pTa disease, 5 had stage pT1 disease and 5 had stage pT2 disease (7 G1, 8 G2 and 4 G3). The overall sensitivity of FISH to detect UTUCs in voided urine specimens was 84.21% (16/19), whereas that of cytology was 42.11% (8/19) (P<0.05). The overall specificity of FISH to detect UTUCs in voided urine specimens was 89.80% (88/98), compared with 94.90% (93/98) of cytology (P>0.05). The positive predictive value (PPV) and negative predictive value of FISH were 80.00% (16/20) and 97.78% (88/90), respectively, whereas those of cytology were 100.00% (8/8) (P>0.05) and 90.29% (93/103) (P>0.05), respectively. The present data indicated that FISH was a method capable of detecting UTUCs in voided urine specimens with good sensitivity and specificity, although it exhibited a high rate of false positivity and low PPV. PMID:27347122

  10. Bladder cancer will grow anywhere: report of a urothelial carcinoma drop metastasis to the vagina and literature review.

    PubMed

    Uhlman, Matthew A; Bevill, Mark D; Goodheart, Michael J; Brown, James A; O'Donnell, Michael A

    2016-08-01

    Urothelial carcinoma is the 2nd most common cancer of the urinary tract and accounts for the majority of cases of bladder cancer. Metastases are not infrequently encountered, increasing with disease stage and are most commonly seen in the bones and lungs. Many other sites have been described including the omentum, liver, and ovaries. An extremely rare site of metastatic disease however is within the vagina. Here we present a case of a probable vaginal 'drop metastasis' from previously treated urothelial carcinoma in the ureter and bladder. PMID:27544563

  11. Accuracy of grading of urothelial carcinoma on urine cytology: an analysis of interobserver and intraobserver agreement

    PubMed Central

    Reid, Michelle D; Osunkoya, Adeboye O; Siddiqui, Momin T; Looney, Stephen W

    2012-01-01

    Background: Urine samples of known urothelial carcinoma were independently graded by 3 pathologists with (MS, MR) and without (AO) fellowship training in cytopathology using a modified version of the 2004 2-tiered World Health Organization classification system. By measuring interobserver and intraobserver agreement among pathologists, compared with the gold standard of biopsy/resection, specimen accuracy and reproducibility of grading in urine was determined. Methods: 44 urine cytology samples were graded as low or high-grade by 3 pathologists with a 2-3 week interval between grading. Pathologists were blinded to their and others’ grades and histologic diagnoses. Coefficient kappa was used to measure interobserver and intraobserver agreement among pathologists. Accuracy was measured by percentage agreement with the biopsy/resection separately for each pathologist, and for all pathologists and occasions combined. Results: The overall accuracy was 77% (95% C.I., 72% - 82%). Pathologist AO was significantly more accurate than MR on occasion 1 (p = 0.006) and 2 (p = 0.039). No other significant differences were found among the observers. Interobserver agreement using coefficient kappa was unacceptably low, with all but one of the kappa value being less than 0.40, the cutoff for a “fair” degree of agreement. Intraobserver agreement, as measured by coefficient kappa, was adequate. Conclusions: Our study underscores the lack of precision and subjective nature of grading urothelial carcinoma on urine samples. There was poor inter- and intraobserver agreement among pathologists despite fellowship training in cytopathology. Clinicians and cytopathologists should be mindful of this pitfall and avoid grading urothelial carcinoma on urine samples, especially since grading may impact patient management. PMID:23119105

  12. Fluorescence spectroscopy incorporating a ratiometric approach for the diagnosis and classification of urothelial carcinoma

    NASA Astrophysics Data System (ADS)

    Anand, Suresh; Cicchi, Riccardo; Crisci, Alfonso; Nesi, Gabriella; Carini, Marco; Pavone, Francesco S.

    2016-02-01

    The current most popular clinical method for the screening of urothelial carcinoma is white light cystoscopy. This method has inherent disadvantages making a strong genesis towards developing more powerful diagnostic techniques. Laser induced intrinsic fluorescence spectroscopy has been studied as an adjunct to current methods for the detection of tumors. This technique allows real time results based on the changes in spectral profile between normal and tumor tissues. We conducted a pilot study based on fluorescence spectroscopy at two wavelengths 378 and 445 nm excitation for the differentiation of urothelial carcinoma. At both the excitation wavelengths, the measured fluorescence signal showed an increased intensity at wavelengths greater than 520 nm. In addition, the emission profile showed modulation at 580 nm which is due to the reabsorption of emitted fluo- rescence due to hemoglobin. Additionally, we developed a tissue characterizing algorithm, based on fluorescence intensity ratios, F510/F600 and F520/F580 at 378 and 445 nm excitation wavelengths respectively. Further, the results were correlated with the pathologists assessment of urothelial carcinoma. This ratiometric classification algorithm yielded 81% sensitivity and 83% specificity at 378 nm and while at 445 nm excitation we achieved a sensitivity and specificity of 85% and 86% for classifying normal and tumor bladder tissues. In this study we have demonstrated the potential of a simple ratiometric algorithm based on fluorescence spectroscopy could be an alternative tool to tissue biopsy. Furthermore, this technique based fiber-based fluorescence spectroscopy could be integrated into an endoscopy system for use in the operating room.

  13. Lynch syndrome and exposure to aristolochic acid in upper-tract urothelial carcinoma: its clinical impact?

    PubMed Central

    Colin, Pierre; Seisen, Thomas; Mathieu, Romain; Shariat, Sharohkh F.

    2016-01-01

    The purpose of the current review was to describe the clinical risk for Lynch syndrome (LS) after exposure to aristolochic acid (AA) in cases of upper urinary-tract urothelial carcinoma (UTUC). A systematic review of the scientific literature was performed using the Medline database (National Library of Medicine, PubMed) using the following keywords: epidemiology, risk factor, AA, Balkan nephropathy (BNe), LS, hereditary cancer, hereditary non-polyposis colorectal cancer (HNPCC), mismatch repair genes, urothelial carcinomas, upper urinary tract, renal pelvis, ureter, Amsterdam criteria, genetic counselling, mismatch repair genes, genetic instability, microsatellite, and Bethesda guidelines. LS is a specific risk for UTUC, which is the third most frequent cancer (in its tumor spectrum) after colon and uterine lesions. Mutation of the MSH2 gene is the most commonly described cause of UTUC in LS. Diagnosis is based on clinical suspicion and is guided by Bethesda and Amsterdam criteria. It is secondarily confirmed by immunohistochemical analyses of the tumor and a search for gene mutations. The presence of LS in patients with UTUC is a favorable prognosis factor for survival during follow-ups. AA is a specific environmental risk factor for UTUC and tubulo-interstitial nephropathy. It has been involved in the development of nephropathies in link with the Balkan disease and intake of Chinese herbal medicine. More broadly, the use of traditional plant medicines from the genus Aristolochia has created worldwide public-health concerns. UTUCs share common risk factors with other urothelial carcinomas such as tobacco or occupational exposure. However, these tumors have also specific risk factors such as AA exposure and LS that clinicians should be aware of because of their clinical implication in further management and follow-up. PMID:27785421

  14. Geographic Variation of Chronic Kidney Disease Prevalence: Correlation with the Incidence of Renal Cell Carcinoma or Urothelial Carcinoma?

    PubMed Central

    Yap, Yit-Sheung; Chuang, Kai-Wen; Chiang, Chun-Ju; Chuang, Hung-Yi; Lu, Sheng-Nan

    2015-01-01

    Background. The aim of this study is to evaluate whether geographic variations in the prevalence of late-stage chronic kidney disease (CKD) exist and are associated with incidence rates of renal cell carcinoma (RCC), upper tract urothelial carcinoma (UTUC), or lower tract urothelial carcinoma (LTUC). Methods. Prevalence rates of late-stage CKD for 366 townships (n > 30) in Taiwan were calculated for 1,518,241 and 1,645,151 subjects aged 40 years or older in years 2010 and 2009, respectively. Late-stage CKD prevalence in year 2010 was used as a training set and its age-adjusted standardized morbidity rates (ASMR) were divided into three groups as defined <1.76%, 1.76% ≤ ASMR < 2.64%, and ≥2.64%, respectively. Year 2009, defined as the validation set, was used to validate the results. Results. The ASMR of late-stage CKD in years 2010 and 2009 were 1.76%, and 2.09%, respectively. Geographic variations were observed, with notably higher rates of disease in areas of the central, southwestern mountainside, and southeastern seaboard. There were no significant differences among different combined risk groups of RCC, UTUC, and LTUC incidence. Conclusion. The substantial geographic variations in the prevalence of late-stage CKD exist, but are not correlated with RCC, UTUC, or LTUC incidence. PMID:26605329

  15. [Case of a Plasmacytoid Urothelial Carcinoma Identified Due to the Hardening of the Abdominal Wall].

    PubMed

    Yanagisawa, Masahiro; Kawakami, Toshifumi; Suzuki, Kotaro; Nakayama, Takashi

    2016-02-01

    The patient was a 75 year-old male. Noticing areas of hardening in the lower abdomen, and consequently feelings of systemic fatigue and difficulty in walking, the patient visited a clinic and was diagnosed with kidney failure prior to the visit to our clinic. Computed tomography and magnetic resonance imaging showed thickness of the rectus abdominis muscle and the bladder wall, and bilateral hydronephrosis was also identified. As no explicit tumor was identified in the bladder, the patient underwent biopsies of the abdominal wall and bladder membrane mucous, and was diagnosed with a plasmacytoid urothelial carcinoma primarily developed in the bladder. The patient displayed a poor general state of health and died five months after the diagnosis. It is known that plasmacytoid urothelial carcinomas progress rapidly and the prognosis is poorer than for the micropapillary variant. It is important to obtain a tissue specimen in the early stage of this disease because there are cases in which no explicit tumor can be identified. Furthermore, the value of carbohydrate antigen (CA) 19-9 of the patient was much higher than would be expected as normal at the first visit. It kept rising during the follow-up and was useful as a marker to indicate the progress of the disease.

  16. Prognostic Value of Beta-Tubulin-3 and c-Myc in Muscle Invasive Urothelial Carcinoma of the Bladder

    PubMed Central

    Massari, Francesco; Bria, Emilio; Ciccarese, Chiara; Munari, Enrico; Modena, Alessandra; Zambonin, Valentina; Sperduti, Isabella; Artibani, Walter; Cheng, Liang; Martignoni, Guido; Tortora, Giampaolo; Brunelli, Matteo

    2015-01-01

    Background To date, putative prognostic biomarkers have shown limited utility from the clinical perspective for bladder urothelial carcinoma. Herein, the expression of beta-tubulin-3 and c-Myc was evaluated to determine their prognostic potential. Methods In formalin fixed-paraffin embedded blocks, immunohistochemical expression of c-Myc and beta-tubulin-3 was evaluated. H score ranging from 0 to 300 was obtained by multiplying the percentage of positive cells by intensity (0–3); c-Myc and beta-tubulin-3 expression was defined: 0: negative, 1: weakly positive, 2: strongly positive. Results beta-tubulin-3 and c-Myc immunoexpression was available for 46 cases. At the univariate analysis, node-involvement, beta-tubulin-3 and c-Myc overexpression discriminate shorter DFS (HR 2.19, p = 0.043; HR 3.10, p = 0.24 and HR 3.05, p = 0.011, respectively); 2-yrs DFS log-rank analysis according to low versus high level of immunoexpression were statistically significant; beta-tubulin-3, 53% low vs 12.7% high (p = value 0.02) and c-Myc 28 low vs 8 high (p-value 0.007). Patients displaying negative beta-tubulin-3/c-Myc had statistically significant better 2-yrs DFS than those with mixed expression or double positivity (54.5% versus 18.7% versus 0%, log-rank p = 0.006). Conclusions c-Myc and beta-tubulin-3 show improvement for prognostic risk stratification in patients with muscle invasive bladder urothelial carcinoma. These molecular pathways may also be candidate to improve predictiveness to targeted therapies. PMID:26046361

  17. Pulmonary tumor thrombotic microangiopathy associated with urothelial carcinoma of the urinary bladder: antemortem diagnosis by pulmonary microvascular cytology.

    PubMed

    Yamakawa, Hideaki; Yoshida, Masahiro; Yamada, Masami; Ishikawa, Takeo; Takagi, Masamichi; Katagi, Hiroaki; Yoshida, Jun; Kosuga, Tsuneharu; Kuwano, Kazuyoshi

    2015-09-01

    PTTM (Pulmonary tumor thrombotic microangiopathy) is very difficult to diagnose before death. We report a case of urothelial carcinoma of the urinary bladder associated with PTTM in which an antemortem diagnosis by PMC (pulmonary microvascular cytology). PMC may represent the only chance for diagnosis and achievement of remission in PTTM. PMID:26401277

  18. Immunohistochemical profile of the penile urethra and differential expression of GATA3 in urothelial versus squamous cell carcinomas of the penile urethra.

    PubMed

    Chaux, Alcides; Han, Jeong S; Lee, Stephen; Gonzalez-Roibon, Nilda; Sharma, Rajni; Burnett, Arthur L; Cubilla, Antonio L; Netto, George J

    2013-12-01

    The penile urethra has a distinctive morphology not yet fully characterized by immunohistochemistry. In addition, both urothelial and squamous cell carcinomas have been reported in the penile urethra, and the distinction between these 2 tumors might be difficult. The purposes of this study are to assess the histology and immunohistochemical profile (CK20, CK7, p63, and GATA3) of the penile urethra and to assess the usefulness of Trans-acting T-cell-specific transcription factor (GATA3) and human papillomavirus detection in distinguishing urothelial versus squamous cell carcinomas. Normal penile urethra was evaluated in 11 total penectomies. The penile urethra was lined by 2 cell layers: a superficial single layer of CK7+, CK20-, and p63- columnar cells and a deep stratified layer of CK7-, CK20-, and p63+ cubical cells. Both layers were GATA3+, supporting urothelial differentiation. In addition, 2 tissue microarrays and 6 surgical specimens of primary tumors of the penile urethra (3 urothelial and 3 squamous cell carcinomas) were evaluated for GATA3 expression. In the tissue microarrays, 22 of 25 upper tract urothelial carcinomas and 0 of 38 penile squamous cell carcinomas were GATA3+. In the surgical specimens, GATA3 was positive in all urothelial carcinomas and negative in all squamous cell carcinomas. Human papillomavirus was detected in 2 of 3 squamous cell carcinomas and in 0 of 3 of the urothelial carcinomas. In conclusion, the penile urethra is covered by epithelial cells that are unique in morphology and immunohistochemical profile. In addition, our study suggests that GATA3 and human papillomavirus detection are useful markers for distinguishing urothelial carcinomas from squamous cell carcinomas of the penile urethra.

  19. Immunohistochemistry and Fluorescence In Situ Hybridization Can Inform the Differential Diagnosis of Low-Grade Noninvasive Urothelial Carcinoma with an Inverted Growth Pattern and Inverted Urothelial Papilloma

    PubMed Central

    Lu, Yong-Ming; Zhang, Hui-Zhi; Wang, Tao; Yang, Xiao-Qun; Sun, Meng-Hong; Wang, Chao-Fu

    2015-01-01

    Urothelial carcinoma (UC) comprises a heterogeneous group of epithelial neoplasms with diverse biological behaviors and variable clinical outcomes. Distinguishing UC histological subtypes has become increasingly important because prognoses and therapy can dramatically differ among subtypes. In clinical work, overlapping morphological findings between low-grade noninvasive UC (LGNUC), which exhibits an inverted growth pattern, and inverted urothelial papilloma (IUP) can make subclassification difficult. We propose a combination of immunohistochemistry (IHC) and molecular cytogenetics for subtyping these clinical entities. In our study, tissue microarray immunohistochemical profiles of Ki-67, p53, cytokeratin 20 (CK20) and cyclinD1 were assessed. Molecular genetic alterations such as the gain of chromosomes 3, 7 or 17 or the homozygous loss of 9p21 were also assessed for their usefulness in differentiating these conditions. Based on our analysis, Ki-67 and CK20 may be useful for the differential diagnosis of these two tumor types. Fluorescence in situ hybridization (FISH) can also provide important data in cases in which the malignant nature of an inverted urothelial neoplasm is unclear. LGNUC with an inverted growth pattern that is negative for both Ki-67 and CK20 can be positively detected using FISH. PMID:26208279

  20. Immunohistochemistry and Fluorescence In Situ Hybridization Can Inform the Differential Diagnosis of Low-Grade Noninvasive Urothelial Carcinoma with an Inverted Growth Pattern and Inverted Urothelial Papilloma.

    PubMed

    Sun, Juan-Juan; Wu, Yong; Lu, Yong-Ming; Zhang, Hui-Zhi; Wang, Tao; Yang, Xiao-Qun; Sun, Meng-Hong; Wang, Chao-Fu

    2015-01-01

    Urothelial carcinoma (UC) comprises a heterogeneous group of epithelial neoplasms with diverse biological behaviors and variable clinical outcomes. Distinguishing UC histological subtypes has become increasingly important because prognoses and therapy can dramatically differ among subtypes. In clinical work, overlapping morphological findings between low-grade noninvasive UC (LGNUC), which exhibits an inverted growth pattern, and inverted urothelial papilloma (IUP) can make subclassification difficult. We propose a combination of immunohistochemistry (IHC) and molecular cytogenetics for subtyping these clinical entities. In our study, tissue microarray immunohistochemical profiles of Ki-67, p53, cytokeratin 20 (CK20) and cyclinD1 were assessed. Molecular genetic alterations such as the gain of chromosomes 3, 7 or 17 or the homozygous loss of 9p21 were also assessed for their usefulness in differentiating these conditions. Based on our analysis, Ki-67 and CK20 may be useful for the differential diagnosis of these two tumor types. Fluorescence in situ hybridization (FISH) can also provide important data in cases in which the malignant nature of an inverted urothelial neoplasm is unclear. LGNUC with an inverted growth pattern that is negative for both Ki-67 and CK20 can be positively detected using FISH. PMID:26208279

  1. High expression of Notch ligand Jagged2 is associated with the metastasis and recurrence in urothelial carcinoma of bladder

    PubMed Central

    Li, Wei; Liu, Min; Feng, Yuan; Huang, Yan-Fei; Xu, Yun-Fei; Che, Jian-Ping; Wang, Guang-Chun; Zheng, Jun-Hua

    2013-01-01

    Background: The Notch signaling pathway is closely related with human organ development and tumorgenisis. Jagged2 is among the most popular topic in Notch studies currently. Recent studies found its vital role in tumor metastasis in breast cancer; however, its expression profile and its prognostic value in urothelial carcinoma of bladder have not been investigated. Methods: Immunohistochemistry was used to detect the expression of Jagged2 in 120 bladder urothelial carcinoma. Moreover, the expression of Jagged2 was analyzed by Western blot in 60 bladder urothelial carcinoma and 20 normal epithelial tissues. MTT assay and flow cytometry and transwell assay were used to examine the proliferative and invasive ability of bladder cancer cells with the treatment of GSIXX (the inhibitor of Jagged2). Prognostic value of Jagged2 expression and its correlation with tumor metastasis and recurrence were evaluated, and the proliferative and invasive ability and cell cycle process of the bladder cancer cells were detected as well. Results: There was a significantly higher Jagged2 expressions in bladder urothelial carcinoma and highly invasive bladder T24 cells than those in bladder normal tissues and the superficial bladder BIU-87 cells. Jagged2 expression was positively correlated with histological grade, p T stage, recurrence, and metastasis. With the increasing concentration of GSIXX, we found that not only the cell proliferation and invasion activity decreased significantly, but also the cell cycle was blocked at G2/M stage. Conclusions: Jagged2 expression status was closely correlated with important histopathologic characteristics (grades and stages) and the recurrence and metastasis of bladder urothelial carcinomas. Furthermore, Jagged2 played an important function on the bladder cancer cells’ proliferation by regulating the cancer cell cycle from G1/S to G2/M and probably promoted the invasion and metastasis of bladder cancer. PMID:24228105

  2. Diagnostic Value of Liquid-Based Cytology in Urothelial Carcinoma Diagnosis: A Systematic Review and Meta-Analysis

    PubMed Central

    Yang, Li; Fu, Sheng-Jun

    2015-01-01

    Objective To evaluate the value of liquid-based cytology (LBC) in the diagnosis of urothelial carcinoma. Method Diagnostic studies were searched for the diagnostic value of LBC in urothelial carcinoma in PubMed, Embase, Cochrane Library, Web of Science, CBM and CNKI. The latest retrieval date was September 2014. The data were extracted and the quality of the included studies was independently assessed by 2 reviewers. Stata 13 software was used to perform the statistical analysis. The research was conducted in compliance with the PRISMA statement. Result Nineteen studies, which included 8293 patients, were evaluated. The results of the meta-analysis showed that the pooled sensitivity and specificity of LBC were 0.58 (0.51–0.65) and 0.96 (0.93–0.98), respectively. The diagnostic odds ratio (DOR) was 31 (18–56) and the area under the curve (AUC) of summary receiver operating characteristic (SROC) was 0.83 (0.80–0.86). The post-test probability was 80% when a positive diagnosis was made. Compared with high grade urothelial carcinoma (HGUC), the sensitivity of detecting low-grade urothelial carcinoma (LGUC) was significantly lower, risk ratio of sensitivity was 0.54 (0.43–0.66), P<0.001. However, no significant sensitivity improvement was observed with LBC when compared with traditional cytospin cytology, risk ratio was 1.03 (0.94–1.14), P = 0.524. Conclusion Despite LBC having a pooled 58% positive rate for urothelial carcinoma diagnosis in our meta-analysis, no significant improvement in sensitivity was observed based on the studies evaluated. Further research is needed to validate these findings. PMID:26241896

  3. A new proposal to risk stratify urothelial carcinomas of the upper urinary tract (UTUCs) in a predefinitive treatment setting: low-risk versus high-risk UTUCs.

    PubMed

    Rouprêt, Morgan; Colin, Pierre; Yates, David R

    2014-08-01

    Risk stratification of upper tract urothelial carcinoma (UTUC) patients and tumours is crucial for highlighting that an alternative to radical extirpative surgery now exists and should be considered for all patients who qualify as having low-risk UTUC.

  4. Clear-cell variant urothelial carcinoma of the bladder: a case report and review of the literature

    PubMed Central

    Kramer, Mario W.; Abbas, Mahmoud; Pertschy, Stefanie; Becker, Jan Ulrich; Kreipe, Hans-Heinrich; Kuczyk, Markus A.; Merseburger, Axel S.; Tezval, Hossein

    2012-01-01

    Clear cell variants of transitional cell carcinomas (TCC) of the bladder are extremely rare tumors. Only 6 cases have been reported until now. We report of a 67 year old man who presented with fast growing tumor disease. While initial diagnosis showed localized bladder tumor, final histopathology revealed pT4, G3, L1 urothelial carcinoma with clear cell differentiation. No more than 14 weeks after initial diagnosis the patient died from multi-organ failure after unsuccessful salvage laparotomy which showed massive tumor burden within the pelvis and peritoneal carcinosis. This case demonstrated an extremely fast tumor growth. Therefore, patients with clear cell urothelial carcinoma should be treated vigorously and without time delay. We present a case of clear cell variant of TCC which exhibited an extremely aggressive behavior. To our knowledge this is the fifth report of this rare disease. PMID:23372912

  5. Reduced 5-Methylcytosine Level as a Potential Progression Predictor in Patients with T1 or Non-Invasive Urothelial Carcinoma

    PubMed Central

    Chung, Chi-Jung; Chang, Chao-Hsiang; Chuu, Chih-Pin; Yang, Chi-Rei; Chang, Yi-Huei; Huang, Chi-Ping; Chen, Wen-Chi; Chung, Mu-Chi; Chang, Han

    2014-01-01

    This study aims to elucidate the level of DNA methylation in urothelial carcinomas (UCs) using 5-methylcytosine (5-MeC) immunohistochemistry (IHC). We examined the relationship among 5-MeC levels, DNA (cytosine-5)-methyltransferase 1 (DNMT1) immunostaining levels, and clinicopathologic features. Tissue samples included 23 normal urothelia and 150 urothelial neoplasia, which comprised 40 non-invasive and 110 invasive UCs. The levels of 5-MeC and DNMT1 were assessed based on their immunoreactivities and then divided into low and high levels. In addition, we collected information on clinical variables, pathologic features, and recurrent status from patient questionnaires and medical records. Chi-square test and multivariate logistic regression model were used for analyses. Results showed that 5-MeC levels were positively associated with DNMT1 levels in UC (p = 0.0288). Both 5-MeC and DNMT1 were low in approximately 50% (76/150) of UC. The percentage of low 5-MeC levels was higher in invasive UC (65/110; 59%) than in normal urothelia (2/23; 13%) and non-invasive UC (18/40; 45%). Clinical factors were independently associated with low 5-MeC levels after adjusting for age and sex, including cancer stages II–IV, presence of UC in situ, and marked inflammation. Low 5-MeC levels in stage I invasive UC were not significantly different from those of non-invasive tumors (p = 0.8478). Low DNMT1 levels were only associated with UC with squamous differentiation (p = 0.0365). Neither 5-MeC nor DNMT1 levels were associated with UC recurrence. In conclusion, a low 5-MeC level could predict the progression of UC invasion into muscle. PMID:25561224

  6. Metachronous urothelial carcinoma of whole urinary tract in a dialysis-dependent patient: A case report

    PubMed Central

    WANG, YIMIN; JIN, BAIYE; YAO, XIAOLIN

    2016-01-01

    Numerous studies have reported an association between end-stage renal disease (ESRD) and malignancy. The predominant malignant tumor that occurs in patients with ESRD in Asian countries is urothelial carcinoma (UC). According to recent research, cases of UC in dialysis-dependent patients are associated with higher recurrence rates and more aggressive biological behavior compared with patients without ESRD. The necessity of 1-step total urinary tract exenteration for dialysis-dependent patients with UC is advocated by certain studies. The current study reports a case of metachronous bladder cancer and bilateral upper urinary tract tumor in a dialysis-dependent patient. Three separate surgeries were performed to remove the bladder, and left and right urinary tract, respectively. The question of whether the stepwise strategy or the 1-step surgery should be selected for such special cases remains in debate. PMID:27313734

  7. [Immunotherapy of Urothelial Carcinoma of the Bladder -  from BCG Vaccines to Targeted Therapy].

    PubMed

    Matoušková, M

    2015-01-01

    Bladder cancer has high prevalence in men and women. Bladder cancer usually originates from urothelium. More than 75% of cases are classified as nonmuscle invasive bladder cancer. Urothelial bladder carcinoma is usually managed by transurethral resection of the bladder tumor. Role of transurethral resection of the bladder tumor is also essential in bladder cancer staging. Local prophylaxis is used in nonmuscle invasive bladder cancer to reduce risk of recurrence. While local chemoprophylaxis is sufficient in low and middle risk patients, intravesical instillation of Mycobacterium bovis bacillus CalmetteGuerin (BCG) is preferred in high risk bladder cancer. Chemotherapy alone or in combination with locoregional treatment is used in advanced bladder cancer. New immunotherapy modalities have proven their efficacy in several clinical studies in advanced bladder cancer.

  8. Renal pelvis urothelial carcinoma of the upper moiety in complete right renal duplex: a case report

    PubMed Central

    Zhang, Yiran; Yu, Quanfeng; Zhang, Zhihong; Liu, Ranlu; Xu, Yong

    2015-01-01

    Urothelial carcinoma (UC) originated from renal pelvis is the common tumor of the urinary system, however, neoplasia of the renal pelvis in duplex kidneys is extremely rare, especially in the complete renal and ureteral duplex cases. We present the first case of renal pelvis UC of the upper moiety in a complete right renal duplex. This male patient has bilateral complete renal and ureteral duplex. To the best of our knowledge, this is the first reported case of renal pelvis UC in a complete renal duplex system. After this experience we feel that the diagnosis of renal pelvis UC in duplex kidneys is not so easy, and once the diagnosis is determined, the whole renal duplex units and bladder cuff or ectopic orifice should be excised radically. PMID:26823906

  9. Relationship of PCNA, C-erbB2 and CD44s expression with tumor grade and stage in urothelial carcinomas of the bladder

    PubMed Central

    Yıldırım, Ayhan; Kösem, Mustafa; Sayar, İlyas; Gelincik, İbrahim; Yavuz, Alparslan; Bozkurt, Aliseydi; Erkorkmaz, Ünal; Bayram, İrfan

    2014-01-01

    In the present study, the intention was to reveal the relationship of histological grade and stage with c-erbB2, CD44s, and PCNA immunoreactivity in bladder urothelial carcinomas (UC). In our study, we evaluated 46 items of transurethral resection material of patients submitted by YYU Faculty of Medicine, Main Department of Pathology, with a mass revealed in their bladder after clinical and radiological studies at our laboratories and who were diagnosed with urothelial carcinomas. PCNA, c-erbB2, and CD44s were applied in an immunohistochemical manner comprised from nine low-malignant potential papillary urothelial neoplasia, 23 low-grade papillary urothelial carcinoma, and 14 high-grade papillary urothelial carcinoma. Immunostaining was scored according to the percentage of positive cells. The immunohistochemical study demonstrated that the c-erbB2 and PCNA staining ratio increased when an increase occurred in stage and grade. The CD44s staining ratio decreased. C-erbB2, PCNA, and CD44s appear to be a useful marker in the assessment of the prognosis and treatment options in urothelial carcinomas. PMID:25035774

  10. Large nested variant of urothelial carcinoma: 23 cases mimicking von Brunn nests and inverted growth pattern of noninvasive papillary urothelial carcinoma.

    PubMed

    Cox, Roni; Epstein, Jonathan I

    2011-09-01

    We describe a rare pattern of urothelial carcinoma (UC) invasion consisting of large, irregular to regular nests, with bland cytology. We prospectively retrieved 23 cases of large nested UC from one of the author's consult files (2001 to 2010). The mean patient age was 63.7 years (39 to 89 y), and 86% were men. There were 18 cases with transurethral resection of the bladder, 2 nephroureterectomy specimens, and 3 radical cystectomy (RCs) specimens. A surface component was present in 19 of 23 cases, with 16 low-grade papillary UCs, 2 low-grade papillary UCs with <5% high-grade UC, and 1 high-grade papillary UC. Twenty of 23 cases invaded into the muscularis propria (MP), 2 into lamina propria with no MP present, and 1 into smooth muscle indeterminate between muscularis mucosae and MP. In 21 cases, the invasive component was composed of medium to large nests that varied from rounded circumscribed borders to a stromal-tumor interface with a more irregular ragged appearance. Two showed a verruciform, pushing border into the MP with the nests having central cyst formation. Cytologically, the nuclei lacked significant nuclear atypia, where at most occasional scattered slightly enlarged, hyperchromatic nuclei with small-indistinct nucleoli were noted. Four cases had focal necrosis and 3 cases had more extensive necrosis. The median mitotic count was 1.5 per 10 high-power fields. The stroma surrounding the large nests typically had a mild-to-moderate fibrous and/or inflammatory reaction; 4 cases exhibited no stromal reaction, whereas 2 cases had a moderate-to-marked stromal response. In 7 of 23 cases, conventional patterns of urothelial invasion were identified, 5 of which composed ≤5% of the neoplasm. One case had angiolymphatic invasion. Four cases had subsequent RC specimens available for review. Two of 4 RC specimens had no residual carcinoma (1 with neoadjuvant radiotherapy), 1 had large nested UC in MP, and 1 had mixed large nested UC and focal conventional UC

  11. Saudi Oncology Society and Saudi Urology Association combined clinical management guidelines for urothelial cell carcinoma of the urinary bladder.

    PubMed

    Alkhateeb, Sultan; Al-Mansour, Mubarak; Alotaibi, Mohammed; Saadeddin, Ahmad; Abusamra, Ashraf; Rabah, Danny; Murshid, Esam; Alsharm, Abdullah; Ahmad, Imran; Kushi, Hussain; Alghamdi, Abdullah; Alghamdi, Khalid; Bazarbashi, Shouki

    2016-01-01

    This is an update to the previously published Saudi guidelines for the evaluation, medical, and surgical management of patients diagnosed with urothelial cell carcinoma of the urinary bladder. It is categorized according to the stage of the disease using the tumor node metastasis staging system 7(th) edition. The guidelines are presented with supporting evidence level, they are based on comprehensive literature review, several internationally recognized guidelines, and the collective expertise of the guidelines committee members (authors) who were selected by the Saudi Oncology Society and Saudi Urological Association. Considerations to the local availability of drugs, technology, and expertise have been regarded. These guidelines should serve as a roadmap for the urologists, oncologists, general physicians, support groups, and health care policy makers in the management of patients diagnosed with urothelial cell carcinoma of the urinary bladder. PMID:27141179

  12. Polyoma (BK) virus associated urothelial carcinoma originating within a renal allograft five years following resolution of polyoma virus nephropathy.

    PubMed

    Salvatore, Steven P; Myers-Gurevitch, Patricia M; Chu, Stacy; Robinson, Brian D; Dadhania, Darshana; Seshan, Surya V

    2016-03-01

    A direct role for BK polyomavirus infection in malignant tumors of renal allografts and urinary tract is emerging. Case reports suggest a link between BK virus (BKV) reactivation and development of malignancy in renal allograft recipients. Herein we describe the first case of BKV positive invasive urothelial carcinoma within the renal allograft, presenting with chronic diarrhea and weight loss 5 years following resolution of BK viremia/nephropathy (BKVN). Unique to our case was the remote history of BK viremia/BKVN, rising titer of anti-HLA antibody and presence of renal limited urothelial carcinoma with microinvasion of malignant cells staining positive for SV40 large T antigen (T-Ag). These findings suggest that persistence of subclinical BKV infection within the renal allograft may play a role in the malignant transformation of epithelial cells. Patients with history of BKVN may be at risk for kidney and urinary tract malignancy despite resolution of BK viremia/BKVN.

  13. Polyoma (BK) virus associated urothelial carcinoma originating within a renal allograft five years following resolution of polyoma virus nephropathy.

    PubMed

    Salvatore, Steven P; Myers-Gurevitch, Patricia M; Chu, Stacy; Robinson, Brian D; Dadhania, Darshana; Seshan, Surya V

    2016-03-01

    A direct role for BK polyomavirus infection in malignant tumors of renal allografts and urinary tract is emerging. Case reports suggest a link between BK virus (BKV) reactivation and development of malignancy in renal allograft recipients. Herein we describe the first case of BKV positive invasive urothelial carcinoma within the renal allograft, presenting with chronic diarrhea and weight loss 5 years following resolution of BK viremia/nephropathy (BKVN). Unique to our case was the remote history of BK viremia/BKVN, rising titer of anti-HLA antibody and presence of renal limited urothelial carcinoma with microinvasion of malignant cells staining positive for SV40 large T antigen (T-Ag). These findings suggest that persistence of subclinical BKV infection within the renal allograft may play a role in the malignant transformation of epithelial cells. Patients with history of BKVN may be at risk for kidney and urinary tract malignancy despite resolution of BK viremia/BKVN. PMID:26709521

  14. Expression of programmed cell death protein 4 (PDCD4) and miR-21 in urothelial carcinoma

    SciTech Connect

    Fischer, Nicolas; Goeke, Friederike; Splittstoesser, Vera; Lankat-Buttgereit, Brigitte; Mueller, Stefan C.; Ellinger, Joerg

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer The tumor suppressor gene PDCD4 is down-regulated in many tumorous entities. Black-Right-Pointing-Pointer We investigate the impact of PDCD4 and its regulating factor miR-21 in urothelial carcinoma. Black-Right-Pointing-Pointer We confirm PDCD4 as a tumor suppressor gene and it could be a diagnostic marker for this tumor. -- Abstract: Background: We investigated the role of the programmed cell death 4 (PDCD4) tumor suppressor gene in specimens of transitional cell carcinoma and of healthy individuals. Methods: PDCD4 immunohistochemical expression was investigated in 294 cases in histologically proven transitional cell carcinoma in different tumorous stages (28 controls, 122 non-muscle invasive urothelial carcinoma, stages Tis-T1, 119 invasive transitional cell carcinoma stages T2-T4 and 25 metastases). MiR-21 expression, an important PDCD4 regulator, was assessed with real-time PCR analysis and showed inverse correlation to tissue PDCD4 expression. Results: Nuclear and cytoplasmatic PDCD4 immunostaining decreased significantly with histopathological progression of the tumor (p < 0001). Controls showed strong nuclear and cytoplasmatic immunohistochemical staining. MiR-21 up regulation in tissue corresponded to PDCD4 suppression. Conclusions: These data support a decisive role for PDCD4 down regulation in transitional cell carcinoma and confirm miR-21 as a negative regulator for PDCD4. Additionally, PDCD4 immunohistochemical staining turns out to be a possible diagnostic marker for transitional cell carcinoma.

  15. Ultrasound and Biomarker Tests in Predicting Cancer Aggressiveness in Tissue Samples of Patients With Bladder Cancer

    ClinicalTrials.gov

    2016-06-09

    Bladder Papillary Urothelial Carcinoma; Stage 0a Bladder Urothelial Carcinoma; Stage 0is Bladder Urothelial Carcinoma; Stage I Bladder Cancer With Carcinoma In Situ; Stage I Bladder Urothelial Carcinoma; Stage II Bladder Urothelial Carcinoma; Stage III Bladder Urothelial Carcinoma; Stage IV Bladder Urothelial Carcinoma

  16. YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage

    PubMed Central

    Ciamporcero, Eric; Shen, He; Ramakrishnan, Swathi; Ku, Sheng Yu; Chintala, Sreenivasulu; Shen, Li; Adelaiye, Remi; Miles, Kiersten Marie; Ullio, Chiara; Pizzimenti, Stefania; Daga, Martina; Azabdaftari, Gissou; Attwood, Kris; Johnson, Candace; Zhang, Jianmin; Barrera, Giuseppina; Pili, Roberto

    2015-01-01

    Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knock-down sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC. PMID:26119935

  17. Urothelial carcinoma with an inverted growth pattern can be distinguished from inverted papilloma by fluorescence in situ hybridization, immunohistochemistry, and morphologic analysis.

    PubMed

    Jones, Timothy D; Zhang, Shaobo; Lopez-Beltran, Antonio; Eble, John N; Sung, Ming-Tse; MacLennan, Gregory T; Montironi, Rodolfo; Tan, Puay-Hoon; Zheng, Suqin; Baldridge, Lee Ann; Cheng, Liang

    2007-12-01

    Inverted papilloma of the urinary bladder and urothelial carcinoma with an inverted (endophytic) growth pattern may be difficult to distinguish histologically, especially in small biopsies. The distinction is important as these lesions have very different biologic behaviors and are treated differently. We examined histologic features and undertook immunohistochemical staining and UroVysion fluorescence in situ hybridization (FISH) to determine whether these methods could aid in making this distinction. We examined histologic sections from 15 inverted papillomas and 29 urothelial carcinomas with an inverted growth pattern. Each tumor was stained with antibodies to Ki-67, p53, and cytokeratin 20. In addition, each tumor was examined with UroVysion FISH for gains of chromosomes 3, 7, and 17 and for loss of chromosome 9p21 signals. None of the inverted papillomas stained positively for Ki-67 or for cytokeratin 20. Only 1 of 15 inverted papillomas stained positively for p53. By contrast, 66%, 59%, and 59% of urothelial carcinomas with an inverted growth pattern stained positively for Ki-67, p53, and cytokeratin 20, respectively. Only 3 of the urothelial carcinomas stained negatively for all 3 immunohistochemical markers. UroVysion FISH produced normal results for all cases of inverted papilloma. By contrast, 21 of 29 cases (72%) of urothelial carcinoma with an inverted growth pattern demonstrated chromosomal abnormalities typical of urothelial cancer and were considered positive by UroVysion FISH criteria. Morphologic features, as well as immunohistochemical stains (including stains for Ki-67, p53, and cytokeratin 20) and/or UroVysion FISH can help to distinguish inverted papilloma from urothelial carcinoma with an inverted growth pattern. PMID:18043040

  18. The occult urothelial cancer.

    PubMed

    Ragonese, Mauro; Racioppi, Marco; D'Agostino, Daniele; Di Gianfrancesco, Luca; Lenci, Niccolò; Bientinesi, Riccardo; Palermo, Giuseppe; Sacco, Emilio; Pinto, Francesco; Bassi, Pier Francesco

    2016-05-24

    Transitional cell carcinoma (TCC) is the tumor that most frequently affects the urinary tract. The most common location is in the bladder; the diagnosis, as the follow-up, is based on urine cytology, endoscopic, and radiological examinations. Urinary cytology is an important non invasive tool used in the diagnosis and follow-up of patients with TCC. A positive urine cytology result is highly predictive of the presence of TCC, even in the presence of normal cystoscopy, because malignant cells may appear in the urine long time before any cystoscopically visible lesion becomes apparent. The presence of a positive urinary cytology, in the absence of clinical or endoscopic evidence of a TCC, can identify an occult urothelial cancer, located in any site of the urinary tract (upper urinary tract, bladder, prostatic urethra). Most of the urothelial tumors of the renal pelvis and ureters are diagnosed by radiological examinations, but we can observe a high rate of false negatives. In order to improve the diagnostic role of urinary cytology and other conventional examinations, numerous molecular markers have been identified; however, the real clinical application remains unclear. Photodynamic diagnosis and narrow band imaging (NBI) cystoscopy increase the diagnostic accuracy of endoscopic examinations in the presence of lesions not easily detectable. The aim of this review is to analyze the current diagnostic standards in the presence of occult urothelial cancer.

  19. A combination of p40, GATA-3 and uroplakin II shows utility in the diagnosis and prognosis of muscle-invasive urothelial carcinoma.

    PubMed

    Leivo, Mariah Z; Elson, Paul J; Tacha, David E; Delahunt, Brett; Hansel, Donna E

    2016-10-01

    Recently developed antibodies against uroplakin II and ΔNp63 (p40) show utility in diagnosing primary bladder urothelial carcinoma, although application in metastatic bladder cancer and patient outcomes has been less well defined. We evaluated these antibodies by immunostain intensity and H-score, in conjunction with GATA-3 immunoreactivity, in 89 patients with muscle-invasive urothelial carcinoma and 35 paired metastasis. The maintenance of immunoreactivity in metastatic lesions and the association to disease recurrence and survival was assessed. Bladder urothelial carcinoma showed immunoreactivity for GATA-3 in 99% (88/89), p40 in 87% (77/89) and uroplakin II in 80% (71/89) of cases, with a positive correlation between GATA-3 and uroplakin II H-score (0.44; p < 0.0001). All lesions were positive for at least one marker, reinforcing the use of these markers as a panel. In 35 patients with paired lymph node metastasis, uroplakin II and GATA-3 were retained in 90% and 75% of patients, respectively, suggesting these markers may have relatively high sensitivity in diagnosing metastatic urothelial carcinoma. High intensity p40 immunostain (3+), however, was significantly associated with reduced patient survival (p = 0.03). These results suggest that whereas GATA-3 and uroplakin II may be most useful in the diagnosis of urothelial carcinoma metastasis, p40 may be additionally suited as a prognostic marker. PMID:27594510

  20. Urothelial carcinoma with oncocytic features: an extremely rare case presenting a diagnostic challenge in urine cytology.

    PubMed

    Tajima, Shogo

    2015-01-01

    Recognizing histological variants in urothelial carcinoma (UC) is important because some may be associated with different clinical outcomes and/or therapeutic approaches; being aware of unusual histological variants may also be crucial in preventing diagnostic misinterpretations. Histological variants based on cytoplasmic features, such as clear-cell, plasmacytoid, rhabdoid, and lipoid-rich variants, are described in invasive UC; however, these cytoplasmic features are not formally defined and not usually encountered in non-invasive UC. Oncocytic cytoplasm has not been well described in either invasive or non-invasive UC. Herein, we report an exceedingly rare case of UC with oncocytic features arising in the right renal pelvis, which presented a diagnostic challenge in urine cytology due to the relatively low nuclear-to-cytoplasmic ratio; however, it could definitively be diagnosed using histological specimens. UC diagnosis is based on the presence of papillary architecture and widespread p53 nuclear accumulation, suggesting malignancy. An oncocytic tumor is generally considered to be not actively dividing, as shown by the low Ki-67 labeling index in this case. In spite of the low proliferative activity, the possibility of intravesicle recurrence (IVR) should be considered since positive preoperative cytology of upper tract UC is a risk factor for IVR after nephroureterectomy. PMID:26339439

  1. Endemic nephropathy and upper urothelial carcinoma--new insights in molecular biology.

    PubMed

    Jankovic Velickovic, Ljubinka; Dolicanin, Zana; Stefanovic, Vladisav

    2014-01-01

    Upper Tract Urothelial Carcinoma (UTUC) is an uncommon disease which occurs more frequently in some regions of Balkan countries than in other areas in the world. Investigation of UTUC in the South Morava River basin and its tributaries where BEN is endemic revealed increased frequency not only of tumour of the renal pelvis and ureter but also of urinary bladder tumours. A comparative morphological and immunohistochemical study of UTUC in the BEN region and control rural and city populations free of BEN, identify growth pattern as the best morphological characteristic which differentiated BEN and control tumours, i.e. solid growth for BEN tumours and papillary for control tumours. Overexpression of tumour suppressor p53 as well as decreased expression of E-CD was detected in BEN tumours. Other cells cycle related molecular markers--Cyclin D1, p16, and HER-2 showed no difference in expression between groups, as well as the proliferative marker Ki-67. Investigation of apoptosis-related markers identifies Bax as a specific marker of BEN-associated UTUC. Decrease of the pro-apoptotic protein Bax together with alteration of Survivin may be indicative of specific disturbances of an intrinsic apoptotic pathway in UTUC arising in endemic areas. PMID:24802310

  2. Homozygous losses detected by array comparative genomic hybridization in multiplex urothelial carcinomas of the bladder.

    PubMed

    Beothe, Tamas; Zubakov, Dmitry; Kovacs, Gyula

    2015-09-01

    Urothelial carcinomas (UCs) may present at first as a solitary or multifocal neoplasm. We applied high resolution array comparative genomic hybridization to 24 solitary and 32 multiplex UCs and used the hidden Markov model algorithm to identify the copy number changes at the probe level. Copy number losses and homozygous deletions at the chromosome 9p region affecting the CDKN2A and MTAP genes were the most frequent alterations in both groups of tumors. We have delineated two new tumor suppressor gene regions at chromosome 9p that harbor the PTPRD and BNC2 genes. Copy number losses at chromosomal regions 2q, 8p, and 18p occurred preferentially in solitary UCs, whereas multiplex UCs displayed loss of large chromosomal regions at 9q, 10q, 11q, 18q, and 21q. Homozygous deletions harboring loci of cell adhesion genes such as claudins, desmocollins, and desmogleins were seen exclusively in multiplex UCs. Amplifications occurred only in invasive G3 UCs irrespective of staging. Our study suggests that solitary and multiplex UCs may have divergent genetic pathways. The biallelic inactivation of cellular adhesion genes by homozygous deletions in multiplex UCs may explain the frequent intravesical spreading of tumor cells. .

  3. High Dickkopf-1 expression is associated with poor prognosis in patients with advanced urothelial carcinoma

    PubMed Central

    SHEN, CHENG-HUANG; HSIEH, HSIAO-YEN; WANG, YUAN-HUNG; CHEN, SYUE-YI; TUNG, CHUN-LIANG; WU, JIANN-DER; LIN, CHANG-TE; CHAN, MICHAEL W.-Y.; HSU, CHENG-DA; CHANG, DECHING

    2010-01-01

    Although Dickkopf-1 (DKK1) has been demonstrated to be associated with tumorigenesis in various types of human tumors, a correlation between DKK1 and urothelial carcinoma (UC) has not been reported. In the present study, the correlation between DKK1 expression and UC progression was investigated. Seventy-five UC patients were enrolled. The expression of DKK1 in serum and UC tissue was detected by ELISA, real-time PCR and Western blotting. Prognostic significance was assessed by using Kaplan-Meier survival estimates and log-rank tests. The results showed that serum levels of DKK1 were significantly higher in the UC patients with muscle-invasive (p=0.0001) and high-grade tumors (p=0.00001) as compared to the controls. A high-serum DKK1 was also associated with poor disease-free survival in the UC patients (hazard ratio=2.44; 95% CI 1.10–5.40; p=0.028). Furthermore, DKK1 was also overexpressed in 93% (41/44) of the UC tissues. Therefore, the findings indicate that the expression of DKK1 is associated with UC progression. PMID:22993615

  4. Preoperative Underweight Patients with Upper Tract Urothelial Carcinoma Survive Less after Radical Nephroureterectomy.

    PubMed

    Kang, Ho Won; Jung, Hae Do; Ha, Yun-Sok; Kim, Tae-Hwan; Kwon, Tae Gyun; Byun, Seok-Soo; Yun, Seok-Joong; Kim, Wun-Jae; Choi, Young Deuk

    2015-10-01

    The prognostic impact of body mass index (BMI) in patients with upper tract urothelial carcinoma (UTUC) is an ongoing debate. Our study aimed to investigate the prognostic role of BMI in patients treated with radical nephroureterectomy (RNU) for UTUC from a multi-institutional Korean collaboration. We retrospectively reviewed data from 440 patients who underwent RNU for UTUC at four institutions in Korea. To avoid biasing the survival estimates, patients who had previous or concomitant muscle-invasive bladder tumors were excluded. BMI was categorized into approximate quartiles with the lowest quartile assigned to the reference group. Kaplan-Meier and multivariate Cox regression analyses were performed to assess the influence of BMI on survival. The lower quartile BMI group showed significantly increased overall mortality (OM) and cancer specific mortality (CSM) compared to the 25%-50% quartiles and upper quartile BMI groups. Kaplan-Meier estimates showed similar results. Based on multivariate Cox regression analysis, preoperative BMI as a continuous variable was an independent predictor for OM and CSM. In conclusion, preoperative underweight patients with UTUC in Korea survive less after RNU. Preoperative BMI may provide additional prognostic information to establish risk factors.

  5. Therapeutic role of template-based lymphadenectomy in urothelial carcinoma of the upper urinary tract

    PubMed Central

    Kondo, Tsunenori; Takagi, Toshio; Tanabe, Kazunari

    2015-01-01

    Lymphadenectomy for urothelial carcinoma of the upper urinary tract has attracted the attention of physicians. The mapping study of lymphatic spread has shown that a relatively wide area should comprise the regional nodes for tumors of the right renal pelvis or the right upper two-thirds of the ureter. A prospective study showed that an anatomical template-based lymphadenectomy significantly improved patient survival in tumors of the renal pelvis. This benefit was more evident for patients with pT2 stage tumors or higher. The risk of regional node recurrence is significant reduced by template-based lymphadenectomy, which is likely to be associated with improved patient survival. The removal of lymph node micrometastases is assumed to be the reason for therapeutic benefit following lymphadenectomy. The number of resected lymph nodes can be used to assess the quality of lymphadenectomy, but not to determine the extent of lymphadenectomy. The guidelines currently recommend lymphadenectomy for patients with muscle-invasive disease, even though the current recommendation grades are still low. The present limitation of lymphadenectomy is the lack of standardization of the extent of lymphadenectomy and the randomized trials. Further studies are warranted to collect the evidence to support lymphadenectomy. PMID:26677437

  6. The genetic difference between Western and Chinese urothelial cell carcinomas: infrequent FGFR3 mutation in Han Chinese patients

    PubMed Central

    Liu, Li; Liu, Tiantian; Ge, Nan; Kong, Feng; Yang, Liu; Björkholm, Magnus; Fan, Yidong; Zhao, Shengtian; Xu, Dawei

    2016-01-01

    Urothelial cell carcinoma (UCC) includes urothelial bladder carcinoma (UBC), renal pelvic carcinoma (RPC) and ureter carcinoma (UC), and its incidence varies dependent on geographical areas and tumor locations, which indicates different oncogenic mechanisms and/or different genetic susceptibility/environment exposure. The activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene and telomerase reverse transcriptase (TERT) promoter are the most frequent genetic events in UCCs. These mutations have clinical utilities in UCC initial diagnostics, prognosis, recurrence monitoring and management. However, the vast majority of the results are obtained from studies of UCC patients in Western countries, and little has been known about these in Han Chinese patients. In the present study, we screened the FGFR3 gene and TERT promoter for mutations in 116 UBC, 91 RPC and 115 UC tumors from Han Chinese patients by using Sanger Sequencing. TERT promoter mutations occurred at a high frequency in these UCC patients, comparable with that seen in Western patients, however, the FGFR3 mutation was surprisingly lower, only 9.4% for UBCs, 8.8% for RPCs and 2.6% for UCs, respectively. Taken together, the FGFR3 gene is an infrequent target in the pathogenesis of Han Chinese UCCs, and its mutation detection and targeted therapy have limited clinical utility in these patients. Our results underscore the need for extensive characterization of cancer genomes from diverse patient populations, thereby contributing to precision medicine for cancer treatment and prevention. PMID:27029078

  7. The genetic difference between Western and Chinese urothelial cell carcinomas: infrequent FGFR3 mutation in Han Chinese patients.

    PubMed

    Yuan, Xiaotian; Liu, Cheng; Wang, Kun; Liu, Li; Liu, Tiantian; Ge, Nan; Kong, Feng; Yang, Liu; Björkholm, Magnus; Fan, Yidong; Zhao, Shengtian; Xu, Dawei

    2016-05-01

    Urothelial cell carcinoma (UCC) includes urothelial bladder carcinoma (UBC), renal pelvic carcinoma (RPC) and ureter carcinoma (UC), and its incidence varies dependent on geographical areas and tumor locations, which indicates different oncogenic mechanisms and/or different genetic susceptibility/environment exposure. The activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene and telomerase reverse transcriptase (TERT) promoter are the most frequent genetic events in UCCs. These mutations have clinical utilities in UCC initial diagnostics, prognosis, recurrence monitoring and management. However, the vast majority of the results are obtained from studies of UCC patients in Western countries, and little has been known about these in Han Chinese patients. In the present study, we screened the FGFR3 gene and TERT promoter for mutations in 116 UBC, 91 RPC and 115 UC tumors from Han Chinese patients by using Sanger Sequencing. TERT promoter mutations occurred at a high frequency in these UCC patients, comparable with that seen in Western patients, however, the FGFR3 mutation was surprisingly lower, only 9.4% for UBCs, 8.8% for RPCs and 2.6% for UCs, respectively. Taken together, the FGFR3 gene is an infrequent target in the pathogenesis of Han Chinese UCCs, and its mutation detection and targeted therapy have limited clinical utility in these patients. Our results underscore the need for extensive characterization of cancer genomes from diverse patient populations, thereby contributing to precision medicine for cancer treatment and prevention.

  8. Collecting and Studying Blood and Tissue Samples From Patients With Locally Recurrent or Metastatic Prostate or Bladder/Urothelial Cancer

    ClinicalTrials.gov

    2016-06-06

    Healthy Control; Localized Urothelial Carcinoma of the Renal Pelvis and Ureter; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter; Recurrent Bladder Carcinoma; Recurrent Prostate Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Stage IV Bladder Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Prostate Cancer

  9. Prognostic Value of Pre-operative Renal Insufficiency in Urothelial Carcinoma: A Systematic Review and Meta-Analysis

    PubMed Central

    Cao, Jian; Zhao, Xiaokun; Zhong, Zhaohui; Zhang, Lei; Zhu, Xuan; Xu, Ran

    2016-01-01

    The effect of pre-operative renal insufficiency on urothelial carcinoma (UC) prognosis has been investigated by numerous studies. While the majority report worse UC outcomes in patients with renal insufficiency, the results between the studies differed wildly. To enable us to better estimate the prognostic value of renal insufficiency on UC, we performed a systematic review and meta-analysis based on the published literature. A total of 16 studies which involved 5,232 patients with UC, investigated the relationship between pre-operative renal insufficiency and disease prognosis. Estimates of combined hazard ratio (HR) for bladder urothelial carcinoma recurrence, cancer-specific survival (CSS) and overall survival (OS) were 1.65 (95% CI, 1.11–2.19), 1.59 (95% CI, 1.14–2.05) and 1.45 (95% CI, 1.19–1.71), respectively; and for upper urinary tract urothelial carcinoma recurrence, CSS and OS were 2.27 (95% CI, 1.42–3.12), 1.02 (95% CI, 0.47–1.57) and 1.52 (95% CI, 1.05–1.99), respectively. Our results indicate that UC patients with pre-operative renal insufficiency tend to have higher recurrence rates and poorer survival compared to those with clinically normal renal function, thus renal function should be closely monitored in these patients. The impact of intervention for renal insufficiency on the prognosis of UC needs to be further studied. PMID:27725745

  10. Multiple cytokeratin-negative malignant tumors composed only of rhabdoid cells in the renal pelvis: a sarcomatoid urothelial carcinoma?

    PubMed Central

    Terada, Tadashi

    2013-01-01

    The author presents a unique case of multiple cytokeratin-negative malignant tumors consisting only of rhabdoid cells in the renal pelvis. A 54-year-old man complained of hematuria. A transurethral endoscopic examination revealed multiple papillary tumors, and transurethral resection of the bladder tumors was performed. Pathologically, they were ordinary papillary urothelial transitional cell carcinomas. Imaging modalities revealed multiple tumors of the right renal pelvis, and nephrectomy was performed. Grossly, three polypoid tumors measuring 2-4 cm were present in the pelvis. Histologically, they were composed only of malignant cells with rhabdoid features. There were no elements of transitional cell carcinoma. Immunohistochemically, the pelvic tumors were positive for vimentin and Ki-67 antigen (labeling=40%). They were negative for pancytokeratins (AE1/3, CAM5.2, KL-1 and polyclonal wide), 34βE12, cytokeratin (CK) 5/6, CK7, CK8, CK14, CK18, CK19, CK20, melanosome, EMA, CEA, desmin, S100 protein, α-smooth muscle actin, myoglobin, myogenin, CD34, p53 protein, p63, CD3, CD20, CD30, CD45, CD45RO, chromograin, synaptophysin, CD56, CD68, and KIT. NSE and PDGFRA were focally present, but this appeared nonspecific. Namely, the pelvic tumors expressed only vimentin. The author speculates that the pelvic multiple malignant “rhabdoid” tumors are not sarcomas but urothelial “rhabdoid” carcinoma with complete loss of CKs. PMID:23573320

  11. A case of concomitant occurrence of solitary fibrous tumor and urothelial high-grade invasive carcinoma of the urinary bladder.

    PubMed

    Spairani, Cinzia; Squillaci, Salvatore; Pitino, Antonio; Ferrari, Mauro; Montefiore, Franco; Rossi, Cristina; Fusco, Walter; Bigatti, Gian Luigi

    2014-05-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm, most commonly arising from the pleura. It has also been recently described to occur in extrapleural sites. To our knowledge, only 16 cases of SFT have been reported in the urinary bladder to date. We report the clinicopathological features of a vesical SFT occurring in a 60-year-old man who presented a concomitant invasive high-grade urothelial cell carcinoma. No similar association has been found in the accessible literature. The morphologic and immunohistochemical clues leading to the correct diagnosis of SFT have been correlated with the data of the literature, and the differential diagnosis is briefly discussed.

  12. Value of Preoperative Superselective Embolization of the Isthmus in a Patient with Upper Urinary Tract Urothelial Carcinoma and Horseshoe Kidney

    SciTech Connect

    Wilhelmsen, Skadi; Janitzky, Andreas; Porsch, Markus; Liehr, Uwe-Bernd; Dudeck, Oliver

    2011-02-15

    Standard treatment for upper urinary tract urothelial carcinoma (UUTUC) implies the radical removal of all urothelium-lined tissue, which requires nephroureterectomy with bladder cuff removal. We report on a patient with a rare coincidence of UUTUC and horseshoe kidney in whom a preoperative angiography helped to identify and subsequently embolize an abberant isthmic feeding artery, which was located in between both collecting systems. Ischemic discoloration of the isthmus area facilitated resection and no major blood loss occurred. Preoperative superselective embolization of the isthmus as the renal split area can be an effective tool to facilitate nephroureterectomy in the case of a horseshoe kidney.

  13. FGFR3b Extracellular Loop Mutation Lacks Tumorigenicity In Vivo but Collaborates with p53/pRB Deficiency to Induce High-grade Papillary Urothelial Carcinoma

    PubMed Central

    Zhou, Haiping; He, Feng; Mendelsohn, Cathy L.; Tang, Moon-shong; Huang, Chuanshu; Wu, Xue-Ru

    2016-01-01

    Missense mutations of fibroblast growth factor receptor 3 (FGFR3) occur in up to 80% of low-grade papillary urothelial carcinoma of the bladder (LGP-UCB) suggesting that these mutations are tumor drivers, although direct experimental evidence is lacking. Here we show that forced expression of FGFR3b-S249C, the most prevalent FGFR3 mutation in human LGP-UCB, in cultured urothelial cells resulted in slightly reduced surface translocation than wild-type FGFR3b, but nearly twice as much proliferation. When we expressed a mouse equivalent of this mutant (FGFR3b-S243C) in urothelia of adult transgenic mice in a tissue-specific and inducible manner, we observed significant activation of AKT and MAPK pathways. This was, however, not accompanied by urothelial proliferation or tumorigenesis over 12 months, due to compensatory tumor barriers in p16-pRB and p19-p53-p21 axes. Indeed, expressing FGFR3b-S249C in cultured human urothelial cells expressing SV40T, which functionally inactivates pRB/p53, markedly accelerated proliferation and cell-cycle progression. Furthermore, expressing FGFR3b-S243C in transgenic mouse urothelium expressing SV40T converted carcinoma-in-situ to high-grade papillary urothelial carcinoma. Together, our study provides new experimental evidence indicating that the FGFR3 mutations have very limited urothelial tumorigenicity and that these mutations must collaborate with other genetic events to drive urothelial tumorigenesis. PMID:27157475

  14. Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma

    PubMed Central

    Porten, Sima; Siefker-Radtke, Arlene O.; Xiao, Lianchun; Margulis, Vitaly; Kamat, Ashish M.; Wood, Christopher G.; Jonasch, Eric; Dinney, Colin P. N.; Matin, Surena F.

    2015-01-01

    Background High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with uniformly poor survival. Neoadjuvant chemotherapy may offer a way to improve clinical outcomes. We compare the survival rates of UTUC patients who received neoadjuvant chemotherapy prior to surgery with patients who did not. Methods Retrospective review of patients with high-risk UTUC who received neoadjuvant chemotherapy followed by surgery in 2004–2008 (study group), compared to a matched cohort who underwent initial surgery in 1993–2003 (control group). The Fisher exact, Wilcoxon rank-sum, and Kaplan-Meier methods were used. The log-rank test and Cox proportional hazards model were used to evaluate association of these two outcomes with patient, treatment, and tumor characteristics in univariate and multivariate models. Results Of 112 patients, 31 were in the study group and 81 in the control group. Patients who received neoadjuvant chemotherapy had improved OS and DSS with a 5-year DSS of 90.1% and 5-year OS rate 80.2%, versus a 5-year DSS and OS of 57.6% for those treated with initial surgery (p = 0.0204 and p = 0.0015, respectively). In multivariate analyses the neoadjuvant group had a lower risk of mortality (OS hazard ratio 0.42 [p = 0.035]; DSS hazard ratio 0.19 [p = 0.006]). Conclusions Neoadjuvant chemotherapy improves survival in patients with UTUC compared with a matched historical cohort of patients treated with initial surgery. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy, in view of the limited opportunity to administer effective cisplatin-based chemotherapy after nephroureterectomy. PMID:24633966

  15. Polymorphisms in cell cycle regulatory genes, urinary arsenic profile and urothelial carcinoma

    SciTech Connect

    Chung, C.-J.; Huang, C.-J.; Pu, Y.-S.; Su, C.-T.; Huang, Y.-K.; Chen, Y.-T.; Hsueh, Y.-M.

    2008-10-15

    Introduction: Polymorphisms in p53, p21 and CCND1 could regulate the progression of the cell cycle and might increase the susceptibility to inorganic arsenic-related cancer risk. The goal of our study was to evaluate the roles of cell cycle regulatory gene polymorphisms in the carcinogenesis of arsenic-related urothelial carcinoma (UC). Methods: A hospital-based case-controlled study was conducted to explore the relationships among the urinary arsenic profile, 8-hydroxydeoxyguanosine (8-OHdG) levels, p53 codon 72, p21 codon 31 and CCND1 G870A polymorphisms and UC risk. The urinary arsenic profile was determined using high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). 8-OHdG levels were measured by high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymerase (PCR-RFLP). Results: Subjects carrying the p21 Arg/Arg genotype had an increased UC risk (age and gender adjusted OR = 1.53; 95% CI, 1.02-2.29). However, there was no association of p53 or CCND1 polymorphisms with UC risk. Significant effects were observed in terms of a combination of the three gene polymorphisms and a cumulative exposure of cigarette smoking, along with the urinary arsenic profile on the UC risk. The higher total arsenic concentration, monomethylarsonic acid percentage (MMA%) and lower dimethylarsinic acid percentage (DMA%), possessed greater gene variant numbers, had a higher UC risk and revealed significant dose-response relationships. However, effects of urinary 8-OHdG levels combined with three gene polymorphisms did not seem to be important for UC risk. Conclusions: The results showed that the variant genotype of p21 might be a predictor of inorganic arsenic-related UC risk.

  16. Identification of circulating microRNA signatures for upper tract urothelial carcinoma detection

    PubMed Central

    TAO, JUN; YANG, XIAO; LI, PENGCHAO; WEI, JIFU; DENG, XIAHENG; CHENG, YIDONG; QIN, CHAO; JU, XIAOBING; MENG, XIAOXIN; LI, JIE; GU, MIN; LU, QIANG; YIN, CHANGJUN

    2015-01-01

    The involvement of circulating microRNAs (miRNAs) in cancer and their potential as diagnostic and prognostic biomarkers are becoming increasingly known. However, the significance of circulating miRNAs in upper tract urothelial carcinoma (UTUC) has remained to be investigated. The present study performed a genome wide serum miRNA analysis using a deep sequencing platform for initial screening. Subsequently, serum samples of 46 UTUC patients and 30 cancer free individuals with hematuria were subjected to a quantitative reverse transcription polymerase chain reaction analysis. The expression of thirteen miRNAs (miR-664a-3p, miR-423-5p, miR-431-5p, miR-191-5p, miR-92a-3p, miR-22-3p, miR-26a-5p, miR-33b-3p, miR-16-5p, let-7a 5p, let-7b-5p, let-7f-5p and let-7c) was significantly different in serum from UTUC patients compared with that in control samples. Receiver operator characteristic analysis showed that 10 miRNAs (miR-664a-3p, miR-431-5p, miR-423-5p, miR-191-5p, miR-33b-3p, miR-26a-5p, miR-22-3p, miR-16-5p, let-7b-5p and let-7c) had the potential to distinguish individuals with UTUC from the controls (areas under the curve >0.8). The present study provided the first evidence for the potential use of circulating miRNAs as biomarkers for UTUC diagnosis, which remains to be verified by further studies. PMID:26323574

  17. CEBPD amplification and overexpression in urothelial carcinoma: a driver of tumor metastasis indicating adverse prognosis

    PubMed Central

    Wang, Yu-Hui; Wu, Wen-Jeng; Wang, Wei-Jan; Huang, Hsuan-Ying; Li, Wei-Ming; Yeh, Bi-Wen; Wu, Ting-Feng; Shiue, Yow-Ling; Sheu, Jim Jinn-Chyuan; Wang, Ju-Ming; Li, Chien-Feng

    2015-01-01

    The molecular aberrations responsible for the progression of urothelial carcinoma (UC) remain largely obscure. To search candidate driver oncogenes in UC, we performed array-based genomic hybridization (aCGH) on 40 UBUC samples. Amplification of 8q11.21 was preferentially identified in patients who developed disease-specific death (53.8%) and distal metastasis (50.0%) but was barely detected in non-eventful cases (3.7% and 0%, respectively). In order to quantify the expression of candidate genes harbored in 8q11.21, laser-capture microdissection coupled with RT-PCR was performed on 32 of the 40 cases submitted to aCGH. With this, we identified CEBPD mRNA expression as most significantly associated with gains of 8q11.21, suggesting amplification-driven expression. By performing CEBPD-specific FISH and immunohistochemistry on 295 UBUCs, we confirmed CEBPD amplification (21.3%) and overexpression (29.8%) were strongly related to each other (p<0.001). Moreover, both were associated with adverse clinicopathologic features and worse outcomes. Furthermore, the clinical significance of CEBPD expression was also confirmed in an independent cohort comprised of 340 UCs from the upper urinary tract. Interestingly, CEBPD knockdown suppressed cell proliferation, migration and, most significantly, cell invasion ability in UC cells. The latter phenotype is attributed to downregulation of MMP2 as identified by RT2 Profiler PCR array. Moreover, expression of CEBPD significantly enhanced MMP2 expression and transcriptional activation by directly binding to its promoter region, as confirmed by promoter reporter assay and chromatin immunoprecipitation assay. Conclusively, CEBPD amplification is a mechanism driving increased mRNA and protein expression that confers aggressiveness in UC through MMP2-mediated cell invasiveness. PMID:26307680

  18. Urinary 8-hydroxydeoxyguanosine and urothelial carcinoma risk in low arsenic exposure area

    SciTech Connect

    Chung, C.-J.; Huang, C.-J.; Pu, Y.-S.; Su, C.-T.; Huang, Y.-K.; Chen, Y.-T.; Hsueh, Y.-M.

    2008-01-01

    Arsenic is a well-documented human carcinogen and is known to cause oxidative stress in cultured cells and animals. A hospital-based case-control study was conducted to evaluate the relationship among the levels of urinary 8-hydroxydeoxyguanosine (8-OHdG), the arsenic profile, and urothelial carcinoma (UC). Urinary 8-OHdG was measured by using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. The urinary species of inorganic arsenic and their metabolites were analyzed by high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). This study showed that the mean urinary concentration of total arsenics was significantly higher, at 37.67 {+-} 2.98 {mu}g/g creatinine, for UC patients than for healthy controls of 21.10 {+-} 0.79 {mu}g/g creatinine (p < 0.01). Urinary 8-OHdG levels correlated with urinary total arsenic concentrations (r = 0.19, p < 0.01). There were significantly higher 8-OHdG levels, of 7.48 {+-} 0.97 ng/mg creatinine in UC patients, compared to healthy controls of 5.95 {+-} 0.21 ng/mg creatinine. Furthermore, female UC patients had higher 8-OHdG levels of 9.22 {+-} 0.75 than those of males at 5.76 {+-} 0.25 ng/mg creatinine (p < 0.01). Multiple linear regression analyses revealed that high urinary 8-OHdG levels were associated with increased total arsenic concentrations, inorganic arsenite, monomethylarsonic acid (MMA), and dimethylarsenate (DMA) as well as the primary methylation index (PMI) even after adjusting for age, gender, and UC status. The results suggest that oxidative DNA damage was associated with arsenic exposure, even at low urinary level of arsenic.

  19. Detection of Copy Number Imbalance in Canine Urothelial Carcinoma With Droplet Digital Polymerase Chain Reaction.

    PubMed

    Mochizuki, H; Shapiro, S G; Breen, M

    2016-07-01

    Urothelial carcinoma (UC) is the most common neoplasm of the canine urinary tract. Clinical presentation of UC is shared with several other, more common urinary tract disorders, and this often delays diagnosis of the UC. Definitive diagnosis of UC requires histopathologic examination of a biopsy specimen, but the cost and invasiveness for these diagnostic tests often result in most diagnoses being made on the basis of clinical findings, diagnostic imaging, and cytologic examination of urine sediment. Regardless of the diagnostic process used, most UCs currently are not diagnosed until they are at an advanced clinical stage and so are associated with poor prognosis. Improved methods for earlier and less invasive detection are needed. In a previous study, the authors demonstrated the presence of highly recurrent DNA copy number aberrations (CNAs) in canine UC and hypothesized that detection of these CNAs in tumor cells can be used as a molecular diagnostic for UC. In this study, a multiplexed droplet digital polymerase chain reaction (ddPCR) assay was detected to detect and quantify CNAs of specific regions of canine chromosomes 8, 13, 19, and 36. The assay was effective at differentiating 31 neoplastic and 25 nonneoplastic bladder tissues based on copy number, with 100% sensitivity and specificity in tissue samples. CNAs were also detected by ddPCR in 67% (12 of 18) of urine DNA specimens derived from UC patients. The findings show that ddPCR is a useful molecular technique to detect CNAs and may be used as a noninvasive molecular diagnostic test for canine UC.

  20. Urinary arsenic profile affects the risk of urothelial carcinoma even at low arsenic exposure

    SciTech Connect

    Pu, Y.-S.; Yang, S.-M.; Huang, Y.-K.; Chung, C.-J.; Huang, Steven K.; Chiu, Allen Wen-Hsiang; Yang, M.-H.; Chen, C.-J.; Hsueh, Y.-M. . E-mail: ymhsueh@tmu.edu.tw

    2007-01-15

    Arsenic exposure is associated with an increased risk of urothelial carcinoma (UC). To explore the association between individual risk and urinary arsenic profile in subjects without evident exposure, 177 UC cases and 313 age-matched controls were recruited between September 2002 and May 2004 for a case-control study. Urinary arsenic species including the following three categories, inorganic arsenic (As{sup III} + As{sup V}), monomethylarsonic acid (MMA{sup V}) and dimethylarsinic acid (DMA{sup V}), were determined with high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Arsenic methylation profile was assessed by percentages of various arsenic species in the sum of the three categories measured. The primary methylation index (PMI) was defined as the ratio between MMA{sup V} and inorganic arsenic. Secondary methylation index (SMI) was determined as the ratio between DMA{sup V} and MMA{sup V}. Smoking is associated with a significant risk of UC in a dose-dependent manner. After multivariate adjustment, UC cases had a significantly higher sum of all the urinary species measured, higher percent MMA{sup V}, lower percent DMA{sup V}, higher PMI and lower SMI values compared with controls. Smoking interacts with the urinary arsenic profile in modifying the UC risk. Differential carcinogenic effects of the urinary arsenic profile, however, were seen more prominently in non-smokers than in smokers, suggesting that smoking is not the only major environmental source of arsenic contamination since the UC risk differs in non-smokers. Subjects who have an unfavorable urinary arsenic profile have an increased UC risk even at low exposure levels.

  1. Association between selected dietary scores and the risk of urothelial cell carcinoma: A prospective cohort study.

    PubMed

    Dugué, Pierre-Antoine; Hodge, Allison M; Brinkman, Maree T; Bassett, Julie K; Shivappa, Nitin; Hebert, James R; Hopper, John L; English, Dallas R; Milne, Roger L; Giles, Graham G

    2016-09-15

    Studies investigating the association of food and nutrient consumption with the risk of urothelial cell carcinoma (UCC) have produced mixed results. We used three common dietary scores, the Mediterranean Diet Score (MDS), the Alternate Healthy Eating Index 2010 (AHEI-2010) and the Dietary Inflammatory Index (DII) to assess the evidence of an association between diet and the risk of UCC. Over a median follow-up time of 21.3 years, 379 incident UCC cases were diagnosed. Dietary scores were calculated using data from a 121-item food frequency questionnaire administered at baseline. We used Cox models to compute hazard ratios (HR) for the association between dietary scores (per one standard deviation) and UCC risk. In order to reflect overall adherence to a healthy diet, a metascore was constructed by summing the quintiles of each of the three scores. None of the dietary scores was associated with the risk of UCC overall. A healthier diet was found to be inversely associated with the risk of invasive (MDS: HR = 0.86, 95% CI: 0.74-1.00, metascore: HR = 0.84, 95% CI: 0.71-0.98), but not superficial disease (heterogeneity between subtypes p = 0.04 and p = 0.03, respectively). Results were consistent but weaker for the DII and the AHEI-2010. We found some evidence of effect modification by smoking, in particular for the metascore (Current: HR = 0.77, 95% CI: 0.58-1.01, Former: HR = 0.77, 95% CI: 0.64-0.92, Never: HR = 1.01, 95% CI: 0.81-1.26, p for heterogeneity = 0.05). A healthy diet may be protective against the risk of invasive, but not superficial, UCC. Promoting healthy dietary habits may help lower the risk of invasive UCC, especially for current and former smokers. PMID:27149545

  2. Integrative analysis of 1q23.3 copy number gain in metastatic urothelial carcinoma

    PubMed Central

    Riester, Markus; Werner, Lillian; Bellmunt, Joaquim; Selvarajah, Shamini; Guancial, Elizabeth A.; Weir, Barbara A.; Stack, Edward C.; Park, Rachel S.; O’Brien, Robert; Schutz, Fabio A. B.; Choueiri, Toni K.; Signoretti, Sabina; Lloreta, Josep; Marchionni, Luigi; Gallardo, Enrique; Rojo, Federico; Garcia, Denise I.; Chekaluk, Yvonne; Kwiatkowski, David; Bochner, Bernard; Hahn, William C.; Ligon, Azra H.; Barletta, Justine A.; Loda, Massimo; Berman, David M.; Kantoff, Philip; Michor, Franziska; Rosenberg, Jonathan E.

    2014-01-01

    Purpose Metastatic urothelial carcinoma (UC) of the bladder is associated with multiple somatic copy number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic UC treated with platinum-based chemotherapy. Experimental Design We obtained overall survival (OS) and array DNA copy number data from metastatic UC patients in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by Nanostring nCounter to identify transcripts from the region that are associated with copy number gain. In addition, expression data from an independent cohort was used to identify candidate genes. Results Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in the both cohorts (adjusted HR 2.96; 95% CI, 1.35 to 6.48; P = 0.01 and adjusted HR 5.03; 95% CI 1.43-17.73; P < 0.001). The F11R, PFDN2, PPOX, USP21 and DEDD genes, all located on 1q23.3, were closely associated with poor outcome. Conclusions 1q23.3 copy number gain displayed association with poor survival in two cohorts of metastatic UC. The identification of the target of this copy number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of poor risk UC patients. Prospective validation of the survival association is necessary to demonstrate clinical relevance. PMID:24486590

  3. Novel Tumor Subgroups of Urothelial Carcinoma of the Bladder Defined by Integrated Genomic Analysis

    PubMed Central

    Taylor, Claire F.; Knowles, Margaret A.

    2012-01-01

    Purpose There is a need for improved subclassification of urothelial carcinoma (UC) at diagnosis. A major aim of this study was to search for novel genomic subgroups. Experimental design We assessed 160 tumors for genome-wide copy number alterations and mutation in genes implicated in UC. These comprised all tumor grades and stages and included 49 high-grade stage T1 (T1G3) tumors. Results Our findings point to the existence of genomic subclasses of the “gold-standard” grade/stage groups. The T1G3 tumors separated into 3 major subgroups that differed with respect to the type and number of copy number events and to FGFR3 and TP53 mutation status. We also identified novel regions of copy number alteration, uncovered relationships between molecular events, and elucidated relationships between molecular events and clinico-pathologic features. FGFR3 mutant tumors were more chromosomally stable than their wild-type counterparts and a mutually exclusive relationship between FGFR3 mutation and overrepresentation of 8q was observed in non-muscle-invasive tumors. In muscle-invasive (MI) tumors, metastasis was positively associated with losses of regions on 10q (including PTEN), 16q and 22q, and gains on 10p, 11q, 12p, 19p, and 19q. Concomitant copy number alterations positively associated with TP53 mutation in MI tumors were losses on 16p, 2q, 4q, 11p, 10q, 13q, 14q, 16q, and 19p, and gains on 1p, 8q, 10q, and 12q. Significant complexity was revealed in events affecting chromosome 9. Conclusions These findings may lead to improved biologic understanding and the development of prognostic biomarkers. Novel regions of copy number alteration may reveal potential therapeutic targets. PMID:22932667

  4. Clinical significance of α‑ and β‑Klotho in urothelial carcinoma of the bladder.

    PubMed

    Hori, Shunta; Miyake, Makito; Onishi, Sayuri; Tatsumi, Yoshihiro; Morizawa, Yosuke; Nakai, Yasushi; Anai, Satoshi; Tanaka, Nobumichi; Fujimoto, Kiyohide

    2016-10-01

    Non-muscle invasive bladder cancer (NMIBC) accounts for ~70% of all bladder cancers. One of the serious clinical issues related to the management of NMIBC is that it has significant potential to progress to muscle invasive bladder cancer (MIBC) after initial treatments. α‑Klotho (KLα), originally identified as an anti‑aging gene, has recently been reported to have antitumor effects in various malignancies. In contrast, β‑Klotho (KLβ) has been reported to have protumoral functions. However, the associations between KLα/KLβ and the biological behavior of urothelial carcinoma remain unclear. In the present study, we evaluated the association between clinicopathological background factors of NMIBC and the expression levels of KLα or KLβ. A high expression level of KLβ, but not KLα, was an independent predictive factor of short progression‑free survival for NMIBC. An elevated level of KLβ correlated with a higher incidence of lymphovascular invasion (LVI). We added in vitro assays using human bladder cancer cell lines to investigate the role of KLβ. Treatment with exogenous KLβ protein increased the proliferation, migration, transendothelial migration abilities and anchorage‑independent growth of the cell lines. In addition, the KLβ concentration in voided urine samples obtained before initial transurethral surgery was quantitated with enzyme‑linked immunosorbent assay (ELISA). The urine KLβ concentration was found to be higher in patients with bladder cancer than that in healthy volunteers. Our results suggest that KLβ plays important roles in tumor invasion and progression, and its concentration may be a valuable urine‑based marker for the detection of bladder cancer. PMID:27573985

  5. Bladder Neck Urothelial Carcinoma: A Urinary Bladder Subsite Carcinoma With Distinct Clinicopathology.

    PubMed

    Xiao, Guang-Qian; Rashid, Hani

    2015-10-01

    To evaluate the clinicopathology of carcinomas originating in the urinary bladder neck, 316 cystectomies for urinary bladder carcinoma performed between January 1, 2008, and December 31, 2013, were analyzed. Clinicopathological parameters were compared between bladder neck carcinomas (BNCs) and non-BNCs. Among the 316 cystectomies were 19 BNCs and 297 non-BNCs. BNCs accounted for 19/316 (6%) of all the cases, with a male-to-female ratio 18:1. Bladder neck location was significantly associated with advanced tumor stage. Ninety percent and 58% BNCs presented at stage ≥T2 and ≥T3, respectively, versus 62% and 38% non-BNCs at ≥T2 and ≥T3, respectively. Significantly higher percentage of lymphovascular invasion and lymph node metastasis were also seen in BNCs (68% and 47%, respectively) than in non-BNCs (29% and 17%, respectively). In conclusion, BNCs present with a significantly higher frequency of muscle invasion and advanced tumor stage, lymphovascular invasion, as well as local and distant metastasis at diagnosis compared with the non-BNCs group. Recognition of these unique clinicopathologic features with early detection and possibly more aggressive management of BNC can potentially have a significant impact on the patient's outcome.

  6. TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR.

    PubMed

    Wang, Kun; Liu, Tiantian; Ge, Nan; Liu, Li; Yuan, Xiaotian; Liu, Jikai; Kong, Feng; Wang, Chang; Ren, Hongbo; Yan, Keqiang; Hu, Sanyuan; Xu, Zhonghua; Björkholm, Magnus; Fan, Yidong; Zhao, Shengtian; Liu, Cheng; Xu, Dawei

    2014-12-15

    TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies. PMID:25474136

  7. Polymorphism of inflammatory genes and arsenic methylation capacity are associated with urothelial carcinoma

    SciTech Connect

    Wu, Chia-Chang; Huang, Yung-Kai; Chung, Chi-Jung; Huang, Chao-Yuan; Pu, Yeong-Shiau; Shiue, Horng-Sheng; Lai, Li-An; Lin, Ying-Chin; Su, Chien-Tien; Hsueh, Yu-Mei

    2013-10-01

    Chronic exposure to arsenic can generate reactive oxidative species, which can induce certain proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). TNF-α, IL-6 and IL-8 have been shown to be involved in the development and progression of various cancers, including bladder cancer. This study aimed to investigate the joint effect of the polymorphism of TNF-α − 308 G/A, IL-6 − 174 G/C, IL-8 − 251 T/A and urinary arsenic profiles on urothelial carcinoma (UC) risk. This study evaluated 300 pathologically-confirmed cases of UC and 594 cancer-free controls. Urinary arsenic species were detected using high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphism of TNF-α − 308 G/A, IL-6 − 174 G/C and IL-8 − 251 T/A was determined using polymerase chain reaction-restriction fragment length polymorphism. The joint effects on UC risk were estimated by odds ratios and 95% confidence intervals using unconditional logistic regression. We found that the TNF-α − 308 A/A and IL-8 − 251 T/T polymorphisms were significantly associated with UC. Moreover, significant dose–response joint effect of TNF-α − 308 A/A or IL-8 − 251 T/T genotypes and arsenic methylation indices were seen to affect UC risk. The present results also showed a significant increase in UC risk in subjects with the IL-8 − 251 T/T genotype for each SD increase in urinary total arsenic and MMA%. In contrast, a significant decrease in UC risk was found in subjects who carried the IL-8 − 251 T/T genotype for each SD increase in DMA%. - Highlights: • Joint effect of the TNF-α -308 A/A genotype and urinary total arsenic affected UC. • Joint effect of the IL-8 -251 T/T genotype and urinary total arsenic affected UC. • Urinary total arsenic level, TNF-α -308 A/A and IL-8 -251 T/T genotype affected UC.

  8. Predictive and Prognostic Value of Ribonucleotide Reductase Regulatory Subunit M1 and Excision Repair Cross-Complementation Group 1 in Advanced Urothelial Carcinoma (UC) Treated with First-Line Gemcitabine Plus Platinum Combination Chemotherapy.

    PubMed

    Kim, Miso; Ku, Ja Hyeon; Kwak, Cheol; Kim, Hyeon Hoe; Lee, Eunsik; Keam, Bhumsuk; Kim, Tae Min; Heo, Dae Seog; Lee, Se-Hoon; Moon, Kyung Chul

    2015-01-01

    Preclinical and clinical studies have suggested that expression of ribonucleotide reductase regulatory subunit M1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) is associated with resistance to gemcitabine and cisplatin, respectively. We evaluated the significance of RRM1 and ERCC1 expression to predict tumor response to gemcitabine plus platinum chemotherapy (GP) and survival in advanced UC. We retrospectively collected tumor samples and reviewed clinical data of 53 patients with unresectable or metastatic UC, who were treated with first-line GP. RRM1 and ERCC1 expression were measured by immunohistochemistry. Among 53 patients, 12 (22.6%) and 26 (49.1%) patients had tumors that demonstrated a high expression for RRM1 and ERCC1, respectively. Twenty-nine (70.7%) of 41 patients with low RRM1 expression achieved a clinical response (complete + partial responses), but only 3 (25.0%) of 12 patients with high RRM1 expression achieved a clinical response after GP (P=0.007). Nineteen (70.4%) of 27 patients with low ERCC1 expression achieved a clinical response, while 13 (50.0%) of 26 patients with high ERCC1 expression achieved a clinical response (P=0.130). High RRM1 expression was associated with shorter progression free survival and overall survival (PFS P=0.006, OS P=0.006). Multivariate analysis confirmed that patients with high RRM1 expression had a significantly greater risk of progression and death than those with low RRM1 expression. ERCC1 status was not a significant predictor for PFS and OS. RRM1 expression was predictive and prognostic of clinical outcome in advanced UC treated with gemcitabine plus platinum combination chemotherapy.

  9. The biological complexity of urothelial carcinoma: Insights into carcinogenesis, targets and biomarkers of response to therapeutic approaches.

    PubMed

    Grivas, Petros D; Melas, Marilena; Papavassiliou, Athanasios G

    2015-12-01

    Bladder cancer is a major cause of morbidity, mortality and health-related costs. Urothelial carcinoma is by far the most common histologic type of bladder cancer and may also arise from the upper urinary tract, e.g. renal pelvis and ureter, as well as from the proximal urethra. There have been no major advances in the development of new systemic therapies for urothelial carcinoma for over two decades, which may be related to prior lack of profound comprehension of biological pathogenetic mechanisms. However, in the last few years there has been a major shift in the development of new promising therapies that stem from improved molecular profiling of this malignancy. Developments in molecular biology, genomics, bioinformatics and immunology provide a solid foundation for therapeutic advances. A plethora of novel treatment targets and biomarkers are being evaluated, but there has been no molecular biomarker with established clinical utility so far. Genomic characterization of each patient's tumor has not been implemented due to the high cost, lack of validated standardized techniques that could be available in different laboratories, as well as absence of validated biomarkers and available therapeutic agents with clinically proven benefit. However, genomic characterization before treatment has now started to be implemented in novel clinical trial designs in order to contribute to proper patient selection based on biomarker-based enrichment strategies. Several "umbrella" or "basket" type, molecular biomarkers-based trials, in which patient eligibility and/or stratification is based on the presence of specific genetic alterations regardless of tissue of origin and/or histology, are being launched. Mathematical models and bioinformatics platforms that perform high level computational integrated pathway analysis may reveal clinical relevant signaling pathways amenable for targeting in individual patient tumors. Moreover, the high mutational burden of urothelial

  10. Androgen receptor facilitates the recruitment of macrophages in tumor microenvironment to promote upper urinary tract urothelial cell carcinoma progression

    PubMed Central

    Chen, Chi-Cheng; Huang, Chi-Ping; Hsieh, Teng-Fu; Chiu, Wei-Kai; Chang, Wen-Ling; Shyr, Chih-Rong

    2016-01-01

    Interactions between infiltrating macrophages in the tumor microenvironment (TME) and tumor cells contribute to tumor progression. The potential impacts of recruited macrophages to the upper urinary tract urothelial cell carcinomas (UUTUCs) progression remain unclear. Here we found human UUTUCs might recruit more macrophages than surrounding normal urothelial cells in human clinical specimens and in in vitro co-culture experiments with UUTUC cells and macrophages. The consequences of recruiting more macrophages to UUTUCs might then enhance UUTUC cell growth, migration and invasion. Further investigation found that the androgen receptor (AR) not only enhanced UUTUC cells capacity to recruit more macrophages, it could also promote the macrophages-enhanced UUTUC cells growth, migration and invasion. Downstream AR target cytokine search found AR might function through modulating CCL5 expression to influence UTTUC progression. Interruption of CCL5 partially reversed the AR-regulated macrophage-enhanced UUTUC progression. AR in UUTUC cells also increased tumor formation in vivo. Taken together, these results suggest that macrophages recruitment may enhance UUTUC progression, modulated by AR-CCL5 signal through alterations in chromatin state to establish a tumor microenvironment with recruited macrophages and cytokines to facilitate cell growth, migration and invasion. PMID:27725899

  11. Skeletal Muscle Metastases to the Flexor Digitorum Superficialis and Profundus from Urothelial Cell Carcinoma and Review of the Literature.

    PubMed

    Guidi, Marco; Fusetti, Cesare; Lucchina, Stefano

    2016-01-01

    Urothelial cell carcinoma (UCC) metastases to skeletal muscle are extremely rare and usually found in patients with advanced stage cancer. The most common sites of bladder cancer metastases are lymph nodes, lung, liver, and bones. Muscle is an unusual site of metastases from a distant primary cancer, due to several protective factors. We present a rare case of 76-year-old patient with metastases in the flexor digitorum superficialis (FDS) and flexor digitorum profundus (FDP) muscles, 2 years after a radical cystectomy for invasive UCC of the bladder. This case is the first description of a forearm lesion, with an extensive infiltration of the volar compartments of the forearm, and the first one with a clear functional impairment. PMID:27648338

  12. Chinese Herbs Containing Aristolochic Acid Associated with Renal Failure and Urothelial Carcinoma: A Review from Epidemiologic Observations to Causal Inference

    PubMed Central

    Yang, Hsiao-Yu; Chen, Pau-Chung; Wang, Jung-Der

    2014-01-01

    Herbal remedies containing aristolochic acid (AA) have been designated to be a strong carcinogen. This review summarizes major epidemiologic evidence to argue for the causal association between AA exposure and urothelial carcinoma as well as nephropathy. The exposure scenarios include the following: Belgian women taking slimming pills containing single material Guang Fang Ji, consumptions of mixtures of Chinese herbal products in the general population and patients with chronic renal failure in Taiwan, occupational exposure in Chinese herbalists, and food contamination in farming villages in valleys of the Danube River. Such an association is corroborated by detecting specific DNA adducts in the tumor tissue removed from affected patients. Preventive actions of banning such use and education to the healthcare professionals and public are necessary for the safety of herbal remedies. PMID:25431765

  13. Skeletal Muscle Metastases to the Flexor Digitorum Superficialis and Profundus from Urothelial Cell Carcinoma and Review of the Literature

    PubMed Central

    Fusetti, Cesare; Lucchina, Stefano

    2016-01-01

    Urothelial cell carcinoma (UCC) metastases to skeletal muscle are extremely rare and usually found in patients with advanced stage cancer. The most common sites of bladder cancer metastases are lymph nodes, lung, liver, and bones. Muscle is an unusual site of metastases from a distant primary cancer, due to several protective factors. We present a rare case of 76-year-old patient with metastases in the flexor digitorum superficialis (FDS) and flexor digitorum profundus (FDP) muscles, 2 years after a radical cystectomy for invasive UCC of the bladder. This case is the first description of a forearm lesion, with an extensive infiltration of the volar compartments of the forearm, and the first one with a clear functional impairment. PMID:27648338

  14. Massive renal urothelial carcinoma with renal vein tumor thrombus, pancreatic infiltration and adrenal metastasis: A case report

    PubMed Central

    Li, Tao; Gao, Liang; Wu, Weilu; Chen, Peng; Bu, Siyuan; Wei, Qiang; Yang, Lu

    2016-01-01

    A 49-year-old female patient presented with a massive left renal tumor, recurrent left flank pain and gross hematuria. The tumor was accompanied by a renal vein tumor thrombus, pancreatic infiltration and a solitary adrenal metastasis. Radical nephrectomy, distal pancreatectomy, ipsilateral adrenalectomy and splenectomy were performed. Histopathological examination suggested high-grade urothelial carcinoma (UC); however, tumor recurrence and multiple metastases were detected only 3 months after the surgery, and the patient succumbed during follow-up 1 month later. To the best of our knowledge, this is the first case of renal UC of such advanced stage with renal vein tumor thrombus, pancreatic infiltration and a solitary adrenal metastasis. PMID:27446406

  15. Expression of pRb, p53, p16 and cyclin D1 and their clinical implications in urothelial carcinoma.

    PubMed

    Lee, Kyungji; Jung, Eun Sun; Choi, Young-Jin; Lee, Kyo Young; Lee, Ahwon

    2010-10-01

    The aim of this study was to assess immunohistochemical expression of p53, pRb, p16, and cyclin D1, alone or in combination, as prognostic indicators and to investigate their correlation with clinocopathologic features of urothelial carcinoma. Immunohistochemical staining for p53, pRb, p16, and cyclin D1 was performed on a tissue microarray from 103 patients with urothelial carcinoma who underwent radical cystectomy. Of the patient samples analyzed, 36 (35%), 61 (59%), 47 (46%) and 30 (29%) had altered expression of p53, pRb, p16, and cyclin D1, respectively. Abnormal expression of p53 and pRb correlated with depth of invasion (P=0.040 and P=0.044, respectively). Cyclin D1 expression was associated with tumor stage and recurrence (P=0.017 and P=0.036, respectively). Altered pRb was significantly correlated with overall survival (P=0.040). According to the expression pattern of pRb and p53, p53/pRb (altered/normal) had worse survival than p53/pRb (normal/altered) (P=0.022). Alteration of all markers had worse survival than all normal (P=0.029). As determined by multivariate analysis, tumor stage, lymph node metastasis and the combined expression of p53 and pRb are independent prognostic factors. In conclusion, immunohistochemical evaluation of cell cycle regulators, especially the p53/pRb combination, might be useful in planning appropriate treatment strategies.

  16. Targeting MACC1 by RNA interference inhibits proliferation and invasion of bladder urothelial carcinoma in T24 cells

    PubMed Central

    Xu, Song-Tao; Ding, Xiang; Ni, Qing-Feng; Jin, Shao-Ju

    2015-01-01

    The purpose of this article is to research on whether MACC1 can serve as a potential target for gene therapy of human bladder urothelial carcinoma (BUC). In this study, the expression of MACC1 gene was knocked down by RNA interference (RNAi) in the T24 cell (human BUC cell). The transcription level of MACC1 was detected by RT-PCR. Activities of MACC1, caspase-3, caspase-8, Bax and Met (mesenchymal-epithelial transition factor) protein were measured by Western blot. The cell proliferation and apoptosis were detected by MTT and flow cytometry. The cell’s invasion ability was performed on Matrigel transwell assay. We also detect MMP2 (metalloproteinase-2) proteins by ELISA. The results showed that the level of MACC1 mRNA and protein was significantly reduced after RNAi. MTT assay showed that the proliferation of T24 cell was decreased due to RNA interference. Apoptosis studies also showed that MACC1 gene interference in T24 loses its anti-apoptotic effects. The expression of apoptosis proteins (Caspase-3, Caspase-8 and Bax) increased significantly due to the MACC1 RNAi. The level of Met protein was down-regulated obviously due to RNAi. Transwell assay showed that invasion abilities of T24 cells were reduced obviously due to MACC1 RNAi. Further studies showed that the secretion of MMP-2 was reduced by RNAi. It can conclude that the ability of proliferation and invasion in T24 cells can be inhibited by RNAi-targeting MACC1. As a result, MACC1 can serve as a potential target for gene therapy of human bladder urothelial carcinoma. PMID:26339359

  17. Global acetylation and methylation changes predict papillary urothelial neoplasia of low malignant potential recurrence

    PubMed Central

    Mazzucchelli, R.; Scarpelli, M.; Lopez-Beltran, A.; Cheng, L.; Bartels, H.; Bartels, P. H.; Alberts, D. S.; Montironi, R.

    2014-01-01

    Papillary urothelial neoplasia of low malignant potential (PUNLMP) recurs in approximately 35% of patients. Conventional histopathological assessment does not distinguish non-recurrent from recurrent PUNLMP. The aim of the study was to explore the differences in global histone acetylation and global DNA methylation between non-recurrent and recurrent PUNLMP. Acetylated histone H3 lysine 9 (AcH3K9) and 5-methylcytosine (5MeC) were investigated by immunohistochemistry (IHC) in 20 PUNLMP cases (10 non-recurrent and 10 recurrent), in 5 cases of normal urothelium (NU) and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). The total optical density of the nuclear staining was measured photometrically in at least 40 nuclei separately for the basal, intermediate and luminal positions in each case. Concerning the total optical density values for both acetylation and methylation, a decrease in staining is observed from non-recurrent PUNLMP to recurrent PUNLMP, at all nuclear locations. For acetylation the mean value in non-recurrent. PUNLMP, intermediate between NU and UC, is closer to the former than to latter. The mean value in recurrent PUNLMP is closer to UC than to NU. In NU, non-recurrent and recurrent PUNLMP the acetylation to methylation ratio decreased from the nuclei in basal position to those in the surface, the average for the above groups being 1.491, 1.611 and 1.746, respectively. Setting the observed values for NU at each sampling location to unity, acetylation shows a steady decrease, the percentages of changes in this nuclear location compared to NU being − 5% in non-recurrent PUNLMP, − 15% in recurrent PUNLMP and − 24% in UC. Concerning methylation, there is slight increase in non-recurrent PUNLMP (+ 5%), a decrease in recurrent PUNLMP (− 19%) followed by a sharp rise for the UC (+ 61%). In conclusion there are differences in global histone acetylation and DNA methylation patterns between non-recurrent and recurrent PUNLMP. Further studies

  18. Gemcitabine plus nedaplatin as salvage therapy is a favorable option for patients with progressive metastatic urothelial carcinoma after two lines of chemotherapy.

    PubMed

    Matsumoto, Kazumasa; Mochizuki, Kohei; Hirayama, Takahiro; Ikeda, Masaomi; Nishi, Morihiro; Tabata, Ken-ichi; Okazaki, Miyoko; Fujita, Tetsuo; Taoka, Yoshinori; Iwamura, Masatsugu

    2015-01-01

    This study was conducted to evaluate the effectiveness of a combination of gemcitabine and nedaplatin therapy among patients with metastatic urothelial carcinoma previously treated with two lines of chemotherapy. Between February 2009 and August 2013, 30 patients were treated with gemcitabine and paclitaxel as a second-line chemotherapy. All had received a first-line chemotherapy consisting of methotrexate, vinblastine, doxorubicin and cisplatin. Ten patients who had measurable histologically proven advanced or metastatic urothelial carcinoma of the urinary bladder and upper urinary tract received gemcitabine 1,000 mg/m2 on days 1, 8 and 15 and nedaplatin 70 mg/m2 on day 2 as a third-line chemotherapy. Tumors were assessed by imaging every two cycles. The median number of treatment cycles was 3.5. One patient had partial response and three had stable disease. The disease-control rate was 40%, the median overall survival was 8.8 months and the median progression-free survival was 5.0 months. The median overall survival times for the first-line and second-line therapies were 29.1 and 13.9 months, respectively. Among disease-controlled patients (n=4), median overall survival was 14.2 months. Myelosuppression was the most common toxicity. There were no therapy-related deaths. Gemcitabine and nedaplatin chemotherapy is a favorable third-line chemotherapeutic option for patients with metastatic urothelial carcinoma. Given the safety and benefit profile seen in this study, further prospective trials are warranted given the implications of our results with regard to strategic chemotherapy for patients with advanced or metastatic urothelial carcinoma.

  19. Micropapillary morphology is an indicator of poor prognosis in patients with urothelial carcinoma treated with transurethral resection and radiochemotherapy.

    PubMed

    Bertz, Simone; Wach, S; Taubert, H; Merten, R; Krause, F S; Schick, S; Ott, O J; Weigert, E; Dworak, O; Rödel, C; Fietkau, R; Wullich, B; Keck, B; Hartmann, A

    2016-09-01

    Purpose of this study was to evaluate prognostic impact of rare variants of urothelial bladder cancer (BC) after treatment with combined radiochemotherapy (RCT). To this end tumour tissue of 238 patients with urothelial carcinoma (UC) treated with transurethral resection of the bladder (TUR-B) and RCT with curative intent was collected. Histomorphological analysis included re-evaluation and semi-quantitative assessment of rare UC subtypes. Additionally, human epidermal growth factor receptor 2 (HER2) chromogenic in situ hybridisation (CISH) was performed in tumours with a micropapillary component exceeding 30 %. Long-term follow-up was available for 200 patients (range 3-282 months). Variant UC histology was found in 45 of 238 tumours, most frequently micropapillary UC (N = 17) including cases with a small fraction of tumour with micropapillary morphology. The mere presence of micropapillary morphology did not affect prognosis. In tumours with extensive (≥30 %) micropapillary morphology (N = 8) Kaplan-Meier analysis revealed significantly worse cancer specific survival (CSS) (P = 0.002) compared to conventional UC (mean survival times 97 months and 229 months, respectively). Univariate Cox regression analysis of cases with ≥30 % micropapillary morphology revealed a hazard ratio of 4.726 (95 % CI 1.629-13.714) for CSS (P = 0.004). CISH revealed HER2 gene amplification in 3/10 tumours with ≥30 % micropapillary component. In conclusion, for BC treated with TUR-B and RCT, the presence of micropapillary morphology in more than 30 % of the tumour is an adverse prognostic factor. Further studies are needed to evaluate a potential benefit of different, especially multimodal treatment strategies for micropapillary UC and also other subtypes of UC. Her2 represents a promising therapeutic target in a subset of micropapillary UC. PMID:27392930

  20. Gene Expression and DNA Methylation Status of Glutathione S-Transferase Mu1 and Mu5 in Urothelial Carcinoma

    PubMed Central

    Wang, Shou-Chieh; Huang, Chin-Chin; Shen, Cheng-Huang; Lin, Lei-Chen; Zhao, Pei-Wen; Chen, Shih-Ying; Deng, Yu-Chiao; Liu, Yi-Wen

    2016-01-01

    Bladder cancer is highly recurrent after therapy, which has an enormous impact on the health and financial condition of the patient. It is worth developing diagnostic tools for bladder cancer. In our previous study, we found that the bladder carcinogen BBN increased urothelial global DNA CpG methylation and decreased GSTM1 protein expression in mice. Here, the correlation of BBN-decreased GSTM1 and GSTM gene CpG methylation status was analyzed in mice bladders. BBN treatment decreased the protein and mRNA expression of GSTM1, and the CpG methylation ratio of GSTM1 gene promoter was slightly increased in mice bladders. Unlike mouse GSTM1, the human GSTM1 gene tends to be deleted in bladder cancers. Among 7 human bladder cancer cell lines, GSTM1 gene is really null in 6 cell lines except one, T24 cells. The CpG methylation level of GSTM1 was 9.9% and 5-aza-dC did not significantly increase GSTM1 protein and mRNA expression in T24 cells; however, the GSTM5 gene was CpG hypermethylated (65.4%) and 5-aza-dC also did not affect the methylation ratio and mRNA expression. However, in other cell lines without GSTM1, 5-aza-dC increased GSTM5 expression and decreased its CpG DNA methylation ratio from 84.6% to 61.5% in 5637, and from 97.4% to 75% in J82 cells. In summary, two biomarkers of bladder tumor were provided. One is the GSTM1 gene which is down-regulated in mice bladder carcinogenesis and is usually deleted in human urothelial carcinoma, while the other is the GSTM5 gene, which is inactivated by DNA CpG methylation. PMID:27404495

  1. Micropapillary morphology is an indicator of poor prognosis in patients with urothelial carcinoma treated with transurethral resection and radiochemotherapy.

    PubMed

    Bertz, Simone; Wach, S; Taubert, H; Merten, R; Krause, F S; Schick, S; Ott, O J; Weigert, E; Dworak, O; Rödel, C; Fietkau, R; Wullich, B; Keck, B; Hartmann, A

    2016-09-01

    Purpose of this study was to evaluate prognostic impact of rare variants of urothelial bladder cancer (BC) after treatment with combined radiochemotherapy (RCT). To this end tumour tissue of 238 patients with urothelial carcinoma (UC) treated with transurethral resection of the bladder (TUR-B) and RCT with curative intent was collected. Histomorphological analysis included re-evaluation and semi-quantitative assessment of rare UC subtypes. Additionally, human epidermal growth factor receptor 2 (HER2) chromogenic in situ hybridisation (CISH) was performed in tumours with a micropapillary component exceeding 30 %. Long-term follow-up was available for 200 patients (range 3-282 months). Variant UC histology was found in 45 of 238 tumours, most frequently micropapillary UC (N = 17) including cases with a small fraction of tumour with micropapillary morphology. The mere presence of micropapillary morphology did not affect prognosis. In tumours with extensive (≥30 %) micropapillary morphology (N = 8) Kaplan-Meier analysis revealed significantly worse cancer specific survival (CSS) (P = 0.002) compared to conventional UC (mean survival times 97 months and 229 months, respectively). Univariate Cox regression analysis of cases with ≥30 % micropapillary morphology revealed a hazard ratio of 4.726 (95 % CI 1.629-13.714) for CSS (P = 0.004). CISH revealed HER2 gene amplification in 3/10 tumours with ≥30 % micropapillary component. In conclusion, for BC treated with TUR-B and RCT, the presence of micropapillary morphology in more than 30 % of the tumour is an adverse prognostic factor. Further studies are needed to evaluate a potential benefit of different, especially multimodal treatment strategies for micropapillary UC and also other subtypes of UC. Her2 represents a promising therapeutic target in a subset of micropapillary UC.

  2. Reproducibility and Prognostic Value of WHO1973 and WHO2004 Grading Systems in TaT1 Urothelial Carcinoma of the Urinary Bladder

    PubMed Central

    Mangrud, Ok Målfrid; Waalen, Rune; Gudlaugsson, Einar; Dalen, Ingvild; Tasdemir, Ilker; Janssen, Emiel A. M.; Baak, Jan P. A.

    2014-01-01

    Background European treatment guidelines of TaT1 urinary bladder urothelial carcinomas depend highly on stage and WHO1973-grade but grading reproducibility is wanting. The newer WHO2004 grading system is still debated and both systems are currently used. Aims To compare reproducibility and prognostic value (of stage progression) of the WHO1973 and WHO2004. Methods One hundred and ninety-three primary urothelial carcinomas were reviewed. Follow-up data were retrieved from the patient records. Kappa statistics and Harrell's C-index were used. Results Median follow-up was 75 months (range 1–127). 17 patients (9%) progressed, 82% of these within and 18% after 60 months. The distribution of WHO73-grades 1, 2 and 3 was 23%, 51% and 26%, interobserver agreement for each individual grade was 66% (kappa = 0.68), while for grades 1&2 versus 3 89% (kappa = 0.68). Intraobserver reproducibility was 68–63% for WHO73 and 88–89% for WHO73 as 1&2 vs.3. Progression free survival rates at 5 years were 95% (grade 1), 98% (grade 2) and 82% (grade 3) and 96% and 82% for grades 1&2 versus 3 (Hazard Ratio, HR, 5.4, p = 0.003). Using WHO2004, 62% were low grade and 38% high grade, inter-observer agreement 87% (kappa = 0.70), intraobserver reproducibility 93%, and progression free 5-year survival rates 97% and 85% (HR 6.6, p = 0.004). Positive and negative predictive values for stage progression within 5 years for the WHO73 (1&2 vs. 3) were 18% and 96%, and 15% and 97% for the WHO04. Using Harrell's C-index, none of the grading systems was prognostically superior. Conclusion None of the grading systems is prognostically stronger than the others. Most importantly, inter-observer reproducibility and sensitivities for stage progression of both systems are low and need improvement for optimal treatment. PMID:24409280

  3. [Risk factors for urothelial carcinoma: drinking measures, smoking and other life style-related risk factors--results of the Berlin Urothelial Study (BUS)].

    PubMed

    Helmert, U; Bronder, E; Klimpel, A; Molzahn, M; Pommer, W

    2000-05-01

    With the exception of smoking and several occupational exposures there is little knowledge about risk factors for urothelial cancer. A case control study in the area of former West Berlin was performed from 1990-1995 to investigate the role of several lifestyle risk factors, such as smoking, drinking behaviour and regular intake of analgesics and laxatives. The study includes 647 hospital-based incident cases with bladder cancer (n = 571), renal pelvis cancer (n = 51), and ureter cancer (n = 25), and 647 population-based controls which were matched individually by sex and age. Data analyses were carried out using standard methods for case control studies (conditional multiple logistic regression analysis). Odds ratios (OR) and 95% confidence intervals (CI) were applied as effect parameter. Statistically significantly increased odds ratios were observed for current smoking (OR: 3.46, 95% CI: 2.50-4.78), previous but now abandoned smoking (OR: 1.51, 95% CI: 1.09-2.81), and for regular intake of laxatives (OR: 2.52, 95% CI: 1.56-4.09). Furthermore, an increased risk for urothelial cancer was observed for daily consumption of three and more litres of cold drinks (OR: 2.65 95% CI: 1.12-6.24). The results underline that lifestyle factors other than smoking may contribute to a higher risk of urothelial cancer. PMID:10893874

  4. Chromatin Phenotype Karyometry Can Predict Recurrence in Papillary Urothelial Neoplasms of Low Malignant Potential

    PubMed Central

    Montironi, Rodolfo; Scarpelli, Marina; Lopez-Beltran, Antonio; Mazzucchelli, Roberta; Alberts, David; Ranger-Moore, James; Bartels, Hubert G.; Hamilton, Peter W.; Einspahr, Janine; Bartels, Peter H.

    2007-01-01

    organization state between non-recurrent and recurrent PUNLMP, thus allowing a very stable method of predicting recurrence of papillary urothelial neoplasms of low malignant potential by karyometry. PMID:17429141

  5. Intraoperative frozen section evaluation of ureteral and urethral margins: studies of 203 consecutive radical cystoprostatectomy for men with bladder urothelial carcinoma

    PubMed Central

    Zhou, Haijun; Ro, Jae Y; Truong, Luan D; Ayala, Alberto G; Shen, Steven S

    2014-01-01

    Intraoperative frozen section (FS) evaluation of ureteral and urethral margins is frequently requested during radical cystoprostatectomy in patients with bladder urothelial carcinoma. However, it is still controversial whether intraoperative FSs of ureteral and urethral margins are necessary in all patients with cystoprostatectomy or a risk-based assessment with limited to the high risk patients is the best approach. A total of 203 radical cystoprostatectomy specimens with FS evaluation on margin status from men treated for bladder urothelial carcinoma from 2003 to 2010 in our institution were reviewed. Clinicopathologic features studied include: patients’ age, pathologic tumor stage, presence of carcinoma in- situ (CIS), and intraoperative FS diagnosis. All 203 patients had intraoperative FS evaluation of ureter, and of these, 37 patients had additional urethra FS evaluation. Of the 203 ureteral FS cases, 17 (8.4%) had positive margin for CIS (16 cases) or CIS with invasive urothelial carcinoma (1 case). All 17 patients with positive ureteral margin on FS had concomitant CIS in the bladder (15.5%; 17 of 110 patients). In contrast, none of the patients without concomitant CIS (n=93) had positive ureteral margins on FS. Among 37 patients who also had FS evaluation on urethral resection margin, 3 patients (8.1%) had positive margins for CIS and all three of them had concomitant CIS in the bladder. Positive ureteral/urethral margin was not associated with patients’ age or tumor stage, but was significantly associated with the presence of CIS in the bladder (p<0.001). Our study demonstrates that presence of concomitant CIS in bladder cancer was often associated with positive ureteral or urethral margin for CIS or invasive carcinoma; therefore, intraoperative FS evaluation may be indicated to these patients with concomitant bladder CIS. In contrast, in patients with no associated concomitant CIS in the bladder, FS of ureteral/urethral margins may not be necessary

  6. Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor

    PubMed Central

    Ide, Hiroki; Miyamoto, Hiroshi

    2015-01-01

    There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression. PMID:26770009

  7. Utility of GATA3 immunohistochemistry in differentiating urothelial carcinoma from prostate adenocarcinoma and squamous cell carcinomas of the uterine cervix, anus, and lung.

    PubMed

    Chang, Alex; Amin, Ali; Gabrielson, Edward; Illei, Peter; Roden, Richard B; Sharma, Rajni; Epstein, Jonathan I

    2012-10-01

    Distinguishing invasive high-grade urothelial carcinoma (UC) from other carcinomas occurring in the genitourinary tract may be difficult. The differential diagnosis includes high-grade prostatic adenocarcinoma, spread from an anal squamous cell carcinoma (SCC), or spread from a uterine cervical SCC. In terms of metastatic UC, the most common problem is differentiating spread of UC to the lung from a primary pulmonary SCC. Immunohistochemical analysis (IHC) for GATA binding protein 3 (GATA3), thrombomodulin (THROMBO), and uroplakin III was performed on a tissue microarray (TMA) containing 35 cases of invasive high-grade UC. GATA3 IHC was also performed on TMAs containing 38 high-grade (Gleason score ≥8) prostatic adenocarcinomas, representative tissue sections from 15 invasive anal SCCs, representative tissue sections from 19 invasive cervical SCCs, and TMAs with 12 invasive cervical carcinomas of the cervix [SCC (n=10), SCC with neuroendocrine features (n=1), and adenosquamous carcinoma (n=1)]. In addition, GATA3 IHC was performed on representative tissue sections from 15 pulmonary UC metastases and a TMA with 25 SCCs of the lung and 5 pulmonary non-small cell carcinomas with squamous features. GATA3, THROMBO, and uroplakin III were positive in 28 (80%), 22 (63%), and 21 (60%) cases of high-grade UC, respectively. All cases of GATA3-positive staining were nonfocal; 25 (89%) cases demonstrated moderate to strong staining, and 3 (11%) demonstrated weak staining. Of the 7 cases that failed to express GATA3, 5 were positive for THROMBO and/or uroplakin III, whereas 2 were negative for all 3 markers. None of the 38 high-grade prostatic adenocarcinomas was positive for GATA3. Weak GATA3 staining was present in occasional basal cells of benign prostate glands, in a few benign atrophic glands, and in urothelial metaplasia. Of the 15 cases of anal SCCs, 2 (7%) cases showed focal weak staining, and 1 (3%) showed focal moderate staining. Weak staining was also rarely

  8. TREATMENT EFFECTS OF WST11 VASCULAR TARGETED PHOTODYNAMIC THERAPY IN UROTHELIAL CELL CARCINOMA AND FEASIBILITY, SAFETY, AND LONG TERM OUTCOMES IN THE UPPER URINARY TRACT OF SWINE

    PubMed Central

    Murray, Katie S; Winter, Ashley G; Corradi, Renato Beluco; LaRosa, Stephen; Jebiwott, Sylvia; Somma, Alexander; Takaki, Haruyuki; Srimathveeravalli, Govindarajan; Lepherd, Michelle; Monette, Sebastien; Kim, Kwanghee; Scherz, Avigdor; Coleman, Jonathan A

    2016-01-01

    Purpose Surgical management of upper tract urothelial carcinoma requires removal of kidney and ureter, compromising renal function. Non-surgical alternatives have potentially prohibitive safety concerns. We examine the feasibility and safety of ablation of the ureter and renal pelvis using endoluminal vascular-targeted photodynamic therapy in a porcine model and report efficacy of WST11 vascular-targeted photodynamic therapy in a murine model. Materials and Methods Following approval, we performed 28 endoluminal ablations in the ureters and renal pelvis of 18 swine. Intravenous infusion of WST11 (4mg/kg) followed by laser illumination (10 minutes) was performed via percutaneous access or retrograde ureteroscopic approach. Animals were followed clinically with laboratory testing, imaging and histology was evaluated at several post-ablation time points. A murine xenograft was created with the 5637 human urothelial cell carcinoma line to determine sensitivity to this therapy. Results At 24 hours, 50 mW/cm laser fluence produced superficial necrosis of the ureter and deeper necrosis (penetrating the muscularis propria or adventitia) was produced by treatment with 200 mW/cm in the ureter and renal pelvis. At 4 weeks, superficial urothelium had regenerated over the treatment site. No symptomatic obstruction, clinically relevant hydronephrosis, or abnormality of lab testing was noted up to 4 weeks. In mice, 80% had no evidence of tumor at 19 days after WST11 vascular-targeted photodynamic therapy. Conclusions Urothelial cell carcinoma appears to be sensitive to WST11 vascular-targeted photodynamic therapy. Depth of WST11 vascular-targeted photodynamic therapy treatment effects can be modulated in a dose-dependent manner by titration of light intensity. Moreover, this treatment modality, applied to the porcine upper urinary tract, is feasible via antegrade and retrograde access. PMID:26860792

  9. Metastasis in urothelial carcinoma mimicking prostate cancer metastasis in Ga-68 prostate-specific membrane antigen positron emission tomography-computed tomography in a case of synchronous malignancy.

    PubMed

    Gupta, Manoj; Choudhury, Partha Sarathi; Gupta, Gurudutt; Gandhi, Jatin

    2016-01-01

    Prostate cancer is the second most common cancer in man. It commonly presents with urinary symptoms, bone pain, or diagnosed with elevated prostate-specific antigen.(PSA) levels. Correct staging and early diagnosis of recurrence by a precise imaging tool are the keys for optimum management. Molecular imaging of prostate cancer with Ga-68 prostate-specific membrane antigen.(PSMA), positron emission tomography-computed tomography.(PET-CT) has recently received significant attention and frequently used with a signature to prostate cancer-specific remark. However, this case will highlight the more cautious use of it. A-72-year-old male treated earlier for synchronous double malignancy.(invasive papillary urothelial carcinoma right ureter and carcinoma prostate) presented with rising PSA.(0.51.ng/ml) and referred for Ga-68 PSMA PET-CT, which showed a positive enlarged left supraclavicular lymph node. Lymph node biopsy microscopic and immunohistochemistry examination revealed metastatic carcinoma favoring urothelial origin. Specificity of PSMA scan to prostate cancer has been seen to be compromised in a certain situation mostly due to neoangiogenesis, and false positives emerged in renal cell cancer, differentiated thyroid cancer, glioblastoma, breast cancer brain metastasis, and paravertebral schwannomas. Understanding the causes of false positive will further enhance the confidence of interpretating PSMA scans. PMID:27385897

  10. Metastasis in urothelial carcinoma mimicking prostate cancer metastasis in Ga-68 prostate-specific membrane antigen positron emission tomography-computed tomography in a case of synchronous malignancy

    PubMed Central

    Gupta, Manoj; Choudhury, Partha Sarathi; Gupta, Gurudutt; Gandhi, Jatin

    2016-01-01

    Prostate cancer is the second most common cancer in man. It commonly presents with urinary symptoms, bone pain, or diagnosed with elevated prostate-specific antigen.(PSA) levels. Correct staging and early diagnosis of recurrence by a precise imaging tool are the keys for optimum management. Molecular imaging of prostate cancer with Ga-68 prostate-specific membrane antigen.(PSMA), positron emission tomography-computed tomography.(PET-CT) has recently received significant attention and frequently used with a signature to prostate cancer-specific remark. However, this case will highlight the more cautious use of it. A-72-year-old male treated earlier for synchronous double malignancy.(invasive papillary urothelial carcinoma right ureter and carcinoma prostate) presented with rising PSA.(0.51.ng/ml) and referred for Ga-68 PSMA PET-CT, which showed a positive enlarged left supraclavicular lymph node. Lymph node biopsy microscopic and immunohistochemistry examination revealed metastatic carcinoma favoring urothelial origin. Specificity of PSMA scan to prostate cancer has been seen to be compromised in a certain situation mostly due to neoangiogenesis, and false positives emerged in renal cell cancer, differentiated thyroid cancer, glioblastoma, breast cancer brain metastasis, and paravertebral schwannomas. Understanding the causes of false positive will further enhance the confidence of interpretating PSMA scans. PMID:27385897

  11. Fluid intake and the risk of urothelial cell carcinomas in the European Prospective Investigation into Cancer and Nutrition (EPIC).

    PubMed

    Ros, Martine M; Bas Bueno-de-Mesquita, H B; Büchner, Frederike L; Aben, Katja K H; Kampman, Ellen; Egevad, Lars; Overvad, Kim; Tjønneland, Anne; Roswall, Nina; Clavel-Chapelon, Francoise; Kaaks, Rudolf; Chang-Claude, Jenny; Boeing, Heiner; Weikert, Steffen; Trichopoulou, Antonia; Orfanos, Philippos; Stasinopulou, Georgia; Saieva, Calogero; Krogh, Vittorio; Vineis, Paolo; Tumino, Rosario; Mattiello, Amalia; Peeters, Petra H M; van Duijnhoven, Fränzel J B; Lund, Eiliv; Gram, Inger T; Chirlaque, Maria D; Barricarte, Aurelio; Rodríguez, Laudina; Molina, Esther; Gonzalez, Carlos; Dorronsoro, Miren; Manjer, Jonas; Ehrnström, Roy; Ljungberg, Börje; Allen, Naomi E; Roddam, Andrew W; Khaw, Kay-Tee; Wareham, Nick; Boffetta, Paolo; Slimani, Nadia; Michaud, Dominique S; Kiemeney, Lambertus A L M; Riboli, Elio

    2011-06-01

    Results from previous studies investigating the association between fluid intake and urothelial cell carcinomas (UCC) are inconsistent. We evaluated this association among 233,236 subjects in the European Prospective Investigation into Cancer and Nutrition (EPIC), who had adequate baseline information on water and total fluid intake. During a mean follow-up of 9.3 years, 513 first primary UCC occurred. At recruitment, habitual fluid intake was assessed by a food frequency questionnaire. Multivariable hazard ratios were estimated using Cox regression stratified by age, sex and center and adjusted for energy intake, smoking status, duration of smoking and lifetime intensity of smoking. When using the lowest tertile of intake as reference, total fluid intake was not associated with risk of all UCC (HR 1.12; 95%CI 0.86-1.45, p-trend = 0.42) or with risk of prognostically high-risk UCC (HR 1.28; 95%CI 0.85-1.93, p-trend = 0.27) or prognostically low-risk UCC (HR 0.93; 95%CI 0.65-1.33, p-trend = 0.74). No associations were observed between risk of UCC and intake of water, coffee, tea and herbal tea and milk and other dairy beverages. For prognostically low-risk UCC suggestions of an inverse association with alcoholic beverages and of a positive association with soft drinks were seen. Increased risks were found for all UCC and prognostically low-risk UCC with higher intake of fruit and vegetable juices. In conclusion, total usual fluid intake is not associated with UCC risk in EPIC. The relationships observed for some fluids may be due to chance, but further investigation of the role of all types of fluid is warranted.

  12. XRCC1 Arg194Trp and Arg399Gln polymorphisms and arsenic methylation capacity are associated with urothelial carcinoma.

    PubMed

    Chiang, Chien-I; Huang, Ya-Li; Chen, Wei-Jen; Shiue, Horng-Sheng; Huang, Chao-Yuan; Pu, Yeong-Shiau; Lin, Ying-Chin; Hsueh, Yu-Mei

    2014-09-15

    The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case-control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genotype of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln by PCR-restriction fragment length polymorphism analysis (PCR-RFLP). Urinary arsenic profiles were measured by high performance liquid chromatography (HPLC) linked with hydride generator and atomic absorption spectrometry. The XRCC1 399 Gln/Gln and 194 Arg/Trp and Trp/Trp genotypes were significantly related to UC, and the odds ratio (OR) and 95% confidence interval (95%CI) were 1.68 (1.03-2.75) and 0.66 (0.48-0.90), respectively. Participants with higher total urinary arsenic levels, a higher percentage of inorganic arsenic (InAs%) and a lower percentage of dimethylarsinic acid (DMA%) had a higher OR of UC. Participants carrying XRCC1 risk diplotypes G-C/G-C, A-C/A-C, and A-T/G-T, and who had higher total arsenic levels, higher InAs%, or lower DMA% compared to those with other XRCC1 diplotypes had a higher OR of UC. Our results suggest that the XRCC1 399 Gln/Gln and 194 Arg/Arg DNA repair genes play an important role in poor arsenic methylation capacity, thereby increasing the risk of UC in non-obvious arsenic exposure areas.

  13. Correlation of Apobec Mrna Expression with overall Survival and pd-l1 Expression in Urothelial Carcinoma

    PubMed Central

    Mullane, Stephanie A.; Werner, Lillian; Rosenberg, Jonathan; Signoretti, Sabina; Callea, Marcella; Choueiri, Toni K.; Freeman, Gordon J.; Bellmunt, Joaquim

    2016-01-01

    Metastatic urothelial carcinoma (mUC) has a very high mutational rate and is associated with an APOBEC mutation signature. We examined the correlation of APOBEC expression with overall survival (OS) and PD-L1 expression in a cohort of 73 mUC patients. mRNA expression of APOBEC3 family of genes (A3A, A3B, A3C, A3F_a, A3F_b, A3G, A3H) was measured using Nanostring. PD-L1 expression, evaluated by immunohistochemistry, on tumor infiltrating mononuclear cells (TIMCs) and tumor cells was scored from 0 to 4, with 2–4 being positive. Wilcoxon’s non-parametric tests assessed the association of APOBEC and PD-L1. The Cox regression model assessed the association of APOBEC with OS. All APOBEC genes were expressed in mUC. Increased A3A, A3D, and A3H expression associates with PD-L1 positive TIMCs (p = 0.0009, 0.009, 0.06). Decreased A3B expression was marginally associated with PD-L1 positive TIMCs expression (p = 0.05). Increased A3F_a and A3F_b expression was associated with increased expression of PD-L1 on tumor cells (p = 0.05). Increased expression of A3D and A3H was associated with longer OS (p = 0.0009). Specific APOBEC genes have different effects on mUC in terms of survival and PD-L1 expression. A3D and A3H may have the most important role in mUC as they are associated with OS and PD-L1 TIMC expression. PMID:27283319

  14. Higher risk of urothelial carcinoma in the upper urinary tract than in the urinary bladder in hemodialysis patients.

    PubMed

    Hsiao, Po-Jen; Hsieh, Po-Fan; Chang, Chao-Hsiang; Wu, Hsi-Chin; Yang, Chi-Rei; Huang, Chi-Ping

    2016-06-01

    Purpose This study used the a nationwide population-based retrospective cohort study with the claims data from the Taiwan National Health Insurance Research Database to investigate the risk of urothelial carcinoma (UC) for hemodialysis (HD) patients. Methods The study population consisted of 2689 patients with end-stage renal disease (ESRD) newly diagnosed in 2000-2002 and underwent maintenance HD. Then, 21,449 reference patients were collected without HD randomly selected and matched with sex and age. The exclusion criteria were previous long-term analgesics and Chinese medication usage. Incidence density rates of UC in upper urinary tract (UTUC) and bladder (UBUC) were estimated for both cohorts by the end of 2012. Hazard ratios (HRs) of UC were measured in association with HD, covariates, and comorbidity. Results The incidence of UC was significantly higher in the HD cohort than in the reference cohort for both UT (21.8 vs. 0.65 per 10,000 person-years) and UB (17.7 vs. 3.55 per 10,000 person-years). The multivariate Cox proportional hazard regression analysis showed that the HRs of UTUC in HD cohort was 33.3 (95% CI = 15.9-69.5) and 5.14 for UBUC (95% CI = 3.24-8.15). The risk increased further for HD patients with comorbidity of hematuria, urinary tract infection (UTI) or hydronephrosis. Conclusion Patients with ESRD on HD are at a high risk of developing UC, especially UTUC in Taiwan. They will be paid more frequent to check urine analysis, urine cytology, and upper urinary tract survey. PMID:26956094

  15. Prognostic Impact of Thrombospodin-2 (THBS2) Overexpression on Patients with Urothelial Carcinomas of Upper Urinary Tracts and Bladders

    PubMed Central

    Chang, I-Wei; Li, Chien-Feng; Lin, Victor Chia-Hsiang; He, Hong-Lin; Liang, Per-In; Wu, Wen-Jeng; Li, Ching-Chia; Huang, Chun-Nung

    2016-01-01

    Purpose: Urothelial carcinoma (UC) is a type of tumor, especially of the urinary bladder, that affects people worldwide. Clarification of its detailed tumor biology and discovery of potential targets for developing treatment strategies are imperative because of frequent recurrences and poor prognosis of advanced UCs. By data mining a published dataset of UC of bladder (UCB) transcriptome (GSE31684) from Gene Expression Omnibus, National Center of Biotechnology Information (GEO, NCBI), we identified that THBS2 was the most significantly upregulated gene among those related to structural molecule activity (GO:0005198). Therefore, we evaluated the clinical significance and prognostic impact of thrombospondin-2 (THBS2) protein, A.K.A. TSP2, which encoded by THBS2 gene. Materials and Methods: THBS2 immunostaining was performed in 340 UCs of upper urinary tract (UC-UUTs) and 295 UCBs; subsequently, both groups were dichotomized into high- and low-expression subgroups. Moreover, statistical analyses were performed to correlate the association between THBS2 expression and clinicopathological parameters with two survival indexes: disease-specific survival (DSS) and metastasis-free survival (MeFS). Results: High THBS2 immunoexpression was significantly associated with advanced primary tumor status, nodal metastasis, and vascular invasion in both UC-UUT and UCB groups (all P ≤ .001). In addition, THBS2 overexpression was linked to adverse DSS and MeFS in univariate analyses and served as an independent prognosticator indicating poor outcomes in both groups in multivariate analyses. Conclusion: THBS2 may play a crucial role in UC progression and may be a novel prognostic marker. Additional investigations to elucidate the molecular pathway are necessary for developing potential THBS2-targeted therapies for UCs. PMID:27471570

  16. Ki‐67 MIB1 labelling index and the prognosis of primary TaT1 urothelial cell carcinoma of the bladder

    PubMed Central

    Quintero, A; Alvarez‐Kindelan, J; Luque, R J; Gonzalez‐Campora, R; Requena, M J; Montironi, R; Lopez‐Beltran, A

    2006-01-01

    Aims To evaluate whether ki‐67 labelling index (LI) has independent prognostic value for survival of patients with bladder urothelial tumours graded according to the 2004 World Health Organisation classification. Methods Ki‐67 LI was evaluated in 164 cases using the grid counting method. Non‐invasive (stage Ta) tumours were: papilloma (n = 5), papillary urothelial neoplasia of low malignant potential (PUNLMP; n = 26), and low (LG; n = 34) or high grade (HG; n = 15) papillary urothelial carcinoma. Early invasive (stage T1) tumours were: LG (n = 58) and HG (n = 26) carcinoma. Statistical analysis included Fisher and χ2 tests, and mean comparisons by ANOVA and t test. Univariate and multivariate survival analyses were performed according to the Kaplan–Meier method with log rank test and Cox's proportional hazard method. Results Mean ki‐67 LI increased from papilloma to PUNLMP, LG, and HG in stage Ta (p<0.0001) and from LG to HG in stage T1 (p = 0.013) tumours. High tumour proliferation (>13%) was related to greater tumour size (p = 0.036), recurrence (p = 0.036), progression (p = 0.035), survival (p = 0.054), and high p53 accumulation (p = 0.015). Ki‐67 LI and tumour size were independent predictors of disease free survival (DFS), but only ki‐67 LI was related to progression free survival (PFS). Cancer specific overall survival (OS) was related to ki‐67 LI, tumour size, and p27kip1 downregulation. Ki‐67 LI was the main independent predictor of DFS (p = 0.0005), PFS (p = 0.0162), and cancer specific OS (p = 00195). Conclusion Tumour proliferation measured by Ki‐67 LI is related to tumour recurrence, stage progression, and is an independent predictor of DFS, PFS, and cancer specific OS in TaT1 bladder urothelial cell carcinoma. PMID:16394286

  17. Molecular analysis of appendiceal mucinous cystadenoma and rectal adenocarcinoma in a patient with urothelial carcinoma: a case report

    PubMed Central

    2013-01-01

    Introduction In this report, we present the case of a patient affected by appendiceal cystadenoma, a colorectal adenocarcinoma, and a concomitant bladder carcinoma, as well as the results of the molecular study of the most relevant mutational pathways involved in these tumors. Case presentation A 68-year-old Italian man was admitted to our unit complaining of macrohematuria, rectorrhagia, and rectal tenesmus for about 2 months. A colonoscopy showed the presence of a rectal lesion at 11cm from the anal margin; multiple biopsies were performed and a diagnosis of moderately differentiated adenocarcinoma was made. Abdominal ultrasonography and total body computed tomography performed subsequently to stage the rectal cancer showed the presence of two round nodules, interpreted as swollen lymph nodes of neoplastic origin, at the anterior aspect of the iliopsoas muscle and a budding lesion affecting the bladder. The patient underwent transurethral biopsy of the lesion in the right retrotrigonal region; the diagnosis was grade II urothelial carcinoma. The patient underwent an open anterior rectal resection with loco-regional lymphadenectomy. An enlarged appendix and a voluminous whitish soft-tissue lesion requiring an appendicectomy were detected perioperatively. Transurethral resection of the bladder lesion was also performed. The histological examination revealed that the nodular lesions in the appendix were due to a cystadenoma. For mutation analysis, genomic deoxyribonucleic acid was isolated from tumor tissue samples; for PIK3CA mutations, screening revealed that all three samples analyzed carried mutations in exon 9. Conclusions Appendiceal mucoceles are rare but require adequate surgical treatment, given their malignant potential and the possibility of causing peritoneal pseudomyxoma. It is essential to make a correct preoperative evaluation based on a colonoscopy rather than ultrasound and computed tomography to exclude synchronous neoplasias often associated with

  18. Urothelial eddies in papillary urothelial neoplasms: a distinct morphologic pattern with low risk for progression

    PubMed Central

    Kim, Misung; Ro, Jae Y; Amin, Mahul B; de Peralta-Venturina, Mariza; Kwon, Ghee Young; Park, Yong Wook; Cho, Yong Mee

    2013-01-01

    We encountered an undescribed histologic feature of papillary urothelial neoplasms: “urothelial eddy”, which was histologically reminiscent of squamous eddy of irritated follicular keratosis of the skin. A review of 756 patients with transurethral resection of bladder tumor revealed 10 patients (1.3%) of papillary urothelial neoplasms with urothelial eddies. All cases were male with a median age of 65 years. Urothelial eddies were characterized by small ovoid nests of ovoid to spindle cells arranged in an onion-skin pattern with fine cytoplasmic processes within wide intercellular space. The cytoplasmic processes mimicked intercellular bridges but ultrastructurally were cytoplasmic microvillous projections. They were of papillary urothelial neoplasm of low malignant potential in seven patients and low-grade urothelial carcinoma in three patients. Nine patients presented as non-invasive tumor and one patient showed microinvasion within papillary stalks. Six patients showed an inverted growth pattern. Their immunoprofile was more similar to that of conventional urothelial carcinoma rather than squamous cell carcinoma: high expressions of GATA3, S100P, uroplakin III, and cytokeratin 7; and low expressions of high molecular weight cytokeratin and p53. The Ki-67 labeling index was low (mean and median values, 2% each). During the follow-up period (mean, 88.7 months), four patients, including the microinvasive patient, showed recurrence with the same grade and stage but neither progressed into muscle-invasive tumor nor caused death. Our results suggest that urothelial eddy is a rare aberrant histology of papillary urothelial neoplasms with indolent behavior and should be discriminated from squamous differentiation of urothelial carcinoma, which has a poor prognosis. PMID:23923064

  19. Arsenic exposure, urinary arsenic speciation, and the incidence of urothelial carcinoma: a twelve-year follow-up study.

    PubMed

    Huang, Yung-Kai; Huang, Ya-Li; Hsueh, Yu-Mei; Yang, Mo-Hsiung; Wu, Meei-Maan; Chen, Shu-Yuan; Hsu, Ling-I; Chen, Chien-Jen

    2008-10-01

    The risk of urothelial carcinoma (UC) and urinary arsenic speciation have been evaluated in a few case-control studies; however, the association has not been verified in a prospective cohort study. The aim of this study was to examine the association between urinary arsenic speciation and the incidence of UC in a cohort study. A total of 1,078 residents of southwestern Taiwan were followed for an average of 12 years. A high-performance liquid chromatography/hydride generator and an atomic absorption spectrometry were used to measure urinary arsenite, arsenate, monomethylarsonic acid (MMA(V)), and dimethylarsinic acid (DMA(V)). The incidence of UC was estimated by examining the National Cancer Registry of Taiwan between January 1985 and December 2001. There were 37 newly diagnosed cases of UC during a follow-up period of 11,655 person-years. Significantly higher percentages of MMA(V) and lower percentages of DMA(V) existed among the patients with UC than among the healthy residents. After adjustment for age, gender, educational level, and smoking status, the percentage of urinary DMA(V) was shown to have an inverse association with the risk of UC, having a relative risk (RR) of the tertile strata of 1.0, 0.3, and 0.3, respectively (p < 0.05 for the trend test). The RR (95% confidence interval) of residents with a cumulative arsenic exposure (CAE) of >/=20 mg/l-year and a higher percentage of MMA(V) or a CAE of > or =20 mg/l-year and a lower percentage of DMA(V) was 3.7 (1.2-11.6) or 4.2 (1.3-13.4) compared to residents with a CAE of <20 mg/l-year and a lower percentage of MMA(V) or a CAE of <20 mg/l-year and a higher percentage of DMA(V )respectively. There was a significant association between inefficient arsenic methylation and the development of UC in the residents in the high CAE exposure strata in an area of southwestern Taiwan endemic for arseniasis.

  20. Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder

    PubMed Central

    2013-01-01

    Background Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear. Methods In this study, the methods of quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate mRNA/ protein expression of YAP 1 in UCBs. Spearman’s rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Results Up-regulated expression of YAP 1 mRNA and protein was observed in the majority of UCBs by qRT-PCR and Western blotting, when compared with their paired normal bladder tissues. By IHC, positive expression of YAP 1 was examined in 113/213 (53.1%) of UCBs and in 6/86 (7.0%) of normal bladder specimens tissues. Positive expression of YAP 1 was correlated with poorer differentiation, higher T classification and higher N classification (P < 0.05). In univariate survival analysis, a significant association between positive expression of YAP 1 and shortened patients’ survival was found (P < 0.001). In different subsets of UCB patients, YAP 1 expression was also a prognostic indicator in patients with grade 2 (P = 0.005) or grade 3 (P = 0.046) UCB, and in patients in pT1 (P = 0.013), pT2-4 (P = 0.002), pN- (P < 0.001) or pT2-4/pN- (P = 0.004) stage. Importantly, YAP 1 expression (P = 0.003) together with pT and pN status (P< 0.05) provided significant independent prognostic parameters in multivariate analysis. Conclusions Our findings provide evidences that positive expression of YAP 1 in UCB may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with UCB. PMID:23870412

  1. XRCC1 Arg194Trp and Arg399Gln polymorphisms and arsenic methylation capacity are associated with urothelial carcinoma

    SciTech Connect

    Chiang, Chien-I; Huang, Ya-Li; Chen, Wei-Jen; Shiue, Horng-Sheng; Huang, Chao-Yuan; Pu, Yeong-Shiau; Lin, Ying-Chin; Hsueh, Yu-Mei

    2014-09-15

    The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case–control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genotype of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln by PCR-restriction fragment length polymorphism analysis (PCR-RFLP). Urinary arsenic profiles were measured by high performance liquid chromatography (HPLC) linked with hydride generator and atomic absorption spectrometry. The XRCC1 399 Gln/Gln and 194 Arg/Trp and Trp/Trp genotypes were significantly related to UC, and the odds ratio (OR) and 95% confidence interval (95%CI) were 1.68 (1.03–2.75) and 0.66 (0.48–0.90), respectively. Participants with higher total urinary arsenic levels, a higher percentage of inorganic arsenic (InAs%) and a lower percentage of dimethylarsinic acid (DMA%) had a higher OR of UC. Participants carrying XRCC1 risk diplotypes G-C/G-C, A-C/A-C, and A-T/G-T, and who had higher total arsenic levels, higher InAs%, or lower DMA% compared to those with other XRCC1 diplotypes had a higher OR of UC. Our results suggest that the XRCC1 399 Gln/Gln and 194 Arg/Arg DNA repair genes play an important role in poor arsenic methylation capacity, thereby increasing the risk of UC in non-obvious arsenic exposure areas. - Highlights: • The XRCC1 399Gln/Gln genotype was significantly associated with increased OR of UC. • The XRCC1 194 Arg/Trp and Trp/Trp genotype had a significantly decreased OR of UC. • Combined effect of the XRCC1 genotypes and poor arsenic methylation capacity on

  2. PinX1 suppresses bladder urothelial carcinoma cell proliferation via the inhibition of telomerase activity and p16/cyclin D1 pathway

    PubMed Central

    2013-01-01

    Background PIN2/TRF1-interacting telomerase inhibitor1 (PinX1) was recently suggested as a putative tumor suppressor in several types of human cancer, based on its binding to and inhibition of telomerase. Moreover, loss of PinX1 has been detected in many human malignancies. However, the possible involvement of PinX1 and its clinical/prognostic significance in urothelial carcinoma of the bladder (UCB) are unclear. Methods The PinX1 expression profile was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC) in UCB tissues and adjacent normal urothelial bladder epithelial tissues. PinX1 was overexpressed and silenced in UCB cell lines to determine its role in tumorigenesis, development of UCB, and the possible mechanism. Results PinX1 expression in UCB was significantly down-regulated at both mRNA and protein level as compared with that in normal urothelial bladder epithelial tissues. PinX1 levels were inversely correlated with tumor multiplicity, advanced N classification, high proliferation index (Ki-67), and poor survival (P < 0.05). Moreover, overexpression of PinX1 in UCB cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing PinX1 dramatically enhanced cell proliferation. Overexpression of PinX1 resulted in G1/S phase arrest and cell growth/proliferation inhibition, while silencing PinX1 led to acceleration of G1/S transition, and cell growth/proliferation promotion by inhibiting/enhancing telomerase activity and via the p16/cyclin D1 pathway. Conclusions These findings suggest that down-regulation of PinX1 play an important role in the tumorigenesis and development of UCB and that the expression of PinX1 as detected by IHC is an independent molecular marker in patients with UCB. PMID:24268029

  3. Prognostic significance of the 2004 WHO/ISUP classification for prediction of recurrence, progression, and cancer-specific mortality of non-muscle-invasive urothelial tumors of the urinary bladder: a clinicopathologic study of 1,515 cases.

    PubMed

    Pan, Chin-Chen; Chang, Yen-Hwa; Chen, Kuang-Kuo; Yu, Hui-Jung; Sun, Chih-Hao; Ho, Donald M T

    2010-05-01

    To verify prognostic significance of the 2004 World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading systems, we retrospectively studied the tumors of 1,515 patients who underwent transurethral resection of primary non-muscle-invasive urothelial tumors (pTa, 1,006 patients; pT1, 509 patients) confined to the bladder. Cases were classified according to the 2004 WHO/ISUP systems as 212 cases of papillary urothelial neoplasm of low malignant potential (PUNLMP), 706 low-grade papillary urothelial carcinomas (LPUCs), and 597 high-grade papillary urothelial carcinomas (HPUCs). PUNLMP showed the statistically significantly lowest recurrence cumulative incidence compared with the other tumor types. There were significant differences and trends for higher progression and cancer-specific mortality cumulative incidence in the following order: PUNLMP, LPUC, pTa HPUC, and pT1 HPUC. No differences of progression and cancer-specific mortality cumulative incidence were found between pTa and pT1 LPUC. Our study validates the usefulness of the 2004 WHO/ISUP system to classify urothelial tumors into prognostically distinct categories that would contribute to the design of therapeutic and monitoring strategies for patients with non-muscle-invasive bladder urothelial tumors.

  4. The prognostic role of lymphovascular invasion in urothelial carcinoma of the bladder.

    PubMed

    Mathieu, Romain; Lucca, Ilaria; Rouprêt, Morgan; Briganti, Alberto; Shariat, Shahrokh F

    2016-08-01

    Outcome prediction in patients with bladder cancer has improved through the development of nomograms and predictive models. However, integration of further characteristics such as lymphovascular invasion (LVI) might increase the accuracy and clinical utility of these instruments. Assessment and reporting of LVI in specimens from transurethral resection of the bladder tumour (TURBT) or biopsy in patients with non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) might enable improved staging, prognostication and clinical decision-making. In NMIBC, presence of LVI in TURBT and biopsy samples seems to be associated with understaging and increased risks of disease recurrence and progression. In MIBC, presence of LVI is associated with features of aggressive disease and predicts recurrence and survival. Integration of LVI status into predictive models might aid clinical decision-making regarding intravesical instillation schedules and regimens, early radical cystectomy in patients with high-grade T1 disease and perioperative chemotherapy. However, LVI assessment is hampered by insufficient reproducibility and reliability, lack of routine evaluation and limited concordance between findings in TURBT and radical cystectomy specimens. Standardization of the pathological criteria defining LVI is warranted to improve its reporting in routine clinical practice and its utility as a care-changing prognostic marker.

  5. Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors

    PubMed Central

    Heidenblad, Markus; Lindgren, David; Jonson, Tord; Liedberg, Fredrik; Veerla, Srinivas; Chebil, Gunilla; Gudjonsson, Sigurdur; Borg, Åke; Månsson, Wiking; Höglund, Mattias

    2008-01-01

    Background Urothelial carcinoma (UC) is characterized by nonrandom chromosomal aberrations, varying from one or a few changes in early-stage and low-grade tumors, to highly rearranged karyotypes in muscle-invasive lesions. Recent array-CGH analyses have shed further light on the genomic changes underlying the neoplastic development of UC, and have facilitated the molecular delineation amplified and deleted regions to the level of specific candidate genes. In the present investigation we combine detailed genomic information with expression information to identify putative target genes for genomic amplifications. Methods We analyzed 38 urothelial carcinomas by whole-genome tiling resolution array-CGH and high density expression profiling to identify putative target genes in common genomic amplifications. When necessary expression profiling was complemented with Q-PCR of individual genes. Results Three genomic segments were frequently and exclusively amplified in high grade tumors; 1q23, 6p22 and 8q22, respectively. Detailed mapping of the 1q23 segment showed a heterogeneous amplification pattern and no obvious commonly amplified region. The 6p22 amplicon was defined by a 1.8 Mb core region present in all amplifications, flanked both distally and proximally by segments amplified to a lesser extent. By combining genomic profiles with expression profiles we could show that amplification of E2F3, CDKAL1, SOX4, and MBOAT1 as well as NUP153, AOF1, FAM8A1 and DEK in 6p22 was associated with increased gene expression. Amplification of the 8q22 segment was primarily associated with YWHAZ (14-3-3-zeta) and POLR2K over expression. The possible importance of the YWHA genes in the development of urothelial carcinomas was supported by another recurrent amplicon paralogous to 8q22, in 2p25, where increased copy numbers lead to enhanced expression of YWHAQ (14-3-3-theta). Homozygous deletions were identified at 10 different genomic locations, most frequently affecting CDKN2A/CDKN2B

  6. Aurora-A/STK-15 is a predictive factor for recurrent behaviour in non-invasive bladder carcinoma: a study of 128 cases of non-invasive neoplasms.

    PubMed

    Compérat, E; Camparo, P; Haus, R; Chartier-Kastler, E; Radenen, B; Richard, F; Capron, F; Paradis, V

    2007-04-01

    Aurora-A, a member of serine/threonine kinase, is implied in mitosis and centrosome maturation. Increasing levels of Aurora-A have been shown to be present in several malignancies and especially in bladder cancer. No immunohistochemical marker has shown to be able to predict the clinical outcome of patients with superficial bladder cancer, except MIB-1, as a predictive marker of relapse and progression. The aim was to investigate the expression of Aurora-A and MIB-1 in tissue micro arrays of superficial bladder cancer representative of pTa papillary urothelial neoplasm with different degrees of aggressiveness (low malignant potential [PUNLMP], non-invasive papillary urothelial carcinoma low grade [NILGC], non-invasive papillary urothelial carcinoma high grade [NIHGC] and carcinoma in situ). We analysed predictive values of both markers, their specificity and sensitivity in tumor recurrence. Aurora-A was a sensitive marker to predict tumor recurrence especially for pTa (PUNLMP, NILGC; PUNLMP p<0.001, NILGC p<0.001) with statistical significant correlation between immunohistochemical staining and clinical outcome. MIB-1 expression displayed statistical difference p=0.002 in the PUNLMP group and p=0.03 in the NILGC group. Aurora-A is a more sensitive marker than MIB-1 to predict relapse in pTa bladder neoplasias. The combination of both markers seems to have a very powerful predictive value of recurrence (p<0.001).

  7. Global acetylation and methylation changes predict papillary urothelial neoplasia of low malignant potential recurrence: a quantitative analysis.

    PubMed

    Mazzucchelli, R; Scarpelli, M; Lopez-Beltran, A; Cheng, L; Bartels, H; Bartels, P H; Alberts, D S; Montironi, R

    2011-01-01

    Papillary urothelial neoplasia of low malignant potential (PUNLMP) recurs in approximately 35% of patients. Conventional histopathological assessment does not distinguish non-recurrent from recurrent PUNLMP. The aim of this study is to explore the differences in global histone acetylation and global DNA methylation between non-recurrent and recurrent PUNLMP. Acetylated histone H3 lysine 9 (AcH3K9) and 5-methylcytosine (5MeC) were investigated by immunohistochemistry (IHC) in 20 PUNLMP cases (10 non-recurrent and 10 recurrent), in 5 cases of normal urothelium (NU) and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). The total optical density of the nuclear staining was measured photometrically in at least 40 nuclei separately for the basal, intermediate and luminal positions in each case. Concerning the total optical density values for both acetylation and methylation, a decrease in staining is observed from non-recurrent PUNLMP to recurrent PUNLMP, at all nuclear locations. For acetylation the mean value in non-recurrent PUNLMP, intermediate between NU and UC, is closer to the former than to latter. The mean value in recurrent PUNLMP is closer to UC than to NU. In NU, non-recurrent and recurrent PUNLMP, the acetylation to methylation ratio decreased from the nuclei in basal position to those in the surface, the average for the above groups being 1.491, 1.611 and 1.746, respectively. Setting the observed values for NU at each sampling location to unity, acetylation shows a steady decrease, the percentages of changes in this nuclear location compared to NU being -5% in non-recurrent PUNLMP, -15% in recurrent PUNLMP and -24% in UC. Concerning methylation, there is a slight increase in non-recurrent PUNLMP (+5%), a decrease in recurrent PUNLMP (-19%) followed by a sharp rise for the UC (+61%). In conclusion, there are differences in global histone acetylation and DNA methylation patterns between non-recurrent and recurrent PUNLMP. Further studies are needed

  8. Long-term oncologic outcomes of laparoscopic nephroureterectomy versus open nephroureterectomy for upper tract urothelial carcinoma: a systematic review and meta-analysis.

    PubMed

    Zhang, Su; Luo, You; Wang, Cheng; Fu, Sheng-Jun; Yang, Li

    2016-01-01

    Background. Several factors have been validated as predictors of disease recurrence in upper tract urothelial carcinoma. However, the oncological outcomes between different surgical approaches (open nephroureterectomy versus laparoscopic nephroureterectomy, ONU vs LNU) remain controversial. Therefore, we performed a meta-analysis to evaluate the oncological outcomes associated with different surgical approaches. Methods. We conducted an electronic search of the PubMed, Embase, ISI Web of Knowledge and Cochrane Library electronic databases through November 2015, screened the retrieved references, collected and evaluated the relevant information. We extracted and synthesized the corresponding hazard ratios (HRs) and 95% confidence intervals (95% CI) using Stata 13. Results. Twenty-one observational studies were eligible for inclusion in the meta-analysis. The results of the meta-analysis showed no differences in the intravesical recurrence-free survival (IRFS), unspecified recurrence-free survival (UnRFS) and overall survival (OS) between LNUandONU. However, improvements in the extravesical recurrence free survival (ExRFS) and cancer specific survival (CSS) were observed inLNU. The pooled hazard ratios were 1.05 (95% CI [0.92-1.18]) for IRFS, 0.80 (95% CI [0.64-0.96]) for ExRFS, 1.10 (95% CI [0.93-1.28]) for UnRFS, 0.91 (95% CI [0.66-1.17]) for OS and 0.79 (95% CI [0.68-0.91]) for CSS. Conclusion. Based on current evidence, LNU could provide equivalent prognostic effects for upper tract urothelial carcinoma, and had better oncological control of ExRFS and CSS compared to ONU. However, considering all eligible studies with the intrinsic bias of retrospective study design, the results should be interpreted with caution. Prospective randomized trials are needed to verify these results.

  9. Long-term oncologic outcomes of laparoscopic nephroureterectomy versus open nephroureterectomy for upper tract urothelial carcinoma: a systematic review and meta-analysis

    PubMed Central

    Zhang, Su; Luo, You; Wang, Cheng; Fu, Sheng-Jun

    2016-01-01

    Background. Several factors have been validated as predictors of disease recurrence in upper tract urothelial carcinoma. However, the oncological outcomes between different surgical approaches (open nephroureterectomy versus laparoscopic nephroureterectomy, ONU vs LNU) remain controversial. Therefore, we performed a meta-analysis to evaluate the oncological outcomes associated with different surgical approaches. Methods. We conducted an electronic search of the PubMed, Embase, ISI Web of Knowledge and Cochrane Library electronic databases through November 2015, screened the retrieved references, collected and evaluated the relevant information. We extracted and synthesized the corresponding hazard ratios (HRs) and 95% confidence intervals (95% CI) using Stata 13. Results. Twenty-one observational studies were eligible for inclusion in the meta-analysis. The results of the meta-analysis showed no differences in the intravesical recurrence-free survival (IRFS), unspecified recurrence-free survival (UnRFS) and overall survival (OS) between LNUandONU. However, improvements in the extravesical recurrence free survival (ExRFS) and cancer specific survival (CSS) were observed inLNU. The pooled hazard ratios were 1.05 (95% CI [0.92–1.18]) for IRFS, 0.80 (95% CI [0.64–0.96]) for ExRFS, 1.10 (95% CI [0.93–1.28]) for UnRFS, 0.91 (95% CI [0.66–1.17]) for OS and 0.79 (95% CI [0.68–0.91]) for CSS. Conclusion. Based on current evidence, LNU could provide equivalent prognostic effects for upper tract urothelial carcinoma, and had better oncological control of ExRFS and CSS compared to ONU. However, considering all eligible studies with the intrinsic bias of retrospective study design, the results should be interpreted with caution. Prospective randomized trials are needed to verify these results. PMID:27280069

  10. Two-micron thulium laser resection of the distal ureter and bladder cuff during nephroureterectomy for upper urinary tract urothelial carcinoma.

    PubMed

    Pang, Kun; Liu, Shi-bo; Wei, Hai-bin; Zhuo, Jian; Li, Mei-li; Xia, Shu-jie; Sun, Xiao-wen

    2014-03-01

    The thulium laser (Tm-laser) technique has been used in the management of many urologic conditions. The present study aimed to evaluate the use of this technique for distal ureter and bladder cuff (DUBC) excision during nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). Fifty-eight patients with UUT-UC who underwent radical nephroureterectomy were included in this retrospective study. DUBC was managed by open excision in 24 cases, by transurethral electrosurgery in 17 cases, and by transurethral Tm-laser in 17 cases. Perioperative measures and oncologic outcomes were compared among the three groups. Furthermore, 11 human ureteral segments were collected to measure the burst pressure and show physical pressure tolerance, and six ureteral segments were assessed histologically to investigate the sealing effect. Operative time and hospital stay were significantly longer, and intraoperative blood loss was significantly greater in the open excision group than in the electrosurgery and Tm-laser groups (P < 0.05 for all). There were no significant differences in these parameters between the electrosurgery and Tm-laser groups. In addition, there were no significant differences in the incidences of bladder tumors and retroperitoneal recurrence of urothelial carcinoma among the three groups. The coagulation time and resection time were significantly shorter in the Tm-laser group than in the electrosurgery group. The mean burst pressure did not differ significantly between the tissues sealed by electrosurgery and by Tm-laser. Histopathological analyses showed that distal ureters were completely sealed by both electrosurgery and Tm-laser. The Tm-laser technique is superior to open excision and comparable to transurethral electrosurgery in the management of DUBC during nephroureterectomy for UUT-UC, offering an alternative treatment option for this condition.

  11. Urinary bladder urothelial carcinoma with concurrent plasmacytoid and micropapillary differentiations: A report of two cases with an emphasis on serum carbohydrate antigen 19-9.

    PubMed

    Makise, Naohiro; Morikawa, Teppei; Takeshima, Yuta; Fujimura, Tetsuya; Homma, Yukio; Fukayama, Masashi

    2015-09-01

    We report two cases of urinary bladder urothelial carcinoma (UC). In both, histological examination of a transurethral resection specimen of the bladder tumor revealed UC with plasmacytoid and micropapillary differentiations. In Case 1, residual plasmacytoid UC deeply invaded the extravesical fat tissue of the radical cystectomy specimen, and metastatic carcinoma was found in almost all the dissected lymph nodes. Despite adjuvant chemotherapy and radiotherapy, the patient died 25 months postdiagnosis. Elevated serum carbohydrate antigen 19-9 (CA19-9) returned to near normal levels after radical cystectomy, but they increased shortly before death. In Case 2, no residual carcinoma was found in the radical cystectomy specimen or lymph nodes. Postoperative serum CA19-9 was maintained at normal levels, and the patient remains alive without recurrence or metastasis. Although plasmacytoid and micropapillary UC are known aggressive variants of UC, plasmacytoid UC may be more aggressive. Serum CA19-9 could serve as a useful biomarker to monitor progression of plasmacytoid UC.

  12. Utility of a triple antibody cocktail intraurothelial neoplasm-3 (IUN-3-CK20/CD44s/p53) and α-methylacyl-CoA racemase (AMACR) in the distinction of urothelial carcinoma in situ (CIS) and reactive urothelial atypia.

    PubMed

    Aron, Manju; Luthringer, Daniel J; McKenney, Jesse K; Hansel, Donna E; Westfall, Danielle E; Parakh, Rugvedita; Mohanty, Sambit K; Balzer, Bonnie; Amin, Mahul B

    2013-12-01

    Urothelial carcinoma in situ (CIS) is a prognostically and therapeutically significant lesion with considerable morphologic overlap with reactive conditions especially in the setting of prior therapy. Various markers including CK20, CD44s, and p53 have been used as an adjunct in making this distinction; however, the utility of these markers in the posttreatment scenario is not fully established. α-Methylacyl-CoA racemase (AMACR) is a tumor-associated marker that is expressed in a subset of high-grade urothelial carcinomas but has not been studied in CIS. This study was undertaken to evaluate the immunoreactivity of CK20, CD44s, and p53 as a triple antibody cocktail intraurothelial neoplasm-3 (IUN-3) in distinguishing CIS from its mimics and to compare its utility with AMACR in the diagnosis of CIS. A total of 135 specimens (7 benign ureters and 128 bladder biopsies-28 reactive, 33 posttherapy reactive, 43 CIS, 24 CIS posttherapy) were included in this study. Immunostaining for p53 (brown, nuclear), CD44s (brown, membranous), and CK20 (red, cytoplasmic and membranous) was performed as a cocktail, and the staining pattern was further classified as: malignant (full-thickness CK20 and/or full-thickness p53 with CD44s negativity), reactive/benign (CK20 limited to the umbrella cell layer, p53 negative, and CD44s positivity ranging from basal to full thickness), and indeterminate (CK20 and p53 positive but not full thickness and/or CD44s positive). AMACR staining was performed in 50 cases. Cytoplasmic staining for AMACR was graded as negative (absent to weak focal staining [<5% cells]) and positive (≥5%). The "IUN-3 malignant" pattern was observed in 84% of cases of CIS without a history of prior therapy and in 71% of the cases of CIS with a history of prior therapy. Cases with posttherapy reactive atypia showed an "IUN-3 reactive" pattern in 84% cases and "IUN-3 indeterminate" pattern in 16% of the cases; the IUN-3 malignant pattern was not identified in any of the

  13. [Clinical use of the ImmunoCyt/uCyt+ and fluorescence in situ hybridisation (FISH) tests for urothelial carcinomas].

    PubMed

    Lodde, Michele; Mian, Christine

    2013-01-01

    In recent decades years, we have witnessed the propagation and marketing of numerous diagnostic tests capable of detecting, in the urine of patients, the presence of urothelial tumor markers. Among None of the different markers studied to date , no one has been able to meet all the requirements of the ideal marker. We present and discuss below we discuss the results reported in the literature of about two tests approved by the Food and Drug Administration [ImmunoCyt/uCyt+ and Fluorescence In Situ Hybridisation (FISH)], which have been and commercially available for about 10 years., ImmunoCyt/uCyt + and Fluorescence In Situ Hybridisation (FISH).

  14. The cAMP responsive element binding protein 1 transactivates epithelial membrane protein 2, a potential tumor suppressor in the urinary bladder urothelial carcinoma.

    PubMed

    Li, Chien-Feng; Wu, Wen-Jeng; Wu, Wen-Ren; Liao, Yu-Jing; Chen, Lih-Ren; Huang, Chun-Nung; Li, Ching-Chia; Li, Wei-Ming; Huang, Hsuan-Ying; Chen, Yi-Ling; Liang, Shih-Shin; Chow, Nan-Haw; Shiue, Yow-Ling

    2015-04-20

    In this study, we report that EMP2 plays a tumor suppressor role by inducing G2/M cell cycle arrest, suppressing cell viability, proliferation, colony formation/anchorage-independent cell growth via regulation of G2/M checkpoints in distinct urinary bladder urothelial carcinoma (UBUC)-derived cell lines. Genistein treatment or exogenous expression of the cAMP responsive element binding protein 1 (CREB1) gene in different UBUC-derived cell lines induced EMP2 transcription and subsequent translation. Mutagenesis on either or both cAMP-responsive element(s) dramatically decreased the EMP2 promoter activity with, without genistein treatment or exogenous CREB1 expression, respectively. Significantly correlation between the EMP2 immunointensity and primary tumor, nodal status, histological grade, vascular invasion and mitotic activity was identified. Multivariate analysis further demonstrated that low EMP2 immunoexpression is an independent prognostic factor for poor disease-specific survival. Genistein treatments, knockdown of EMP2 gene and double knockdown of CREB1 and EMP2 genes significantly inhibited tumor growth and notably downregulated CREB1 and EMP2 protein levels in the mice xenograft models. Therefore, genistein induced CREB1 transcription, translation and upregulated pCREB1(S133) protein level. Afterward, pCREB1(S133) transactivated the tumor suppressor gene, EMP2, in vitro and in vivo. Our study identified a novel transcriptional target, which plays a tumor suppressor role, of CREB1.

  15. [A Case Report of Suspected Tuberculous Granuloma in the Kidney after BCG Perfusion Therapy for Urothelial Carcinoma of the Renal Pelvis].

    PubMed

    Kobayashi, Shin; Hori, Junichi; Okazaki, Satoshi; Hashizume, Kazumi; Watanabe, Masaki; Wada, Naoki; Kita, Masafumi; Azumi, Makoto; Iwata, Tatsuya; Matsumoto, Seiji; Kakizaki, Hidehiro

    2016-01-01

    A 66-year-old male patient was referred to our hospital for bilateral renal pelvic tumors. Ureteroscopic biopsy revealed urothelial carcinoma (UC) of low grade (G1) of the renal pelvis. Renal sparing treatment with systemic chemotherapy and percutaneous tumor resection was performed. However, during subsequent follow up, a recurrent tumor was found on the left ureter. After ureteroscopic laser ablation of the tumor, Bacillus Calmette-Guerin (BCG) perfusion therapy (once a week, total 6 weeks) was performed via a single J ureteral catheter with no adverse events. Later, another recurrent recurrence was found on the right ureter, and was managed by ureteroscopic laser ablation followed by BCG perfusion therapy via a single J ureteral catheter. However, the patient developed high fever with chill from the day after initial BCG perfusion therapy on the right side. Although we started antibiotics, high fever continued. Then antituberculous drugs were administered and his condition was improved. Computed tomographic scan revealed a right renal mass 57 mm in diameter, which was consistent with tuberculous granuloma. The tuberculous granuloma persisted despite the continuation of anti-tuberculous drugs. In exceptional cases of upper tract UC such as single kidney and bilateral tumor, BCG perfusion therapy has been used as adjunctive treatment to cure or prevent UC. However, dosages and administration methods of BCG perfusion therapy for upper tract UC still remain to be standardized. Serious adverse events after BCG perfusion therapy require prompt and proper management including the use of anti-tuberculous drugs.

  16. Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways.

    PubMed

    Hsieh, Hsiao-Yen; Shen, Cheng-Huang; Lin, Ru-Inn; Feng, Yu-Min; Huang, Shih-Yuan; Wang, Yuan-Hung; Wu, Shu-Fen; Hsu, Cheng-Da; Chan, Michael W Y

    2016-01-01

    Cyproheptadine, a serotonin antagonist, has recently been reported to function as a novel therapeutic agent by inhibiting PI3K/AKT signaling in several human cancers. However, the therapeutic effect of cyproheptadine in urothelial carcinoma (UC) has never been explored. In this study, we determined the effect of cyproheptadine on the growth of five human UC cell lines and an in vivo xenograft model. The results showed that cyproheptadine exerted an inhibitory effect on the proliferation of UC cells both in vitro and in vivo. Cyproheptadine also induced cell cycle arrest in the G1 phase, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest were associated with the reduction of c-Myc, induction of p21 and p27, and the stabilization of Rb expression. In addition, the suppression of the GSK3β/TSC2/mTOR pathway and deregulation of the GSK3β/β-catenin signaling were observed in cyproheptadine-treated UC cells. Furthermore, cyproheptadine-induced apoptosis was associated with ANGPTL4 expression followed by activation of caspase3 and PARP in UC cells. Our experimental results provide evidence that cyproheptadine is a suitable therapeutic agent for the treatment of UC.

  17. [A Case Report of Suspected Tuberculous Granuloma in the Kidney after BCG Perfusion Therapy for Urothelial Carcinoma of the Renal Pelvis].

    PubMed

    Kobayashi, Shin; Hori, Junichi; Okazaki, Satoshi; Hashizume, Kazumi; Watanabe, Masaki; Wada, Naoki; Kita, Masafumi; Azumi, Makoto; Iwata, Tatsuya; Matsumoto, Seiji; Kakizaki, Hidehiro

    2016-01-01

    A 66-year-old male patient was referred to our hospital for bilateral renal pelvic tumors. Ureteroscopic biopsy revealed urothelial carcinoma (UC) of low grade (G1) of the renal pelvis. Renal sparing treatment with systemic chemotherapy and percutaneous tumor resection was performed. However, during subsequent follow up, a recurrent tumor was found on the left ureter. After ureteroscopic laser ablation of the tumor, Bacillus Calmette-Guerin (BCG) perfusion therapy (once a week, total 6 weeks) was performed via a single J ureteral catheter with no adverse events. Later, another recurrent recurrence was found on the right ureter, and was managed by ureteroscopic laser ablation followed by BCG perfusion therapy via a single J ureteral catheter. However, the patient developed high fever with chill from the day after initial BCG perfusion therapy on the right side. Although we started antibiotics, high fever continued. Then antituberculous drugs were administered and his condition was improved. Computed tomographic scan revealed a right renal mass 57 mm in diameter, which was consistent with tuberculous granuloma. The tuberculous granuloma persisted despite the continuation of anti-tuberculous drugs. In exceptional cases of upper tract UC such as single kidney and bilateral tumor, BCG perfusion therapy has been used as adjunctive treatment to cure or prevent UC. However, dosages and administration methods of BCG perfusion therapy for upper tract UC still remain to be standardized. Serious adverse events after BCG perfusion therapy require prompt and proper management including the use of anti-tuberculous drugs. PMID:26932332

  18. Comparing the joint effect of arsenic exposure, cigarette smoking and risk genotypes of vascular endothelial growth factor on upper urinary tract urothelial carcinoma and bladder cancer.

    PubMed

    Wang, Yuan-Hung; Yeh, Shauh-Der; Wu, Meei-Maan; Liu, Chi-Tung; Shen, Cheng-Hung; Shen, Kun-Hung; Pu, Yeong-Shiau; Hsu, Ling-I; Chiou, Hung-Yi; Chen, Chien-Jen

    2013-11-15

    Arsenic exposure and cigarette smoking are environmental risk factors for urothelial carcinoma (UC). Vascular endothelial growth factor (VEGF) is the key regulator of angiogenesis in various malignancies. This study investigates the joint effect of arsenic exposure, cigarette smoking, and VEGF polymorphisms on UC risk. This was a hospital-based case-control study consisting of 730 histopathologically confirmed UC cases, including 470 bladder cancers, 260 upper urinary tract UCs (UUTUCs), and 850 age-matched controls, recruited from September 1998 to December 2009. UC risk was estimated by odds ratios and 95% confidence intervals using unconditional logistic regression. Ever smokers with high arsenic exposure had significantly increased risks of 5.7 and 6.4 for bladder cancer and UUTUC, respectively. Moreover, ever smokers with high arsenic exposure carrying 1 or 2 risk genotypes of the VEGF gene had a significantly increased risk of 6.6 for bladder cancer and a strikingly higher risk of 9.9 for UUTUC. Additionally, UUTUC cases with high arsenic exposure carrying 1 or 2 risk genotypes of the VEGF gene had a non-significant increased risk of advanced tumor stage. Our findings suggest that arsenic exposure, cigarette smoking, and risk genotypes of VEGF contribute to a higher risk of UUTUC than of bladder cancer.

  19. Overexpression of RNF2 Is an Independent Predictor of Outcome in Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy.

    PubMed

    Li, Xiang-Dong; Chen, Si-Liang; Dong, Pei; Chen, Jie-Wei; Wang, Feng-Wei; Guo, Sheng-Jie; Jiang, Li-Juan; Zhou, Fang-Jian; Xie, Dan; Liu, Zhuo-Wei

    2016-02-12

    RNF2 (ring finger protein 2) is frequently overexpressed in several types of human cancer, but the status of RNF2 amplification and expression in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance is unclear. In this study, immunohistochemical analysis and fluorescence in situ hybridization (FISH) were used to examine the expression and amplification of RNF2 in 184 UCB patients after radical cystectomy. Overexpression of RNF2 was observed in 44.0% of UCBs and was found to significantly associate with shortened overall and cancer-specific survival (P < 0.001). In different subsets of UCBs, RNF2 overexpression was also identified as a prognostic indicator in patients with pT1, pT2, pN(-), and/or negative surgical margins (P < 0.05). Importantly, RNF2 overexpression together with pT status and surgical margin status provided significant independent prognostic parameters in multivariate analysis (P < 0.01). FISH results showed amplification of RNF2 in 8/79 (10.1%) of informative UCB cases. Additionally, RNF2 overexpression was significantly associated with RNF2 gene amplification (P = 0.004) and cell proliferation (P = 0.003). These findings suggested that overexpression of RNF2, as examined by immunohistochemical analysis, might serve as a novel prognostic biomarker and potential therapeutic target for UCB patients who undergo radical cystectomy.

  20. Evolving Immunotherapy Strategies in Urothelial Cancer

    PubMed Central

    Brancato, Sam J.; Lewi, Keidren; Agarwal, Piyush K.

    2016-01-01

    The treatment of nonmuscle-invasive urothelial carcinoma with bacillus Calmette-Guérin (BCG) represents the importance of immunotherapy in the treatment of cancer. Despite its clinical efficacy, up to 30% of patients will ultimately experience progression to muscle-invasive disease. This, along with an improved understanding of the biologic pathways involved, has led to efforts to improve, enhance, or alter the immune response in the treatment of urothelial carcinoma. A number of novel therapeutic approaches currently are being pursued, including recombinant BCG to induce T helper type 1 (Th1) immune responses, nonlive Mycobacterium agents, targeted agents toward cancer-associated antigens, immune-modulating vaccines, and adoptive T-cell therapies. Here, we review the current and future immunotherapy treatment options for patients with urothelial cancer. PMID:25993187

  1. Loss of expression of the SWI/SNF complex is a frequent event in undifferentiated/dedifferentiated urothelial carcinoma of the urinary tract.

    PubMed

    Agaimy, Abbas; Bertz, Simone; Cheng, Liang; Hes, Ondrej; Junker, Kerstin; Keck, Bastian; Lopez-Beltran, Antonio; Stöckle, Michael; Wullich, Bernd; Hartmann, Arndt

    2016-09-01

    Loss of the SWI/SNF chromatin remodeling complex has been recently implicated in the pathogenesis of dedifferentiated carcinomas from different organs, but its possible role in undifferentiated urothelial carcinoma (UC) has not been studied to date. In this study, we analyzed by immunohistochemistry 14 undifferentiated UCs (11 from bladder and 3 from renal pelvis) with a nondescript anaplastic or rhabdoid morphology, using commercially available antibodies against the SWI/SNF components SMARCB1 (INI1), SMARCA2, SMARCA4, SMARCC1, SMARCC2, and ARID1A. Patients were eight females and six males aged 40 to 84 years (median, 65). All tumors were muscle-invasive (9 were T3-4). A conventional UC component was seen in eight cases and varied from in situ to papillary. The undifferentiated component comprised 60-100 % of the tumors. Histologically, most tumors showed diffuse dyscohesive or pseudoalveolar growth of variably sized cells with frequent rhabdoid features. Transition from conventional to undifferentiated UC was abrupt, except in one case. The undifferentiated component almost always expressed pan-cytokeratin AE1/AE3 (13/14) and variably vimentin (8/14) and GATA3 (9/14). Complete loss of at least one SWI/SNF subunit limited to the undifferentiated component was detected in 10/14 cases (71 %). SMARCA2 was most frequently lost (six) followed by ARID1A (four), SMARCB1/INI1 (two), SMARCA4 (one), and SMARCC1 (one). This is the first study exploring SWI/SNF expression in undifferentiated UC of the urinary tract. Our results are in line with recent studies reporting involvement of the SWI/SNF complex in the dedifferentiation process of a variety of epithelial neoplasms in different organs, including the urinary tract, and association with aggressive clinical course. PMID:27339451

  2. Loss of expression of the SWI/SNF complex is a frequent event in undifferentiated/dedifferentiated urothelial carcinoma of the urinary tract.

    PubMed

    Agaimy, Abbas; Bertz, Simone; Cheng, Liang; Hes, Ondrej; Junker, Kerstin; Keck, Bastian; Lopez-Beltran, Antonio; Stöckle, Michael; Wullich, Bernd; Hartmann, Arndt

    2016-09-01

    Loss of the SWI/SNF chromatin remodeling complex has been recently implicated in the pathogenesis of dedifferentiated carcinomas from different organs, but its possible role in undifferentiated urothelial carcinoma (UC) has not been studied to date. In this study, we analyzed by immunohistochemistry 14 undifferentiated UCs (11 from bladder and 3 from renal pelvis) with a nondescript anaplastic or rhabdoid morphology, using commercially available antibodies against the SWI/SNF components SMARCB1 (INI1), SMARCA2, SMARCA4, SMARCC1, SMARCC2, and ARID1A. Patients were eight females and six males aged 40 to 84 years (median, 65). All tumors were muscle-invasive (9 were T3-4). A conventional UC component was seen in eight cases and varied from in situ to papillary. The undifferentiated component comprised 60-100 % of the tumors. Histologically, most tumors showed diffuse dyscohesive or pseudoalveolar growth of variably sized cells with frequent rhabdoid features. Transition from conventional to undifferentiated UC was abrupt, except in one case. The undifferentiated component almost always expressed pan-cytokeratin AE1/AE3 (13/14) and variably vimentin (8/14) and GATA3 (9/14). Complete loss of at least one SWI/SNF subunit limited to the undifferentiated component was detected in 10/14 cases (71 %). SMARCA2 was most frequently lost (six) followed by ARID1A (four), SMARCB1/INI1 (two), SMARCA4 (one), and SMARCC1 (one). This is the first study exploring SWI/SNF expression in undifferentiated UC of the urinary tract. Our results are in line with recent studies reporting involvement of the SWI/SNF complex in the dedifferentiation process of a variety of epithelial neoplasms in different organs, including the urinary tract, and association with aggressive clinical course.

  3. Urothelial Tumors of the Urinary Bladder in Young Patients: A Clinicopathologic Study of 59 Cases

    PubMed Central

    Stanton, Melissa L.; Xiao, Li; Czerniak, Bogdan A.; Guo, Charles C.

    2014-01-01

    Context Urothelial tumors are rare in young patients. Because of its rarity, the natural history of the disease in young patients remains poorly understood. Objective To understand the pathologic and clinical features of urothelial tumors of the urinary bladder in young patients. Design We identified 59 young patients with urothelial tumors of the urinary bladder treated at our institution and analyzed the tumors’ pathologic features and the patients’ clinical outcomes. Results All patients were 30 years old or younger, with a mean age of 23.5 years (range, 4 to 30). Thirty-eight patients were male, and 21 were female. Most tumors were noninvasive papillary urothelial tumors (n = 49), including papillary urothelial neoplasms of low malignant potential (n = 7), low-grade papillary urothelial carcinomas (n = 38), and high-grade papillary urothelial carcinomas (n = 4). Only a minority of urothelial tumors were invasive, invading the lamina propria (n = 5), muscularis propria (n = 4), or perivesical soft tissue (n = 1). Clinical follow-up information was available for 41 patients, with a mean follow-up time of 77 months. Of 31 patients with noninvasive papillary urothelial tumors, only 1 patient later developed an invasive urothelial carcinoma and died of the disease, and 30 of these patients were alive at the end of follow-up, although 10 had local tumor recurrences. In the 10 patients with invasive urothelial carcinomas, 3 patients died of the disease and 5 others were alive with metastases. Conclusion Urothelial tumors in young patients are mostly noninvasive papillary carcinomas and have an excellent prognosis; however, a small subset of patients may present with high-grade invasive urothelial carcinomas that result in poor clinical outcomes. PMID:24079760

  4. High-grade microscopic hematuria in adult men can predict urothelial malignancy

    PubMed Central

    Kotb, Ahmed Fouad; Attia, Doaa

    2014-01-01

    Introduction: Microscopic hematuria in men younger than 40 is a confusing issue to urologists, especially when these men have normal radiological findings. We report our experience in looking for urologic malignancy in this group of patients. Methods: We conducted a prospective study for men with vague urological symptoms. We included men under 40 years old, men with microscopic hematuria greater than 25 red blood cells/high power field in 2 properly collected mid-stream urine samples, and men with free urine culture and normal multiphasic computed tomography abdomen and pelvis studies. All patients underwent diagnostic cystoscurethroscopy. If there were no lesions, multiple random biopsies were taken. In cases of apparently normal cystoscopic findings and associated renal colic, uretroscopy was done to the suspected side. Results: Only 20 patients fulfilled our inclusion criteria. The mean age of the patients were 34; 2 patients presented with pain. The other 18 patients were presenting with mild recurrent lower urinary tract symptoms. Cystoscopy showed small papillary low-grade tumour in 3 patients. All random biopsies were free of malignancy. Unilateral uretroscopy for the 2 cases presented with pain detected carcinoma in situ in one of them. Conclusion: Cystoscopy is highly recommended for young adult men, with significant levels of microscopic hematuria, due to the 20% incidence rate of associated urological malignancy. Random bladder biopsies, in the absence of suspicious lesions, have no diagnostic role, and should not be done. Uretroscopy is advised for patients with microscopic hematuria and loin pain, even in the absence of suspicious radiological findings. PMID:25132893

  5. Factors predictive of survival in ampullary carcinoma.

    PubMed Central

    Howe, J R; Klimstra, D S; Moccia, R D; Conlon, K C; Brennan, M F

    1998-01-01

    OBJECTIVE: To review the recent Memorial Sloan-Kettering Cancer Center experience with adenocarcinoma of the ampulla of Vater and to identify clinicopathologic factors that have an impact on patient survival. SUMMARY BACKGROUND DATA: The prognosis for patients with tumors of the ampulla of Vater is improved relative to other periampullary neoplasms. Identification of independent prognostic factors in ampullary tumors has been limited by small numbers of tumors and a lack of pathologic review. METHODS: Data were collected prospectively for patients presenting with periampullary carcinomas to the Memorial Sloan-Kettering Cancer Center between October 15, 1983 and June 30, 1995. The correlation between clinicopathologic variables and survival of ampullary carcinoma was tested by the Kaplan-Meier method and log-rank test, and Cox proportional hazards regression. Survival of patients with periampullary adenocarcinomas was compared by the Kaplan-Meier method. RESULTS: In 123 patients presenting with ampullary carcinoma, 101 tumors (82.1%) were resected. Factors significantly correlated with improved survival were resection (p < 0.01), and in resected tumors, negative nodes (p = 0.04) and margins (p = 0.02) independently predicted for improved survival. In periampullary tumors, the highest rates of resection and overall survival (median, 43.6 months) were found in ampullary carcinomas. CONCLUSIONS: Factors predictive of improved survival in ampullary carcinoma include resection, negative margins, and negative nodes. Improved overall survival in ampullary relative to periampullary adenocarcinoma is due in part to a significantly higher rate of resection. Images Figure 1. PMID:9671071

  6. The expression of ERCC1 and BRCA1 predicts prognosis of platinum-based chemotherapy in urothelial cancer

    PubMed Central

    Song, Wenhui; Ma, Hongshun

    2016-01-01

    Objective To investigate the expression and clinical significance of ERCC1 and BRCA1 genes in urothelial cancer patients. Methods Forty-two urothelial cancer patients who did not receive platinum-based chemotherapy during January 2009 to May 2013 were enrolled. The expression levels of ERCC1 and BRCA1 were determined by immunohistochemistry and the median survival time (MST) for these patients was calculated. Results ERCC1-positive patients who received oxaliplatin-based chemotherapy had a shorter MST than ERCC1-negative patients (P<0.05), whereas there is no difference of MST between BRCA1-positive and -negative patients. Furthermore, MST in ERCC1 and BRCA1 double-positive patients was shorter than ERCC1 and BRCA1 double-negative patients (P<0.05). The positive expression of ERCC1 had a significant positive correlation with BRCA1 (r=0.313, P=0.044). Conclusion The expression level of ERCC1 may be used as a prognostic marker for urothelial cancer patients who received postoperative adjuvant chemotherapy. PMID:27366083

  7. Calculator for ovarian carcinoma subtype prediction.

    PubMed

    Kalloger, Steve E; Köbel, Martin; Leung, Samuel; Mehl, Erika; Gao, Dongxia; Marcon, Krista M; Chow, Christine; Clarke, Blaise A; Huntsman, David G; Gilks, C Blake

    2011-04-01

    With the emerging evidence that the five major ovarian carcinoma subtypes (high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous) are distinct disease entities, management of ovarian carcinoma will become subtype specific in the future. In an effort to improve diagnostic accuracy, we set out to determine if an immunohistochemical panel of molecular markers could reproduce consensus subtype assignment. Immunohistochemical expression of 22 biomarkers were examined on tissue microarrays constructed from 322 archival ovarian carcinoma samples from the British Columbia Cancer Agency archives, for the period between 1984 and 2000, and an independent set of 242 cases of ovarian carcinoma from the Gynaecologic Tissue Bank at Vancouver General Hospital from 2001 to 2008. Nominal logistic regression was used to produce a subtype prediction model for each of these sets of cases. These models were then cross-validated against the other cohort, and then both models were further validated in an independent cohort of 81 ovarian carcinoma samples from five different centers. Starting with data for 22 markers, full model fit, backwards, nominal logistic regression identified the same nine markers (CDKN2A, DKK1, HNF1B, MDM2, PGR, TFF3, TP53, VIM, WT1) as being most predictive of ovarian carcinoma subtype in both the archival and tumor bank cohorts. These models were able to predict subtype in the respective cohort in which they were developed with a high degree of sensitivity and specificity (κ statistics of 0.88±0.02 and 0.86±0.04, respectively). When the models were cross-validated (ie using the model developed in one case series to predict subtype in the other series), the prediction equation's performances were reduced (κ statistics of 0.70±0.04 and 0.61±0.04, respectively) due to differences in frequency of expression of some biomarkers in the two case series. Both models were then validated on the independent series of 81 cases, with very good to

  8. The effect of cigarette smoke and arsenic exposure on urothelial carcinoma risk is modified by glutathione S-transferase M1 gene null genotype

    SciTech Connect

    Chung, Chi-Jung; Huang, Chao-Yuan; Pu, Yeong-Shiau; Shiue, Horng-Sheng; Su, Chien-Tien; Hsueh, Yu-Mei

    2013-01-15

    Inter-individual variation in the metabolism of xenobiotics, caused by factors such as cigarette smoking or inorganic arsenic exposure, is hypothesized to be a susceptibility factor for urothelial carcinoma (UC). Therefore, our study aimed to evaluate the role of gene–environment interaction in the carcinogenesis of UC. A hospital-based case–control study was conducted. Urinary arsenic profiles were measured using high-performance liquid chromatography–hydride generator-atomic absorption spectrometry. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism technique. Information about cigarette smoking exposure was acquired from a lifestyle questionnaire. Multivariate logistic regression was applied to estimate the UC risk associated with certain risk factors. We found that UC patients had higher urinary levels of total arsenic, higher percentages of inorganic arsenic (InAs%) and monomethylarsonic acid (MMA%) and lower percentages of dimethylarsinic acid (DMA%) compared to controls. Subjects carrying the GSTM1 null genotype had significantly increased UC risk. However, no association was observed between gene polymorphisms of CYP1A1, EPHX1, SULT1A1 and GSTT1 and UC risk after adjustment for age and sex. Significant gene–environment interactions among urinary arsenic profile, cigarette smoking, and GSTM1 wild/null polymorphism and UC risk were observed after adjustment for potential risk factors. Overall, gene–environment interactions simultaneously played an important role in UC carcinogenesis. In the future, large-scale studies should be conducted using tag-SNPs of xenobiotic-metabolism-related enzymes for gene determination. -- Highlights: ► Subjects with GSTM1 null genotype had significantly increased UC risk. ► UC patients had poor arsenic metabolic ability compared to controls. ► GSTM1 null genotype may modify arsenic related UC risk.

  9. Maintenance monotherapy with Gemcitabine following cisplatin-based primary combination chemotherapy in surgically treated advanced urothelial carcinoma: A matched-pair single institution analysis

    PubMed Central

    KALOGIROU, CHARIS; SVISTUNOV, ANDREY; KREBS, MARKUS; LAUSENMEYER, EVA MARIA; VERGHO, DANIEL; RIEDMILLER, HUBERTUS; KOCOT, ARKADIUS

    2016-01-01

    The role of maintenance therapy with Gemcitabine (GEM) following cisplatin-based combination chemotherapy (CBCC) in patients with surgically treated advanced urothelial carcinoma (UC) remains to be fully elucidated. In the present case control study, a retrospective analysis was performed to evaluate the role of GEM monotherapy following surgical intervention for advanced UC. Between 1999 and 2013, 38 patients were identified with surgically treated advanced UC after having completed CBCC, who were additionally treated quarterly with two consecutive GEM (1,250 mg/m2) infusions as maintenance therapy. This collective was matched by propensity score matching to a control collective (n=38) that received primary CBCC alone, and the overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) rates were determined for the two collectives using Kaplan-Meier estimates and the log-rank test. Regression analysis was performed using the Cox proportional hazards model. The median follow-up time was 37 months (interquartile range: 9–148). Interestingly, patients treated with GEM following primary chemotherapy had a significantly improved outcome with respect to the 5-year OS (46.2 vs. 26.4%, P=0.0314) and 5-year CSS (61.3 vs. 33.4%, P=0.0386) rates. Notably, the 5-year PFS rate did not differ between the two groups (10.3 vs. 16.1%, P=0.134). It is proposed that additional GEM maintenance monotherapy is able to improve survival rates following primary CBCC in surgically treated patients with advanced UC, suggesting a possible treatment option for patients with, e.g., unclear disease status, or those who would require an active maintenance therapy in the future. Prospective studies should further determine the impact of GEM monotherapy with respect to PFS rates in groups comprising larger numbers of patients. PMID:27073682

  10. Decision Based on Narrow Band Imaging Cystoscopy without a Referential Normal Standard Rather Increases Unnecessary Biopsy in Detection of Recurrent Bladder Urothelial Carcinoma Early after Intravesical Instillation

    PubMed Central

    Song, Phil Hyun; Cho, Seok; Ko, Young Hwii

    2016-01-01

    Purpose The purpose of this study was to calculate the operating characteristics of narrowband imaging (NBI) cystoscopy versus traditional white light cystoscopy (WLC) in common clinical scenarios involving suspicion of bladder urothelial carcinoma (UC). Materials and Methods Sixty-three consecutive patients initially underwent WLC and then NBI in a single session for evaluation of microscopic hematuria (group I, n=20), gross hematuria (group II, n=19), and follow-up for prior UC (group III, n=24), by an experienced urologist. All lesions that were abnormal in contrast with adjacent normal mucosa were diagnosed as positive and biopsied. Results Sixty-six biopsies from 47 patients were performed. Pathologic examination showed 17 cases of UC from 21 sites. While the overall sensitivity of NBI was similar to that of WLC (100% vs. 94.1%), the specificity of NBI was significantly lower than that of WLC (50% vs. 86.9%, p < 0.001), particularly in group III (38.9% vs. 88.9%, p=0.004). Based on identification by NBI only, 23 additional biopsies from 18 cases were performed for identification of one patient with UC, who belonged to group III. In this group, to identify this specific patient, 15 additional biopsies were performed from 10 patients. All seven cases with positive findings from NBI within 2 months after the last intravesical therapy were histologically proven as negative. Conclusion In evaluation for recurrence early after intravesical instillation, the decision based on NBI increased unnecessary biopsy in the absence of an established standard for judging NBI. PMID:25761489

  11. The small conductance calcium-activated potassium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells.

    PubMed

    Steinestel, Konrad; Eder, Stefan; Ehinger, Konstantin; Schneider, Juliane; Genze, Felicitas; Winkler, Eva; Wardelmann, Eva; Schrader, Andres J; Steinestel, Julie

    2016-05-01

    Metastasis is the survival-determining factor in urothelial carcinoma (UC) of the urinary bladder. The small conductance calcium-activated potassium channel 3 (SK3) enhances tumor cell invasion in breast cancer and malignant melanoma. Since Edelfosine, a glycerophospholipid with antitumoral properties, effectively inhibits SK3 channel activity, our goal was to evaluate SK3 as a potential molecular target to inhibit the gain of an invasive phenotype in UC. SK3 protein expression was analyzed in 208 tissue samples and UC cell lines. Effects of Edelfosine on SK3 expression and intracellular calcium levels as well as on cell morphology, cell survival and proliferation were assessed using immunoblotting, potentiometric fluorescence microscopy, and clonogenic/cell survival assay; furthermore, we analyzed the effect of Edelfosine and SK3 RNAi knockdown on tumor cell migration and invasion in vitro and in vivo. We found that SK3 is strongly expressed in muscle-invasive UC and in the RT112 cellular tumor model. Higher concentrations of Edelfosine have a strong antitumoral effect on UC cells, while 1 μM effectively inhibits migration/invasion of UC cells in vitro and in vivo comparable to the SK3 knockdown phenotype. Taken together, our results show strong expression of SK3 in muscle-invasive UC, consistent with the postulated role of the protein in tumor cell invasion. Edelfosine is able to effectively inhibit migration and invasion of UC cells in vitro and in vivo in an SK3-dependent way, pointing towards a possible role for Edelfosine as an antiinvasive drug to effectively inhibit UC cell invasion and metastasis.

  12. Mutations in TP53, but not FGFR3, in urothelial cell carcinoma of the bladder are influenced by smoking: contribution of exogenous versus endogenous carcinogens.

    PubMed

    Wallerand, Hervé; Bakkar, Ashraf A; de Medina, Sixtina Gil Diez; Pairon, Jean-Claude; Yang, Yu-Ching; Vordos, Dimitri; Bittard, Hugues; Fauconnet, Sylvie; Kouyoumdjian, Jean-Claude; Jaurand, Marie-Claude; Zhang, Zuo-Feng; Radvanyi, François; Thiery, Jean-Paul; Chopin, Dominique K

    2005-01-01

    Smoking is a major risk factor for urothelial cell carcinoma of the bladder (UCC). Mutations in the FGFR3 and TP53 genes have been shown to define two distinct pathways in superficial papillary and invasive UCC disease, respectively. We investigated the relationship between smoking and these mutations by means of denaturing high performance liquid chromatography and sequencing for 110 primary UCC of the bladder. This study included 48 current smokers, 31 ex-smokers and 31 non-smokers. Thirty-five of the tumors were stage pTa, 40 pT1 and 35 > or =pT2. Fourteen of the tumors were grade 1, 37 were grade 2 and 59 grade 3. Smoking was associated with high stage (P = 0.03) and high grade tumors (P = 0.006). Twenty-two of the 110 tumors studied harbored TP53 mutations (20%) and 43 harbored FGFR3 mutations (39%). Odds ratios (OR) were higher for TP53 mutations in current smokers [OR, 2.25; 95% confidence interval (95% CI), 0.65-7.75] and ex-smokers (OR, 1.62; 95% CI, 0.41-6.42) than in non-smokers. Double TP53 mutations and the A:T-->G:C TP53 mutation pattern was found only in current smokers. Patients with the FGFR3(wild-type)/TP53(mutated) genotype had significantly higher levels of tobacco consumption, as measured in pack-years (P = 0.01). Smoking influenced neither the frequency nor the pattern of FGFR3 mutations. Our results suggest that smoking is associated with invasive and high grade UCCs, at initial presentation, and influenced TP53 or the molecular pathway defined by these mutations. In contrast, FGFR3 mutations are not affected by smoking and probably result from endogenous alterations. These data have potential implications for clinical management and prevention strategies.

  13. The small conductance calcium-activated potassium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells.

    PubMed

    Steinestel, Konrad; Eder, Stefan; Ehinger, Konstantin; Schneider, Juliane; Genze, Felicitas; Winkler, Eva; Wardelmann, Eva; Schrader, Andres J; Steinestel, Julie

    2016-05-01

    Metastasis is the survival-determining factor in urothelial carcinoma (UC) of the urinary bladder. The small conductance calcium-activated potassium channel 3 (SK3) enhances tumor cell invasion in breast cancer and malignant melanoma. Since Edelfosine, a glycerophospholipid with antitumoral properties, effectively inhibits SK3 channel activity, our goal was to evaluate SK3 as a potential molecular target to inhibit the gain of an invasive phenotype in UC. SK3 protein expression was analyzed in 208 tissue samples and UC cell lines. Effects of Edelfosine on SK3 expression and intracellular calcium levels as well as on cell morphology, cell survival and proliferation were assessed using immunoblotting, potentiometric fluorescence microscopy, and clonogenic/cell survival assay; furthermore, we analyzed the effect of Edelfosine and SK3 RNAi knockdown on tumor cell migration and invasion in vitro and in vivo. We found that SK3 is strongly expressed in muscle-invasive UC and in the RT112 cellular tumor model. Higher concentrations of Edelfosine have a strong antitumoral effect on UC cells, while 1 μM effectively inhibits migration/invasion of UC cells in vitro and in vivo comparable to the SK3 knockdown phenotype. Taken together, our results show strong expression of SK3 in muscle-invasive UC, consistent with the postulated role of the protein in tumor cell invasion. Edelfosine is able to effectively inhibit migration and invasion of UC cells in vitro and in vivo in an SK3-dependent way, pointing towards a possible role for Edelfosine as an antiinvasive drug to effectively inhibit UC cell invasion and metastasis. PMID:26619845

  14. Poor Preoperative Glycemic Control Is Associated with Dismal Prognosis after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Korean Multicenter Study

    PubMed Central

    Kang, Sung Gu; Hwang, Eu Chang; Jung, Seung Il; Yu, Ho Song; Chung, Ho Seok; Kang, Taek Won; Kwon, Dong Deuk; Hwang, Jun Eul; Kim, Jun Seok; Noh, Joon Hwa; You, Jae Hyung; Kim, Myung Ki; Oh, Tae Hoon; Seo, Ill Young; Baik, Seung; Kim, Chul-Sung; Kang, Seok Ho; Cheon, Jun

    2016-01-01

    Purpose The purpose of this study is to evaluate the effect of diabetes mellitus (DM) and preoperative glycemic control on prognosis in Korean patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU). Materials and Methods A total of 566 patients who underwent RNU at six institutions between 2004 and 2014 were reviewed retrospectively. Kaplan-Meier and Cox regression analyses were performed to assess the association between DM, preoperative glycemic control, and recurrence-free, cancer-specific, and overall survival. Results The median follow-up period was 33.8 months (interquartile range, 41.4 months). A total of 135 patients (23.8%) had DM and 67 patients (11.8%) had poor preoperative glycemic control. Patients with poor preoperative glycemic control had significantly shorter median recurrence-free, cancer-specific, and overall survival than patients with good preoperative glycemic control and non-diabetics (all, p=0.001). In multivariable Cox regression analysis, DM with poor preoperative glycemic control showed association with worse recurrence-free survival (hazard ratio [HR], 2.26; 95% confidence interval [CI], 1.31 to 3.90; p=0.003), cancer-specific survival (HR, 2.96; 95% CI, 1.80 to 4.87; p=0.001), and overall survival (HR, 2.13; 95% CI, 1.40 to 3.22; p=0.001). Conclusion Diabetic UTUC patients with poor preoperative glycemic control had significantly worse oncologic outcomes than diabetic UTUC patients with good preoperative glycemic control and non-diabetics. Further investigation is needed to elucidate the exact mechanism underlying the impact of glycemic control on UTUC treatment outcome. PMID:27034146

  15. [Analgesics and laxatives as risk factors for cancer in the efferent urinary tract--results of the Berlin Urothelial Carcinoma Study].

    PubMed

    Bronder, E; Klimpel, A; Helmert, U; Greiser, E; Molzahn, M; Pommer, W

    1999-01-01

    A retrospective case-control study (1990-1995), the Berlin Urothelial Cancer Study (BUS), examined analgesics and laxatives as risks for the induction of urothelial cancer in renal pelvis, ureter and bladder. Especially for renal pelvis cancer could observe substance and dose specific risk of compound analgesics. The analgesic substances Phenacetin, Paracetamol, Acetylsalicylic acid (ASA) and Pyrazolones were assessed. Besides a risk of contact laxatives (chemical or anthranoide ingredients) for urothelial cancer was found, not yet described. The highest risk shows the anthranoide plant Senna. Thus this study confirms the risk of specific analgesic ingredients and found an evidence for a new risk of contact laxatives. As both, analgesics and contact laxatives, are typical OTC--("Over the counter") products, a severe controlling is demanded and for laxatives further studies are needed. PMID:10436491

  16. Neoadjuvant Intravesical Vaccine Therapy in Treating Patients With Bladder Carcinoma Who Are Undergoing Cystectomy

    ClinicalTrials.gov

    2014-12-22

    Bladder Adenocarcinoma; Bladder Squamous Cell Carcinoma; Bladder Urothelial Carcinoma; Recurrent Bladder Carcinoma; Stage I Bladder Cancer; Stage II Bladder Cancer; Stage III Bladder Cancer; Stage IV Bladder Cancer

  17. Comparative Gene Expression Analyses Identify Luminal and Basal Subtypes of Canine Invasive Urothelial Carcinoma That Mimic Patterns in Human Invasive Bladder Cancer.

    PubMed

    Dhawan, Deepika; Paoloni, Melissa; Shukradas, Shweta; Choudhury, Dipanwita Roy; Craig, Bruce A; Ramos-Vara, José A; Hahn, Noah; Bonney, Patty L; Khanna, Chand; Knapp, Deborah W

    2015-01-01

    More than 160,000 people are expected to die from invasive urothelial carcinoma (iUC) this year worldwide. Research in relevant animal models is essential to improving iUC management. Naturally-occurring canine iUC closely resembles human iUC in histopathology, metastatic behavior, and treatment response, and could provide a relevant model for human iUC. The molecular characterization of canine iUC, however, has been limited. Work was conducted to compare gene expression array results between tissue samples from iUC and normal bladder in dogs, with comparison to similar expression array data from human iUC and normal bladder in the literature. Considerable similarities between enrichment patterns of genes in canine and human iUC were observed. These included patterns mirroring basal and luminal subtypes initially observed in human breast cancer and more recently noted in human iUC. Canine iUC samples also exhibited enrichment for genes involved in P53 pathways, as has been reported in human iUC. This is particularly relevant as drugs targeting these genes/pathways in other cancers could be repurposed to treat iUC, with dogs providing a model to optimize therapy. As part of the validation of the results and proof of principal for evaluating individualized targeted therapy, the overexpression of EGFR in canine bladder iUC was confirmed. The similarities in gene expression patterns between dogs and humans add considerably to the value of naturally-occurring canine iUC as a relevant and much needed animal model for human iUC. Furthermore, the finding of expression patterns that cross different pathologically-defined cancers could allow studies of dogs with iUC to help optimize cancer management across multiple cancer types. The work is also expected to lead to a better understanding of the biological importance of the gene expression patterns, and the potential application of the cross-species comparisons approach to other cancer types as well. PMID:26352142

  18. A review of bovine urothelial tumours and tumour-like lesions of the urinary bladder.

    PubMed

    Roperto, S; Borzacchiello, G; Brun, R; Leonardi, L; Maiolino, P; Martano, M; Paciello, O; Papparella, S; Restucci, B; Russo, V; Salvatore, G; Urraro, C; Roperto, F

    2010-01-01

    Four hundred bovine urothelial tumours and tumour-like lesions were classified in accordance with the 2004 World Health Organization (WHO) morphological classification for human urothelial tumours. The spectrum of neoplastic lesions of the urinary bladder of cattle is becoming wider and bovine urothelial tumours share striking morphological features with their human counterparts. A classification system based on the WHO scheme would also be appropriate for the classification of bovine bladder tumours. Bovine urothelial tumours are most often multiple. Four distinct growth patterns of bovine urothelial tumours and tumour-like lesions are recognized: flat, exophytic or papillary, endophytic and invasive. Carcinoma in situ (CIS) is the most common flat urothelial lesion, accounting for approximately 4% of urothelial tumours. CIS is detected adjacent to papillary and invasive tumours in 80-90% of cases. Approximately 3% of papillary lesions are papillomas and approximately 5% are 'papillary urothelial neoplasms of low malignant potential' (PUNLMP). Low-grade carcinoma is the most common urothelial tumour of cattle. High-grade carcinomas, and low and high-grade invasive tumours, are less commonly seen. Bovine papillomavirus (BPV) infection and ingestion of bracken fern both play a central role in carcinogenesis of these lesions.

  19. SUCCINCT: An Open-label, Single-arm, Non-randomised, Phase 2 Trial of Gemcitabine and Cisplatin Chemotherapy in Combination with Sunitinib as First-line Treatment for Patients with Advanced Urothelial Carcinoma

    PubMed Central

    Geldart, Thomas; Chester, John; Casbard, Angela; Crabb, Simon; Elliott, Tony; Protheroe, Andrew; Huddart, Robert A.; Mead, Graham; Barber, Jim; Jones, Robert J.; Smith, Joanna; Cowles, Robert; Evans, Jessica; Griffiths, Gareth

    2015-01-01

    Gemcitabine and cisplatin chemotherapy (GC regimen) represents a standard treatment for advanced urothelial carcinoma. We performed an open-label, single-arm, non-randomised, phase 2 trial evaluating the addition of sunitinib to standard GC chemotherapy (SGC regimen). Overall, 63 treatment-naïve participants were recruited and received up to six 21-d cycles of cisplatin 70 mg/m2 (intravenously [IV], day 1) and gemcitabine 1000 mg/m2 (IV, days 1 and 8) combined with sunitinib 37.5 mg (orally, days 2–15). Following review of toxicity after the first six patients, the sunitinib dose was reduced to 25 mg for all patients. Overall response rate was 64%, with response noted in 37 of 58 patients. At 6 mo, 30 of 58 assessable patients (52%; 90% confidence interval [CI], 40–63%) were progression free. Median overall survival was 12 mo (95% CI, 9–15) and was heavily influenced by Bajorin prognostic group. Grade 3–4 toxicities were predominantly haematologic and limited the deliverability of the triple SGC regimen. The trial did not meet its prespecified primary end point of >60% patients progression free at 6 mo. Cumulative myelosuppression led to treatment delays of gemcitabine and cisplatin and dose reduction and/or withdrawal of sunitinib in the majority of cases. The triple-drug combination was not well tolerated. Phase 3 evaluation of the triple SGC regimen in advanced transitional cell carcinoma is not recommended. Patient summary The addition of sunitinib to standard cisplatin and gemcitabine chemotherapy was poorly tolerated and did not improve outcomes in advanced urothelial carcinoma. Treatment delivery was limited by myelotoxicity. PMID:25465968

  20. Expression of cathepsin D in urothelial carcinoma of the urinary bladder: an immunohistochemical study including correlations with extracellular matrix components, CD44, p53, Rb, c-erbB-2 and the proliferation indices.

    PubMed

    Ioachim, Elli; Charchanti, Antonia; Stavropoulos, Nikolaos; Athanassiou, Evangelia; Bafa, Maria; Agnantis, Niki J

    2002-01-01

    The immunohistochemical Cathepsin D (CD) expression of tumor and stromal cells was investigated in a series of 77 urothelial carcinomas of the urinary bladder with the intention to evaluate its prognostic significance and its contribution to the metastatic potential of bladder cancer. CD expression (clone D13A) was correlated with the expression of extracellular matrix components (collagen type IV, laminin, fibronectin), CD44, p53, pRb, proliferation indices (PCNA and MIB1) as well as with other conventional clininopathological features. CD expression (> 10% of positive tumor cells) was observed in 77.9% of the carcinomas. Stromal CD expression was detected in all cases. Linear collagen type IV and laminin deposit at the tumor-stroma border (in > 25% of the BM) was found in 26% and 57.6% of the cases, respectively. The CD of cancer cells (CCCD) was inversely-correlated with the CD of the stromal cells (p = 0.039), tumor grade (p = 0.0028), tumor stage (p = 0.0046), p53 protein (p = 0.05) and positively-correlated with CD44 (p = 0.002) and pRb (p = 0.05). The stromal cells CD (SCCD) showed a statistically significant positive correlation with tumor grade (p < 0.0001) and stage (p = 0.0001), and the proliferation indices PCNA and MIB1 (p = 0.0001 and p = 0.0002, respectively). These data suggest that both CD of tumor and stromal cells could play important roles in the expansion of urothelial carcinoma of the urinary bladder. PMID:12530091

  1. Predictive markers in advanced renal cell carcinoma.

    PubMed

    Michaelson, M Dror; Stadler, Walter M

    2013-08-01

    Predictive markers of response to therapy are increasingly important in advanced renal cell carcinoma (RCC) due to the proliferation of treatment options in recent years. Different types of potential predictive markers may include clinical, toxicity-based, serum, tissue, and radiologic biomarkers. Clinical factors are commonly used in overall prognostic models of RCC but have limited utility in predicting response to therapy. Correlation between development of particular toxicities and response to therapy has been noted, such as the correlation between hypertension and response to angiogenesis-targeted therapy. Serum and tissue biomarkers will be covered in detail elsewhere, but factors such as serum lactate dehydrogenase (LDH) and circulating cytokines show promise in this regard. Finally, baseline or early treatment radiology studies may have predictive ability for longer term efficacy, with most studies to date focusing on functional imaging modalities such as positron emission tomography (PET) scans, dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), and DCE ultrasound (US). The ultimate goal of developing predictive biomarkers is to enable rational and personalized treatment strategies for patients with advanced RCC. PMID:23972709

  2. Bilateral ovarian metastases from ureteric urothelial cancer: Initial case report and distinguishing role of immunohistochemistry

    PubMed Central

    Venkatramani, Vivek; Banerji, John Samuel; Manojkumar, Ramani

    2015-01-01

    Urothelial cancers of the upper tract are aggressive malignancies with a propensity for distant metastases. Transitional cell carcinoma can also develop de novo in the ovaries and differentiation between these lesions requires immunohistochemistry. We report a case of right lower ureteric urothelial carcinoma with metastases to both ovaries. To our knowledge, this is the first reported case of bilateral ovarian metastases from an upper tract primary, diagnosed with immunohistochemistry. PMID:25624971

  3. Urothelial cancer of the urinary bladder: can lessons learned be applied to the upper urinary tract?

    PubMed

    Krabbe, Laura M; Hutchinson, Ryan C; Margulis, Vitaly

    2016-08-01

    Even though urothelial cancer may occur anywhere in the urinary tract, it is most commonly found in the urinary bladder. Due to its higher incidence, this disease is studied in the bladder much more frequently than in the upper urinary tract. The question that arises is, to what extent can concepts and treatment paradigms derived from lower tract disease be applied to urothelial carcinoma of the upper urinary tract? This review aims at providing an overview of established care concepts in urothelial carcinoma of the bladder and applicability of these findings to tumors of the upper urinary tract.

  4. Viable tumor volume: volume of interest within segmented metastatic lesions, a pilot study of proposed computed tomography response criteria for urothelial cancer

    PubMed Central

    Folio, Les Roger; Turkbey, Evrim B.; Steinberg, Seth M.; Apolo, Andrea B.

    2015-01-01

    Objectives To evaluate the ability of new computed tomography (CT) response criteria for solid tumors such as urothelial cancer (VTV; viable tumor volume) to predict overall survival (OS) in patients with metastatic bladder cancer treated with cabozantinib. Materials and Methods We compared the relative capabilities of VTV, RECIST, MASS (morphology, attenuation, size, and structure), and Choi criteria, as well as volume measurements, to predict OS using serial follow-up contrast-enhanced CT exams in patients with metastatic urothelial carcinoma. Kaplan-Meier curves and 2-tailed log-rank tests compared OS based on early RECIST 1.1 response against each of the other criteria. A Cox proportional hazards model assessed response at follow-up exams as a time-varying covariate for OS. Results We assessed 141 lesions in 55 CT scans from 17 patients with urothelial metastasis, comparing VTV, RECIST, MASS, and Choi criteria, and volumetric measurements, for response assessment. Median follow-up was 4.5 months, range was 2–14 months. Only the VTV criteria demonstrated a statistical association with OS (p = 0.019; median OS 9.7 vs. 3.5 months). Conclusion This pilot study suggests that VTV is a promising tool for assessing tumor response and predicting OS, using criteria that incorporate tumor volume and density in patients receiving antiangiogenic therapy for urothelial cancer. Larger studies are warranted to validate these findings. PMID:26149529

  5. Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis.

    PubMed

    He, Feng; Mo, Lan; Zheng, Xiao-Yong; Hu, Changkun; Lepor, Herbert; Lee, Eva Y-H P; Sun, Tung-Tien; Wu, Xue-Ru

    2009-12-15

    Defects in pRb tumor suppressor pathway occur in approximately 50% of the deadly muscle-invasive urothelial carcinomas in humans and urothelial carcinoma is the most prevalent epithelial cancer in long-term survivors of hereditary retinoblastomas caused by loss-of-function RB1 mutations. Here, we show that conditional inactivation of both RB1 alleles in mouse urothelium failed to accelerate urothelial proliferation. Instead, it profoundly activated the p53 pathway, leading to extensive apoptosis, and selectively induced pRb family member p107. Thus, pRb loss triggered multiple fail-safe mechanisms whereby urothelial cells evade tumorigenesis. Additional loss of p53 in pRb-deficient urothelial cells removed these p53-dependent tumor barriers, resulting in late-onset hyperplasia, umbrella cell nuclear atypia, and rare-occurring low-grade, superficial papillary bladder tumors, without eliciting invasive carcinomas. Importantly, mice deficient in both pRb and p53, but not those deficient in either protein alone, were highly susceptible to subthreshold carcinogen exposure and developed invasive urothelial carcinomas that strongly resembled the human counterparts. The invasive lesions had a marked reduction of p107 but not p130 of the pRb family. Our data provide compelling evidence, indicating that urothelium, one of the slowest cycling epithelia, is remarkably resistant to transformation by pRb or p53 deficiency; that concurrent loss of these two tumor suppressors is necessary but insufficient to initiate urothelial tumorigenesis along the invasive pathway; that p107 may play a critical role in suppressing invasive urothelial tumor formation; and that replacing/restoring the function of pRb, p107, or p53 could be explored as a potential therapeutic strategy to block urothelial tumor progression.

  6. Management of muscle invasive, locally advanced and metastatic urothelial carcinoma of the bladder: a literature review with emphasis on the role of surgery

    PubMed Central

    Abufaraj, Mohammad; Gust, Kilian; Moschini, Marco; Foerster, Beat; Soria, Francesco; Mathieu, Romain

    2016-01-01

    Locally advanced (T3b, T4 and N1−N3) and metastatic urothelial bladder cancer (BCa) is a lethal disease with poor survival outcomes. Combination chemotherapy remains the treatment of choice in patients with metastatic disease and an important part of treatment in addition to radical cystectomy (RC) in patients with locally advanced tumour. Approximately half of patients who underwent RC for muscle invasive BCa relapse after surgery with either local recurrence or distant metastasis. This review focuses on the management of muscle invasive, locally advanced and metastatic BCa with emphasis on the role of surgery; to summarize the current knowledge in order to enhance clinical decision-making and counselling process. PMID:27785430

  7. Next-Generation Sequencing and In Silico Analysis Facilitate Prolonged Response to Pazopanib in a Patient With Metastatic Urothelial Carcinoma of the Renal Pelvis.

    PubMed

    Hahn, Andrew W; Giri, Smith; Patel, Dilan; Sluder, Heather; Vanderwalde, Ari; Martin, Mike G

    2015-10-01

    With the advent of widespread tumor genetic profiling, an increased number of mutations with unknown significance are being identified. Often, a glut of uninterpretable findings may confuse the clinician and provide little or inappropriate guidance in therapeutic decision-making. This report describes a method of protein modeling by in silico analysis (ie, using computer simulation) that is easily accessible to the practicing clinician without need for further laboratory analysis, which can potentially serve as a guide in therapeutic decisions based on poorly characterized tumor mutations. An example of this model is given wherein poorly characterized KIT, PDGFRB, and ERBB2 mutations were discovered in a patient with treatment-refractory metastatic transitional cell carcinoma of the renal pelvis. The KIT and PDGFRB mutations were predicted to be pathogenic using in silico analysis, whereas the ERBB2 mutation was predicted to be benign. Based on these findings, the patient was treated with pazopanib and achieved a partial response that lasted for 7.5 months. We propose that in silico analysis be explored as a potential means to further characterize genetic abnormalities found by tumor profiling assays, such as next-generation sequencing. PMID:26483058

  8. Pure Lymphoepithelioma-Like Carcinoma Originating from the Urinary Bladder

    PubMed Central

    Nagai, Takashi; Naiki, Taku; Kawai, Noriyasu; Iida, Keitaro; Etani, Toshiki; Ando, Ryosuke; Hamamoto, Shuzo; Sugiyama, Yosuke; Okada, Atsushi; Mizuno, Kentaro; Umemoto, Yukihiro; Yasui, Takahiro

    2016-01-01

    Lymphoepithelioma-like carcinoma of the urinary bladder (LELCB) is a rare variant of infiltrating urothelial carcinoma. We report a case of LELCB in a 43-year-old man. Ultrasonography and cystoscopy revealed two bladder tumors, one on the left side of the trigone and the other on the right side of the trigone. Transurethral resection of the bladder tumors was performed and pathological analysis revealed undifferentiated carcinoma. We therefore performed radical cystectomy and urinary diversion. Immunohistochemically the tumor cells were positive for cytokeratin, but negative for Epstein-Barr virus-encoded small RNA in situ hybridization as found for previous cases of LELCB. The final pathological diagnosis was a lymphoepithelioma-like variant of urothelial carcinoma with perivesical soft tissue invasion. For adjuvant systemic chemotherapy, three courses of cisplatin were administered. The patient subsequently became free of cancer 72 months postoperatively. Based on the literature, pure or predominant LELCB types show favorable prognoses due to their sensitivity to chemotherapy or radiotherapy. An analysis of the apparent diffusion coefficient (ADC) values of bladder tumors examined in our institution revealed that the ADC value measured for this LELCB was relatively low compared to conventional urothelial carcinomas. This suggests that measuring the ADC value of a lymphoepithelioma-like carcinoma prior to operation may be helpful in predicting LELCB. PMID:27099604

  9. Increased Upper and Lower Tract Urothelial Carcinoma in Patients with End-Stage Renal Disease: A Nationwide Cohort Study in Taiwan during 1997–2008

    PubMed Central

    Wang, Shuo-Meng; Lai, Ming-Nan; Chen, Pau-Chung; Pu, Yeong-Shiau; Lai, Ming-Kuen; Hwang, Jing-Shiang; Wang, Jung-Der

    2014-01-01

    Background. Urothelial cancer (UC) is the leading cancer of patients with end-stage renal disease (ESRD) in Taiwan. The aims of this study were to explore the time trends of UC incidences and propose possible etiologic factors. Methods. Abstracting from the National Health Insurance Research Database (NHIRD), there were 90,477 newly diagnosed cases of ESRD between 1997 and 2008 covering the patients aged 40–85. Among them, 2,708 had developed UC after diagnosis of ESRD. The CIR40–85 (cumulative incidence rate) of upper tract UC (UTUC) and lower tract UC (LTUC) were calculated for ESRD patients and general population, as well as SIR40–85 (standardized incidence ratio) for comparison. Results. Female ESRD patients were found to have 9–18 times of elevated risks of UC, while those of males were increased up to 4–14 times. The time trends of CIR40–84 and SIR40–84 of UTUC in females appear to decline after calendar year 2000. These trends may be related to AA associated herbal products after 1998. Conclusions. Patients with ESRD are at increased risks for both LTUC and UTUC in Taiwan. We hypothesize that the time trends associate with the consumption of aristolochic acid in Chinese herbal products (female predominant). PMID:25025033

  10. From Clinical Trials to the Front Line: Vinflunine for Treatment of Urothelial Cell Carcinoma at the National Cancer Institute of Naples

    PubMed Central

    Facchini, Gaetano; Della Pepa, Chiara; Cavaliere, Carla; Cecere, Sabrina C.; Di Napoli, Marilena; D'Aniello, Carmine; Crispo, Anna; Iovane, Gelsomina; Maiolino, Piera; Tramontano, Teresa; Piscitelli, Raffaele; Pisconti, Salvatore; Montella, Maurizio; Berretta, Massimiliano; Sorrentino, Domenico; Perdonà, Sisto; Pignata, Sandro

    2016-01-01

    Background: The efficacy of Vinflunine, after failure of platinum-based chemotherapy in patients with metastatic or recurrent Transitional Cell Cancer of the Urothelial Tract, TCCU, has been demonstrated in an international, randomized, phase III trial comparing Vinflunine plus Best Supportive Care, BSC, with BSC alone. On the basis of that study vinflunine has been approved by the European Medicine Association, EMA, for treatment of TCCU patients after failure of a platinum treatment. However, since data in clinical trials often differ from routine clinical practice due to unselected population and less strict monitoring, “real life” experiences are very helpful to verify the efficacy of a new therapy. Methods: This was a spontaneous, observational, retrospective study involving 43 patients with metastatic TCCU treated with vinflunine at our cancer center, data about demographics, disease characteristics, and previous treatments were collected and outcome and toxicities of vinflunine were analyzed. Results: 41 of 43 patients were eligible for RR analysis, the Overall RR was 12%, the Disease Control Rate was 29%; when including only patients treated in II line the DCR rose to 33%; the median PFS and the median OS were 2.2 and 6.9 months, respectively. Conclusion: Our findings were consistent with the outcome data emerged in the phase III randomized trial and in the other observational studies conducted all around Europe in the last 2–3 years. This experience supports the use of vinflunine in patients with advanced TTCU as effective and manageable antineoplastic drug. PMID:27199753

  11. Combined cytotoxic effect of UV-irradiation and TiO2 microbeads in normal urothelial cells, low-grade and high-grade urothelial cancer cells.

    PubMed

    Imani, Roghayeh; Veranič, Peter; Iglič, Aleš; Kreft, Mateja Erdani; Pazoki, Meysam; Hudoklin, Samo

    2015-03-01

    The differentiation of urothelial cells results in normal terminally differentiated cells or by alternative pathways in low-grade or high-grade urothelial carcinomas. Treatments with traditional surgical and chemotherapeutical approaches are still inadequate and expensive, as bladder tumours are generally highly recurrent. In such situations, alternative approaches, using irradiation of the cells and nanoparticles, are promising. The ways in which urothelial cells, at different differentiation levels, respond to UV-irradiation (photolytic treatment) or to the combination of UV-irradiation and nanoparticles (photocatalytic treatment), are unknown. Here we tested cytotoxicity of UV-irradiation on (i) normal porcine urothelial cells (NPU), (ii) human low-grade urothelial cancer cells (RT4), and (iii) human high-grade urothelial cancer cells (T24). The results have shown that 1 minute of UV-irradiation is enough to kill 90% of the cells in NPU and RT4 cultures, as determined by the live/dead viability assay. On the other hand, the majority of T24 cells survived 1 minute of UV-irradiation. Moreover, even a prolonged UV-irradiation for 30 minutes killed <50% of T24 cells. When T24 cells were pre-supplemented with mesoporous TiO2 microbeads and then UV-irradiated, the viability of these high-grade urothelial cancer cells was reduced to <10%, which points to the highly efficient cytotoxic effects of TiO2 photocatalysis. Using electron microscopy, we confirmed that the mesoporous TiO2 microbeads were internalized into T24 cells, and that the cell's ultrastructure was heavily compromised after UV-irradiation. In conclusion, our results show major differences in the sensitivity to UV-irradiation among the urothelial cells with respect to cell differentiation. To achieve an increased cytotoxicity of urothelial cancer cells, the photocatalytic approach is recommended.

  12. Combined cytotoxic effect of UV-irradiation and TiO2 microbeads in normal urothelial cells, low-grade and high-grade urothelial cancer cells.

    PubMed

    Imani, Roghayeh; Veranič, Peter; Iglič, Aleš; Kreft, Mateja Erdani; Pazoki, Meysam; Hudoklin, Samo

    2015-03-01

    The differentiation of urothelial cells results in normal terminally differentiated cells or by alternative pathways in low-grade or high-grade urothelial carcinomas. Treatments with traditional surgical and chemotherapeutical approaches are still inadequate and expensive, as bladder tumours are generally highly recurrent. In such situations, alternative approaches, using irradiation of the cells and nanoparticles, are promising. The ways in which urothelial cells, at different differentiation levels, respond to UV-irradiation (photolytic treatment) or to the combination of UV-irradiation and nanoparticles (photocatalytic treatment), are unknown. Here we tested cytotoxicity of UV-irradiation on (i) normal porcine urothelial cells (NPU), (ii) human low-grade urothelial cancer cells (RT4), and (iii) human high-grade urothelial cancer cells (T24). The results have shown that 1 minute of UV-irradiation is enough to kill 90% of the cells in NPU and RT4 cultures, as determined by the live/dead viability assay. On the other hand, the majority of T24 cells survived 1 minute of UV-irradiation. Moreover, even a prolonged UV-irradiation for 30 minutes killed <50% of T24 cells. When T24 cells were pre-supplemented with mesoporous TiO2 microbeads and then UV-irradiated, the viability of these high-grade urothelial cancer cells was reduced to <10%, which points to the highly efficient cytotoxic effects of TiO2 photocatalysis. Using electron microscopy, we confirmed that the mesoporous TiO2 microbeads were internalized into T24 cells, and that the cell's ultrastructure was heavily compromised after UV-irradiation. In conclusion, our results show major differences in the sensitivity to UV-irradiation among the urothelial cells with respect to cell differentiation. To achieve an increased cytotoxicity of urothelial cancer cells, the photocatalytic approach is recommended. PMID:25385056

  13. A significantly joint effect between arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of urothelial carcinoma

    SciTech Connect

    Wang, Y.-H.; Yeh, S.-D.; Shen, K.-H.; Shen, Cheng-Huang; Juang, G.-D.; Hsu, L.-I; Chiou, H.-Y.; Chen, C.-J.

    2009-11-15

    Cigarette smoking, arsenic and occupational exposures are well-known risk factors for the development of urothelial carcinoma (UC). Therefore, the aim of this study is to investigate whether the effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures on risk of UC could be modified by genetic polymorphisms of cytochrome P450 2E1 and glutathione S-transferase omega. A hospital-based case-control study consisted of 520 histologically confirmed UC cases, and 520 age- and gender-matched cancer-free controls were carried out from September 1998 to December 2007. Genotyping of CYP2E1, GSTO1 and GSTO2 was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Subjects with both of cigarette smoking and alcohol consumption have a significantly increased UC risk (odds ratio [OR] = 2.9; 95% confidence interval [CI] = 1.9-4.4). Significantly increased UC risks of 1.5 and 1.9 were found for study subjects with high arsenic exposure and those who have been exposed to two or more occupational exposures, respectively. A significantly increased UC risk of 3.9 was observed in study subjects with H2-H2 diplotype of GSTO1 and GSTO2. The significantly highest UC risk of 9.0 was found for those with all environmental risk factors of cigarette smoking, alcohol consumption, arsenic and occupational exposures and two or more risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2. Our findings suggest that a significantly joint effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of UC was found.

  14. The role of c-FLIP splice variants in urothelial tumours

    PubMed Central

    Ewald, F; Ueffing, N; Brockmann, L; Hader, C; Telieps, T; Schuster, M; Schulz, W A; Schmitz, I

    2011-01-01

    Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells. One important regulator of apoptosis is the cellular FLICE-inhibitory protein (c-FLIP), which is overexpressed, for example, in melanoma and Hodgkin's lymphoma cells. Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis. In particular, we investigated the role of the c-FLIP splice variants c-FLIPlong (c-FLIPL) and c-FLIPshort (c-FLIPS), which can have opposing functions. We observed diminished expression of the c-FLIPL isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIPS was unchanged. Overexpression and RNA interference studies in urothelial cell lines nevertheless demonstrated that c-FLIP remained a crucial factor conferring resistance towards induction of apoptosis by death ligands CD95L and TRAIL. Isoform-specific RNA interference showed c-FLIPL to be of particular importance. Thus, urothelial carcinoma cells appear to fine-tune c-FLIP expression to a level sufficient for protection against activation of apoptosis by the extrinsic pathway. Therefore, targeting c-FLIP, and especially the c-FLIPL isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours. PMID:22190004

  15. Study of the reproducibility of the 2004 World Health Organization classification of urothelial neoplasms.

    PubMed

    Sharma, Pallavi; Kini, Hema; Pai, Radha R; Sahu, Kaushalya K; Kini, Jyoti

    2015-01-01

    The aim of the study was to evaluate urinary bladder biopsies showing papillary urothelial neoplastic lesions based on the 2004 WHO/ISUP classification of Urothelial Neoplasms of the Urinary Bladder, to assess the reproducibility of the bladder carcinoma grade. Fifty consecutive transurethral tumor resection biopsies were evaluated by four pathologists independently. The final diagnoses of each pathologist were subjected to statistical analysis to assess the degree of interobserver variability and reproducibility of this classification. Significant interobserver variation was found in the reporting of urothelial neoplasms. In 22 instances there was difference in opinion between PUNLMP and low-grade carcinoma, and in 59 instances between low and high grade carcinoma. The 4 observers never unanimously agreed on the diagnosis of PUNLMP.

  16. Role of isoenzyme M2 of pyruvate kinase in urothelial tumorigenesis

    PubMed Central

    Liu, Yan; He, Feng; Zhang, Fenglin; Huang, Kuo-How; Wu, Xue-Ru

    2016-01-01

    The conversion of precancerous lesions to full-fledged cancers requires the affected cells to surpass certain rate-limiting steps. We recently showed that activation of HRAS proto-oncogene in urothelial cells of transgenic mice causes simple urothelial hyperplasia (SUH) which is persistent and whose transition to low-grade papillary urothelial carcinoma (UC) must undergo nodular urothelial hyperplasia (NUH). We hypothesized that NUH, which has acquired fibrovascular cores, plays critical roles in mesenchymal-to-epithelial signaling, breaching the barriers of urothelial tumor initiation. Using proteomics involving two-dimensional gel electrophoresis, immunoblotting with pan-phosphotyrosine antibody and MALDI-mass spectrometry, we identified isoform 2 of pyruvate kinase (PKM2) as the major tyrosine-phosphorylated protein switched on during NUH. We extended this finding using specimens from transgenic mice, human UC and UC cell lines, establishing that PKM2, but not its spliced variant PKM1, was over-expressed in low-grade and, more prominently, high-grade UC. In muscle-invasive UC, PKM2 was co-localized with cytokeratins 5 and 14, UC progenitor markers. Specific inhibition of PKM2 by siRNA or shRNA suppressed UC cell proliferation via increased apoptosis, autophagy and unfolded protein response. These results strongly suggest that PKM2 plays an important role in the genesis of low-grade non-invasive and high-grade invasive urothelial carcinomas. PMID:26992222

  17. Normal and neoplastic urothelial stem cells: getting to the root of the problem

    PubMed Central

    Ho, Philip Levy; Kurtova, Antonina; Chan, Keith Syson

    2012-01-01

    Most epithelial tissues contain self-renewing stem cells that mature into downstream progenies with increasingly limited differentiation potential. It is not surprising that cancers arising from such hierarchically organized epithelial tissues retain features of cellular differentiation. Accumulating evidence suggests that the urothelium of the urinary bladder is a hierarchically organized tissue, containing tissue-specific stem cells that are important for both normal homeostasis and injury response. The phenotypic and functional properties of cancer stem cells (CSCs; also known as tumour-initiating cells) from bladder cancer tissue have been studied in detail. Urothelial CSCs are not isolated by a ‘one-marker-fits-all’ approach; instead, various cell surface marker combinations (possibly reflecting the cell-of-origin) are used to isolate CSCs from distinct differentiation subtypes of urothelial carcinomas. Additional CSC markers, including cytokeratin 14 (CK14), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), and tumour protein 63 (p63), have revealed prognostic value for urothelial carcinomas. Signalling pathways involved in normal stem cell self-renewal and differentiation are implicated in the malignant transformation of different subsets of urothelial carcinomas. Early expansion of primitive CK14+ cells—driven by genetic pathways such as STAT3—can lead to the development of carcinoma in situ, and CSC-enriched urothelial carcinomas are associated with poor clinical outcomes. Given that bladder CSCs are the proposed root of malignancy and drivers of cancer initiation and progression for urothelial carcinomas, these cells are ideal targets for anticancer therapies. PMID:22890301

  18. Diagnostic utility of p53 and CK20 immunohistochemical expression grading urothelial malignancies

    PubMed Central

    2014-01-01

    Introduction Current grading system in application by WHO/ISUP divides urothelial malignancies in low and high grade by morphologic criteria while strict segregation may become cumbersome in limited tissue specimens. As grading these carcinomas are of utmost prognostic significance after depth of invasion, therefore we evaluated the role of immunohistochemical expression of p53 and cytokeratin 20 as an adjuctive tool in grading urothelial carcinoma. Methods The study was conducted in Aga khan university hospital, Histopathology section from December 2010 till June 2011 for duration of six months. It involved 95 cases of urothelial carcinomas diagnosed on trans-uretheral resection specimens of bladder growth. Immunohistochemical expression of p53 and cytokeratin 20 was performed according to standard protocols and correlated with grade and depth of invasion. Results There were 48 cases (50.5%) of low grade and 47 cases (49.5%) of high grade urothelial carcinoma included in the study. Male to female ratio was 4.3:1. Majority of patients (80%) were seen in 45 to 90 years age group. Diffuse positive expression of cytokerain 20 was noted in 33 cases (68.8%) of high grade and 19 (40.4%) low grade tumors. Strong positive expression of p53 was seen in 35 cases (72.9%) of high grade while only 17 cases (36.2%) of low grade tumors showed strong p53 expression. Conclusion Significant difference in expression of Cytokeratin 20 and p53 was found between low and high grade urothelial carcinoma. Therefore we suggest combined use of these markers may be helpful in assigning grade to urothelial carcinoma especially when histologic features are borderline. PMID:25089155

  19. A Model to Predict the Risk of Keratinocyte Carcinomas.

    PubMed

    Whiteman, David C; Thompson, Bridie S; Thrift, Aaron P; Hughes, Maria-Celia; Muranushi, Chiho; Neale, Rachel E; Green, Adele C; Olsen, Catherine M

    2016-06-01

    Basal cell and squamous cell carcinomas of the skin are the commonest cancers in humans, yet no validated tools exist to estimate future risks of developing keratinocyte carcinomas. To develop a prediction tool, we used baseline data from a prospective cohort study (n = 38,726) in Queensland, Australia, and used data linkage to capture all surgically excised keratinocyte carcinomas arising within the cohort. Predictive factors were identified through stepwise logistic regression models. In secondary analyses, we derived separate models within strata of prior skin cancer history, age, and sex. The primary model included terms for 10 items. Factors with the strongest effects were >20 prior skin cancers excised (odds ratio 8.57, 95% confidence interval [95% CI] 6.73-10.91), >50 skin lesions destroyed (odds ratio 3.37, 95% CI 2.85-3.99), age ≥ 70 years (odds ratio 3.47, 95% CI 2.53-4.77), and fair skin color (odds ratio 1.75, 95% CI 1.42-2.15). Discrimination in the validation dataset was high (area under the receiver operator characteristic curve 0.80, 95% CI 0.79-0.81) and the model appeared well calibrated. Among those reporting no prior history of skin cancer, a similar model with 10 factors predicted keratinocyte carcinoma events with reasonable discrimination (area under the receiver operator characteristic curve 0.72, 95% CI 0.70-0.75). Algorithms using self-reported patient data have high accuracy for predicting risks of keratinocyte carcinomas.

  20. Genomic aberrations are rare in urothelial neoplasms of patients 19 years or younger.

    PubMed

    Wild, P J; Giedl, J; Stoehr, R; Junker, K; Boehm, S; van Oers, J M M; Zwarthoff, E C; Blaszyk, H; Fine, S W; Humphrey, P A; Dehner, L P; Amin, M B; Epstein, J I; Hartmann, A

    2007-01-01

    Urothelial neoplasms in patients 19 years of age or younger are rare, and the data regarding clinical outcome are conflicting. Molecular data are not available. Urothelial tumours from 14 patients aged 4 to 19 years were analysed, including FGFR3 and TP53 mutation screening, comparative genomic hybridization (CGH), UroVysion FISH analysis, polymerase chain reaction for human papillomavirus (HPV), microsatellite analysis using the NIH consensus panel for detection of microsatellite instability (MSI) and six markers for loss of heterozygosity on chromosome arms 9p, 9q, and 17p and immunohistochemistry for TP53, Ki-67, CK20 and the mismatch repair proteins (MRPs) hMSH2, hMLH1, and hMSH6. Based on the 2004 WHO classification, one urothelial papilloma, seven papillary urothelial neoplasms of low malignant potential (PUNLMPs), five low-grade, and one high-grade papillary urothelial carcinoma were included. No multifocal tumours were found and recurrence was seen in only one patient with a urothelial papilloma. All patients were alive with no evidence of disease at a median follow-up of 3.0 years. We found no mutations in FGFR3, deletions of chromosome arms 9p, 9q or 17p, MSI or MRP loss, or HPV positivity in any of the patients. Three cases showed chromosome alterations in CGH analyses, urothelial dedifferentiation with CK20 overexpression, or aneuploidy, and one TP53 mutation with TP53 overexpression was found. Urothelial neoplasms in people younger than 20 years are predominantly low grade and are associated with a favourable clinical outcome. Genetic alterations frequently seen in older adults are extremely rare in young patients. Urothelial neoplasms in children and young adults appear to be biologically distinct and lack genetic instability in most cases. PMID:17072825

  1. Diagnostic algorithm for papillary urothelial tumors in the urinary bladder

    PubMed Central

    Shim, Jung-Weon; Cho, Kang Su; Choi, Young-Deuk; Park, Yong-Wook; Lee, Dong-Wha; Han, Woon-Sup; Shim, Sang-In; Kim, Hyun-Jung

    2008-01-01

    Papillary urothelial neoplasms with deceptively bland cytology cannot be easily classified. We aimed to design a new algorithm that could differentiate between these neoplasms based on a scoring system. We proposed a new scoring system that enables to reproducibly diagnose non-invasive papillary urothelial tumors. In this system, each lesion was given individual scores from 0 to 3 for mitosis and cellular thickness, from 0 to 2 for cellular atypia, and an additional score for papillary fusion. These scores were combined to form a summed score allowing the tumors to be ranked as follows: 0–1 = UP, 2–4 = low malignant potential (LMP), 5–7 = low-grade transitional cell carcinoma (TCC), and 8–9 = high-grade TCC. In addition to the scoring system, ancillary studies of MIB and p53 indexes with CK20 expression pattern analyses were compared together with clinical parameters. The MIB index was strongly correlated with disease progression. Four of the 22 LMP patients (18.2%) had late recurrences, two of these four (9.1%) had progression to low-grade carcinoma. The MIB index for LMP patients was strongly associated with recurrence (recurrence vs. non-recurrence, 16.5 vs. 8.1, p < 0.001). The proposed scoring system could enhance the reproducibility to distinguish papillary urothelial neoplasms. PMID:18311491

  2. New and contemporary markers of prognosis in nonmuscle invasive urothelial cancer

    PubMed Central

    Nazim, Syed M

    2015-01-01

    Nonmuscle invasive (NMI) urothelial cancer (UC) is associated with varied biological potential. It is characterized by frequent recurrence and progression, which thus worsens the oncological outcome. Nearly three-quarters of NMI UCs recur within 5 years, whereas half can progress during follow-up. Progression is particularly seen in T1 and carcinoma in situ (CIS). Undoubtedly, NMI UC is one of the most expensive cancers to manage. The European Organisation for Research and Treatment of Cancer (EORTC) risk calculator is a commonly used tool for assessing the recurrence and progression potential of a newly diagnosed cancer. The parameters used in the assessment are tumor size and number, pathological stage and grade of the cancer, presence of CIS, and prior recurrence rate. The main advantages of the EORTC tool are its ease of use and the lack of need to run expensive molecular tests. However, reproducibility of pathologic stage and grade is modest, which is a concern to clinicians. Molecular markers have potential for predicting the clinical outcome of NMI UC, given that clinico-pathologic variables are not sufficient for prediction of prognosis in an individual. Significant work has been done in the past 2 decades in understanding the molecular biology of bladder cancer; however, the translational value of this knowledge remains poor. The role for molecular markers in predicting recurrence seems limited because multifocal disease and incomplete treatment are probably more important for recurrence than the molecular features of a resected tumor. Urinary markers have very limited value in prognostication of bladder cancer and are used (mainly as an adjunct to cytology) for detection and surveillance of urothelial cell cancer recurrence. Prediction of progression with molecular markers holds considerable promise. Nevertheless, the contemporary value of molecular markers over clinico-pathologic indexes is limited. PMID:26279824

  3. Retroperitoneoscopic renal pelvis resection as treatment of the urothelial tumor in a solitary kidney

    PubMed Central

    Słojewski, Marcin; Gołąb, Adam; Petrasz, Piotr

    2013-01-01

    Urothelial carcinoma of the upper urinary tract is relatively rare. The standard treatment is invariably radical nephroureterectomy. In selected cases organ sparing surgery is justified. We present the case of the tumor of the kidney pelvis in a solitary organ where laparoscopic approach was successfully applied. PMID:24707368

  4. Risk prediction models for hepatocellular carcinoma in different populations

    PubMed Central

    Ma, Xiao; Yang, Yang; Tu, Hong; Gao, Jing; Tan, Yu-Ting; Zheng, Jia-Li; Bray, Freddie; Xiang, Yong-Bing

    2016-01-01

    Hepatocellular carcinoma (HCC) is a malignant disease with limited therapeutic options due to its aggressive progression. It places heavy burden on most low and middle income countries to treat HCC patients. Nowadays accurate HCC risk predictions can help making decisions on the need for HCC surveillance and antiviral therapy. HCC risk prediction models based on major risk factors of HCC are useful and helpful in providing adequate surveillance strategies to individuals who have different risk levels. Several risk prediction models among cohorts of different populations for estimating HCC incidence have been presented recently by using simple, efficient, and ready-to-use parameters. Moreover, using predictive scoring systems to assess HCC development can provide suggestions to improve clinical and public health approaches, making them more cost-effective and effort-effective, for inducing personalized surveillance programs according to risk stratification. In this review, the features of risk prediction models of HCC across different populations were summarized, and the perspectives of HCC risk prediction models were discussed as well. PMID:27199512

  5. Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer

    PubMed Central

    POYET, CÉDRIC; HERMANNS, THOMAS; ZHONG, QING; DRESCHER, EVA; EBERLI, DANIEL; BURGER, MAXIMILIAN; HOFSTAEDTER, FERDINAND; HARTMANN, ARNDT; STÖHR, ROBERT; ZWARTHOFF, ELLEN C.; SULSER, TULLIO; WILD, PETER J.

    2015-01-01

    In addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical significance it may possess with regard to BC. The present study aimed to investigate the immunoreactivity of FGFR3 in primary urothelial bladder tumours, with regard to clinicopathological features and FGFR3 mutation status. Tissue microarrays were used to immunohistochemically analyse FGFR3 expression in 255 primary, unselected patients with BC. FGFR3 mutations were detected using SNaPshot analysis. Positive FGFR3 immunoreactivity was identified in 113/207 analysable cases (54.6%), and was significantly associated with FGFR3 mutation (P<0.001), low tumour stage (P<0.001), low histological grade (P<0.001) and a papillary growth pattern (P<0.001). Positive FGFR3 immunostaining (P=0.002) and FGFR3 mutation (P=0.002) were found to be significantly associated with increased disease-specific survival following univariate analysis, demonstrating a median follow-up period of 75 months. Using multivariate analyses, FGFR3 immunoreactivity was found not to be independent of classical pathological parameters. Immunohistochemical expression of FGFR3 is an early occurrence during the carcinogenesis of papillary non-invasive BC. The presence of FGFR3 immunoreactivity in non-invasive papillary urothelial carcinomas may be utilised as an indicator of tumours possessing low-grade features and good prognosis. PMID:26722237

  6. Genes involved in differentiation, stem cell renewal, and tumorigenesis are modulated in telomerase-immortalized human urothelial cells.

    PubMed

    Chapman, Emma J; Kelly, Gavin; Knowles, Margaret A

    2008-07-01

    The expression of hTERT, the catalytic subunit of telomerase, immortalizes normal human urothelial cells (NHUC). Expression of a modified hTERT, without the ability to act in telomere maintenance, did not immortalize NHUC, confirming that effects at telomeres are required for urothelial immortalization. Previous studies indicate that inhibition of telomerase has an immediate effect on urothelial carcinoma (UC) cell line viability, before sufficient divisions to account for telomere attrition, implicating non-telomere effects of telomerase in UC. We analyzed the effects of telomerase on gene expression in isogenic mortal and hTERT-transduced NHUC. hTERT expression led to consistent alterations in the expression of genes predicted to be of phenotypic significance in tumorigenesis. A subset of expression changes were detected soon after transduction with hTERT and persisted with continued culture. These genes (NME5, PSCA, TSPYL5, LY75, IGFBP2, IGF2, CEACAM6, XG, NOX5, KAL1, and HPGD) include eight previously identified as polycomb group targets. TERT-NHUC showed overexpression of the polycomb repressor complex (PRC1 and PRC4) components, BMI1 and SIRT1, and down-regulation of multiple PRC targets and genes associated with differentiation. TERT-NHUC at 100 population doublings, but not soon after transduction, showed increased saturation density and an attenuated differentiation response, indicating that these are not acute effects of telomerase expression. Some of the changes in gene expression identified may contribute to tumorigenesis. Expression of NME5 and NDN was down-regulated in UC cell lines and tumors. Our data supports the concept of both telomere-based and non-telomere effects of telomerase and provides further rationale for the use of telomerase inhibitors in UC. PMID:18644980

  7. Multiple Mechanisms Mediate Resistance to Sorafenib in Urothelial Cancer

    PubMed Central

    Knievel, Judith; Schulz, Wolfgang A.; Greife, Annemarie; Hader, Christiane; Lübke, Tobias; Schmitz, Ingo; Albers, Peter; Niegisch, Günter

    2014-01-01

    Genetic and epigenetic changes in the mitogen activated protein kinase (MAPK) signaling render urothelial cancer a potential target for tyrosine kinase inhibitor (TKI) treatment. However, clinical trials of several TKIs failed to prove efficacy. In this context, we investigated changes in MAPK signaling activity, downstream apoptotic regulators and changes in cell cycle distribution in different urothelial cancer cell lines (UCCs) upon treatment with the multikinase inhibitor sorafenib. None of the classical sorafenib targets (vascular endothelial growth factor receptor 1/-receptor 2, VEGFR1/-R2; platelet-derived growth factor receptor α/-receptor β, PDGFR-α/-β; c-KIT) was expressed at significant levels leaving RAF proteins as its likely molecular target. Low sorafenib concentrations paradoxically increased cell viability, whereas higher concentrations induced G1 arrest and eventually apoptosis. MAPK signaling remained partly active after sorafenib treatment, especially in T24 cells with an oncogenic HRAS mutation. AKT phosphorylation was increased, suggesting compensatory activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Sorafenib regularly down regulated the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) protein, but combinatorial treatment with ABT-737 targeting other B-cell lymphoma 2 (Bcl-2) family proteins did not result in synergistic effects. In summary, efficacy of sorafenib in urothelial cancer cell lines appears hampered by limited effects on MAPK signaling, crosstalk with further cancer pathways and an anti-apoptotic state of UCCs. These observations may account for the lack of efficacy of sorafenib in clinical trials and should be considered more broadly in the development of signaling pathway inhibitors for drug therapy in urothelial carcinoma. PMID:25387078

  8. Contemporary Evaluation and Management of Upper Tract Urothelial Cancer.

    PubMed

    Mandalapu, Rao S; Matin, Surena F

    2016-08-01

    Radical nephroureterectomy with en bloc bladder cuff excision and regional lymphadenectomy is the gold standard for the management of high-grade and high-risk upper tract urothelial carcinomas. There are a few prospective randomized controlled studies in this uncommon and often aggressive disease to support level-1 management guidelines. However, recent developments in imaging, minimally invasive techniques, lymphatic dissemination, and bladder cancer prevention raise the hope for improved risk stratification and treatments without compromising, and hopefully improving, oncological outcomes. Multimodality approaches in terms of neoadjuvant, adjuvant topical, and systemic chemotherapeutic regimens are promising, with 2 prospective trials either open or in development.

  9. Bovine papillomavirus type 2 infection and microscopic patterns of urothelial tumors of the urinary bladder in water buffaloes.

    PubMed

    Maiolino, Paola; Ozkul, Ayhan; Sepici-Dincel, Aylin; Roperto, Franco; Yücel, Gözde; Russo, Valeria; Urraro, Chiara; Lucà, Roberta; Riccardi, Marita Georgia; Martano, Manuela; Borzacchiello, Giuseppe; Esposito, Iolanda; Roperto, Sante

    2013-01-01

    Microscopic patterns of thirty-four urothelial tumors of the urinary bladder of water buffaloes from the Marmara and Black Sea Regions of Turkey are here described. All the animals grazed on lands rich in bracken fern. Histological diagnosis was assessed using morphological parameters recently suggested for the urinary bladder tumors of cattle. Papillary carcinoma was the most common neoplastic lesion (22/34) observed in this study, and low-grade carcinoma was more common (seventeen cases) than high-grade carcinoma (five cases). Papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), and invasive carcinomas were less frequently seen. Carcinoma in situ (CIS) was often detected associated with some papillary and invasive carcinomas. De novo (primary) CIS was rare representing 3% of tumors of this series. A peculiar feature of the most urothelial tumors was the presence in the tumor stroma of immune cells anatomically organized in tertiary lymphoid organs (TLOs). Bovine papillomavirus type-2 (PV-2) E5 oncoprotein was detected by molecular and immunohistochemistry procedures. Early protein, E2, and late protein, L1, were also detected by immunohistochemical studies. Morphological and molecular findings show that BPV-2 infection contributes to the development of urothelial bladder carcinogenesis also in water buffaloes.

  10. Bovine Papillomavirus Type 2 Infection and Microscopic Patterns of Urothelial Tumors of the Urinary Bladder in Water Buffaloes

    PubMed Central

    Maiolino, Paola; Özkul, Ayhan; Sepici-Dincel, Aylin; Roperto, Franco; Yücel, Gözde; Russo, Valeria; Urraro, Chiara; Lucà, Roberta; Riccardi, Marita Georgia; Martano, Manuela; Borzacchiello, Giuseppe; Esposito, Iolanda; Roperto, Sante

    2013-01-01

    Microscopic patterns of thirty-four urothelial tumors of the urinary bladder of water buffaloes from the Marmara and Black Sea Regions of Turkey are here described. All the animals grazed on lands rich in bracken fern. Histological diagnosis was assessed using morphological parameters recently suggested for the urinary bladder tumors of cattle. Papillary carcinoma was the most common neoplastic lesion (22/34) observed in this study, and low-grade carcinoma was more common (seventeen cases) than high-grade carcinoma (five cases). Papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), and invasive carcinomas were less frequently seen. Carcinoma in situ (CIS) was often detected associated with some papillary and invasive carcinomas. De novo (primary) CIS was rare representing 3% of tumors of this series. A peculiar feature of the most urothelial tumors was the presence in the tumor stroma of immune cells anatomically organized in tertiary lymphoid organs (TLOs). Bovine papillomavirus type-2 (PV-2) E5 oncoprotein was detected by molecular and immunohistochemistry procedures. Early protein, E2, and late protein, L1, were also detected by immunohistochemical studies. Morphological and molecular findings show that BPV-2 infection contributes to the development of urothelial bladder carcinogenesis also in water buffaloes. PMID:23762866

  11. Protein Profiling of Bladder Urothelial Cell Carcinoma

    PubMed Central

    Hu, Jinghai; Ye, Fei; Cui, Miao; Lee, Peng; Wei, Chengguo; Hao, Yuanyuan; Wang, Xiaoqing; Wang, Yanbo; Lu, Zhihua; Galsky, Matthew; McBride, Russell; Wang, Li; Wang, Dongwen; Cordon-Cardo, Carlos; Wang, Chunxi; Zhang, David Y.

    2016-01-01

    This study aimed to detect protein changes that can assist to understand the underlying biology of bladder cancer. The data showed forty five proteins were found to be differentially expressed comparing tumors vs non-tumor tissues, of which EGFR and cdc2p34 were correlated with muscle invasion and histological grade. Ten proteins (ß-catenin, HSP70, autotaxin, Notch4, PSTPIP1, DPYD, ODC, cyclinB1, calretinin and EPO) were able to classify muscle invasive BCa (MIBC) into 2 distinct groups, with group 2 associated with poorer survival. Finally, 3 proteins (P2X7, cdc25B and TFIIH p89) were independent factors for favorable overall survival. PMID:27626805

  12. Protein Profiling of Bladder Urothelial Cell Carcinoma.

    PubMed

    Hu, Jinghai; Ye, Fei; Cui, Miao; Lee, Peng; Wei, Chengguo; Hao, Yuanyuan; Wang, Xiaoqing; Wang, Yanbo; Lu, Zhihua; Galsky, Matthew; McBride, Russell; Wang, Li; Wang, Dongwen; Cordon-Cardo, Carlos; Wang, Chunxi; Zhang, David Y

    2016-01-01

    This study aimed to detect protein changes that can assist to understand the underlying biology of bladder cancer. The data showed forty five proteins were found to be differentially expressed comparing tumors vs non-tumor tissues, of which EGFR and cdc2p34 were correlated with muscle invasion and histological grade. Ten proteins (ß-catenin, HSP70, autotaxin, Notch4, PSTPIP1, DPYD, ODC, cyclinB1, calretinin and EPO) were able to classify muscle invasive BCa (MIBC) into 2 distinct groups, with group 2 associated with poorer survival. Finally, 3 proteins (P2X7, cdc25B and TFIIH p89) were independent factors for favorable overall survival. PMID:27626805

  13. Role of angiogenesis in urothelial bladder carcinoma

    PubMed Central

    Górnicka, Barbara

    2016-01-01

    Introduction Bladder cancer is the most common urinary tract malignancy in western countries. In recent years, extensive research has suggested that angiogenesis plays an important role in bladder cancer biology, contributing to tumor growth and progression. Material and methods In this review, we discuss general mechanisms of angiogenesis and highlight the influence of pro- and anti-angiogenic factors, and cancer stem cells on bladder cancer biology, their relation to disease progression, and potential use in novel targeted therapies. Results Expression of a number of proangiogenic factors, including HIF-1, VEGF, bFGF, IL-8 and MMPs, as well as anti-angiogenic factor TSP-1, was found to be altered in bladder tumors. Involvement of cancer stem cells in bladder cancer development was also proposed. Conclusions High expression of most pro-angiogenic factors correlated with disease progression and shorter patient survival, but discrepancies between studies urge us to continue evaluating the significance of angiogenesis in bladder cancer. PMID:27729991

  14. Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder carcinoma. A tissue microarray study of 158 cases.

    PubMed

    Compérat, Eva; Camparo, Philippe; Haus, Rachel; Chartier-Kastler, Emmanuel; Bart, Stephane; Delcourt, Annick; Houlgatte, Alain; François, Richard; Capron, Fréderique; Vieillefond, Annick

    2006-03-01

    P63 is a member of the p53 family, which plays a role in the differentiation of urothelium and is supposed to play a role in urothelial carcinogenesis. P53 and MIB-1 are recognised in many studies as predictive markers of progression, but few studies in the literature have examined p63. The aims of our study were to explore the expression of p63 in bladder carcinomas and to compare this expression to p53 and MIB-1, as well as to stage and grade. Tissue microarrays were performed on 158 urothelial carcinomas (56 pTa, 45 pT1 and 57>or=pT2). Immunohistochemical studies were performed with p63, p53 and MIB-1 antibodies. In our study we observed that p63 immunostaining is present in all cell layers in papillary urothelial neoplasm of low malignant potential (PUNLMP), but partially lost in non-invasive papillary urothelial carcinoma low grade (NILGC) and in pT1/>or=pT2 bladder cancers. P53 and MIB-1 displayed lower expression in PUNLMP/NILGC vs non-invasive papillary urothelial carcinoma high grade (NIHGC)/pT1, but there was no correlation between the expression of p63, p53 and MIB-1. Our study demonstrates that p63 expression distinguishes between PUNLMP/NILGC and NIHGC/pT1 (p=4.10(5)). A statistical difference disserving pTa and pT1/>or=pT2 with a statistical significance (p<10(-6)) could also be observed. P63 should be considered as an additional biomarker that might help pathologists to classify their patients.

  15. The prophylaxis of nonindustrial urothelial tumours

    PubMed Central

    Mount, Balfour M.

    1973-01-01

    Present knowledge concerning carcinogenesis and the natural history of urothelial tumours precludes firm conclusions relative to nonindustrial prophylaxis. However, a number of measures are consistent with current data and may be instituted for those patients with a demonstrated propensity to urothelial tumours. Their acceptability is based on the lack of associated toxicity for the patient. These measures include the elimination of significant infection, cigarettes, artificial sweeteners, analgesic abuse and coffee, the administration of vitamins C and B6, and in selected cases, the use of thiotepa. It is emphasized that the merit of these steps in altering the natural history of urothelial tumours is uncertain. PMID:4197537

  16. Highly Selective Anti-Cancer Activity of Cholesterol-Interacting Agents Methyl-β-Cyclodextrin and Ostreolysin A/Pleurotolysin B Protein Complex on Urothelial Cancer Cells

    PubMed Central

    Resnik, Nataša; Repnik, Urška; Kreft, Mateja Erdani; Sepčić, Kristina; Maček, Peter; Turk, Boris; Veranič, Peter

    2015-01-01

    Cholesterol content can vary distinctly between normal and cancer cells, with elevated levels in cancer cells. Here, we investigated cholesterol sequestration with methyl-β-cyclodextrin (MCD), and pore-formation with the ostreolysin A/pleurotolysin B (OlyA/PlyB) protein complex that binds to cholesterol/sphingomyelin-rich membrane domains. We evaluated the effects on viability of T24 invasive and RT4 noninvasive human urothelial cancer cells and normal porcine urothelial (NPU) cells. Cholesterol content strongly correlated with cancerous transformation, as highest in the T24 high-grade invasive urothelial cancer cells, and lowest in NPU cells. MCD treatment induced prominent cell death of T24 cells, whereas OlyA/PlyB treatment resulted in greatly decreased viability of the RT4 low-grade noninvasive carcinoma cells. Biochemical and transmission electron microscopy analyses revealed that MCD and OlyA/PlyB induce necrotic cell death in these cancer cells, while viability of NPU cells was not significantly affected by either treatment. We conclude that MCD is more toxic for T24 high-grade invasive urothelial cancer cells, and OlyA/PlyB for RT4 low-grade noninvasive urothelial cancer cells, and neither is toxic for NPU cells. The cholesterol and cholesterol/sphingomyelin-rich membrane domains in urothelial cancer cells thus constitute a selective therapeutic target for elimination of urothelial cancer cells. PMID:26361392

  17. Highly Selective Anti-Cancer Activity of Cholesterol-Interacting Agents Methyl-β-Cyclodextrin and Ostreolysin A/Pleurotolysin B Protein Complex on Urothelial Cancer Cells.

    PubMed

    Resnik, Nataša; Repnik, Urška; Kreft, Mateja Erdani; Sepčić, Kristina; Maček, Peter; Turk, Boris; Veranič, Peter

    2015-01-01

    Cholesterol content can vary distinctly between normal and cancer cells, with elevated levels in cancer cells. Here, we investigated cholesterol sequestration with methyl-β-cyclodextrin (MCD), and pore-formation with the ostreolysin A/pleurotolysin B (OlyA/PlyB) protein complex that binds to cholesterol/sphingomyelin-rich membrane domains. We evaluated the effects on viability of T24 invasive and RT4 noninvasive human urothelial cancer cells and normal porcine urothelial (NPU) cells. Cholesterol content strongly correlated with cancerous transformation, as highest in the T24 high-grade invasive urothelial cancer cells, and lowest in NPU cells. MCD treatment induced prominent cell death of T24 cells, whereas OlyA/PlyB treatment resulted in greatly decreased viability of the RT4 low-grade noninvasive carcinoma cells. Biochemical and transmission electron microscopy analyses revealed that MCD and OlyA/PlyB induce necrotic cell death in these cancer cells, while viability of NPU cells was not significantly affected by either treatment. We conclude that MCD is more toxic for T24 high-grade invasive urothelial cancer cells, and OlyA/PlyB for RT4 low-grade noninvasive urothelial cancer cells, and neither is toxic for NPU cells. The cholesterol and cholesterol/sphingomyelin-rich membrane domains in urothelial cancer cells thus constitute a selective therapeutic target for elimination of urothelial cancer cells. PMID:26361392

  18. Expression of claudins and their prognostic significance in noninvasive urothelial neoplasms of the human urinary bladder.

    PubMed

    Székely, Eszter; Törzsök, Péter; Riesz, Péter; Korompay, Anna; Fintha, Attila; Székely, Tamás; Lotz, Gábor; Nyirády, Péter; Romics, Imre; Tímár, József; Schaff, Zsuzsa; Kiss, András

    2011-10-01

    The members of the claudin family are major integral transmembrane protein constituents of tight junctions. Normal and neoplastic tissues can be characterized by unique qualitative and quantitative distribution of claudin subtypes, which may be related to clinicopathological features. Differential diagnosis and prognosis of nonmuscle invasive tumor entities of urinary bladder epithelium are often challenging. The aim was to investigate the expression profile of claudins in inverted urothelial papillomas (IUPs), urothelial papillomas (UPs), papillary urothelial neoplasms of low malignant potential (PUNLMPs), and intraepithelial (Ta), low-grade urothelial cell carcinomas (LG-UCCs) in order to reveal potential prognostic and differential diagnostic values of certain claudins. Claudin-1, -2, -4, and -7 protein expressions detected by immunohistochemistry and clinical data were analyzed in 15 IUPs, 20 UPs, 20 PUNLMPs, and 20 LG-UCCs. UPs, PUNLMPs, and LG-UCCs showed significantly decreased claudin-1 expression in comparison to IUPs. LG-UCCs expressing claudin-4 over the median were associated with significantly shorter recurrence-free survival. PUNLMPs expressing claudin-1 over the median revealed significantly longer recurrence-free survival. High claudin-1 protein expression might help to differentiate IUP from UPs, PUNLMPs, and LG-UCCs. High claudin-4 expression may determine an unfavorable clinical course of LG-UCCs, while high claudin-1 expression in PUNLMP was associated with markedly better clinical outcome.

  19. Expression of Claudins and Their Prognostic Significance in Noninvasive Urothelial Neoplasms of the Human Urinary Bladder

    PubMed Central

    Székely, Eszter; Törzsök, Péter; Riesz, Péter; Korompay, Anna; Fintha, Attila; Székely, Tamás; Lotz, Gábor; Nyirády, Péter; Romics, Imre; Tímár, József; Schaff, Zsuzsa; Kiss, András

    2011-01-01

    The members of the claudin family are major integral transmembrane protein constituents of tight junctions. Normal and neoplastic tissues can be characterized by unique qualitative and quantitative distribution of claudin subtypes, which may be related to clinicopathological features. Differential diagnosis and prognosis of nonmuscle invasive tumor entities of urinary bladder epithelium are often challenging. The aim was to investigate the expression profile of claudins in inverted urothelial papillomas (IUPs), urothelial papillomas (UPs), papillary urothelial neoplasms of low malignant potential (PUNLMPs), and intraepithelial (Ta), low-grade urothelial cell carcinomas (LG-UCCs) in order to reveal potential prognostic and differential diagnostic values of certain claudins. Claudin-1, -2, -4, and -7 protein expressions detected by immunohistochemistry and clinical data were analyzed in 15 IUPs, 20 UPs, 20 PUNLMPs, and 20 LG-UCCs. UPs, PUNLMPs, and LG-UCCs showed significantly decreased claudin-1 expression in comparison to IUPs. LG-UCCs expressing claudin-4 over the median were associated with significantly shorter recurrence-free survival. PUNLMPs expressing claudin-1 over the median revealed significantly longer recurrence-free survival. High claudin-1 protein expression might help to differentiate IUP from UPs, PUNLMPs, and LG-UCCs. High claudin-4 expression may determine an unfavorable clinical course of LG-UCCs, while high claudin-1 expression in PUNLMP was associated with markedly better clinical outcome. PMID:21832144

  20. Fire fighters, combustion products, and urothelial cancer.

    PubMed

    Golka, Klaus; Weistenhöfer, Wobbeke

    2008-01-01

    Urothelial cancer may be induced by different workplace chemicals, including carcinogenic aromatic amines, coke oven fumes, and cigarette smoking. The general impact of combustion products on urothelial cancer risk of exposed persons is still controversial. This raises the question whether fire fighters may have an increased risk for urothelial cancer. The present review compiles the literature on combustion products, possibly relevant for fire fighters, and the available studies on urinary bladder cancer risk in fire fighters. Chemical analyses of smoke from experimental fires as well as from fires in cities, wildlands, and industry do not indicate a generally elevated risk of bladder cancer in fire fighters. This is supported by studies on bladder cancer in fire fighters. Based on mortality studies, studies on exposures, and cancer incidence, we conclude that an elevated risk of urothelial cancer in fire fighters, in general, is not confirmed. Only in professional fire fighters more severely exposed for decades, having started their career some decades before, occupational exposure might be discussed as causative for urothelial cancer.

  1. Urothelial Bladder Cancer Urinary Biomarkers

    PubMed Central

    Noon, Aidan P

    2014-01-01

    Abstract Urothelial bladder cancer is the fourth most prevalent male malignancy in the United States and also one of the ten most lethal. Superficial or non-muscle-invasive bladder cancer has a high rate of recurrence and can progress to muscle invasive disease. Conventional surveillance requires regular cystoscopy and is used often with urinary cytology. Unfortunately, the cystoscopy procedure is invasive for patients and costly for health care providers. Urinary biomarkers have the potential to improve bladder cancer diagnosis, the efficiency and also the cost-effectiveness of follow up. It may also be possible for urinary biomarkers to help prognosticate particularly for patients with high-grade bladder cancer who may want enhanced assessment of their risk of disease progression. In this review the important historical urinary biomarkers and the newly emerging biomarkers are discussed. As will be presented, although many of the tests have good performance characteristics, unfortunately no single test can fulfill all the roles currently provided by cystoscopy and cytology. It is likely that in the future, urinary biomarker testing will be used selectively in a personalized manner to try and improve prognostication or reduce the necessity for invasive cystoscopy in patients understanding the limits of the test.

  2. Lipid peroxidation product acrolein as a predictive biomarker of prostate carcinoma relapse after radical surgery.

    PubMed

    Custovic, Zajim; Zarkovic, Kamelija; Cindric, Marina; Cipak, Ana; Jurkovic, Ilija; Sonicki, Zdenko; Uchida, Koji; Zarkovic, Neven

    2010-05-01

    Cancer recurrence after radical surgery might happen even in the case of patients with localized prostate carcinoma treated by radical prostatectomy. Therefore, identifying predictive markers of tumour recurrence is very important, so this study evaluated the presence of lipid peroxidation product acrolein in primary prostate carcinomas, assuming that acrolein could be involved in prostate carcinogenesis as was recently shown for colon cancer. Samples obtained by radical prostatectomy of 70 patients were analysed, out of which 27 patients suffered afterwards from tumour recurrence, while 43 patients were disease free. Immunohistochemistry using genuine monoclonal antibodies against acrolein-protein adducts revealed the association of acrolein with progression of carcinoma. The logistic regression combining clinical parameters together with the biochemical markers of disease and acrolein immunohistochemistry has shown that the relapse might be predicted with 90% accuracy if tumour-positive surgical margins, stage of disease and the intensity of acrolein presence in tumour stroma were taken together.

  3. Clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old.

    PubMed

    Compérat, Eva; Larré, Stéphane; Roupret, Morgan; Neuzillet, Yann; Pignot, Géraldine; Quintens, Hervé; Houéde, Nadine; Roy, Catherine; Durand, Xavier; Varinot, Justine; Vordos, Dimitri; Rouanne, Mathieu; Bakhri, Mohammed Adnan; Bertrand, Priscilla; Jeglinschi, Stephane Calin; Cussenot, Olivier; Soulié, Michel; Pfister, Christian

    2015-05-01

    Urothelial bladder cancer (UBC) is rare in young patients and as a result little information as to tumor type and clinical course are available. We present clinicopathological data of a large series of patients less than 40 years with bladder carcinoma. We included in this retrospective study covering the period from 1992 to 2013 patients less than 40 years with a first diagnosis of bladder cancer. Lesions were classified according to the WHO 2004 classification by uropathologists of ten centers. Stage, grade, multifocality, smoking habits, recurrence, and survival were studied. The cohort comprised of 152 patients, 113 males and 39 females with a mean age of 33.2 years. The large majority of the patients (142) was diagnosed with an urothelial carcinoma, the ten others with various histopathological diagnoses. In the age group less than 30 years old, 40.3 % of the cases concerned a papillary urothelial neoplasia of low malignant potential (PUNLMP). In the age group over 30 years, the proportion of PUNLMP decreased to 27.2 %. Only 5.6 % of the UBC was associated with carcinoma in situ. In 14.1 %, a high grade muscle invasive UC was found; 7.0 % had lymph node and 4.9 % distant metastasis at time of presentation. Four patients presented with a history of schistosomiasis; all had an infiltrating carcinoma. After initial resection, 36 patients relapsed, 17 % as PUNLMP, 53 % as pTa low grade, and 30 % as pTa-pT2 high grade UC. During follow-up, 6 % of the patients died. PUNLMP is the most frequent entity in this patient group. It is important that the PUNLMP entity is maintained in future classification systems.

  4. [Experience with combination chemotherapy consisting of methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) in advanced urothelial cancer].

    PubMed

    Nishio, Y; Shirahase, T; Shichiri, Y; Habuchi, T; Matsuda, T; Nishimura, K; Hida, S; Okada, Y; Yoshida, O

    1988-08-01

    The M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) regimen was used to treat 6 patients with metastatic transitional cell carcinoma of the urothelial tract. Three patients showed a partial response, all of them were made surgically disease free. Two of them are still alive 1 year and for 6 months after surgery with no evidence of disease and one other died of disease 11 months after surgery. The response in one case was no change and that in two others was a progressive disease. From our experience, we suggest that treatment with M-VAC is effective but that surgery after M-VAC appears essential for the successful management of the patients with metastatic transitional cell carcinoma of the urothelial tract.

  5. [Urinary tumor marker for urothelial cancer].

    PubMed

    Ohtani, M; Iwasaki, A; Shiraiwa, H

    2001-11-01

    The urinary tumor markers BTA, BFP and NMP22 used for urothelial cancer in Japan are reviewed briefly. We also evaluate and compare the sensitivity and specificity of BTA, BFP and NMP22 with urine cytology in detecting bladder cancer in 24 of our patients. The results showed that the sensitivity with urine cytology, BTA, BFP and NMP22 was 37, 54, 66 and 62% respectively. The specificity of BTA, BFP and NMP22 with urine cytology was 100, 65, 60 and 70% respectively. The sensitivity with BTA, BFP and NMP22 for urothelial cancer was higher than that with urine cytology. However, all except for urine cytology showed high false positive rates (83-90%) for urinary tract infection. These markers may thus complement urine cytology, which has a low sensitivity for urothelial cancer. Quite possibly they could act as low-cost and useful tumor markers, which could in turn reduce the number of invasive cystoscopic examinations. However, considering their high false positive rates for benign disease such as urinary tract infection, we must acknowledge that an ideal urothelial tumor marker, which is simple, non-invasive, inexpensive and accurate with high sensitivity and specificity has yet to be developed.

  6. A new cluster-based oversampling method for improving survival prediction of hepatocellular carcinoma patients.

    PubMed

    Santos, Miriam Seoane; Abreu, Pedro Henriques; García-Laencina, Pedro J; Simão, Adélia; Carvalho, Armando

    2015-12-01

    Liver cancer is the sixth most frequently diagnosed cancer and, particularly, Hepatocellular Carcinoma (HCC) represents more than 90% of primary liver cancers. Clinicians assess each patient's treatment on the basis of evidence-based medicine, which may not always apply to a specific patient, given the biological variability among individuals. Over the years, and for the particular case of Hepatocellular Carcinoma, some research studies have been developing strategies for assisting clinicians in decision making, using computational methods (e.g. machine learning techniques) to extract knowledge from the clinical data. However, these studies have some limitations that have not yet been addressed: some do not focus entirely on Hepatocellular Carcinoma patients, others have strict application boundaries, and none considers the heterogeneity between patients nor the presence of missing data, a common drawback in healthcare contexts. In this work, a real complex Hepatocellular Carcinoma database composed of heterogeneous clinical features is studied. We propose a new cluster-based oversampling approach robust to small and imbalanced datasets, which accounts for the heterogeneity of patients with Hepatocellular Carcinoma. The preprocessing procedures of this work are based on data imputation considering appropriate distance metrics for both heterogeneous and missing data (HEOM) and clustering studies to assess the underlying patient groups in the studied dataset (K-means). The final approach is applied in order to diminish the impact of underlying patient profiles with reduced sizes on survival prediction. It is based on K-means clustering and the SMOTE algorithm to build a representative dataset and use it as training example for different machine learning procedures (logistic regression and neural networks). The results are evaluated in terms of survival prediction and compared across baseline approaches that do not consider clustering and/or oversampling using the

  7. Glutamine synthetase predicts adjuvant TACE response in hepatocellular carcinoma

    PubMed Central

    Zhang, Bo; Liu, Kai; Zhang, Jian; Dong, Liwei; Jin, Zhichao; Zhang, Xinji; Xue, Feng; He, Jia

    2015-01-01

    Background: Adjuvant transcatheter arterial chemoembolization (TACE) is associated with better outcome and reduced tumor recurrence in hepatocellular carcinoma (HCC) patients. This study aimed to investigate the relationship between glutamine synthetase (GS) expression and survival of HCC patients after postoperative adjuvant TACE. Methods: We retrospectively analyzed 554 HCC patients in two independent cohorts who underwent curative resection. Immunohistochemistry assay was used to investigate the expression of GS protein and evaluate the association with survival and the response to adjuvant TACE. Results: In training cohort, patients with low GS expression who received postoperative adjuvant TACE showed a better overall survival (OS) (P<0.001) and less early phase recurrence (P=0.016). Adjuvant TACE was an independent prognostic factor for 5-year OS (HR=0.408, 95% CI 0.261-0.639, P<0.001) and early phase recurrence (HR=0.592, 95% CI 0.376-0.931, P=0.023). The same result was confirmed in validation cohort. Patients with high GS expression in both cohorts did not have a significant response to adjuvant TACE in OS and early phase recurrence. Conclusions: GS status in tumor might be a useful tool in the selection of HCC patients who would be likely to benefit from postoperative adjuvant TACE. PMID:26884995

  8. Trivalent arsenicals induce lipid peroxidation, protein carbonylation, and oxidative DNA damage in human urothelial cells.

    PubMed

    Wang, Tsing-Cheng; Jan, Kun-Yan; Wang, Alexander S S; Gurr, Jia-Ran

    2007-02-01

    Drinking arsenic-contaminated water is associated with an increased risk of bladder cancer. Arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonous acid (MMA(III)), monomethylarsonic acid (MMA(V)), dimethylarsinous acid (DMA(III)), and dimethylarsinic acid (DMA(V)) have all been detected in the urine of people who drink arsenic-contaminated water. The aim of this research was to investigate which of these arsenicals are more hazardous to human urothelial cells. The results indicate that iAs(III), MMA(III), and DMA(III) were more potent in inducing cytotoxicity, lipid peroxidation, protein carbonylation, oxidative DNA damage, nitric oxide, superoxide, hydrogen peroxide, and cellular free iron than MMA(V), DMA(V), and iAs(V) in human urothelial carcinoma and transformed cells. However, the results did not show convincingly that the trivalent arsenicals were more potent than pentavalent arsenicals in decreasing the intracellular contents of total thiol, protein thiol, and reduced glutathione. Induction of oxidative DNA damage was observed with 0.2 microM of iAs(III), MMA(III), or DMA(III) as early as 1h. Because of its high oxidative damage, higher proportion in urine, and lower cytotoxicity, DMA(III) may be the most hazardous arsenical to human urothelial cells.

  9. Minichromosome maintenance complex component 7 has an important role in the invasion of papillary urothelial neoplasia

    PubMed Central

    GUAN, BINGXIN; WANG, XIAOYING; YANG, JINGYAN; ZHOU, CHENGJUN; MENG, YAN

    2015-01-01

    The aims of the present study were to investigate the expression of minichromosome maintenance complex component 7 (MCM7) and determine its association with tumor proliferation and invasion in pathological tumor (pT)a and pT1 papillary urothelial neoplasia. The MCM7, MCM3 and Ki67 proteins were detected in 154 cases of urothelial neoplasia using immunohistochemical analysis. The expression of MCM7 significantly increased (P<0.001) as the pathological stage and grade progressed between inverted papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), pTa tumor and pT1 tumor. However, no statistically significant difference in MCM7 staining was observed between low-grade pTa tumors and PUNLMP (P=0.2294). In contrast to MCM7, MCM3 was highly expressed in all stages of urothelial neoplasia, with no statistically significant differences observed between the tumor types (P=0.2993, 0.3885 and 0.8489 for pTa tumors, PUNLMP and inverted papiloma, respectively). Furthermore, MCM7 expression was elevated with increased tumor grade and was positively correlated with Ki67 expression (rs=0.9106, P<0.001). However, MCM3 expression was not correlated with MCM7 or Ki67 expression (rs=0.0734, P=0.3657 and rs=0.0638, P=0.4318, respectively). In conclusion, MCM7 overexpression may simultaneously promote tumor proliferation and invasion. Furthermore, it may be a reliable marker for the pathological differential diagnosis of pTa and pT1 papillary urothelial neoplasms; therefore, MCM7 expression may be used to predict tumor prognosis and behavior. PMID:26622601

  10. Compensatory Paracrine Mechanisms That Define The Urothelial Response to Injury in Partial Bladder Outlet Obstruction

    SciTech Connect

    Bassuk, James; Lendvay, Thomas S.; Sweet, Robert; Han, Chang-Hee; Soygur, Tarkan; Cheng, Jan-Fang; Plaire, J. Chadwick; Charleston, Jay S.; Charleston, Lynne B.; Bagai, Shelly; Cochrane, Kimberly; Rubio, Eric; Bassuk, James A.; Fuchs, Elaine

    2007-06-21

    Diseases and conditions affecting the lower urinary tract are a leading cause of dysfunctional sexual health, incontinence, infection, and kidney failure. The growth, differentiation, and repair of the bladder's epithelial lining are regulated, in part, by fibroblast growth factor (FGF)-7 and -10 via a paracrine cascade originating in the mesenchyme (lamina propria) and targeting the receptor for FGF-7 and -10 within the transitional epithelium (urothelium). The FGF-7 gene is located at the 15q15-q21.1 locus on chromosome 15 and four exons generate a 3.852-kb mRNA. Five duplicated FGF-7 gene sequences that localized to chromosome 9 were predicted not to generate functional protein products, thus validating the use of FGF-7-null mice as an experimental model. Recombinant FGF-7 and -10 induced proliferation of human urothelial cells in vitro and transitional epithelium of wild-type and FGF-7-null mice in vivo.To determine the extent that induction of urothelial cell proliferation during the bladder response to injury is dependent on FGF-7, an animal model of partial bladder outlet obstruction was developed. Unbiased stereology was used to measure the percentage of proliferating urothelial cells between obstructed groups of wild-type and FGF-7-null mice. The stereological analysis indicated that a statistical significant difference did not exist between the two groups, suggesting that FGF-7 is not essential for urothelial cell proliferation in response to partial outlet obstruction. In contrast, a significant increase in FGF-10 expression was observed in the obstructed FGF-7-null group, indicating that the compensatory pathway that functions in this model results in urothelial repair.

  11. Urothelial neoplasm of the bladder in childhood and adolescence: a rare disease

    PubMed Central

    Polat, Haci; Utangac, Mehmet M.; Gulpinar, Murat T.; Cift, Ali; Erdogdu, Ibrahim Halil; Turkcu, Gul

    2016-01-01

    ABSTRACT Purpose: Bladder tumors are rare in children and adolescents. For this reason, the diagnosis is sometimes delayed in pediatric patients. We aimed to describe the diagnosis, treatment, and follow-up methods of bladder urothelial neoplasms in children and adolescents. Materials and Methods: We carried out a retrospective multicenter study involving patients who were treated between 2008 and 2014. Eleven patients aged younger than 18 years were enrolled in the study. In all the patients, a bladder tumor was diagnosed using ultrasonography and was treated through transurethral resection of the bladder (TURBT). Results: Nine of the 11 patients (82%) were admitted with gross hematuria. The average delay in diagnosis was 3 months (range, 0–16 months) until the ultrasonographic diagnosis was performed from the first episodes of macroscopic hematuria. A single exophytic tumor (1–4cm) was present in each patient. The pathology of all patients was reported as superficial urothelial neoplasm: two with papilloma, one with papillary urothelial neoplasm of low malignant potential (PUNLMP), four with low grade pTa, and four with low grade pT1. No recurrence was observed during regular cystoscopic and ultrasonographic follow-up. Conclusions: Regardless of the presence of hematuria, bladder tumors in children are usually not considered because urothelial carcinoma in this population is extremely rare, which causes a delay in diagnosis. Fortunately, the disease has a good prognosis and recurrences are infrequent. Cystoscopy may be unnecessary in the follow-up of children with bladder tumors. We believe that ultrasonography is sufficient in follow-up. PMID:27256177

  12. Diagnosis and treatment in primary bladder small cell carcinoma: Literature review.

    PubMed

    Celik, Orcun; Ekin, Gokhan; Ipekci, Tumay; Budak, Salih; Ilbey, Yusuf Ozlem

    2016-03-01

    Small cell bladder carcinoma is a rare and frequently fatal disease. It can be distinguished from classical urothelial carcinoma microscopically and immunohistochemically. Small cell bladder carcinoma has histologically similar properties with other small cell carcinomas in other organs. It has a worse prognosis when compared to urothelial bladder cancer. Multimodal treatments are recommended although there is no widely accepted consensus regarding to the treatment algorithm because of its rarity. In this review, clinical properties and diagnosis of small cell bladder carcinoma, its histopathological and immunohistochemical properties and treatment modalities are examined. PMID:27072176

  13. [Systemic chemotherapy for transitional cell carcinoma of the urothelium].

    PubMed

    Lehmann, J; Retz, M; Hack, M; Siemer, S; Stöckle, M

    2003-10-01

    Moderate activity of systemic chemotherapy for advanced urothelial cancer has been reported for more than 30 years. Only with the advent of potent combination therapy in the mid eighties of the past century clinically significant response rates as well as prolonged survival has been documented. This review summarizes seven Phase-III trials of systemic chemotherapy for advanced urothelial carcinoma as well as results from adjuvant and neoadjuvant Phase-III trials for muscle-invasive bladder cancer including the most recent reports.

  14. Differential microRNA expression in aristolochic acid-induced upper urothelial tract cancers ex vivo

    PubMed Central

    TAO, LE; ZENG, YIGANG; WANG, JUN; LIU, ZHIHONG; SHEN, BING; GE, JIFU; LIU, YONG; GUO, YIFENG; QIU, JIANXIN

    2015-01-01

    Aristolochic acid (AA) is a carcinogenic, mutagenic and nephrotoxic compound commonly isolated from members of the plant family of Aristolochiaceae (such as Aristolochia and Asarum) and used in Chinese herbal medicine. Use of AA and AA-containing plants causes chronic kidney disease (CKD) and upper urinary tract carcinoma (UUC); however, the underlying mechanism remains to be defined. miRNAs regulate a number of biological processes, including cell proliferation, differentiation and metabolism. This study explored differentially expressed miRNAs between AA-induced upper urothelial tract cancer (AAN-UUC) and non-AAN-UUC tissues. Patients with AAN-UUC and non-AAN-UUC (n=20/group) were recruited in the present study. Five tissue samples from each group were used for miRNA microarray profiling and the rest of the tissue samples were subjected to reverse transcription-quantitative polymerase chain reaction analysis including seven selected miRNAs for confirmation. A total of 29 miRNAs were differentially expressed between AAN-UUC and non-AAN-UUC tissues (P<0.05). TargenScan and Gene ontology analyses predicted the functions and targeted genes of these differentially expressed miRNAs, i.e. Akt3, FGFR3, PSEN1, VEGFa and AR. Subsequently, expression of the selected differentially expressed miRNAs (Hsa-miR-4795-5p, Hsa-miR-488, Hsa-miR-4784, Hsa-miR-330, Hsa-miR-3916, Hsa-miR-4274 and Hsa-miR-181c) was validated in another set of tissue samples. A total of 29 miRNAs were identified to be differentially expressed between AAN-UUC and non-AAN-UUC tissues and these miRNA target genes in FGFR3 and Akt pathways, which regulate cell growth and tumor progression, respectively. PMID:26397152

  15. GATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas.

    PubMed

    Davis, Drew G; Siddiqui, Momin T; Oprea-Ilies, Gabriela; Stevens, Keith; Osunkoya, Adeboye O; Cohen, Cynthia; Li, Xiaoxian Bill

    2016-01-01

    GATA-3, a member of the GATA family of zinc-finger DNA binding proteins, and FOXA1, a member of the forkhead transcription factor family, are both associated with estrogen receptor expression. Both GATA-3 and FOXA1 are useful markers for breast carcinoma, but their expression in the different breast cancer subtypes and other neoplasms has not been thoroughly evaluated. We examined the expression of GATA-3 and FOXA1 in estrogen receptor-positive, Her2/neu-positive, and triple-negative breast carcinomas as well as in 10 other common carcinomas, including hepatocellular, colonic, pancreatic, gastric, endometrial (endometrioid), lung, prostatic, renal cell, urothelial, and ovarian serous carcinomas. Primary and metastatic melanomas and mesotheliomas were also evaluated. GATA-3 and FOXA1 staining of estrogen receptor-positive breast carcinomas was seen in 96.6% and 96.2%, respectively. In triple-negative breast carcinomas, GATA-3 and FOXA1 staining was seen in 21.6% and 15.9%, respectively. Among the other tumors, GATA-3 staining was only seen in urothelial carcinoma (70.9%) and FOXA1 staining was only seen in prostatic (87.5%), urothelial (5.1%) carcinomas, and mesotheliomas (40.0%). In conclusion, GATA-3 and FOXA1 are excellent breast carcinoma markers; however, their utility is limited in the triple-negative subtype. The utility of FOXA1 in diagnosing prostatic carcinoma and mesothelioma warrants further investigation.

  16. Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma

    PubMed Central

    Van Hees, Stijn; Michielsen, Peter; Vanwolleghem, Thomas

    2016-01-01

    Chronic hepatitis B virus (HBV) infected patients have an almost 100-fold increased risk to develop hepatocellular carcinoma (HCC). HCC is the fifth most common and third most deadly cancer worldwide. Up to 50% of newly diagnosed HCC cases are attributed to HBV infection. Early detection improves survival and can be achieved through regular screening. Six-monthly abdominal ultrasound, either alone or in combination with alpha-fetoprotein serum levels, has been widely endorsed for this purpose. Both techniques however yield limited diagnostic accuracy, which is not improved when they are combined. Alternative circulating or histological markers to predict or diagnose HCC are therefore urgently needed. Recent advances in systems biology technologies have enabled the identification of several new putative circulating biomarkers. Although results from studies assessing combinations of these biomarkers are promising, evidence for their clinical utility remains low. In addition, most of the studies conducted so far show limitations in design. Attention must be paid for instance to different ethnicities and different etiologies when studying biomarkers for hepatocellular carcinoma. This review provides an overview on the current understandings and recent progress in the field of diagnostic and predictive circulating biomarkers for hepatocellular carcinoma in chronically infected HBV patients and discusses the future prospects. PMID:27729734

  17. Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

    PubMed Central

    Karni-Schmidt, Orit; Castillo-Martin, Mireia; HuaiShen, Tian; Gladoun, Nataliya; Domingo-Domenech, Josep; Sanchez-Carbayo, Marta; Li, Yingchun; Lowe, Scott; Prives, Carol; Cordon-Cardo, Carlos

    2011-01-01

    The TP63 gene, a member of the TP53 tumor suppressor gene family, can be expressed as at least six isoforms due to alternative promoter use and alternative splicing. The lack of p63 isoform–specific antibodies has limited the analysis of the biological significance of p63. We report a novel set of well-defined antibodies to examine p63 isoforms in mouse and human urothelium during embryogenesis and tumor progression, respectively. We provide evidence that basal and intermediate urothelial cells express p63 isoforms, with the TAp63 variant the first to be detected during development, whereas umbrella cells are characterized by a p63-negative phenotype. Notably, we report that p63-null mice develop a bladder with an abnormal urothelium, constituted by a single layer of cells that express uroplakin II and low molecular weight cytokeratins, consistent with an umbrella cell phenotype. Finally, analysis of 202 human bladder carcinomas revealed a new categorization of invasive tumors into basal-like (positive for ΔNp63 and high molecular weight cytokeratins and negative for low molecular weight cytokeratins) versus luminal-like (negative for ΔNp63 and high molecular weight cytokeratins and positive for low molecular weight cytokeratins) phenotypes, with ΔNp63 expression associated with an aggressive clinical course and poor prognosis. This study highlights the relevance of p63 isoforms in both urothelial development and bladder carcinoma progression, with ΔNp63 acting as an oncogene in certain invasive bladder tumors. PMID:21356385

  18. Prognostic significance of mucin expression in urothelial bladder cancer

    PubMed Central

    Stojnev, Slavica; Ristic-Petrovic, Ana; Velickovic, Ljubinka Jankovic; Krstic, Miljan; Bogdanovic, Dragan; Khanh, Do Throng; Ristic, Ana; Conic, Irena; Stefanovic, Vladisav

    2014-01-01

    Urothelial bladder cancer (UBC) is a common genitourinary malignancy, accounting for more than 160.000 deaths per year worldwide. Overexpression and aberrant glycosylation of mucins are frequent traits of many human cancers derived from epithelial cells, and are found to have prognostic significance in various carcinomas. The aim of this study was to further elucidate the features and significance of mucin expression in UBC. We investigated the relationship between mucin expression and clinicopathological characteristics in 539 cases of UBC by immunohistochemical analysis of MUC1, MUC2, MUC4, MUC5AC and MUC6 expression profiles. MUC1 stained 61.8% of the tumors and correlated with high tumor grade (P = 0.013). The expression of MUC2 and MUC6 was associated with low tumor grade (P < 0.000 and P < 0.022, respectively), and low pathologic stage (P < 0.001 and P = 0.001, respectively). MUC2 negative tumors were more frequently associated with the finding of carcinoma in situ in tumor surroundings (P = 0.019). UBC with divergent differentiation correlated with MUC1, MUC4 and MUC5AC staining. MUC4 expression was directly linked to cancer specific death (P = 0.027), while MUC2 and MUC6 showed inverse correlation to cancer-specific death (P < 0.001 and P = 0.005, respectively). Kaplan-Meier analyses showed that expression of MUC2 and MUC6 in UBC was significantly associated with better overall survival of the patients (P < 0.001, respectively). In Cox regression model, the absence of MUC6 expression emerged as independent predictor of death outcome. In conclusion, this study identifies MUC2 and MUC6 expression as markers of UBC with less aggressive behavior and useful predictors of better survival. PMID:25197366

  19. Analysis of the Distribution and Temporal Trends of Grade and Stage in Urothelial Bladder Cancer in Northern New England from 1994 to 2004

    PubMed Central

    Schned, Alan R.; Lenz, Petra; Moore, Lee E.; Johnson, Alison; Jones, Michael; Kida, Masatoshi; Silverman, Debra T.; Schwenn, Molly; Kelsey, Karl T.; Andrew, Angeline S.; Baris, Dalsu; Karagas, Margaret R.

    2012-01-01

    We investigate the distribution of bladder tumor category and stage in Northern New England by geographic region, smoking status and over time. 1091 incident bladder cancer cases from the New England Bladder Cancer Study (NEBCS), a large population-based case-control study carried out in Maine, New Hampshire and Vermont (2001–2004), and 680 bladder cancer cases from previous case-control studies in New Hampshire (1994–2000) were used in the analysis. Of 1091 incident bladder cancer cases from the NEBCS, 26.7% of tumors were papillary urothelial neoplasms of low malignant potential (PUNLMP), 26.8% low-grade papillary urothelial carcinomas (PUC-LG), 31.3% high-grade papillary urothelial carcinomas (PUC-HG), 9.1% non-papillary urothelial carcinomas (non-PUC), and 4.3% carcinoma in situ (CIS). Approximately 70% of cases were non-invasive (Tis/Ta), and all PUNLMP cases were of the Ta category. By contrast, half of all PUC-HG carcinomas were invasive. Short-term time trend analysis within the NEBCS (2001–2004) indicated an increase in the percentage of PUNLMP (p-trend<0.0001) paralleled by a decrease in PUC-LG (p-trend=0.02), and for PUC-LG an increase in the percentage of non-invasive tumors (p-trend 0.04). Our findings suggest possible short-term trends with an increase in the percentage of PUNLMP and a change in the percentage of PUC-LG towards non-invasive disease. PMID:24683496

  20. Analysis of the Distribution and Temporal Trends of Grade and Stage in Urothelial Bladder Cancer in Northern New England from 1994 to 2004.

    PubMed

    Schned, Alan R; Lenz, Petra; Moore, Lee E; Johnson, Alison; Jones, Michael; Kida, Masatoshi; Silverman, Debra T; Schwenn, Molly; Kelsey, Karl T; Andrew, Angeline S; Baris, Dalsu; Karagas, Margaret R

    2012-01-01

    We investigate the distribution of bladder tumor category and stage in Northern New England by geographic region, smoking status and over time. 1091 incident bladder cancer cases from the New England Bladder Cancer Study (NEBCS), a large population-based case-control study carried out in Maine, New Hampshire and Vermont (2001-2004), and 680 bladder cancer cases from previous case-control studies in New Hampshire (1994-2000) were used in the analysis. Of 1091 incident bladder cancer cases from the NEBCS, 26.7% of tumors were papillary urothelial neoplasms of low malignant potential (PUNLMP), 26.8% low-grade papillary urothelial carcinomas (PUC-LG), 31.3% high-grade papillary urothelial carcinomas (PUC-HG), 9.1% non-papillary urothelial carcinomas (non-PUC), and 4.3% carcinoma in situ (CIS). Approximately 70% of cases were non-invasive (Tis/Ta), and all PUNLMP cases were of the Ta category. By contrast, half of all PUC-HG carcinomas were invasive. Short-term time trend analysis within the NEBCS (2001-2004) indicated an increase in the percentage of PUNLMP (p-trend<0.0001) paralleled by a decrease in PUC-LG (p-trend=0.02), and for PUC-LG an increase in the percentage of non-invasive tumors (p-trend 0.04). Our findings suggest possible short-term trends with an increase in the percentage of PUNLMP and a change in the percentage of PUC-LG towards non-invasive disease.

  1. Urothelial cells in smears from cervix uteri

    PubMed Central

    Palaoro, Luis Alberto; Guerra, Fernando; Angeleri, Anabela; Palamas, Marta; Melba, Sardi-Segovia; Rocher, Adriana Esther

    2012-01-01

    Objectives: To establish the cytological criteria to identify the urothelial cells in cervical smears in order to avoid mistakes in the cytological diagnosis. Materials and Methods: Cervical smears from 34 post menopausal women with vesicovaginal fistulas, advanced bladder prolapse and genital erosive lichen planes (vulvar kraurosis) (Group 1) and transitional cell metaplasia of the cervix (TCM, Group 2) were stained with Papanicolaou technique. The cervical samples were taken during the routine annual examination for prevention of the uterine cancer. Results: The smears of cervix from Group 1 showed urothelial cells from the three layers of the transitional epithelium. The umbrella cells are the bigger ones with relatively large nuclei. Frequently, they are multinucleated with single or multiple nucleoli and a typical “frothy” cytoplasm (cytoplasmic vacuoles). The cells of the Group 2 showed nuclei with oval to spindled shapes, some tapered ends, less cytoplasm than squamous metaplastic cells, powdery chromatin, small nucleoli and nuclear grooves. Conclusions: The umbrella cells may be mistaken for dysplastic cells originating in low grade squamous intraepithelial lesions lesions (LSILs) due to their nuclear and cytoplasm sizes. Therefore, it is important to know the possibility of their appearance in the cervical smears, especially in post menopausal patients in order to avoid a false diagnosis of an intraepithelial lesion. It is unlikely that deeper cells of urothelium would be confused with high grade squamous intraepithelial lesion (HSIL) cells. However, their presence might be a reason of mistake in the diagnosis. TCM is an under-recognized metaplastic phenomenon of the cervix and vagina, which is a mimicker of high-grade squamous intraepithelial lesion. The differential characteristic between umbrella cells, cells from TCM and the deeper urothelial cells, and LSIL and HSIL are detailed in the present paper. PMID:22438615

  2. Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients

    PubMed Central

    Lee, Hye Won; Ahn, Sang Hoon

    2016-01-01

    Chronic hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Applying the same strategies for antiviral therapy and HCC surveillance to all chronic hepatitis B (CHB) patients would be a burden worldwide. To properly manage CHB patients, it is necessary to identify and classify the risk for HCC development in such patients. Several HCC risk scores based on risk factors such as cirrhosis, age, male gender, and high viral load have been used, and have negative predictive values of ≥ 95%. Most of these have been derived from, and internally validated in, treatment-naïve Asian CHB patients. Herein, we summarized various HCC prediction models, including IPM (Individual Prediction Model), CU-HCC (Chinese University-HCC), GAG-HCC (Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-HCC), NGM-HCC (Nomogram-HCC), REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B), and Page-B score. To develop a noninvasive test of liver fibrosis, we also introduced a new scoring system that uses liver stiffness values from transient elastography, including an LSM (Liver Stiffness Measurement)-based model, LSM-HCC, and mREACH-B (modified REACH-B). PMID:27729738

  3. Precise Classification of Cervical Carcinomas Combined with Somatic Mutation Profiling Contributes to Predicting Disease Outcome

    PubMed Central

    Spaans, Vivian M.; Trietsch, Marjolijn D.; Peters, Alexander A. W.; Osse, Michelle; ter Haar, Natalja; Fleuren, Gert J.; Jordanova, Ekaterina S.

    2015-01-01

    Introduction Squamous cell carcinoma (SCC), adenocarcinoma (AC), and adenosquamous carcinoma (ASC) are the most common histological subtypes of cervical cancer. Differences in the somatic mutation profiles of these subtypes have been suggested. We investigated the prevalence of somatic hot-spot mutations in three well-defined cohorts of SCC, AC, and ASC and determined the additional value of mutation profiling in predicting disease outcome relative to well-established prognostic parameters. Materials and Methods Clinicopathological data were collected for 301 cervical tumors classified as SCC (n=166), AC (n=55), or ASC (n=80). Mass spectrometry was used to analyze 171 somatic hot-spot mutations in 13 relevant genes. Results In 103 (34%) tumors, 123 mutations were detected (36% in SCC, 38% in AC, and 28% in ASC), mostly in PIK3CA (20%) and KRAS (7%). PIK3CA mutations occurred more frequently in SCC than AC (25% vs. 11%, P=0.025), whereas KRAS mutations occurred more frequently in AC than SCC (24% vs. 3%, P<0.001) and ASC (24% vs. 3%, P<0.001). A positive mutation status correlated with worse disease-free survival (HR 1.57, P=0.043). In multivariate analysis, tumor diameter, parametrial infiltration, and lymph node metastasis, but not the presence of a somatic mutation, were independent predictors of survival. Conclusion Potentially targetable somatic mutations occurred in 34% of cervical tumors with different distributions among histological subtypes. Precise classification of cervical carcinomas in combination with mutation profiling is valuable for predicting disease outcome and may guide the development and selection of tumor-specific treatment approaches. PMID:26197069

  4. Prediction of clinical phenotypes in invasive breast carcinomas from the integration of radiomics and genomics data

    PubMed Central

    Guo, Wentian; Li, Hui; Zhu, Yitan; Lan, Li; Yang, Shengjie; Drukker, Karen; Morris, Elizabeth; Burnside, Elizabeth; Whitman, Gary; Giger, Maryellen L.; Ji, Yuan; TCGA Breast Phenotype Research Group

    2015-01-01

    Abstract. Genomic and radiomic imaging profiles of invasive breast carcinomas from The Cancer Genome Atlas and The Cancer Imaging Archive were integrated and a comprehensive analysis was conducted to predict clinical outcomes using the radiogenomic features. Variable selection via LASSO and logistic regression were used to select the most-predictive radiogenomic features for the clinical phenotypes, including pathological stage, lymph node metastasis, and status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Cross-validation with receiver operating characteristic (ROC) analysis was performed and the area under the ROC curve (AUC) was employed as the prediction metric. Higher AUCs were obtained in the prediction of pathological stage, ER, and PR status than for lymph node metastasis and HER2 status. Overall, the prediction performances by genomics alone, radiomics alone, and combined radiogenomics features showed statistically significant correlations with clinical outcomes; however, improvement on the prediction performance by combining genomics and radiomics data was not found to be statistically significant, most likely due to the small sample size of 91 cancer cases with 38 radiomic features and 144 genomic features. PMID:26835491

  5. Mincle, an Innate Immune Receptor, Is Expressed in Urothelial Cancer Cells of Papillomavirus-Associated Urothelial Tumors of Cattle

    PubMed Central

    Roperto, Sante; Russo, Valeria; Esposito, Iolanda; Ceccarelli, Dora Maria; Paciello, Orlando; Avallone, Luigi; Capparelli, Rosanna; Roperto, Franco

    2015-01-01

    Background Mincle, macrophage-inducible C-type lectin, is a member of C-type lectin receptors. It plays an important role in anti-mycobacterial and anti-fungal immunity. Furthermore it senses dead cells through its primary ligand SAP130. Materials and Findings We examined ten urothelial tumors of the urinary bladder of cattle. Eight of them expressed E5 cDNA of bovine papillomaviruses type 2 (BPV-2) and type 13 (BPV-13) that belong to Deltapapillomavirus genus. Two of them were not examined for detection of E5 cDNA. Mincle expression appeared to occur in urothelial neoplastic cells only. No mincle expression was detected in urothelial cells from healthy cattle. Mincle expression was characterized by a membranous pattern in papillary urothelial cancers; isolated and/or clustered urothelial cells showing a strong cytoplasmic immunoreactivity were primarily seen in invasive urothelial cancers. Conclusion This is the first study about the expression of mincle in veterinary oncology and the first report which describes the expression of functional mincle receptor in neoplastic cells in medical literature. As it has been shown that urothelial cancer cells have the ability to function as antigen-presenting cells (APCs), it is conceivable that mincle expression is involved in the presentation of cancer cell antigens to cells of the immune system. Furthermore, since expression of mincle contributes to the control of Mycobacterium bovis BCG infection, this study has exciting clinical implications in comparative medicine keeping in mind that Bacillus Calmette-Guérin (BCG) immunotherapy is currently the most effective treatment of non-muscle invasive bladder cancer in man. Mincle expression in urothelial tumor cells warrants further study to better understand the role, if any, of this receptor in bladder cancer. Future studies will provide insights in the role of mincle receptor of urothelial cancer cells in antitumor immunotherapy. PMID:26513724

  6. Abnormal DNA content predicts the occurrence of carcinomas in non-dysplastic oral white patches.

    PubMed

    Sudbø, J; Ried, T; Bryne, M; Kildal, W; Danielsen, H; Reith, A

    2001-10-01

    The majority of oral squamous cell carcinomas (OSCCs) are preceded by visible changes in the oral mucosa, most often white patches. Although the histological finding of dysplasia in oral white patches signals increased risk of developing OSCC, this may also occur in non-dysplastic lesions. However, no reliable markers exist to predict the occurrence of OSCC in these patients. From a total of 263 patients diagnosed with oral white patches, biopsies from 45 patients were selected on the criteria that the patients had lesions histologically proven to be non-dysplastic. The lesions were analyzed with respect to their DNA content. The clinical outcome of the patients was known from the Cancer Registry of Norway, and these data were compared to the DNA content of their lesions. Among the 45 patients, five cases (11%) later developed an OSCC. Four of the cases that subsequently developed an OSCC were among the five aneuploid (abnormal) cases (P=0.001). One aneuploid lesion did not develop a carcinoma during a follow-up time of 120 months. The fifth case that subsequently developed an OSCC was diploid (normal), and developed into an OSCC after an observation time of 73 months (P=0.001). In conclusion, aberrant DNA content reliably predicts the occurrence of OSCC in patients that otherwise would be regarded as at very low risk. Normal DNA content indicates low risk. PMID:11564576

  7. Urothelial bladder cancer in young adults: Diagnosis, treatment and clinical behaviour

    PubMed Central

    Gunlusoy, Bülent; Ceylan, Yasin; Degirmenci, Tansu; Kozacioglu, Zafer; Yonguc, Tarık; Bozkurt, Halil; Aydogdu, Ozgü; Sen, Volkan

    2015-01-01

    Introduction: The aim of the study is to reveal pathologic characteristics and clinical behaviour of patients 40 years old or younger diagnosed with and treated for urothelial bladder carcinoma. Methods: We retrospectively analyzed the clinical and pathologic data of 91 patients, initially diagnosed and treated at our institution from May 1996 to December 2014. Cancer recurrence was defined as new occurrence of bladder cancer at the same or different sites of the bladder. Cancer progression was defined as an increase in stage or grade in any of the recurrences. Results: The mean age was 33.8 (range: 17–40) years. The pathological examination after transurethral resection revealed 83 (91.2%) patients with non-muscle invasive urothelial bladder cancer, and 8 (8.8%) patients with muscle invasive urothelial bladder cancer. According to the distribution of grade, there were 75, 4 and 12 patients with grade 1, grade 2 and grade 3 diseases, respectively. Initial cancer staging was: pTa with 40 patients (43.9%), pT1 with 43 patients (47.2%), pT2 with 7 patients (7.6%), and pT3 with 1 patient (1.2%). While 17 (18.6%) patients recurred in the follow-up, 10 (10.9%) patients had progression. There were no differences in recurrence and progression rates in the Ta and T1 stages between groups (p = 0.233, p = 0.511, respectively). Conclusion: The risk of progression increased as the number of relapses increased. The clinical behaviour of high-stage and high-grade disease in younger patients is similar to the older group. PMID:26664508

  8. Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy

    PubMed Central

    Song, Il Han; Kim, So Mi; Choo, Young Kwang

    2013-01-01

    Hepatocellular carcinoma (HCC) is a grave primary liver cancer that has a limited therapeutic option because it is generally diagnosed later in an advanced stage due to its aggressive biologic behavior. The early detection of HCC has a great impact on the treatment efficacy and survival of patients at high risk for cancer. Potential host, environmental, and virus-related risk factors have been introduced. Hepatitis B virus (HBV) is a major cause of end-stage liver diseases such as liver cirrhosis or HCC in endemic areas, and its serologic or virologic status is considered an important risk factor. HCC risk prediction derived from the identification of major risk factors is necessary for providing adequate screening/surveillance strategies to high-risk individuals. Several risk prediction models for HBV-related HCC have been presented recently with simple, efficient, and readily available to use parameters applicable to average- or unknown-risk populations as well as high-risk individuals. Predictive scoring systems of risk estimation to assess HCC development can provide the way to an evidence-based clinical approach for cost- and effort-effective outcomes, capable of inducing a personalized surveillance program according to risk stratification. In this review, the concepts and perspectives of the risk prediction of HCC are discussed through the analysis of several risk prediction models of HBV-related HCC. PMID:24379609

  9. Histologic grading of urothelial papillary neoplasms: impact of combined grading (two-numbered grading system) on reproducibility.

    PubMed

    Tuna, Burçin; Yörükoglu, Kutsal; Düzcan, Ender; Sen, Sait; Nese, Nalan; Sarsık, Banu; Akder, Aysegul; Sayhan, Sehnaz; Mungan, Uğur; Kirkali, Ziya

    2011-06-01

    The clinical management of tumor patients is often strongly influenced by the tumor grade. The presence of heterogeneity is well recognized in a variety of tumors. Overall grade is based on highest grade area identified within a tumor. Urothelial carcinoma often contains different histological grades within the same tumor. This study investigates the impact of a combined grading system on the reproducibility of papillary urothelial neoplasms. A set prepared for an earlier study consisting of ten cases of each category (papillary urothelial neoplasm of low malignant potential (PUNLMP), LGPUC, and HGPUC) was used. Agreement between pairs of pathologists was evaluated using κ statistics for the combined scoring system. Interobserver agreement was fair to substantial as reflected by κ values ranging from 0.24 to 0.74 (mean κ = 0.43). The combined scores of 2 and 3 which included PUNLMP showed the lowest degree of agreement and when this category was excluded from the analysis, interobserver agreement increased significantly (mean κ = 0.65; ranging from 0.43 to 0.92) in terms of combined scores of 4, 5, and 6. PUNLMP has been shown to be the least reproducible component of a combined scoring system even among experienced observers. Exclusion of PUNLMP from grading scheme seems to improve interobserver variability.

  10. Expression profiles of variation integration genes in bladder urothelial carcinoma.

    PubMed

    Wang, J M; Wang, Y Q; Gao, Z L; Wu, J T; Shi, B K; Yu, C C

    2014-01-01

    Bladder cancer is a common cancer worldwide and its incidence continues to increase. There are approximately 261,000 cases of bladder cancer resulting in 115,000 deaths annually. This study aimed to integrate bladder cancer genome copy number variation information and bladder cancer gene transcription level expression data to construct a causal-target module network of the range of bladder cancer-related genomes. Here, we explored the control mechanism underlying bladder cancer phenotype expression regulation by the major bladder cancer genes. We selected 22 modules as the initial module network to expand the search to screen more networks. After bootstrapping 100 times, we obtained 16 key regulators. These 16 key candidate regulatory genes were further expanded to identify the expression changes of 11,676 genes in 275 modules, which may all have the same regulation. In conclusion, a series of modules associated with the terms 'cancer' or 'bladder' were considered to constitute a potential network.

  11. ADAM17 is associated with EMMPRIN and predicts poor prognosis in patients with uterine cervical carcinoma.

    PubMed

    Xu, Qin; Ying, Mingang; Chen, Guilin; Lin, Ang; Xie, Yunqing; Ohara, Noriyuki; Zhou, Dongmei

    2014-08-01

    Metalloproteinase activities of a disintegrin and metalloproteinase 17 (ADAM17), amphiregulin (AREG), extracellular matrix metalloproteinase inducer (EMMPRIN), and matrix metalloproteinases (MMPs) are involved in tumor biology. In patients with uterine cervical carcinoma, the expression and prognostic significance of ADAM17 remain to be fully elucidated. The expression of ADAM17, AREG, EMMPRIN, phospho-epidermal growth factor receptor (p-EGFR), phospho-extracellular signal-regulated kinase (p-ERK), MMP-2, and MMP-9 was assessed by immunohistochemistry and/or Western blotting from cervical carcinoma cell lines, SiHa and HeLa cells, and cervical carcinoma tissues. AREG activity was measured by ELISA assay. The correlation of ADAM17, AREG, EMMPRIN, and MMP-9 expression with patients' survival rates was assessed by Kaplan-Meier and Cox regression analyses. RNA interference (RNAi) experiment was performed using small interfering mRNA to ADAM17 and EMMPRIN. ADAM17, EMMPRIN, and MMP-9 protein content was overexpressed in cervical carcinoma tissues compared with normal cervical tissues (P < 0.05). Strong expression of ADAM17, AREG, EMMPRIN, and MMP-9 was significantly associated with stages, lymph node metastasis, differentiation, and parametrium invasion (P < 0.05). Overexpression of ADAM17, AREG, EMMPRIN, and MMP-9 was significantly correlated with short progression-free survival and overall survival (P < 0.05). Multivariate analysis suggested that lymph node metastasis, parametrium invasion, and ADAM17 expression were independent prognostic indicators for cervical cancer. ADAM17 RNAi decreased EMMPRIN, p-EGFR, p-ERK, MMP-2, and MMP-9 proteins in SiHa and HeLa cells. ELISA assay revealed that AREG activity was stimulated by ADAM17 and was reversed by ADAM17 RNAi in SiHa and HeLa cells. Our data suggest that the increased expression of ADAM17 in cervical cancer is significantly associated with aggressive progression and poor prognosis. ADAM17 may be a

  12. Role of biomarkers in the prediction and diagnosis of hepatocellular carcinoma

    PubMed Central

    Khattab, Mahmoud; Fouad, Magdy; Ahmed, Elham

    2015-01-01

    The prevalence of hepatocellular carcinoma (HCC) has progressively increased in recent years and is now the fifth and the second most common cancer in the World and in Egypt, respectively. Much work has focused in the development of assays for detecting hepatic carcinogensis before the observance of hepatic focal lesions. Particular attention has been directed towards HCC-specific biomarkers for use in the early diagnosis of HCC and in the confirmation of radiological studies. Although a number of biomarkers have been identified, none have been considered reliable indicators of early HCC lesions. This review presents a few of the most relevant HCC biomarkers and suggests improvements to the accuracy of diagnostic assays through their combined use. Furthermore, we present an algorithm for the biomarker-based diagnosis of HCC and highlight its important role in the early prediction of HCC. PMID:26483869

  13. Predicting clinical outcome in feline oral squamous cell carcinoma: tumour initiating cells, telomeres and telomerase.

    PubMed

    Yoshikawa, H; Maranon, D G; Battaglia, C L R; Ehrhart, E J; Charles, J B; Bailey, S M; LaRue, S M

    2014-09-11

    Feline oral squamous cell carcinoma (SCC) has very poor prognosis. Here, a retrospective pilot study was conducted on 20 feline oral SCC patients who underwent stereotactic radiation therapy (SRT), to evaluate: (1) the value of putative tumour initiating cell (TIC) markers of human head and neck SCC (CD44, Bmi-1); (2) telomere length (TL) specifically in putative TICs; and (3) tumour relative telomerase activity (TA). Significant inverse correlations were found between treatment outcomes and Bmi-1 expression, supporting the predictive value of Bmi-1 as a negative prognostic indicator. While TL exhibited a wide range of variability, particularly in very short fractions, many tumours possessed high levels of TA, which correlated with high levels of Bmi-1, Ki67 and EGFR. Taken together, our results imply that Bmi-1 and telomerase may represent novel therapeutic targets in feline oral SCC, as their inhibition - in combination with SRT - would be expected to have beneficial treatment outcome. PMID:25212092

  14. Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives.

    PubMed

    Joosten, S C; Hamming, L; Soetekouw, P M; Aarts, M J; Veeck, J; van Engeland, M; Tjan-Heijnen, V C

    2015-01-01

    The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on future perspectives in the treatment of metastasized RCC. PMID:25446042

  15. CT-scan prediction of thyroid cartilage invasion for early laryngeal squamous cell carcinoma.

    PubMed

    Hartl, Dana M; Landry, Guillaume; Bidault, François; Hans, Stéphane; Julieron, Morbize; Mamelle, Gérard; Janot, François; Brasnu, Daniel F

    2013-01-01

    Treatment choice for laryngeal cancer may be influenced by the diagnosis of thyroid cartilage invasion on preoperative computed tomography (CT). Our objective was to determine the predictive value of CT for thyroid cartilage invasion in early- to mid-stage laryngeal cancer. Retrospective study (1992-2008) of laryngeal squamous cell carcinoma treated with open partial laryngectomy and resection of at least part of the thyroid cartilage. Previous laser surgery, radiation therapy, chemotherapy and second primaries were excluded. CT prediction of thyroid cartilage invasion was determined by specialized radiologists. Tumor characteristics and pathologic thyroid cartilage invasion were compared to the radiologic assessment. 236 patients were treated by vertical (20 %), supracricoid (67 %) or supraglottic partial laryngectomy (13 %) for tumors staged cT1 (26 %), cT2 (55 %), and cT3 (19 %). The thyroid cartilage was invaded on pathology in 19 cases (8 %). CT's sensitivity was 10.5 %, specificity 94 %, positive predictive value 13 %, and negative predictive value 92 %. CT correctly predicted thyroid cartilage invasion in only two cases for an overall accuracy of 87 %. Among the false-positive CT's, tumors involving the anterior commissure were significantly over-represented (61.5 % vs. 27 %, p = .004). Tumors with decreased vocal fold (VF) mobility were significantly over-represented in the group of false-negatives (41 vs. 13 %, p = .0035). Preoperative CT was not effective in predicting thyroid cartilage invasion in these early- to mid-stage lesions, overestimating cartilage invasion for AC lesions and underestimating invasion for lesions with decreased VF mobility.

  16. NSE can predict the sensitivity to definitive chemoradiotherapy of small cell carcinoma of esophagus.

    PubMed

    Yan, Hongjiang; Wang, Renben; Jiang, Shumei; Zhu, Kunli; Feng, Rui; Xu, Xiaoqing; Meng, Xiangjiao

    2014-01-01

    Patients with esophageal small cell carcinoma undergoing definitive chemoradiotherapy (CRT) seem to have disparity in tumor response. The identification of CRT sensitivity-related tumor markers would be helpful for selecting patients most likely to benefit from CRT. The aim of this study was to examine the predictive value of biological markers in small cell carcinoma of the esophagus (SCEC) patients treated with definitive CRT. Pretreatment serum levels of neurone-specific enolase (NSE), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), and carcinoembryonic antigen (CEA) were measured by immunoradiometric assays, while the tumor responses were evaluated according to the World Health Organization response criteria. The relationships between pretreatment expression of NSE, CYFRA21-1, CEA, and the tumor response to CRT were analyzed. The effective rates (complete response + partial response) in NSE high and low groups were 10.80 % (9/82) and 37.98 % (31/82), respectively (P = 0.003).The results from statistical analysis indicated that the effectiveness of CRT was significantly associated with the serum levels of NSE before treatment (P = 0.002). The overall survival (OS) of the patients with high NSE levels was worse than that of those with low NSE levels (P = 0.004). In multivariate analysis, low level of NSE was the most significant independent predictor of good OS (P = 0.003). The result showed a promising predictive value of NSE regarding to the sensitivity of tumors to CRT. NSE may be a reliable surrogate marker of CRT efficacy in patients with SCEC.

  17. Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there?

    PubMed Central

    Shao, Yu-Yun; Hsu, Chih-Hung; Cheng, Ann-Lii

    2015-01-01

    Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-β1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast-enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC. PMID:26420960

  18. Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there?

    PubMed

    Shao, Yu-Yun; Hsu, Chih-Hung; Cheng, Ann-Lii

    2015-09-28

    Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-β1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast-enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC.

  19. A nomogram for predicting survival of nasopharyngeal carcinoma patients with metachronous metastasis.

    PubMed

    Zeng, Zixun; Shen, Lujun; Wang, Yue; Shi, Feng; Chen, Chen; Wu, Ming; Bai, Yutong; Pan, Changchuan; Xia, Yunfei; Wu, Peihong; Li, Wang

    2016-07-01

    Patients with metachronous metastatic nasopharyngeal carcinoma (NPC) differ significantly in survival outcomes. The aim of this study is to build a clinically practical nomogram incorporating known tumor prognostic factors to predict survival for metastatic NPC patients in epidemic areas.A total of 860 patients with metachronous metastatic nasopharyngeal carcinoma were analyzed retrospectively. Variables assessed were age, gender, body mass index, Karnofsky Performance Status (KPS), Union for International Cancer Control (UICC) T and N stages, World Health Organization (WHO) histology type, serum lactate dehydrogenase (sLDH) level, serum Epstein-Barr virus (EBV) level, treatment modality, specific metastatic location (lung/liver/bone), number of metastatic location(s) (isolated vs multiple), and number of metastatic lesion(s) in metastatic location(s) (single vs multiple). The independent prognostic factors for overall survival (OS) by Cox-regression model were utilized to build the nomogram.Independent prognostic factors for OS of metastatic NPC patients included age, UICC N stage, KPS, sLDH, number of metastatic locations, number of metastatic lesions, involvement of liver metastasis, and involvement of bone metastasis. Calibration of the final model suggested a c-index of 0.68 (95% confidence interval [CI], 0.65-0.69). Based on the total point (TP) by nomogram, we further subdivided the study cohort into 4 groups. Group 1 (TP < 320, 208 patients) had the lowest risk of dying. Discrimination was visualized by the differences in survival between these 4 groups (group 2/group 1: hazard ratio [HR] = 1.61, 95%CI: 1.24-2.09; group 3/group 1: HR = 2.20, 95%CI: 1.69-2.86; and group 4/group 1: HR = 3.66, 95%CI: 2.82-4.75).The developed nomogram can help guide the prognostication of patients with metachronous metastatic NPC in epidemic areas. PMID:27399084

  20. Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population.

    PubMed

    Duarte-Salles, Talita; Misra, Sandeep; Stepien, Magdalena; Plymoth, Amelie; Muller, David; Overvad, Kim; Olsen, Anja; Tjønneland, Anne; Baglietto, Laura; Severi, Gianluca; Boutron-Ruault, Marie-Christine; Turzanski-Fortner, Renee; Kaaks, Rudolf; Boeing, Heiner; Aleksandrova, Krasimira; Trichopoulou, Antonia; Lagiou, Pagona; Bamia, Christina; Pala, Valeria; Palli, Domenico; Mattiello, Amalia; Tumino, Rosario; Naccarati, Alessio; Bueno-de-Mesquita, H B As; Peeters, Petra H; Weiderpass, Elisabete; Quirós, J Ramón; Agudo, Antonio; Sánchez-Cantalejo, Emilio; Ardanaz, Eva; Gavrila, Diana; Dorronsoro, Miren; Werner, Mårten; Hemmingsson, Oskar; Ohlsson, Bodil; Sjöberg, Klas; Wareham, Nicholas J; Khaw, Kay-Tee; Bradbury, Kathryn E; Gunter, Marc J; Cross, Amanda J; Riboli, Elio; Jenab, Mazda; Hainaut, Pierre; Beretta, Laura

    2016-09-01

    We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and α-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14-1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis. Cancer Prev Res; 9(9); 758-65. ©2016 AACR. PMID:27339170

  1. Fibroblast growth factor-10 is a mitogen for urothelial cells

    SciTech Connect

    Bagai, Shelly; Rubio, Eric; Cheng, Jang-Fang; Sweet, Robert; Thomas, Regi; Fuchs, Elaine; Grady, Richard; Mitchell, Michael; Bassuk, James A.

    2002-02-01

    Fibroblast Growth Factor (FGF)-10 plays an important role in regulating growth, differentiation, and repair of the urothelium. This process occurs through a paracrine cascade originating in the mesenchyme (lamina propria) and targeting the epithelium (urothelium). In situ hybridization analysis demonstrated that (i) fibroblasts of the human lamina propria were the cell type that synthesized FGF-10 RNA and (ii) the FGF-10 gene is located at the 5p12-p13 locus of chromosome 5. Recombinant (r) preparations of human FGF-10 were found to induce proliferation of human urothelial cells in vitro and of transitional epithelium of wild-type and FGF7-null mice in vivo. Mechanistic studies with human cells indicated two modes of FGF-10 action: (i) translocation of rFGF-10 into urothelial cell nuclei and (ii) a signaling cascade that begins with the heparin-dependent phosphorylation of tyrosine residues of surface transmembrane receptors. The normal urothelial phenotype, that of quiescence, is proposed to be typified by negligible levels of FGF-10. During proliferative phases, levels of FGF-10 rise at the urothelial cell surface and/or within urothelial cell nuclei. An understanding of how FGF-10 works in conjunction with these other processes will lead to better management of many diseases of the bladder and urinary tract.

  2. Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas

    PubMed Central

    Pennington, Kathryn P.; Walsh, Tom; Harrell, Maria I.; Lee, Ming K.; Pennil, Christopher C.; Rendi, Mara H.; Thornton, Anne; Norquist, Barbara M.; Casadei, Silvia; Nord, Alexander S.; Agnew, Kathy J.; Pritchard, Colin C.; Scroggins, Sheena; Garcia, Rochelle L.; King, Mary-Claire; Swisher, Elizabeth M.

    2013-01-01

    Purpose Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination (HR) DNA repair genes is uncertain. Experimental Design Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the HR pathway. Results 31% of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 HR genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Non-serous ovarian carcinomas had similar rates of HR mutations to serous carcinomas (28% vs. 31%, p=0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic HR mutations was highly predictive of primary platinum sensitivity (p=0.0002) and improved overall survival (p=0.0006), with median overall survival 66 months in germline HR mutation carriers, 59 months in cases with a somatic HR mutation, and 41 months for cases without an HR mutation. Conclusions Germline or somatic mutations in HR genes are present in almost one-third of ovarian carcinomas, including both serous and non-serous histologies. Somatic BRCA1/2 mutations and mutations in other HR genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of HR mutations in non-serous carcinomas supports their inclusion in PARP inhibitor clinical trials. PMID:24240112

  3. Identification of serologic biomarkers for predicting microvascular invasion in hepatocellular carcinoma

    PubMed Central

    Jin, Yun; Zhou, Jia-Le; Geng, Yan-Hua; Jin, Xing; Zhang, Xiao-Xiao; Yang, Jun-Jie; Qian, Cheng-Ming; Zhou, Dong-Er; Liu, Da-Ren; Peng, Shu-You; Luo, Yan; Zheng, Lei; Li, Jiang-Tao

    2016-01-01

    Microvascular invasion (MVI) of hepatocellular carcinoma (HCC) is a major risk factor for early recurrence and poor survival after curative surgical therapies. However, MVI can only be diagnosed by pathological examination following resection. The aim of this study is to identify serologic biomarkers for predicting MVI preoperatively to help facilitate treatment decisions. We used the sero-proteomic approach to identify antigens that induce corresponding antibody responses either specifically in the serum from MVI (+) patients or from MVI (−) patients. Six antigens were subsequently identified as HSP 70, HSP 90, alpha-enolase (Eno-1), Annexin A2, glutathione synthetase and beta-actin by mass spectrometry. The antibodies titers in sera corresponding to four of these six antigens were measured by ELISA and compared between 35 MVI (+) patients and 26 MVI (−) patients. The titers of anti-HSP 70 antibodies were significantly higher in MVI (−) patients than those in MVI (+) patients; and the titers of anti-Eno-1 antibodies were significantly lower in MVI (−) patients than those in MVI (+) patients. The results were subjected to multivariate analysis together with other clinicopathologic factors, suggesting that antibodies against HSP 70 and Eno-1 in sera are potential biomarkers for predicting MVI in HCC prior to surgical resection. These biomarkers should be further investigated as potential therapeutic targets. PMID:26918350

  4. Value of MR histogram analyses for prediction of microvascular invasion of hepatocellular carcinoma

    PubMed Central

    Huang, Ya-Qin; Liang, He-Yue; Yang, Zhao-Xia; Ding, Ying; Zeng, Meng-Su; Rao, Sheng-Xiang

    2016-01-01

    Abstract The objective is to explore the value of preoperative magnetic resonance (MR) histogram analyses in predicting microvascular invasion (MVI) of hepatocellular carcinoma (HCC). Fifty-one patients with histologically confirmed HCC who underwent diffusion-weighted and contrast-enhanced MR imaging were included. Histogram analyses were performed and mean, variance, skewness, kurtosis, 1th, 10th, 50th, 90th, and 99th percentiles were derived. Quantitative histogram parameters were compared between HCCs with and without MVI. Receiver operating characteristics (ROC) analyses were generated to compare the diagnostic performance of tumor size, histogram analyses of apparent diffusion coefficient (ADC) maps, and MR enhancement. The mean, 1th, 10th, and 50th percentiles of ADC maps, and the mean, variance. 1th, 10th, 50th, 90th, and 99th percentiles of the portal venous phase (PVP) images were significantly different between the groups with and without MVI (P <0.05), with area under the ROC curves (AUCs) of 0.66 to 0.74 for ADC and 0.76 to 0.88 for PVP. The largest AUC of PVP (1th percentile) showed significantly higher accuracy compared with that of arterial phase (AP) or tumor size (P <0.001). MR histogram analyses—in particular for 1th percentile for PVP images—held promise for prediction of MVI of HCC. PMID:27368028

  5. Anatomic Invasive Depth Predicts Delayed Cervical Lymph Node Metastasis of Tongue Squamous Cell Carcinoma.

    PubMed

    Mitani, Sohei; Tomioka, Toshifumi; Hayashi, Ryuichi; Ugumori, Toru; Hato, Naohito; Fujii, Satoshi

    2016-07-01

    Delayed cervical lymph node metastasis (CLNM) is the most negative prognostic factor of tongue squamous cell carcinoma (SCC). This study analyzed the relationship between clinicopathologic factors, including anatomic invasive depth (AID), and CLNM. A total of 212 patients with clinically node-negative (cN0) tongue SCC who had undergone partial glossectomy through the mouth were eligible for this retrospective study. The deepest portions where tongue SCC cells invaded as determined by microscopic analyses were classified into 5 categories, including epithelial and submucosal tissue, lateral extrinsic tongue muscle (ETM), intrinsic tongue muscles (ITM), paralingual and sublingual spaces, and medial ETM according to AID. We examined the relationship between clinicopathologic factors including AID and delayed CLNM. Multivariate analysis demonstrated that AID was an independent predictive factor for delayed CLNM (P=0.0022; odds ratio=7.1). Deeper invasion than ITM, including ITM, paralingual and sublingual spaces, and medial ETM, had high sensitivity and negative predictive value for delayed CLNM (94.4% and 95.7%, respectively). Precise elucidation of AID may be useful for the preoperative decision for performing elective neck dissection. None of 11 patients in whom the deepest portion where tumor invaded to lateral ETM (according to AID) showed delayed CLNM, although tongue SCC T4a tumor is defined by the presence of invasion of cancer cells to ETM. Tumors with invasion to lateral ETM might have to be excluded from the pathologic T4a category. PMID:27186852

  6. [Plasma Biomarkers as Predictive Factors for Advanced Hepatocellular Carcinoma with Sorafenib].

    PubMed

    Shiozawa, Kazue; Watanabe, Manabu; Ikehara, Takashi; Matsukiyo, Yasushi; Kogame, Michio; Shinohara, Mie; Kikuchi, Yoshinori; Igarashi, Yoshinori; Sumino, Yasukiyo

    2016-07-01

    We examined plasma biomarkers as predictive factors for advanced hepatocellular carcinoma(ad-HCC)patients treated with sorafenib. We analyzed a-fetoprotein(AFP), AFP-L3, des-g-carboxy prothrombin(DCP), neutrophil-to-lymphocyte ratio(NLR), platelet-to-lymphocyte ratio(PLR), and vascular endothelial growth factor(VEGF)before sorafenib therapy, and changes in AFP-L3, NLR, PLR, and VEGF 1 month after sorafenib therapy in 16 patients. High AFP-L3(hazard ratio: 1.058, 95%CI: 1.019-1.098, p=0.003)and high NLR(hazard ratio: 1.475, 95%CI: 1.045-2.082, p=0.027)were significantly associated with poor prognosis in ad-HCC patients treated with sorafenib. There were no significant differences in changes in AFP-L3, NLR, PLR, and VEGF 1 month after sorafenib therapy. We suggest that AFP-L3 and NLR levels before sorafenib therapy in patients with ad-HCC are an important predictive factor for the therapeutic effect of sorafenib and patient survival. PMID:27431630

  7. Evaluation and Integration of Genetic Signature for Prediction Risk of Nasopharyngeal Carcinoma in Southern China

    PubMed Central

    Winkler, Cheryl A.; Li, Ji; Guan, Li; Tang, Minzhong; Liao, Jian; Deng, Hong; de Thé, Guy; Zeng, Yi; O'Brien, Stephen J.

    2014-01-01

    Genetic factors, as well as environmental factors, play a role in development of nasopharyngeal carcinoma (NPC). A number of single nucleotide polymorphisms (SNPs) have been reported to be associated with NPC. To confirm these genetic associations with NPC, two independent case-control studies from Southern China comprising 1166 NPC cases and 2340 controls were conducted. Seven SNPs in ITGA9 at 3p21.3 and 9 SNPs within the 6p21.3 HLA region were genotyped. To explore the potential clinical application of these genetic markers in NPC, we further evaluate the predictive/diagnostic role of significant SNPs by calculating the area under the curve (AUC). Results. The reported associations between ITGA9 variants and NPC were not replicated. Multiple loci of GABBR1, HLA-F, HLA-A, and HCG9 were statistically significant in both cohorts (Pcombined range from 5.96 × 10−17 to 0.02). We show for the first time that these factors influence NPC development independent of environmental risk factors. This study also indicated that the SNP alone cannot serve as a predictive/diagnostic marker for NPC. Integrating the most significant SNP with IgA antibodies status to EBV, which is presently used as screening/diagnostic marker for NPC in Chinese populations, did not improve the AUC estimate for diagnosis of NPC. PMID:25180181

  8. High SPARC Expression Starting from Dysplasia, Associated with Breast Carcinoma, Is Predictive for Bone Metastasis without Enhancement of Plasma Levels

    PubMed Central

    Maroni, Paola; Bendinelli, Paola; Morelli, Daniele; Drago, Lorenzo; Luzzati, Alessandro; Perrucchini, Giuseppe; Bonini, Chiara; Matteucci, Emanuela; Desiderio, Maria Alfonsina

    2015-01-01

    In order to become established in the skeleton, metastatic cells disseminating from the breast carcinoma need to acquire organ-specific traits. There are no effective predictors for who will develop bone metastasis to guide long-term predictive therapy. Our purpose was to individuate events critical for bone colonization to make a molecular classification of breast carcinoma useful for bone-metastasis outcome. In dysplasia adjacent to carcinoma and in pair-matched specimens of bone metastasis we examined SPARC expression and localization as well as Endothelin 1/ETAR signals by immunohistochemistry, and the evaluation of plasma levels of SPARC by ELISA was also performed. In patients with breast carcinoma metastasizing to bone, SPARC and Endothelin 1/ETAR axis were highly expressed from dysplasia until bone metastasis, but the SPARC plasma level was as low as that of normal women, in contrast to patients that never develop bone metastasis, suggesting that circulating SPARC was counter adhesive. Altogether, the early identification of SPARC/Endothelin 1/ETAR in dysplastic lesions would be important to devise therapies preventing metastasis engraftment, since often carcinoma cells spread to distant organs at the time or even before patients present with cancer. PMID:26703564

  9. High SPARC Expression Starting from Dysplasia, Associated with Breast Carcinoma, Is Predictive for Bone Metastasis without Enhancement of Plasma Levels.

    PubMed

    Maroni, Paola; Bendinelli, Paola; Morelli, Daniele; Drago, Lorenzo; Luzzati, Alessandro; Perrucchini, Giuseppe; Bonini, Chiara; Matteucci, Emanuela; Desiderio, Maria Alfonsina

    2015-01-01

    In order to become established in the skeleton, metastatic cells disseminating from the breast carcinoma need to acquire organ-specific traits. There are no effective predictors for who will develop bone metastasis to guide long-term predictive therapy. Our purpose was to individuate events critical for bone colonization to make a molecular classification of breast carcinoma useful for bone-metastasis outcome. In dysplasia adjacent to carcinoma and in pair-matched specimens of bone metastasis we examined SPARC expression and localization as well as Endothelin 1/ETAR signals by immunohistochemistry, and the evaluation of plasma levels of SPARC by ELISA was also performed. In patients with breast carcinoma metastasizing to bone, SPARC and Endothelin 1/ETAR axis were highly expressed from dysplasia until bone metastasis, but the SPARC plasma level was as low as that of normal women, in contrast to patients that never develop bone metastasis, suggesting that circulating SPARC was counter adhesive. Altogether, the early identification of SPARC/Endothelin 1/ETAR in dysplastic lesions would be important to devise therapies preventing metastasis engraftment, since often carcinoma cells spread to distant organs at the time or even before patients present with cancer. PMID:26703564

  10. High SPARC Expression Starting from Dysplasia, Associated with Breast Carcinoma, Is Predictive for Bone Metastasis without Enhancement of Plasma Levels.

    PubMed

    Maroni, Paola; Bendinelli, Paola; Morelli, Daniele; Drago, Lorenzo; Luzzati, Alessandro; Perrucchini, Giuseppe; Bonini, Chiara; Matteucci, Emanuela; Desiderio, Maria Alfonsina

    2015-11-26

    In order to become established in the skeleton, metastatic cells disseminating from the breast carcinoma need to acquire organ-specific traits. There are no effective predictors for who will develop bone metastasis to guide long-term predictive therapy. Our purpose was to individuate events critical for bone colonization to make a molecular classification of breast carcinoma useful for bone-metastasis outcome. In dysplasia adjacent to carcinoma and in pair-matched specimens of bone metastasis we examined SPARC expression and localization as well as Endothelin 1/ETAR signals by immunohistochemistry, and the evaluation of plasma levels of SPARC by ELISA was also performed. In patients with breast carcinoma metastasizing to bone, SPARC and Endothelin 1/ETAR axis were highly expressed from dysplasia until bone metastasis, but the SPARC plasma level was as low as that of normal women, in contrast to patients that never develop bone metastasis, suggesting that circulating SPARC was counter adhesive. Altogether, the early identification of SPARC/Endothelin 1/ETAR in dysplastic lesions would be important to devise therapies preventing metastasis engraftment, since often carcinoma cells spread to distant organs at the time or even before patients present with cancer.

  11. Cell-cycle distribution of urothelial tumour cells as measured by flow cytometry.

    PubMed Central

    Collste, L. G.; Darzynkiewicz, Z.; Traganos, F.; Sharpless, T. K.; Devonec, M.; Claps, M. L.; Whitmore, W. F.; Melamed, M. R.

    1979-01-01

    The fraction of cells in S + G2 + mitosis from 54 urothelial tumours was calculated by flow cytometry after acridine orange (AO) staining of cells obtained by bladder irrigation or biopsy. Fluorescence signals emitted by the AO-stained DNA and RNA of each cell were separated optically and measured for 5,000 cells per specimen. The patients were classified by the histology of their tumours and clinical data into 5 diagnostic categories: NED (no evidence of disease, but history of bladder tumour), 3; papilloma, 8; non-invasive papillary carcinoma, 8; carcinoma in situ, 17 and invasive carcinoma, 18. The fraction of cells with DNA values in S + G2 + M of the cell cycle varied between 7 and 57% of the total, with a wide range within each diagnostic category, but no statistically significant differences between the groups. The proportion of cells in S + G2 + M from an individual tumour was not correlated with histologic grade or clinical behaviour. The possibility that some tumour cells with DNA values above G1 level are quiescent cells arrested at S or G2 is discussed. PMID:526428

  12. Radiation therapy for nasopharyngeal carcinoma: the predictive value of interim survival assessment

    PubMed Central

    Toya, Ryo; Murakami, Ryuji; Saito, Tetsuo; Murakami, Daizo; Matsuyama, Tomohiko; Baba, Yuji; Nishimura, Ryuichi; Hirai, Toshinori; Semba, Akiko; Yumoto, Eiji; Yamashita, Yasuyuki; Oya, Natsuo

    2016-01-01

    Pretreatment characteristics are suggested as predictive and/or prognostic factors for nasopharyngeal carcinoma (NPC); however, individual tumor radiosensitivities have previously not been considered. As boost planning is recommended for NPC, we performed interim assessments of magnetic resonance (MR) images for boost planning and retrospectively evaluated their predictive value for the survival of NPC patients. Radiation therapy via elective nodal irradiation (median dose: 39.6 Gy) with/without chemotherapy was used to treat 63 NPC patients. Boost irradiation (median total dose: 70 Gy) was performed based on the interim assessment. The largest lymph node (LN) was measured on MR images acquired at the time of interim assessment. The site of first failure was local in 8 (12.7%), regional in 7 (11.1%), and distant in 12 patients (19.0%). All 7 patients with regional failure harbored LNs ≥15 mm at interim assessment. We divided the 63 patients into two groups based on LN size [large (≥15 mm), n = 10 and small (<15 mm), n = 53]. Univariate analysis showed that 5-year overall survival (OS) and cause-specific survival (CSS) rates for large LNs were significantly lower than for small LNs (OS: 12.5% vs 70.5%, P < 0.001 and CSS: 25.0% vs 80.0%, P < 0.001). Multivariate analysis showed that large LNs were a significantly unfavorable factor for both OS (hazard ratio = 4.543, P = 0.002) and CSS (hazard ratio = 6.020, P = 0.001). The results suggest that LN size at interim assessment could predict survival in NPC patients. PMID:27242338

  13. BRAF mutation is not predictive of long-term outcome in papillary thyroid carcinoma.

    PubMed

    Henke, Lauren E; Pfeifer, John D; Ma, Changquing; Perkins, Stephanie M; DeWees, Todd; El-Mofty, Samir; Moley, Jeffrey F; Nussenbaum, Brian; Haughey, Bruce H; Baranski, Thomas J; Schwarz, Julie K; Grigsby, Perry W

    2015-06-01

    The BRAF mutation occurs commonly in papillary thyroid carcinoma (PTC). Previous investigations of its utility to predict recurrence-free survival (RFS) and disease-specific survival (DSS) have reported conflicting results and its role remains unclear. The purpose of this retrospective study was to determine the incidence of the BRAF mutation and analyze its relationship to clinicopathologic risk factors and long-term outcomes in the largest, single-institution American cohort to date. BRAF mutational status was determined in 508 PTC patients using RFLP analysis. The relationships between BRAF mutation status, patient and tumor characteristics, RFS, and DSS were analyzed. The BRAF mutation was present in 67% of patients. On multivariate analysis, presence of the mutation predicted only for capsular invasion (HR, 1.7; 95% CI, 1.1-2.6), cervical lymph node involvement (HR, 1.7; 95% CI, 1.1-2.7), and classic papillary histology (HR, 1.8; 95% CI 1.1-2.9). There was no significant relationship between the BRAF mutation and RFS or DSS, an observation that was consistent across univariate, multivariate, and Kaplan-Meier analyses. This is the most extensive study to date in the United States to demonstrate that BRAF mutation is of no predictive value for recurrence or survival in PTC. We found correlations of BRAF status and several clinicopathologic characteristics of high-risk disease, but limited evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that BRAF is minimally prognostic in PTC. However, prevalence of the BRAF mutation is 70% in the general population, providing the opportunity for targeted therapy.

  14. EMX2 Is a Predictive Marker for Adjuvant Chemotherapy in Lung Squamous Cell Carcinomas

    PubMed Central

    Zhang, Yi; Tolani, Bhairavi; Mo, Minli; Zhang, Hua; Zheng, Qingfeng; Yang, Yue; Cheng, Runfen; Jin, Joy Q.; Luh, Thomas W.; Yang, Cathryn; Tseng, Hsin-Hui K.; Giroux-Leprieur, Etienne; Woodard, Gavitt A.; Hao, Xishan; Wang, Changli; Jablons, David M.; He, Biao

    2015-01-01

    Background Squamous cell carcinomas (SCC) account for approximately 30% of non-small cell lung cancer (NSCLC). Current staging methods do not adequately predict outcome for this disease. EMX2 is a homeo-domain containing transcription factor known to regulate a key developmental pathway. This study assessed the significance of EMX2 as a prognostic and predictive marker for resectable lung SCC. Methods Two independent cohorts of patients with lung SCC undergoing surgical resection were studied. EMX2 protein expression was examined by immunohistochemistry, Western blot, or immunofluorescence. EMX2 expression levels in tissue specimens were scored and correlated with patient outcomes. Chemo-sensitivity of lung SCC cell lines stably transfected with EMX2 shRNAs to cisplatin, carboplatin, and docetaxel was examined in vitro. Results EMX2 expression was down-regulated in lung SCC tissue samples compared to their matched adjacent normal tissues. Positive EMX2 expression was significantly associated with improved overall survival in stage I lung SCC patients, and in stage II/IIIA lung SCC patients receiving adjuvant chemotherapy. EMX2 expression was also associated with expression of EMT markers in both lung SCC cell lines and tissue samples. Knock-down of EMX2 expression in lung SCC cells promoted chemo-resistance and cell migration. Conclusions EMX2 expression is down-regulated in lung SCC and its down-regulation is associated with chemo-resistance in lung SCC cells, possibly through regulation of Epithelial-to-Mesenchymal Transition (EMT). EMX2 may serve as a novel prognostic marker for stage I lung SCC patients and a prediction marker for stage II/IIIA lung SCC patients receiving adjuvant chemotherapy. PMID:26132438

  15. Quantitative analysis of nuclear shape in oral squamous cell carcinoma is useful for predicting the chemotherapeutic response.

    PubMed

    Ogura, Maki; Yamamoto, Yoichiro; Miyashita, Hitoshi; Kumamoto, Hiroyuki; Fukumoto, Manabu

    2016-06-01

    The number of people afflicted with oral carcinoma in Japan has increased in recent years. Although preoperative neoadjuvant therapy with cisplatin and 5-fluorouracil are performed, chemotherapeutic response varies widely among the patients. With the aim of establishing novel indices to predict the therapeutic response to chemotherapy, we investigated the relationship between morphological features of pre-treatment oral carcinoma nuclei and the chemotherapeutic response using quantifying morphology of cell nuclei in pathological specimen images. We measured 4 morphological features of the nucleus of oral squamous cell carcinoma cases classified by the response to chemotherapy: No Change (NC) group, Partial Response (PR) group and Complete Response (CR) group. Furthermore, we performed immunohistochemical staining for p53 and Ki67 and calculated their positive rates in cancer tissues. Compactness and symmetry of the nucleus were significantly higher and nuclear edge response was significantly lower in cancer cells with lower chemotherapeutic responses compared high chemotherapeutic responders. As for positive rates of p53 and Ki67, there were no significant differences between any of the response groups. Morphological features of cancer cell nuclei in pathological specimens are sensitive predictive factors for the chemotherapeutic response to oral squamous cell carcinoma.

  16. Value of E-PASS models for predicting postoperative morbidity and mortality in resection of perihilar cholangiocarcinoma and gallbladder carcinoma

    PubMed Central

    Haga, Yoshio; Miyamoto, Atsushi; Wada, Yasuo; Takami, Yuko; Takeuchi, Hitoshi

    2015-01-01

    Background It has previously been reported that a general risk model, Estimation of Physiologic Ability and Surgical Stress (E-PASS), and its modified version, mE-PASS, had a high predictive power for postoperative mortality and morbidity in a variety of gastrointestinal surgeries. This study evaluated their utilities in proximal biliary carcinoma resection. Methods E-PASS variables were collected in patients undergoing resection of perihilar cholangiocarcinoma and gallbladder carcinoma in Japanese referral hospitals. Results Analysis of 125 patients with gallbladder cancer and 97 patients with perihilar cholangiocarcinoma (n = 222). Fifty-six patients (25%) underwent liver resection with either hemihepatectomy or extended hemihepatectomy. The E-PASS models showed a high discrimination power to predict in-hospital mortality; areas under the receiver operating characteristic curve (95% confidence intervals) were 0.85 (0.76–0.94) for E-PASS and 0.82 (0.73–0.91) for mE-PASS. The predicted mortality rates correlated with the severity of postoperative complications (Spearman's rank correlation coefficient: ρ = 0.51, P < 0.001 for E-PASS; ρ = 0.47, P < 0.001 for mE-PASS). Conclusions The E-PASS models examined herein may accurately predict postoperative morbidity and mortality in proximal biliary carcinoma resection. These models will be useful for surgical decision-making, informed consent, and risk adjustments in surgical audits. PMID:27017167

  17. CD86+/CD206+, Diametrically Polarized Tumor-Associated Macrophages, Predict Hepatocellular Carcinoma Patient Prognosis

    PubMed Central

    Dong, Pingping; Ma, Lijie; Liu, Longzi; Zhao, Guangxi; Zhang, Si; Dong, Ling; Xue, Ruyi; Chen, She

    2016-01-01

    Tumor-associated macrophages (TAMs), the most abundant infiltrating immune cells in tumor microenvironment, have distinct functions in hepatocellular carcinoma (HCC) progression. CD68+ TAMs represent multiple polarized immune cells mainly containing CD86+ antitumoral M1 macrophages and CD206+ protumoral M2 macrophages. TAMs expression and density were assessed by immunohistochemical staining of CD68, CD86, and CD206 in tissue microarrays from 253 HCC patients. Clinicopathologic features and prognostic value of these markers were evaluated. We found that CD68+ TAMs were not associated with clinicopathologic characteristics and prognosis in HCC. Low presence of CD86+ TAMs and high presence of CD206+ TAMs were markedly correlated with aggressive tumor phenotypes, such as multiple tumor number and advanced tumor-node-metastasis (TNM) stage; and were associated with poor overall survival (OS) (p = 0.027 and p = 0.024, respectively) and increased time to recurrence (TTR) (p = 0.037 and p = 0.031, respectively). In addition, combined analysis of CD86 and CD206 provided a better indicator for OS (p = 0.011) and TTR (p = 0.024) in HCC than individual analysis of CD86 and CD206. Moreover, CD86+/CD206+ TAMs predictive model also had significant prognosis value in α-fetoprotein (AFP)-negative patients (OS: p = 0.002, TTR: p = 0.005). Thus, these results suggest that combined analysis of immune biomarkers CD86 and CD206 could be a promising HCC prognostic biomarker. PMID:26938527

  18. A simple prognostic score system predicts the prognosis of solitary large hepatocellular carcinoma following hepatectomy

    PubMed Central

    Shen, Jun-yi; Li, Chuan; Wen, Tian-fu; Yan, Lv-nan; Li, Bo; Wang, Wen-tao; Yang, Jia-yin; Xu, Ming-qing

    2016-01-01

    Abstract Solitary large hepatocellular carcinomas (SLHCC) form a heterogeneous group of patients with different survival probabilities. The aim of our study was to develop a simple prognostic index for identifying prognostic subgroups of SLHCC patients. A retrospective analysis of clinical data from 268 patients with operable SLHCC was conducted to investigate prognostic factors and to construct a score system based on risk factors. A Cox proportional hazard regression analysis was used to evaluate the variables associated with prognosis. Survival analyses were performed using Kaplan–Meier survival curves. Three variables remained in the final multivariate model: platelet to lymphocyte ratio (PLR), microvascular invasion (MVI), and tumor size with hazard ratios equal to 1.004 (95% confidence interval: 1.001–1.006), 1.092 (1.044–1.142), and 2.233 (1.125–2.233), respectively. A score of 1 was assigned to each risk factor. Patient scores were determined based on these risk factors; thus, the scores ranged between 0 and 3. Ultimately, three categories (0, 1–2, 3) were defined. Patients with scores of 3 had a 5-year survival rate of 25.4%, whereas patients with a score of 0 had a 5-year survival rate of 52.1%. The prognosis significantly worsened as the score increased. Similar results were found among cirrhotic and noncirrhotic patients. Our simple prognostic index successfully predicts SLHCC survival. PMID:27495033

  19. Serum miRNAs as predictive and preventive biomarker for pre-clinical hepatocellular carcinoma.

    PubMed

    Li, Liang; Chen, Jianguo; Chen, Xin; Tang, Jing; Guo, Huan; Wang, Xiaofeng; Qian, Ji; Luo, Guijuan; He, Fangping; Lu, Xiaomei; Ding, Yibo; Yang, Yingchen; Huang, Wentao; Hou, Guojun; Lin, Ximeng; Ouyang, Qin; Li, Hengyu; Wang, Ruoyu; Jiang, Feng; Pu, Rui; Lu, Jianhua; Jin, Mudan; Tan, Yexiong; Gonzalez, Frank J; Cao, Guangwen; Wu, Mengchao; Wen, Hao; Wu, Tangchun; Jin, Li; Chen, Lei; Wang, Hongyang

    2016-04-10

    The extremely poor prognosis of patients with symptomatic hepatocellular carcinoma (HCC) diagnosed clinically at advanced stages suggests an urgent need for biomarkers that can be used for prospective surveillance and pre-clinical screening for early presence of pre-malignant lesions and tumors. In a retrospective longitudinal phase 3 biomarker study in seven medical centers of China, time-series and 6 months interval-serum samples were collected from chronic hepatitis B virus infected (CHB) patient cohorts at the pre-malignant or pre-clinical stages (average 6 months prior to clinical diagnosis) and CHB patients that did not develop cancer, and circulating miRNAs measured. A set of serum miRNAs including miR-193a-3p, miR-369-5p, miR-672, miR-429 and let-7i* were identified in pre-clinical HCC patients and have the potential to screen for CHB patients at high risk to develop HCC 6-12 months after miRNAs measurement. These circulating miRNAs combined with the conventional screening tools using α-fetoprotein and ultrasound, may have great promise for the prediction and prevention of HCC in high-risk populations. PMID:26850373

  20. Dectin-1 predicts adverse postoperative prognosis of patients with clear cell renal cell carcinoma

    PubMed Central

    Xia, Yu; Liu, Li; Bai, Qi; Wang, Jiajun; Xi, Wei; Qu, Yang; Xiong, Ying; Long, Qilai; Xu, Jiejie; Guo, Jianming

    2016-01-01

    Dectin-1, a classical pattern-recognition receptor, was now identified as an important regulator in immune homeostasis and cancer immunity through its extensive ligands binding functions and subsequent cytokines production. The aim of this study was to assess the clinical significance of dectin-1 expression in 290 patients with clear cell renal cell carcinoma (ccRCC) through immunohistochemistry on tissue microarrays. We found that dectin-1 was predominantly expressed on ccRCC cells, in accordance with several other online databases. Moreover, Kaplan-Meier method was conducted and high expression of tumoral dectin-1 was associated with shorter patient recurrence free survival (RFS) and overall survival (OS) (P < 0.001 for both). In multivariate analyses, tumoral dectin-1 expression was also confirmed as an independent prognostic factor for patients’ survival together with other clinical parameters (P < 0.001 for RFS and OS). After incorporating these characteristics including tumoral dectin-1 expression, two nomograms were constructed to predict ccRCC patients’ RFS and OS (c-index 0.796 and 0.812, respectively) and performed better than existed integrated models (P < 0.001 for all models comparisons). In conclusion, high tumoral dectin-1 expression was an independent predictor of adverse clinical outcome in ccRCC patients. This molecule and established nomograms might help clinicians in future decision making and therapeutic developments. PMID:27600310

  1. Dectin-1 predicts adverse postoperative prognosis of patients with clear cell renal cell carcinoma.

    PubMed

    Xia, Yu; Liu, Li; Bai, Qi; Wang, Jiajun; Xi, Wei; Qu, Yang; Xiong, Ying; Long, Qilai; Xu, Jiejie; Guo, Jianming

    2016-01-01

    Dectin-1, a classical pattern-recognition receptor, was now identified as an important regulator in immune homeostasis and cancer immunity through its extensive ligands binding functions and subsequent cytokines production. The aim of this study was to assess the clinical significance of dectin-1 expression in 290 patients with clear cell renal cell carcinoma (ccRCC) through immunohistochemistry on tissue microarrays. We found that dectin-1 was predominantly expressed on ccRCC cells, in accordance with several other online databases. Moreover, Kaplan-Meier method was conducted and high expression of tumoral dectin-1 was associated with shorter patient recurrence free survival (RFS) and overall survival (OS) (P < 0.001 for both). In multivariate analyses, tumoral dectin-1 expression was also confirmed as an independent prognostic factor for patients' survival together with other clinical parameters (P < 0.001 for RFS and OS). After incorporating these characteristics including tumoral dectin-1 expression, two nomograms were constructed to predict ccRCC patients' RFS and OS (c-index 0.796 and 0.812, respectively) and performed better than existed integrated models (P < 0.001 for all models comparisons). In conclusion, high tumoral dectin-1 expression was an independent predictor of adverse clinical outcome in ccRCC patients. This molecule and established nomograms might help clinicians in future decision making and therapeutic developments. PMID:27600310

  2. Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma.

    PubMed

    Nishida, Naoshi; Kitano, Masayuki; Sakurai, Toshiharu; Kudo, Masatoshi

    2015-10-01

    Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC.

  3. Prognostic nutritional index predicts prognosis in patients with metastatic nasopharyngeal carcinoma

    PubMed Central

    Wei, Gan-Bao; Lu, Yao-Yong; Liao, Rong-Wei; Chen, Qing-Sheng; Zhang, Kun-Qiang

    2016-01-01

    Objective This study aimed to investigate the prognostic value of Onodera’s prognostic nutritional index (PNI) in patients with metastatic nasopharyngeal carcinoma (NPC). Methods A total of 187 patients with metastatic NPC treated with cisplatin-based chemotherapy were retrospectively reviewed. The PNI was calculated using the following formula: serum albumin level (gram per liter) +0.005× peripheral lymphocyte count (per cubic millimeter). A receiver operating characteristics curve for overall survival (OS) with the highest Youden index was determined to calculate the best cutoff value of PNI. The relationship between PNI and clinicopathological parameters was compared with the χ2 test. Survival analysis was applied to evaluate the predictive value of PNI. Results The median PNI in this study was 49.0 (ranging from 32.2 to 78.4). The best cutoff value of PNI for OS was 51.0 according to the receiver operating characteristics analysis. The median OS time was 13.0 months. The multivariate analysis indicated that the complete response (hazard ratio 0.681, 95% confidence interval 0.574–0.902; P=0.013) and PNI (hazard ratio 1.732, 95% confidence interval 1.216–2.892; P=0.005) were independent prognostic factors for OS in patients with metastatic NPC. Conclusion This study revealed that PNI is a simple and effective predictor for overall survival in patients with metastatic NPC. PMID:27729804

  4. Predictive Factor of Local Recurrence after Balloon-Occluded TACE with Miriplatin (MPT) in Hepatocellular Carcinoma

    PubMed Central

    Ishikawa, Toru; Abe, Satoshi; Inoue, Ryousuke; Sugano, Tomoyuki; Watanabe, Yuhsuke; Iwanaga, Akito; Seki, Keiichi; Honma, Terasu; Nemoto, Takeo; Takeda, Keiko; Yoshida, Toshiaki

    2014-01-01

    Background Miriplatin (MPT) is a novel platinum complex used in TACE that shows promise for the treatment of hepatocellular carcinoma (HCC). However, rapid washout has been reported in some cases. Therefore, various methods of administration with MPT have been attempted to increase its therapeutic efficacy. One hopeful method is balloon-occluded TACE (B-TACE), but the therapeutic efficacy of B-TACE with MPT has not been evaluated. Aim To investigate the treatment outcomes and factors involved in local recurrence after B-TACE with MPT in HCC. Methods This study included 51 patients (55 nodules) with HCC lesions equal or less than 5 cm in diameter who underwent B-TACE with MPT between January 2012 and June 2013. Local recurrence after B-TACE with MPT and factors associated with local recurrence were evaluated. Results The overall local recurrence rate was 11.1% at 6 months and 26.2% at 12 months. The local recurrence rate did differ significantly depending on CT values immediately after B-TACE with MPT. Multivariate analysis also showed that the CT value after B-TACE with MPT was the only factor related to local recurrence after B-TACE. Conclusions B-TACE with MPT achieves relatively good local control of HCC. The plain CT value immediately after B-TACE with MPT is a predictive factor for local recurrence. In patients with unsatisfactory CT values, locoregional therapy or additional treatment is required. PMID:25047920

  5. A novel scoring system predicts adjuvant chemolipiodolization benefit for hepatocellular carcinoma patients after hepatectomy

    PubMed Central

    Xia, Yong; Li, Jun; Wang, Kui; Yan, Zhen-lin; Wan, Xu-ying; Shi, Le-hua; Yang, Tian; Lau, Wan Yee; Wu, Meng-chao; Shen, Feng

    2016-01-01

    Our aim in this study was to develop a prognostic scoring system with which to identify patients most likely to benefit from adjuvant chemolipiodolization (ACL) after liver resection for hepatocellular carcinoma (HCC). Data from 1150 HCC patients who underwent liver resection between 2002 and 2008 at the Eastern Hepatobiliary Surgery Hospital were used to develop the scoring system. Patients were stratified into prognostic subgroups using the new scoring system, and the outcomes of patients who received ACL and those who did not were compared in each subgroup. Using data from 379 patients operated on between 2008 and 2010 for validation, the scoring system had a concordance index (C-index) of 0.75 for predicting post-resectional overall survival (OS). It optimally stratified patients into three prognostic subgroups with scores of 0–5, 6–9 and ≥ 10, having better, medium and worse survival outcomes, respectively. A difference in OS between ACL and non-ACL patients was only detected in the subgroup with scores ≥ 10 (1-, 3-, and 5-year OS rates: 63.9%, 22.6%, and 9.0% vs. 33.8%, 5.6%, and 2.8%, p = 0.001). Our proposed scoring system provides an effective tool for selecting the patients most likely to benefit from ACL. PMID:27027439

  6. Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma.

    PubMed

    Nishida, Naoshi; Kitano, Masayuki; Sakurai, Toshiharu; Kudo, Masatoshi

    2015-10-01

    Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC. PMID:26488287

  7. BINNING SOMATIC MUTATIONS BASED ON BIOLOGICAL KNOWLEDGE FOR PREDICTING SURVIVAL: AN APPLICATION IN RENAL CELL CARCINOMA

    PubMed Central

    Kim, Dokyoon; Li, Ruowang; Dudek, Scott M.; Wallace, John R.; Ritchie, Marylyn D.

    2014-01-01

    Enormous efforts of whole exome and genome sequencing from hundreds to thousands of patients have provided the landscape of somatic genomic alterations in many cancer types to distinguish between driver mutations and passenger mutations. Driver mutations show strong associations with cancer clinical outcomes such as survival. However, due to the heterogeneity of tumors, somatic mutation profiles are exceptionally sparse whereas other types of genomic data such as miRNA or gene expression contain much more complete data for all genomic features with quantitative values measured in each patient. To overcome the extreme sparseness of somatic mutation profiles and allow for the discovery of combinations of somatic mutations that may predict cancer clinical outcomes, here we propose a new approach for binning somatic mutations based on existing biological knowledge. Through the analysis using renal cell carcinoma dataset from The Cancer Genome Atlas (TCGA), we identified combinations of somatic mutation burden based on pathways, protein families, evolutionary conversed regions, and regulatory regions associated with survival. Due to the nature of heterogeneity in cancer, using a binning strategy for somatic mutation profiles based on biological knowledge will be valuable for improved prognostic biomarkers and potentially for tailoring therapeutic strategies by identifying combinations of driver mutations. PMID:25592572

  8. Noninvasive Fibrosis Marker Can Predict Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation

    PubMed Central

    Chung, Hyun Ah; Kim, Jeong-Han; Hwang, Young; Choi, Hong Seok; Ko, Soon Young; Choe, Won Hyeok; Kwon, So Young

    2016-01-01

    Background/Aims: Tumor recurrence after curative therapy is common for patients with hepatocellular carcinoma (HCC). As fibrosis and chronic inflammation contribute to the progression of HCC, we aimed to identify the predictive value of inflammatory and fibrosis markers for HCC recurrence after curative therapy using radiofrequency ablation (RFA). Materials and Methods: We retrospectively reviewed the records of patients with HCC treated with RFA between October 2005 and September 2013. The median duration of follow-up was 40 months (4–95 months). Inflammatory and fibrosis markers and demographic and clinical data were analyzed by Cox proportional hazards model using univariate and multivariate analyses and longitudinal analysis. Results: A total of 98 patients were included for analysis. There were 54 cases of HCC recurrence (55.1%). The aspartate aminotransferase-to-platelet ratio index (APRI; 2.3 ± 1.8 vs. 1.3 ± 1.4, P = 0.018) was significantly higher in the recurrence group than in the recurrence-free group. In multivariate analysis, APRI (hazard ratio, 2.64; confidence interval, 1.488–4.714; P = 0.001) was an independent risk factor for tumor recurrence. In particular, patients with APRI >1.38 showed a higher recurrence rate than patients with APRI ≤1.38 (P < 0.001). Longitudinal analysis showed persistently higher APRI values when assessed 12 months after RFA in patients who developed recurrence during follow-up than those who remained recurrence-free. Conclusions: These findings show that a high APRI value is associated with HCC recurrence after RFA. Therefore, APRI could play an important role in predicting HCC recurrence after RFA. PMID:26831608

  9. Body Composition Features Predict Overall Survival in Patients With Hepatocellular Carcinoma

    PubMed Central

    Singal, Amit G; Zhang, Peng; Waljee, Akbar K; Ananthakrishnan, Lakshmi; Parikh, Neehar D; Sharma, Pratima; Barman, Pranab; Krishnamurthy, Venkataramu; Wang, Lu; Wang, Stewart C; Su, Grace L

    2016-01-01

    Objectives: Existing prognostic models for patients with hepatocellular carcinoma (HCC) have limitations. Analytic morphomics, a novel process to measure body composition using computational image-processing algorithms, may offer further prognostic information. The aim of this study was to develop and validate a prognostic model for HCC patients using body composition features and objective clinical information. Methods: Using computed tomography scans from a cohort of HCC patients at the VA Ann Arbor Healthcare System between January 2006 and December 2013, we developed a prognostic model using analytic morphomics and routine clinical data based on multivariate Cox regression and regularization methods. We assessed model performance using C-statistics and validated predicted survival probabilities. We validated model performance in an external cohort of HCC patients from Parkland Hospital, a safety-net health system in Dallas County. Results: The derivation cohort consisted of 204 HCC patients (20.1% Barcelona Clinic Liver Cancer classification (BCLC) 0/A), and the validation cohort had 225 patients (22.2% BCLC 0/A). The analytic morphomics model had good prognostic accuracy in the derivation cohort (C-statistic 0.80, 95% confidence interval (CI) 0.71–0.89) and external validation cohort (C-statistic 0.75, 95% CI 0.68–0.82). The accuracy of the analytic morphomics model was significantly higher than that of TNM and BCLC staging systems in derivation (P<0.001 for both) and validation (P<0.001 for both) cohorts. For calibration, mean absolute errors in predicted 1-year survival probabilities were 5.3% (90% quantile of 7.5%) and 7.6% (90% quantile of 12.5%) in the derivation and validation cohorts, respectively. Conclusion: Body composition features, combined with readily available clinical data, can provide valuable prognostic information for patients with newly diagnosed HCC. PMID:27228403

  10. Distinct patterns of ALDH1A1 expression predict metastasis and poor outcome of colorectal carcinoma

    PubMed Central

    Xu, Sen-Lin; Zeng, Dong-Zu; Dong, Wei-Guo; Ding, Yan-Qing; Rao, Jun; Duan, Jiang-Jie; Liu, Qing; Yang, Jing; Zhan, Na; Liu, Ying; Hu, Qi-Ping; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Yu, Shi-Cang; Bian, Xiu-Wu

    2014-01-01

    Purpose: Aldehyde dehydrogenase 1A1 (ALDH1A1) has been proposed as a candidate biomarker for colorectal carcinoma (CRC). However, the heterogeneity of its expression makes it difficult to predict the outcome of CRC. The aim of this study was to evaluate the diagnostic and prognostic value of this molecule in CRC. Methods and Results: In this study, we examined ALDH1A1 expression by immunohistochemistry including 406 cases of primary CRC with corresponding adjacent mucosa, with confirmation of real-time PCR and Western blotting. We found that the expression patterns of ALDH1A1 were heterogeneous in the CRC and corresponding adjacent tissues. We defined the ratio of ALDH1A1 level in adjacent mucosa to that in tumor tissues as RA/C and found that the capabilities of tumor invasion and metastasis in the tumors with RA/C < 1 were significantly higher than those with RA/C ≥ 1. Follow-up data showed the worse prognoses in the CRC patients with RA/C < 1. For understanding the underlying mechanism, the localization of β-catenin was detected in the CRC tissues with different patterns of ALDH1A1 expression from 221 patients and β-catenin was found preferentially expressed in cell nuclei of the tumors with RA/C < 1 and ALDH1A1high expression of HT29 cell line, indicating that nuclear translocation of β-catenin might contribute to the increased potentials of invasion and metastasis. Conclusion: Our results indicate that RA/C is a novel biomarker to reflect the distinct expression patterns of ALDH1A1 for predicting metastasis and prognosis of CRC. PMID:25031716

  11. A Simple Risk Model to Predict Survival in Patients With Carcinoma of Unknown Primary Origin

    PubMed Central

    Huang, Chen-Yang; Lu, Chang-Hsien; Yang, Chan-Keng; Hsu, Hung-Chih; Kuo, Yung-Chia; Huang, Wen-Kuan; Chen, Jen-Shi; Lin, Yung-Chang; Chia-Yen, Hung; Shen, Wen-Chi; Chang, Pei-Hung; Yeh, Kun-Yun; Hung, Yu-Shin; Chou, Wen-Chi

    2015-01-01

    Abstract Carcinoma of unknown primary origin (CUP) is characterized by diverse histological subtypes and clinical presentations, ranging from clinically indolent to frankly aggressive behaviors. This study aimed to identify prognostic factors of CUP and to develop a simple risk model to predict survival in a cohort of Asian patients. We retrospectively reviewed 190 patients diagnosed with CUP between 2007 and 2012 at a single medical center in Taiwan. The clinicopathological parameters and outcomes of our cohort were analyzed. A risk model was developed using multivariate logistic regression and a prognostic score was generated. The prognostic score was calculated based on 3 independent prognostic variables: the Eastern Cooperative Oncology Group (ECOG) scale (0 points if the score was 1, 2 points if it was 2–4), visceral organ involvement (0 points if no involvement, 1 point if involved), and the neutrophil-to-lymphocyte ratio (0 points if ≤3, 1 point if >3). Patients were stratified into good (score 0), intermediate (score 1–2), and poor (score 3–4) prognostic groups based on the risk model. The median survival (95% confidence interval) was 1086 days (500–1617, n = 42), 305 days (237–372, n = 75), and 64 days (44–84, n = 73) for the good, intermediate, and poor prognostic groups, respectively. The c-statistics using the risk model and ECOG scale for the outcome of 1-year mortality were 0.80 and 0.70 (P = 0.038), respectively. In this study, we developed a simple risk model that accurately predicted survival in patients with CUP. This scoring system may be used to help patients and clinicians determine appropriate treatments. PMID:26632736

  12. FOXO4 and FOXD3 are predictive of prognosis in gastric carcinoma patients

    PubMed Central

    Han, Fang; Liu, Shenxiang; Yuan, Xin; Tong, Jiandong

    2016-01-01

    Forkhead box (FOX) transcription factor family plays an important role in cancer growth and metastasis. This study aimed to determine the predictive ability of FOX genes in gastric carcinoma. A total of 360 patients with gastric from The Cancer Genome Atlas (TCGA) cohorts were collected in this study. The expression profile of FOX family were obtained from the TCGA RNAseq database. Clinicopathological characteristics, including age, gender, tumor node metastasis (TNM), tumor grade, and overall survival were collected. Univariate and multivariate Cox proportional hazards model were used to assess the risk factors for survival, and the results were further validated in in-house cohort. In the TCGA cohort, FOXO4 (HR = 0.613, 95%CI 0.452–0.832) and FOXD3 (HR = 1.704, 95%CI 1.212–2.397) were shown independently predictive of overall survival in gastric cancer after Cox proportional hazards analysis. The finding was validated in our in-house cohort, which demonstrated that both FOXO4 and FOXD3 were independent predictors for overall survival (FOXO4 high, HR: 0.445, 95%CI 0.277–0.715, P = 0.001, FOXD3 high, HR: 1.927, 95%CI 1.212–3.063, P = 0.006) and disease free survival (FOXO4 high, HR: 0.628, 95%CI 0.420–0.935, P = 0.022, FOXD3 high, HR: 1.698, 95%CI 1.136–2.540, P = 0.010). Collectively, FOX family paly critical roles in gastric cancer, and FOXO4 and FOXD3 were identified as independent prognostic factors for survival outcomes of gastric cancer. Further functional study is needed to understand more about FOX family in gastric cancer. PMID:27027443

  13. Predicting DNA-mediated drug delivery in interior carcinoma using electromagnetically excited nanoparticles.

    PubMed

    Ghosh, Soham; Das, Tamal; Chakraborty, Suman; Das, Sarit K

    2011-09-01

    Tumor-site-specific delivery of anti-cancer drugs remains one of the most prevailing problems in cancer treatment. While conventional means of chemo-delivery invariably leave different degrees of side-effects on healthy tissues, in recent times, intelligent chemical designs have been exploited to reduce the cross-consequences. In particular, the strategies involving superparamaganetic nanoparticles with surface assembled oligonucleotides as therapeutic carrier have raised affirmative promises. Process is designed in such a way that the therapeutic molecules are released preferentially at target site as the complementary oligonucleotide chains dissociate over the heat generated by the nanoparticles under the excitation of low frequency electromagnetic energy. In spite of the preliminary demonstrations, analytical comprehension of the entire process especially on the purview of non-trivial interactions between stochastic phase-transition phenomena of oligonucleotide chains and hierarchical organization of in vivo transport processes remains unknown. Here, we propose an integrated computational predictive model to interpret the efficacy of drug delivery in the aforementioned process. The basic physics of heat generation by superparamagnetic nanoparticles in presence of external electromagnetic field has been coupled with transient biological heat transfer model and the statistical mechanics based oligonucleotide denaturation dynamics. Conjunctionally, we have introduced a set of hierarchically appropriate transport processes to mimic the in vivo drug delivery system. The subsequent interstitial diffusion and convection of the various species involved in the process over time was simulated assuming a porous media model of the carcinoma. As a result, the model predictions exhibit excellent congruence with available experimental results. To delineate a broader spectrum of a priori speculations, we have investigated the effects of different tunable parameters such as

  14. Four-protein signature accurately predicts lymph node metastasis and survival in oral squamous cell carcinoma.

    PubMed

    Zanaruddin, Sharifah Nurain Syed; Saleh, Amyza; Yang, Yi-Hsin; Hamid, Sharifah; Mustafa, Wan Mahadzir Wan; Khairul Bariah, A A N; Zain, Rosnah Binti; Lau, Shin Hin; Cheong, Sok Ching

    2013-03-01

    The presence of lymph node (LN) metastasis significantly affects the survival of patients with oral squamous cell carcinoma (OSCC). Successful detection and removal of positive LNs are crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the LNs, where up to a third of clinically diagnosed metastasis-negative (N0) patients actually have metastasis-positive LNs in the neck. We developed a molecular signature in the primary tumor that could predict LN metastasis in OSCC. A total of 211 cores from 55 individuals were included in the study. Eleven proteins were evaluated using immunohistochemical analysis in a tissue microarray. Of the 11 biomarkers evaluated using receiver operating curve analysis, epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2/neu), laminin, gamma 2 (LAMC2), and ras homolog family member C (RHOC) were found to be significantly associated with the presence of LN metastasis. Unsupervised hierarchical clustering-demonstrated expression patterns of these 4 proteins could be used to differentiate specimens that have positive LN metastasis from those that are negative for LN metastasis. Collectively, EGFR, HER-2/neu, LAMC2, and RHOC have a specificity of 87.5% and a sensitivity of 70%, with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated that the LN signature could independently predict disease-specific survival (P = .036). The 4-protein LN signature validated in an independent set of samples strongly suggests that it could reliably distinguish patients with LN metastasis from those who were metastasis-free and therefore could be a prognostic tool for the management of patients with OSCC.

  15. Four-protein signature accurately predicts lymph node metastasis and survival in oral squamous cell carcinoma.

    PubMed

    Zanaruddin, Sharifah Nurain Syed; Saleh, Amyza; Yang, Yi-Hsin; Hamid, Sharifah; Mustafa, Wan Mahadzir Wan; Khairul Bariah, A A N; Zain, Rosnah Binti; Lau, Shin Hin; Cheong, Sok Ching

    2013-03-01

    The presence of lymph node (LN) metastasis significantly affects the survival of patients with oral squamous cell carcinoma (OSCC). Successful detection and removal of positive LNs are crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the LNs, where up to a third of clinically diagnosed metastasis-negative (N0) patients actually have metastasis-positive LNs in the neck. We developed a molecular signature in the primary tumor that could predict LN metastasis in OSCC. A total of 211 cores from 55 individuals were included in the study. Eleven proteins were evaluated using immunohistochemical analysis in a tissue microarray. Of the 11 biomarkers evaluated using receiver operating curve analysis, epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2/neu), laminin, gamma 2 (LAMC2), and ras homolog family member C (RHOC) were found to be significantly associated with the presence of LN metastasis. Unsupervised hierarchical clustering-demonstrated expression patterns of these 4 proteins could be used to differentiate specimens that have positive LN metastasis from those that are negative for LN metastasis. Collectively, EGFR, HER-2/neu, LAMC2, and RHOC have a specificity of 87.5% and a sensitivity of 70%, with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated that the LN signature could independently predict disease-specific survival (P = .036). The 4-protein LN signature validated in an independent set of samples strongly suggests that it could reliably distinguish patients with LN metastasis from those who were metastasis-free and therefore could be a prognostic tool for the management of patients with OSCC. PMID:23026198

  16. Efficacy of contrast-enhanced ultrasound washout rate in predicting hepatocellular carcinoma differentiation.

    PubMed

    Feng, Yan; Qin, Xia-Chuan; Luo, Yan; Li, Yong-Zhong; Zhou, Xiang

    2015-06-01

    The aim of this retrospective study was to evaluate the efficacy of contrast-enhanced ultrasound (CEUS) washout rate in predicting hepatocellular carcinoma (HCC) differentiation. Two hundred seventy-one patients underwent liver resection for HCC between April 2008 and December 2012 after being examined by CEUS using the contrast agent SonoVue with a low mechanical index (<0.1) in a routine procedure. Contrast agent washout rates obtained from video images were divided into four categories from slow to fast: WR1 = no washout in all phases (slowest); WR2 = washout after 120 s from contrast injection (late-phase washout); WR3 = washout between 41 and 120 s from contrast injection (portal venous washout); WR4 = washout before 40 s from contrast injection (fastest washout rate). HCC nodules were graded as well, moderately and poorly differentiated. Spearman rank correlation and χ(2)-tests were used to assess group relationships and differences. Receiver operating characteristic curve analysis was used to determine the diagnostic predictive value of CEUS. Among the 271 patients, 18 (6.6%) had well differentiated, 150 (55.4%) had moderately differentiated and 103 (38.0%) had poorly differentiated HCC. Statistical tests indicated that washout rate was significantly correlated with tumor differentiation (p < 0.05), and the poorly differentiated HCCs had earlier washout. At the cutoff point of WR4, CEUS based on washout rate performed poorly in distinguishing poorly differentiated from moderately and well-differentiated HCCs, with a sensitivity, specificity and accuracy (area under the curve) of 24%, 97% and 0.68, respectively. However, at the cutoff point of WR2, the sensitivity, specificity and accuracy of CEUS in differentiating well-differentiated HCC from other HCCs were significantly better: 98%, 78% and 0.96, respectively. Thus, CEUS washout rate may have a role in identifying patients with well-differentiated HCC.

  17. Early prediction of response of sorafenib on hepatocellular carcinoma by CT perfusion imaging: an animal study

    PubMed Central

    Shi, G; Wang, L; Liu, X; Wu, R

    2014-01-01

    Objective: This study evaluated the feasibility of CT perfusion parameters for the early efficacy prediction of sorafenib in the treatment of hepatocellular carcinoma (HCC) in rats. Methods: CT hepatic perfusion measurements were performed in the livers of 40 rats implanted with rat HCC. The rats in the experimental group (n = 28) were treated by oral gavage with sorafenib (20 mg per day), whereas the rats in the control group (n = 12) were treated by normal saline. Rats were classified into the responder group if the maximum diameter of their tumour had decreased 21 days after treatment, whereas the other rats were classified into the non-responder group. Data were analysed using the Pearson correlation analysis or analysis of variance. Results: CT perfusion was used to depict haemodynamic changes before and after treatment. The arterial liver perfusion was significantly decreased in the responder group on Day 11 after treatment with sorafenib (from 71.5 to 53.4 ml min−1 100 ml−1), whereas no significant changes were observed in the non-responder group (p = 0.87). The maximum diameter of the tumour was also significantly decreased in the responder group on Day 21 after treatment (p = 0.042), whereas the maximum tumour diameter was significantly increased in the control group (p = 0.001). Conclusion and advances in knowledge: CT perfusion could be used to quantitatively analyse the haemodynamic changes in the treatment of HCC with sorafenib, which indicates that this approach may be developed for the early prediction of treatment efficacy for sorafenib. PMID:24452058

  18. Decreased expression of pyruvate dehydrogenase A1 predicts an unfavorable prognosis in ovarian carcinoma

    PubMed Central

    Li, Yaqing; Huang, Ruixia; Li, Xiaoli; Li, Xiaoran; Yu, Dandan; Zhang, Mingzhi; Wen, Jianguo; Goscinski, Mariusz Adam; Trope, Claes G; Nesland, Jahn M; Suo, Zhenhe

    2016-01-01

    Pyruvate dehydrogenase A1 (PDHA1) serves as a gate-keeper enzyme link between glycolysis and the mitochondrial citric acid cycle. The inhibition of PDHA1 in cancer cells can result in an increased Warburg effect and a more aggressive phenotype in cancer cells. This study was conducted to investigate the expression of PDHA1 in ovarian cancer and the correlation between PDHA1 expression and the prognosis of patients. The PDHA1 protein expression in 3 ovarian cancer cell lines (OVCAR-3, SKOV-3 and ES-2) and 248 surgically removed ovarian carcinoma samples was immunocytochemically examined. Statistical analyses were performed to evaluate the correlations between PDHA1 expression and the clinicopathological characteristics of the patients as well as the predictive value of PDHA1. The results showed the presence of variable expression of PDHA1 in the three ovarian cancer cell lines. Of the 248 ovarian cancer tissue specimens, 45 cases (18.1%) were negative in tumor cells for PDHA1, 162 cases (65.3%) displayed a low expression level, and 41 cases (16.5%) had a relatively high PDHA1 staining. The expression of PDHA1 was associated with the histological subtype (P=0.004) and FIGO stage (P=0.002). The median OS time in the PDHA1 negative group, low expression group and high expression group were 0.939 years, 1.443 years and 9.900 years, respectively. The median PFS time in the above three groups were 0.287 years, 0.586 years and 9.900 years, respectively. Furthermore, the high expression of PDHA1 in ovarian carcinoma cells was significantly associated with better OS and PFS by statistical analyses. Multivariate analyses showed that PDHA1 expression was also an independent prognostic factor for higher OS in ovarian cancer patients (HR=0.705, 95% CI 0.541-0.918, P=0.01). Our study indicated that the decreased expression of PDHA1 might be an independent prognostic factor in unfavorable outcomes. PMID:27725912

  19. Nomograms for predicting survival and recurrence in patients with adenoid cystic carcinoma. An international collaborative study

    PubMed Central

    Ganly, Ian; Amit, Moran; Kou, Lei; Palmer, Frank L.; Migliacci, Jocelyn; Katabi, Nora; Yu, Changhong; Kattan, Michael W.; Binenbaum, Yoav; Sharma, Kanika; Naomi, Ramer; Abib, Agbetoba; Miles, Brett; Yang, Xinjie; Lei, Delin; Bjoerndal, Kristine; Godballe, Christian; Mücke, Thomas; Wolff, Klaus-Dietrich; Fliss, Dan; Eckardt, André M.; Chiara, Copelli; Sesenna, Enrico; Ali, Safina; Czerwonka, Lukas; Goldstein, David P.; Gil, Ziv; Patel, Snehal G.

    2016-01-01

    Background Due to the rarity of adenoid cystic carcinoma (ACC), information on outcome is based upon small retrospective case series. The aim of our study was to create a large multiinstitutional international dataset of patients with ACC in order to design predictive nomograms for outcome. Methods ACC patients managed at 10 international centers were identified. Patient, tumor, and treatment characteristics were recorded and an international collaborative dataset created. Multivariable competing risk models were then built to predict the 10 year recurrence free probability (RFP), distant recurrence free probability (DRFP), overall survival (OS) and cancer specific mortality (CSM). All predictors of interest were added in the starting full models before selection, including age, gender, tumor site, clinical T stage, perineural invasion, margin status, pathologic N-status, and M-status. Stepdown method was used in model selection to choose predictive variables. An external dataset of 99 patients from 2 other institutions was used to validate the nomograms. Findings Of 438 ACC patients, 27.2% (119/438) died from ACC and 38.8% (170/438) died of other causes. Median follow-up was 56 months (range 1–306). The nomogram for OS had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N-status and M-status) with a concordance index (CI) of 0.71. The nomogram for CSM had the same variables, except margin status, with a concordance index (CI) of 0.70. The nomogram for RFP had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N status and perineural invasion) (CI 0.66). The nomogram for DRFP had 6 variables (gender, clinical T stage, tumor site, pathologic N-status, perineural invasion and margin status) (CI 0.64). Concordance index for the external validation set were 0.76, 0.72, 0.67 and 0.70 respectively. Interpretation Using an international collaborative database we have created the first nomograms which

  20. Combinations of biomarkers and Milan criteria for predicting hepatocellular carcinoma recurrence after liver transplantation.

    PubMed

    Chaiteerakij, Roongruedee; Zhang, Xiaodan; Addissie, Benyam D; Mohamed, Essa A; Harmsen, William S; Theobald, Paul J; Peters, Brian E; Balsanek, Joseph G; Ward, Melissa M; Giama, Nasra H; Moser, Catherine D; Oseini, Abdul M; Umeda, Naoki; Venkatesh, Sudhakar; Harnois, Denise M; Charlton, Michael R; Yamada, Hiroyuki; Satomura, Shinji; Algeciras-Schimnich, Alicia; Snyder, Melissa R; Therneau, Terry M; Roberts, Lewis R

    2015-05-01

    Growing evidence suggests that pretransplant alpha-fetoprotein (AFP) predicts outcomes of hepatocellular carcinoma (HCC) patients treated with liver transplantation. We aimed to determine whether pretransplant AFP, Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3), and des-gamma-carboxyprothrombin (DCP) predicted HCC recurrence after transplantation. A retrospective cohort study of 313 HCC patients undergoing transplantation between 2000 and 2008 was conducted, and 48 (15.3%) developed recurrence during a median follow-up of 90.8 months. The 127 patients with available serum drawn before transplantation were included; they included 86 without recurrence and 41 with recurrence. Serum was tested for AFP, AFP-L3%, and DCP in a blinded fashion with the μTASWako i30 immunoanalyzer. All biomarkers were significantly associated with HCC recurrence. The hazard ratios (HRs) were 3.5 [95% confidence interval (CI), 1.9-6.7; P < 0.0001] for DCP ≥ 7.5 ng/mL and 2.8 (95% CI, 1.4-5.4; P = 0.002) for AFP ≥ 250 ng/mL. The HR increased to 5.2 (95% CI, 2.3-12.0; P < 0.0001) when AFP ≥ 250 ng/mL and DCP ≥7.5 ng/mL were considered together. When they were combined with the Milan criteria, the HR increased from 2.6 (95% CI, 1.4-4.7; P = 0.003) for outside the Milan criteria to 8.6 (95% CI, 3.0-24.6; P < 0.0001) for outside the Milan criteria and AFP ≥ 250 ng/mL and to 7.2 (95% CI, 2.8-18.1; P < 0.0001) for outside the Milan criteria and DCP ≥7.5 ng/mL. Our findings suggest that biomarkers are useful for predicting the risk of HCC recurrence after transplantation. Using both biomarkers and the Milan criteria may be better than using the Milan criteria alone in optimizing the decision of liver transplantation eligibility. PMID:25789635

  1. Superparamagnetic nanoparticle assisted hyperthermia and cooling protocol for optimum damage of internal carcinoma using computational predictive model

    NASA Astrophysics Data System (ADS)

    Ghosh, Soham; Gupta, Debabrata Das; Chakraborty, Suman; Das, Sarit K.

    2013-09-01

    A predictive model has been developed for superparamagnetic nanoparticle assisted hyperthermia in presence of external electromagnetic field to affect necrosis of internal carcinoma. Effect of different parameters on tissue temperature rise is tested and finally damage is analyzed to get a definitive measure of tissue destruction. A cooling protocol has been predicted to obtain maximum tumor destruction while maintaining minimum damage of the healthy tissue. We propose the comprehensive modeling strategy outlined here as the precursor to the development of efficient therapeutic planning tools for cancer patients.

  2. Bladder papillary urothelial neoplasm of low malignant potential in Chinese: a clinical and pathological analysis

    PubMed Central

    Zhang, Xin-Ke; Wang, Ying-Ying; Chen, Jie-Wei; Qin, Tao

    2015-01-01

    Papillary urothelial neoplasm of low malignant potential (PUNLMP) had the incidence of low and definitive recurrence. Therefore, few studies showed that the relationship between pathological factors and the prognosis of patients with PUNLMP. The aim of this study assessed the linkage of pathological factors and prognosis of patients with PUNLMP including the presence or absence of mitoses and the thickness of urothelium. A retrospective analysis of 71 patients with PUNLMP was enrolled between January 2007 and June 2013. The clinicopathological factors consisting of tumor diameter, multifocality, the presence or absence of mitoses and cell thickness of urothelium were retrieved, Log-rank test and Cox proportional hazards regression models were used for univariate and multivariate analyses to evaluate the associations of these factors with recurrence-free survival (RFS) and progression-free survival (PFS).The incidence of recurrence and progression for PUNLMP was 19.7% and 16.9%, respectively. Patients with grade progression represented 85.7% in the recurrent patients. No patients had stage progression and no cases died from invasive urothelial carcinoma. Univariate analysis showed that the presence of mitoses, tumor diameter greater than or equal to 0.8 cm, multifocality were significantly correlated with worse RFS (P < 0.05) and PFS (P < 0.05). Multivariate analysis demonstrated that the presence of mitoses, tumor multifocality were significantly independent biomarkers for worse RFS (P < 0.05) and PFS (P < 0.05). Although the rare and infrequent mitoses were found for PUNLMP, the presence of mitoses and tumor multifocality were still the independent and poor predictors for the prognosis of PUNLMP. In addition, once the PUNLMP appeared to the recurrence, the inevitable grade progression could be determined, herein, long-term follow-up was necessary to be warranted, especially for patients with multiple lesions and the presence of mitoses. PMID:26191263

  3. Bladder papillary urothelial neoplasm of low malignant potential in Chinese: a clinical and pathological analysis.

    PubMed

    Zhang, Xin-Ke; Wang, Ying-Ying; Chen, Jie-Wei; Qin, Tao

    2015-01-01

    Papillary urothelial neoplasm of low malignant potential (PUNLMP) had the incidence of low and definitive recurrence. Therefore, few studies showed that the relationship between pathological factors and the prognosis of patients with PUNLMP. The aim of this study assessed the linkage of pathological factors and prognosis of patients with PUNLMP including the presence or absence of mitoses and the thickness of urothelium. A retrospective analysis of 71 patients with PUNLMP was enrolled between January 2007 and June 2013. The clinicopathological factors consisting of tumor diameter, multifocality, the presence or absence of mitoses and cell thickness of urothelium were retrieved, Log-rank test and Cox proportional hazards regression models were used for univariate and multivariate analyses to evaluate the associations of these factors with recurrence-free survival (RFS) and progression-free survival (PFS).The incidence of recurrence and progression for PUNLMP was 19.7% and 16.9%, respectively. Patients with grade progression represented 85.7% in the recurrent patients. No patients had stage progression and no cases died from invasive urothelial carcinoma. Univariate analysis showed that the presence of mitoses, tumor diameter greater than or equal to 0.8 cm, multifocality were significantly correlated with worse RFS (P<0.05) and PFS (P<0.05). Multivariate analysis demonstrated that the presence of mitoses, tumor multifocality were significantly independent biomarkers for worse RFS (P<0.05) and PFS (P<0.05). Although the rare and infrequent mitoses were found for PUNLMP, the presence of mitoses and tumor multifocality were still the independent and poor predictors for the prognosis of PUNLMP. In addition, once the PUNLMP appeared to the recurrence, the inevitable grade progression could be determined, herein, long-term follow-up was necessary to be warranted, especially for patients with multiple lesions and the presence of mitoses.

  4. A theoretical model of cytosolic calcium elevation following wounding in urothelial cell monolayers

    NASA Astrophysics Data System (ADS)

    Appleby, Peter A.; Shabir, Saqib; Southgate, Jennifer; Walker, Dawn

    2013-02-01

    Scratch wounding of a urothelial cell monolayer triggers a number of events including the release of soluble, diffusible signalling factors and mechanical stimulation of cells at the wound edge. These events cause a sustained elevation in cytosolic calcium concentration in the cells surrounding the wound and a transient rise in those further away. The precise form of this calcium transient is believed to play a central role in determining the subsequent response of individual cells and ultimately leads to a co-ordinated, population-level response that rapidly closes the wound. Here we present a framework for modelling the initial phases of this process. We combine a PDE model of diffusion in the extracellular medium and an ODE model of calcium signalling that has been tailored to represent urothelial cells. The ODE model is capable of generating a wide range of calcium transients, including spikes, bursts, oscillations and sustained elevations in the cytosolic calcium concentration. In multi-cell simulations of scratch wounding in a perfusion flow we find that the spatial position of the cells relative to the wound site leads to distinct classes of calcium response, with cells proximal to the wound exhibiting a sustained elevation and cells distal to the wound exhibiting a more transient elevation. We compare these results to existing experimental data and generate a number of novel predictions that could be used to test the model experimentally.

  5. The role of GATA3 in breast carcinomas: a review.

    PubMed

    Asch-Kendrick, Rebecca; Cimino-Mathews, Ashley

    2016-02-01

    GATA3 is a zinc-binding transcription factor that regulates the differentiation of many human tissue types, including the mammary gland. In surgical pathology, immunohistochemistry for GATA3 is largely used to support urothelial or breast origin in a carcinoma of unknown origin. GATA3 is sensitive but not entirely specific in this setting. Although GATA3 labeling is highest in estrogen receptor-positive carcinomas, it also labels estrogen receptor-negative carcinomas and thus has particular diagnostic utility in the setting of triple-negative breast carcinomas, which are typically negative for other mammary-specific markers. PMID:26772397

  6. Skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma treated with sorafenib.

    PubMed

    Imai, Kenji; Takai, Koji; Hanai, Tatsunori; Ideta, Takayasu; Miyazaki, Tsuneyuki; Kochi, Takahiro; Suetsugu, Atsushi; Shiraki, Makoto; Shimizu, Masahito

    2015-01-01

    The aim of this study was to determine whether skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma (HCC) that is being treated with sorafenib. We evaluated 40 consecutive HCC patients who received sorafenib treatment. The skeletal muscle cross-sectional area was measured by computed tomography at the third lumbar vertebra (L3), from which the L3 skeletal muscle index (L3 SMI) was obtained. The factors contributing to overall survival, sorafenib dose reduction, and discontinuation of sorafenib were analyzed using the Cox proportional hazards model. L3 SMI (p = 0.020) and log (α-fetoprotein (AFP)) (p = 0.010) were identified as independent prognostic factors in HCC patients treated with sorafenib. The initial dose of sorafenib (p = 0.008) was an independent risk factor for sorafenib dose reduction, and log (AFP) (p = 0.008) was the only significant risk factor for the discontinuation of this drug. L3 SMI was not a risk factor for either dose reduction (p = 0.423) or the discontinuation (p = 0.132) of sorafenib. A multiple linear regression analysis determined the following relationship between skeletal muscle mass (assessed as L3 SMI) and the explanatory factors: L3 SMI = -0.1896 × (Age) - 10.3441 × (Child-Pugh score) - 9.3922 × (log (AFP)) + 1.6139 × (log (AFP)) × (Child-Pugh score) + 112.9166. Skeletal muscle depletion is inversely associated with age, Child-Pugh score, and log (AFP). Moreover, it is an independent prognostic factor for HCC patients treated with sorafenib. PMID:25927582

  7. Elevated Preoperative Serum Gamma-glutamyltranspeptidase Predicts Poor Prognosis for Hepatocellular Carcinoma after Liver Transplantation.

    PubMed

    Fu, Shun-Jun; Zhao, Qiang; Ji, Fei; Chen, Mao-Gen; Wu, Lin-Wei; Ren, Qing-Qi; Guo, Zhi-Yong; He, Xiao-Shun

    2016-01-01

    Gamma-glutamyltransferase (γ-GGT) is a membrane-bound enzyme that is involved in biotransformation, nucleic acid metabolism, and tumourigenesis. Elevated serum γ-GGT levels are related to an increased cancer risk and worse prognosis in many cancers. In the present study, we evaluated the prognostic value of preoperative serum γ-GGT in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). A total of 130 HCC patients after LT were included in the study. The optimal cut-off value of γ-GGT was 128U/L by receiver operating characteristic analysis, with a sensitivity and specificity of 60.0% and 72.9%, respectively. Elevated preoperative serum γ-GGT was significantly associated with high alpha-fetoprotein (AFP), large tumor size, and macro- and micro-vascular invasion. The 1-, 3-, 5-year disease-free survival (DFS) and overall survival (OS) rates of HCC patients in the γ-GGT > 128U/L group were poorer than those in the γ-GGT ≤ 128U/L group. Stratification analysis revealed that γ-GGT exhibited a greater predictive value for DFS and OS in HCC patients beyond the Milan criteria and no macro-vascular invasion. In conclusion, elevated preoperative serum γ-GGT was significantly associated with advanced tumor stage and aggressive tumor behaviors, and serum γ-GGT can be considered as a prognostic factor for HCC patients after LT, especially for patients beyond the Milan criteria or without macro-vascular invasion. PMID:27381639

  8. Postoperative aspartate aminotransferase to platelet ratio index change predicts prognosis for hepatocellular carcinoma.

    PubMed

    Peng, Wei; Li, Chuan; Wen, Tian-Fu; Yan, Lv-Nan; Li, Bo; Wang, Wen-Tao; Yang, Jia-Yin; Xu, Ming-Qing

    2016-07-01

    An elevated preoperative aspartate aminotransferase (AST) to platelet ratio index (APRI) is reported to be a prognostic factor for patients with hepatocellular carcinoma (HCC) after treatment. However, delta APRI (ΔAPRI), which represents the change from preoperative to postoperative APRI, has received little attention. The present study was designed to evaluate the prognostic value of ΔAPRI in patients with small HCC after liver resection.A retrospective cohort study analyzing 244 patients with small HCC who had undergone liver resection was conducted. Medical data were retrieved from our prospectively maintained database. Patients were divided into 2 groups according to ΔAPRI as follows: group A (ΔAPRI ≥0.02) and group B (ΔAPRI <0.02). The association of demographic and clinical data, overall survival (OS), and recurrence-free survival (RFS) were statistically compared in the 2 groups, and a multivariate analysis was used to identify prognostic factors.The 1, 3, and 5-year OS of patients in group A were 94.2%, 79.5%, and 62.3%, respectively, and 95.1%, 87.9%, and 84.6%, respectively, for patients in group B (P = 0.001). The corresponding 1, 3, and 5-year RFS was 69.0%, 44.7 %, and 28.1%, and 77.4%, 57.0%, and 54.2% for patients in the 2 groups, respectively (P = 0.009). The results of a multivariate analysis indicated that ΔAPRI was an independent prognostic factor for both OS (P = 0.001, hazard ratio 3.115, 95% confidence interval 1.642-5.912) and RFS (P = 0.006, hazard ratio 1.689, 95% confidence interval 1.163-2.452).A positive ΔAPRI after liver resection predicts decreased OS and RFS in patients with small HCC.

  9. Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma.

    PubMed

    Kucharz, Jakub; Giza, Agnieszka; Dumnicka, Paulina; Kuzniewski, Marek; Kusnierz-Cabala, Beata; Bryniarski, Pawel; Herman, Roma; Zygulska, Aneta Lidia; Krzemieniecki, Krzysztof

    2016-10-01

    Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, is a first-line treatment for metastatic renal cell carcinoma (mRCC) in patients in 'low' and 'intermediate' Memorial Sloan Kettering Cancer Center and Heng risk groups. Disruptions of hematopoiesis, such as anemia, neutropenia, and thrombocytopenia, are typically observed during sunitinib treatment. When it comes to RBC parameters, an increase in mean cell volume (MCV) tends to occur, meeting the criteria for macrocytosis in some patients (MCV > 100 fL). We examined changes in RBC parameters of 27 mRCC patients treated with sunitinib (initial dose of 50 mg/day, 6-week treatment: 4 weeks on, 2 weeks off) and correlated them with progression-free survival time (PFS). Patients who had macrocytosis after 3 treatment cycles had significantly longer PFS than those whose MCV stayed less than 100 fL (not reached vs. 11.2 months, p < 0.001). We also found a correlation between MCV values after the first and third treatment cycles and the risk of progression: HR of 0.9 (0.81-0.99) and 0.76 (0.65-0.90) per 1 fL increase in MCV, respectively. The mechanism of MCV elevation during sunitinib treatment has not yet been fully explained. One of the probable causes is sunitinib's inhibitory influence on c-Kit kinase, as is the case with imatinib. For mRCC patients, this phenomenon could help predict PFS, but since our sample was small, further studies are essential. PMID:27573381

  10. Elevated Preoperative Serum Gamma-glutamyltranspeptidase Predicts Poor Prognosis for Hepatocellular Carcinoma after Liver Transplantation

    PubMed Central

    Fu, Shun-Jun; Zhao, Qiang; Ji, Fei; Chen, Mao-Gen; Wu, Lin-Wei; Ren, Qing-Qi; Guo, Zhi-Yong; He, Xiao-Shun

    2016-01-01

    Gamma-glutamyltransferase (γ-GGT) is a membrane-bound enzyme that is involved in biotransformation, nucleic acid metabolism, and tumourigenesis. Elevated serum γ-GGT levels are related to an increased cancer risk and worse prognosis in many cancers. In the present study, we evaluated the prognostic value of preoperative serum γ-GGT in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). A total of 130 HCC patients after LT were included in the study. The optimal cut-off value of γ-GGT was 128U/L by receiver operating characteristic analysis, with a sensitivity and specificity of 60.0% and 72.9%, respectively. Elevated preoperative serum γ-GGT was significantly associated with high alpha-fetoprotein (AFP), large tumor size, and macro- and micro-vascular invasion. The 1-, 3-, 5-year disease-free survival (DFS) and overall survival (OS) rates of HCC patients in the γ-GGT > 128U/L group were poorer than those in the γ-GGT ≤ 128U/L group. Stratification analysis revealed that γ-GGT exhibited a greater predictive value for DFS and OS in HCC patients beyond the Milan criteria and no macro-vascular invasion. In conclusion, elevated preoperative serum γ-GGT was significantly associated with advanced tumor stage and aggressive tumor behaviors, and serum γ-GGT can be considered as a prognostic factor for HCC patients after LT, especially for patients beyond the Milan criteria or without macro-vascular invasion. PMID:27381639

  11. Plasma matrix metalloproteinase 1 improves the detection and survival prediction of esophageal squamous cell carcinoma

    PubMed Central

    Chen, Yu-Kuei; Tung, Chun-Wei; Lee, Jui-Ying; Hung, Yi-Chun; Lee, Chien-Hung; Chou, Shah-Hwa; Lin, Hung-Shun; Wu, Ming-Tsang; Wu, I-Chen

    2016-01-01

    This study aimed to identify noninvasive protein markers capable of detecting the presence and prognosis of esophageal squamous-cell carcinoma (ESCC). Analyzing microarray expression data collected from 17-pair ESCC specimens, we identified one protein, matrix metalloproteinase-1 (MMP1), as a possibly useful marker. Plasma MMP1 was then measured by enzyme-linked immunosorbent assay (ELISA) in 210 ESCC patients and 197 healthy controls. ESCC patients had higher mean levels of MMP1 than controls (8.7 ± 7.5 vs. 6.7 ± 4.9 ng/mL, p < 0.0001). Using the highest quartile level (9.67 ng/mL) as cut-off, we found a 9.0-fold risk of ESCC in those with higher plasma MMP1 after adjusting for covariates (95% confidence interval = 2.2, 36.0). Heavy smokers and heavy drinkers with higher plasma MMP1 had 61.4- and 31.0 times the risk, respectively, than non-users with lower MMP1. In the survival analysis, compared to those with MMP1 ≤ 9.67 ng/mL, ESCC patients with MMP1 > 9.67 ng/mL had a 48% increase in the risk of ESCC death (adjusted hazard ratio = 1.48; 95% CI = 1.04–2.10). In conclusion, plasma MMP1 may serve as a noninvasive marker of detecting the presence and predicting the survival of ESCC. PMID:27436512

  12. Serum Gamma-Glutamyl-Transferase Independently Predicts Outcome After Transarterial Chemoembolization of Hepatocellular Carcinoma: External Validation

    SciTech Connect

    Guiu, Boris Deschamps, Frederic; Boulin, Mathieu; Boige, Valerie; Malka, David; Ducreux, Michel; Hillon, Patrick; Baere, Thierry de

    2012-10-15

    Purpose: An Asian study showed that gamma glutamyl transpeptidase (GGT) can predict survival after transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). This study was designed to validate in a European population this biomarker as an independent predictor of outcome after TACE of HCC and to determine a threshold value for clinical use. Methods: In 88 consecutive patients treated by TACE for HCC, the optimal threshold for GGT serum level was determined by a ROC analysis. Endpoints were time-to-treatment failure (TTTF) and overall survival (OS). All multivariate models were internally validated using bootstrapping (90 replications). Results: Median follow-up lasted 373 days, and median overall survival was 748 days. The optimal threshold for GGT was 165 U/L (sensitivity: 89.3%; specificity: 56.7%; area under the ROC curve: 0.7515). Median TTTF was shorter when GGT was {>=}165 U/L (281 days vs. 850 days; P < 0.001). GGT {>=}165 U/L (hazard ratio (HR) = 2.06; P = 0.02), WHO PS of 2 (HR = 5.4; P = 0.002), and tumor size (HR = 1.12; P = 0.014) were independently associated with shorter TTTF. Median OS was shorter when GGT was {>=}165 U/L (508 days vs. not reached; P < 0.001). GGT {>=} 165 U/L (HR = 3.05; P = 0.029), WHO PS of 2 (HR = 12.95; P < 0.001), alfa-fetoprotein (HR = 2.9; P = 0.01), and tumor size (HR = 1.096; P = 0.013) were independently associated with shorter OS. The results were confirmed by bootstrapping. Conclusions: Our results provide in a European population the external validation of GGT as an independent predictor of outcome after TACE of HCC. A serum level of GGT {>=} 165 U/L is independently associated with both shorter TTTF and OS.

  13. Urinary bladder carcinoma with divergent differentiation featuring small cell carcinoma, sarcomatoid carcinoma, and liposarcomatous component.

    PubMed

    Yasui, Mariko; Morikawa, Teppei; Nakagawa, Tohru; Miyakawa, Jimpei; Maeda, Daichi; Homma, Yukio; Fukayama, Masashi

    2016-09-01

    Both small cell carcinoma and sarcomatoid carcinoma of the urinary bladder are highly aggressive tumors, and a concurrence of these tumors is extremely rare. We report a case of urinary bladder cancer with small cell carcinoma as a predominant component, accompanied by sarcomatoid carcinoma and conventional urothelial carcinoma (UC). Although the small cell carcinoma component had resolved on receiving chemoradiotherapy, rapid growth of the residual tumor led to a fatal outcome. A 47-year-old man presented with occasional bladder irritation and had a 2-year history of asymptomatic hematuria. Cystoscopy revealed a huge mass in the urinary bladder, and transurethral resection was performed. Microscopically, small cell carcinoma was detected as the major tumor component. Spindle-shaped sarcomatoid cells were also observed that were intermingled with small cell carcinoma and conventional UC. In addition, a sheet-like growth of the lipoblast-like neoplastic cells was observed focally. Initially, by providing chemoradiotherapy, we achieved a marked tumor regression; however, the tumor rapidly regrew after the completion of chemoradiotherapy, and the patient underwent radical cystectomy. Only conventional UC and sarcomatoid carcinoma were identified in the cystectomy specimen. The patient died of the disease 4 months after cystectomy. Urinary bladder cancer may include a combination of multiple aggressive histologies as in the present case. Because the variation in the tumor components may affect the efficacy of therapy, a correct diagnosis of every tumor component is necessary.

  14. Urinary bladder carcinoma with divergent differentiation featuring small cell carcinoma, sarcomatoid carcinoma, and liposarcomatous component.

    PubMed

    Yasui, Mariko; Morikawa, Teppei; Nakagawa, Tohru; Miyakawa, Jimpei; Maeda, Daichi; Homma, Yukio; Fukayama, Masashi

    2016-09-01

    Both small cell carcinoma and sarcomatoid carcinoma of the urinary bladder are highly aggressive tumors, and a concurrence of these tumors is extremely rare. We report a case of urinary bladder cancer with small cell carcinoma as a predominant component, accompanied by sarcomatoid carcinoma and conventional urothelial carcinoma (UC). Although the small cell carcinoma component had resolved on receiving chemoradiotherapy, rapid growth of the residual tumor led to a fatal outcome. A 47-year-old man presented with occasional bladder irritation and had a 2-year history of asymptomatic hematuria. Cystoscopy revealed a huge mass in the urinary bladder, and transurethral resection was performed. Microscopically, small cell carcinoma was detected as the major tumor component. Spindle-shaped sarcomatoid cells were also observed that were intermingled with small cell carcinoma and conventional UC. In addition, a sheet-like growth of the lipoblast-like neoplastic cells was observed focally. Initially, by providing chemoradiotherapy, we achieved a marked tumor regression; however, the tumor rapidly regrew after the completion of chemoradiotherapy, and the patient underwent radical cystectomy. Only conventional UC and sarcomatoid carcinoma were identified in the cystectomy specimen. The patient died of the disease 4 months after cystectomy. Urinary bladder cancer may include a combination of multiple aggressive histologies as in the present case. Because the variation in the tumor components may affect the efficacy of therapy, a correct diagnosis of every tumor component is necessary. PMID:27461832

  15. Is immediate postoperative CA15.3 assay a predictive marker of early postoperative recurrence of carcinoma breast?

    PubMed

    Sarkar, Diptendra Kumar; Panda, Nilanjan; Biswas, Subikas; Saha, M L; Majumder, A

    2012-03-01

    Breast cancer is still an enigma. Systemic metastasis is an important prognostic factor. Tumour marker can predict occult systemic metastasis. To evaluate the immediate postoperative CA15.3 as predictor of early recurrence, a study was carried out in 48 patients of carcinoma breast in whom immediate postoperative marker level was done. In follow-up, recurrence was noted and relation with tumour size and stage done. Null hypothesis and 't' test were used for analysis. Relation of tumour size with marker is weak but strong relation exists between tumour stage with marker and recurrence with marker. CA15.3 predicts tumour load, can also predict occult residual/occult metastatic disease better than other prognostic markers which only predict tumour behaviour.

  16. Preoperative CT-based nomogram for predicting overall survival in women with non-endometrioid carcinomas of the uterine corpus

    PubMed Central

    Lakhman, Yulia; Yakar, Derya; Goldman, Debra A.; Katz, Seth S.; Vargas, Hebert A.; Miccò, Maura; Zheng, Junting; Moskowitz, Chaya S.; Soslow, Robert A.; Hricak, Hedvig; Abu-Rustum, Nadeem R.; Sala, Evis

    2016-01-01

    Purpose To develop a preoperative CT-based nomogram for predicting overall survival (OS) in patients with non-endometrioid carcinomas of the uterine corpus. Methods Waiving informed consent, the institutional review board approved this HIPAA-compliant, retrospective study of 193 women with histopathologically proven uterine papillary serous carcinomas (UPSC), uterine clear cell carcinomas (UCCC), and uterine carcinosarcomas (UCS) who underwent primary surgical resection between May 1998 and December 2011, and had a preoperative CT ≤ 6 weeks before surgery. All CT scans were reviewed for local or/and regional tumor extent, presence of pelvic or/and paraaortic adenopathy, and presence of distant metastases. Univariate survival analysis was performed using log-rank test and Cox regression. Variables shown significant by the univariate analysis were evaluated with the multivariable Cox regression analysis and the results were used to create a nomogram for predicting OS. The predictive accuracy of the nomogram was assessed with the concordance probability index (c-index) and a 3-year calibration plot. Results Mean patient age was 67.2 years (range: 49.0–85.9); histology included UPSC (n=116), UCCC (n=27), and UCS (n=50). Median follow-up was 38.1 months (0.9–168.5 months). At multivariate analysis, patient age, ascites, and omental implants on CT were significant adverse predictors of OS and were used to build the nomogram. Concordance index for the nomogram was 0.640±0.028. Conclusion We developed a nomogram with a good concordance probability at predicting OS based on readily available pretreatment clinical and imaging characteristics. This preoperative nomogram has the potential to improve initial treatment planning and patient counseling. PMID:25549782

  17. Are we closer to seeing carcinoma in situ in the upper urinary tract?

    PubMed Central

    Aboumarzouk, Omar

    2016-01-01

    Introduction There is observed increase in detection rate of upper urinary tract urothelial cancer worldwide. This is a result of improved imaging as well as implementation of novel technologies of direct visualization of upper urinary tract. Standard techniques still remain insufficient to diagnose flat urothelial lesions. Carcinoma in situ is characterized by flat disordered proliferation of urothelial cells with marked cytologic abnormality, which occur within one cell layer as well as full thickness urothelium and therefore requires a better technology to pick up early and subtle mucosal changes. Material and methods The review presents available diagnostic tools in detection of upper urinary tract urothelial cancer and their ability to depict carcinoma in situ. Results Ureterorenoscopy is an investigation of choice as various promising techniques are under pilot investigations to enhance visualization of upper urinary tract carcinoma in situ. So far only photodynamic diagnosis has been reported to be as effective in detection of carcinoma in situ in the upper as within the lower urinary tract. Conclusions Although we are close to see upper urinary tract carcinoma in situ all new promising diagnostic techniques still require further validation in multicenter clinical trials to indicate any change to current recommendations. PMID:27551552

  18. CXCL17 Expression Predicts Poor Prognosis and Correlates with Adverse Immune Infiltration in Hepatocellular Carcinoma

    PubMed Central

    Xu, Jing; Liu, Chao-Qun; Zhen, Zuo-Jun; Chen, Huan-Wei; Ji, Yong; Wu, Zhi-Peng; Hu, Jian-Yuan; Zheng, Limin; Lau, Wan Yee

    2014-01-01

    CXC ligand 17 (CXCL17) is a novel CXC chemokine whose clinical significance remains largely unknown. In the present study, we characterized the prognostic value of CXCL17 in patients with hepatocellular carcinoma (HCC) and evaluated the association of CXCL17 with immune infiltration. We examined CXCL17 expression in 227 HCC tissue specimens by immunohistochemical staining, and correlated CXCL17 expression patterns with clinicopathological features, prognosis, and immune infiltrate density (CD4 T cells, CD8 T cells, B cells, natural killer cells, neutrophils, macrophages). Kaplan-Meier survival analysis showed that both increased intratumoral CXCL17 (P = 0.015 for overall survival [OS], P = 0.003 for recurrence-free survival [RFS]) and peritumoral CXCL17 (P = 0.002 for OS, P<0.001 for RFS) were associated with shorter OS and RFS. Patients in the CXCL17low group had significantly lower 5-year recurrence rate compared with patients in the CXCL17high group (peritumoral: 53.1% vs. 77.7%, P<0.001, intratumoral: 58.6% vs. 73.0%, P = 0.001, respectively). Multivariate Cox proportional hazards analysis identified peritumoral CXCL17 as an independent prognostic factor for both OS (hazard ratio [HR] = 2.066, 95% confidence interval [CI] = 1.296–3.292, P = 0.002) and RFS (HR = 1.844, 95% CI = 1.218–2.793, P = 0.004). Moreover, CXCL17 expression was associated with more CD68 and less CD4 cell infiltration (both P<0.05). The combination of CXCL17 density and immune infiltration could be used to further classify patients into subsets with different prognosis for RFS. Our results provide the first evidence that tumor-infiltrating CXCL17+ cell density is an independent prognostic factor that predicts both OS and RFS in HCC. CXCL17 production correlated with adverse immune infiltration and might be an important target for anti-HCC therapies. PMID:25303284

  19. Increased programmed death ligand-1 expression predicts poor prognosis in hepatocellular carcinoma patients

    PubMed Central

    Gu, Xiaobin; Gao, Xian-Shu; Xiong, Wei; Guo, Wei; Han, Linjun; Bai, Yun; Peng, Chuan; Cui, Ming; Xie, Mu

    2016-01-01

    Purpose Accumulating studies have investigated the prognostic and clinical significance of programmed death ligand-1 (PD-L1) expression in patients with hepatocellular carcinoma (HCC); however, the results were conflicting and inconclusive. We conducted a meta-analysis to combine controversial data to precisely evaluate this issue. Methods Relevant studies were thoroughly searched on PubMed, Web of Science, and Embase until April 2016. Eligible studies were evaluated by selection criteria. Hazard ratio (HR) with 95% confidence interval (CI) was used to estimate the prognostic role of PD-L1 for overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS). Odds ratio (OR) with 95% CI were selected to assess the relationship between PD-L1 and clinicopathological features of HCC patients. Publication bias was tested using Begg’s funnel plot. Results A total of seven studies published from 2009 to 2016 were included for meta-analysis. The data showed that high PD-L1 expression was correlated to shorter OS (HR =2.09, 95% CI: 1.66–2.64, P<0.001) as well as poor DFS/RFS (HR =2.3, 95% CI: 1.46–3.62, P<0.001). In addition, increased PD-L1 expression was also associated with tumor differentiation (HR =1.51, 95% CI: 1–2.29, P=0.05), vascular invasion (HR =2.16, 95% CI: 1.43–3.27, P<0.001), and α-fetoprotein (AFP; HR =1.46, 95% CI: 1–2.14, P=0.05), but had no association with tumor stage, tumor size, hepatitis history, sex, age, or tumor multiplicity. No publication bias was found for all analyses. Conclusion This meta-analysis revealed that overexpression of PD-L1 was predictive for shortened OS and DFS/RFS in HCC. Furthermore, increased PD-L1 expression was associated with less differentiation, vascular invasion, and AFP elevation. PMID:27536144

  20. Low preoperative albumin-globulin score predicts favorable survival in esophageal squamous cell carcinoma.

    PubMed

    Zhang, Fei; Sun, Peng; Wang, Zhi-Qiang; Wang, De Shen; Wang, Yun; Zhang, Dong-Sheng; Wang, Feng-Hua; Fu, Jian-Hua; Xu, Rui-Hua; Li, Yu-Hong

    2016-05-24

    This study retrospectively investigated the prognostic significance of the preoperative albumin-globulin score (AGS) and albumin/globulin ratio (AGR) in esophageal squamous cell carcinoma (ESCC). A cohort of 458 newly diagnosed ESCC patients who underwent radical esophagectomy in Sun Yat-sen University Cancer Center (Guangzhou, China) between January 2006 and December 2010 were selected into this study. The optimal cut-off value was identified to be 45.6 g/L, 26.9 g/L and 1.30 for albumin (ALB), globulin (GLB) and AGR in terms of survival, respectively. Patients with low ALB levels (< 45.6 g/L) and high GLB levels (≥ 26.9 g/L) were assigned an AGS of 2, those with only one of the two abnormalities were assigned an AGS of 1, and those with neither of the two abnormalities were assigned an AGS of 0. Univariate survival analysis showed that low AGS (0) was significantly associated with favorable disease free survival (DFS) [hazard ratio (HR), 0.635; 95% confidence interval (CI), 0.441-0.914; P = 0.015] and overall survival (OS) (HR, 0.578; 95% CI, 0.387-0.862; P = 0.007), and it remained an independent predictor for OS (HR, 0.630; 95% CI, 0.418-0.952; P = 0.028), but not for DFS (HR, 0.697; 95% CI, 0.479-1.061; P = 0.060) in multivariate models. High AGR (≥ 1.30) was also correlated with favorable DFS (HR, 0.626; 95% CI, 0.430-0.910; P = 0.014) and OS (HR, 0.622; 95% CI, 0.422-0.916; P = 0.016) in univariate analysis, but it failed to be an independent prognostic indicator for DFS (HR, 0.730; 95% CI, 0.494-1.078; P = 0.114) or OS (HR, 0.759; 95% CI, 0.507-1.137; P = 0.181) by multivariate analysis. Low preoperative AGS could serve as a valuable and convenient biochemical marker to predict favorable long-term survival in ESCC patients. PMID:27105522

  1. Expression of miRNAs and ZEB1 and ZEB2 correlates with histopathological grade in papillary urothelial tumors of the urinary bladder.

    PubMed

    Lee, Heejeong; Jun, Sun-Young; Lee, Youn-Soo; Lee, Hee Jin; Lee, Weon Sun; Park, Chul Soo

    2014-02-01

    Histopathological grading of papillary urothelial tumors (PUTs) of the urinary bladder is subjective and poorly reproducible. We investigated the relationship between the expression of frequently deregulated microRNAs (miRNAs) as well as their target genes (ZEB1/ZEB2) and bladder cancer histopathological grade in an attempt to find a miRNA that might allow more reliable grading of PUTs. We measured the expression levels of four miRNAs (miR-145, miR-205, miR-125b, and miR-200c) in 120 formalin-fixed, paraffin-embedded bladder tumor tissue samples using real-time PCR assays. ZEB1 and ZEB2 expression was assessed in the same bladder tissues by immunohistochemistry. MiR-205 distinguished low-grade papillary urothelial carcinoma (LG) from high-grade papillary urothelial carcinoma (HG), and miR-145 distinguished HG from infiltrating carcinoma (CA) with an area under the receiver operator characteristic curve (AUC) of 0.992 and 0.997, respectively (sensitivity/specificity of 95.8/96.7 % and 100/91.7 %, respectively; p < 0.05). The expression level of miR-125b was significantly lower in LG than in PUNLMP, with an AUC value of 0.870 (93.3 % sensitivity and 84.2 % specificity; p < 0.05). ZEB1 immunoreactivity was more frequently detected in HG than in LG (57 % vs 13 %, p < 0.01) and in HG than in CA (57 % vs 17 %, p < 0.01). ZEB2 immunoreactivity was more frequent in CA than in HG (83 % vs 54 %, p < 0.05). ZEB1/ZEB2 and miRNAs expression seems to reliably distinguish between different grades of PUTs of the urinary bladder. They might well serve as useful complementary diagnostic biomarkers for grading of papillary urothelial tumors.

  2. A Global Risk Score (GRS) to Simultaneously Predict Early and Late Tumor Recurrence Risk after Resection of Hepatocellular Carcinoma1

    PubMed Central

    Dekervel, Jeroen; Popovic, Dusan; van Malenstein, Hannah; Windmolders, Petra; Heylen, Line; Libbrecht, Louis; Bulle, Ashenafi; De Moor, Bart; Van Cutsem, Eric; Nevens, Frederik; Verslype, Chris; van Pelt, Jos

    2016-01-01

    OBJECTIVES: Recurrence of hepatocellular carcinoma can arise from the primary tumor (“early recurrence”) or de novo from tumor formation in a cirrhotic environment (“late recurrence”). We aimed to develop one simple gene expression score applicable in both the tumor and the surrounding liver that can predict the recurrence risk. METHODS: We determined differentially expressed genes in a cell model of cancer aggressiveness. These genes were first validated in three large published data sets of hepatocellular carcinoma from which we developed a seven-gene risk score. RESULTS: The gene score was applied on two independent large patient cohorts. In the first cohort, with only tumor data available, it could predict the recurrence risk at 3 years after resection (68 ± 10% vs 35 ± 7%, P = .03). In the second cohort, when applied on the tumor, this gene score predicted early recurrence (62 ± 5% vs 37 ± 4%, P < .001), and when applied on the surrounding liver tissue, the same genes also correlated with late recurrence. Four patient classes with each different time patterns and rates of recurrence could be identified based on combining tumor and liver scores. In a multivariate Cox regression analysis, our gene score remained significantly associated with recurrence, independent from other important cofactors such as disease stage (P = .007). CONCLUSIONS: We developed a Global Risk Score that is able to simultaneously predict the risk of early recurrence when applied on the tumor itself, as well as the risk of late recurrence when applied on the surrounding liver tissue. PMID:27084430

  3. Identification of methylation markers for the prediction of nodal metastasis in oral and oropharyngeal squamous cell carcinoma.

    PubMed

    Melchers, L J; Clausen, M J A M; Mastik, M F; Slagter-Menkema, L; van der Wal, J E; Wisman, G B A; Roodenburg, J L N; Schuuring, E

    2015-01-01

    Hypermethylation is an important mechanism for the dynamic regulation of gene expression, necessary for metastasizing tumour cells. Our aim is to identify methylation tumour markers that have a predictive value for the presence of regional lymph node metastases in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). Significantly differentially expressed genes were retrieved from four reported microarray expression profiles comparing pN0 and pN+ head-neck tumours, and one expression array identifying functionally hypermethylated genes. Additional metastasis-associated genes were included from the literature. Thus genes were selected that influence the development of nodal metastases and might be regulated by methylation. Methylation-specific PCR (MSP) primers were designed and tested on 8 head-neck squamous cell carcinoma cell lines and technically validated on 10 formalin-fixed paraffin-embedded (FFPE) OOSCC cases. Predictive value was assessed in a clinical series of 70 FFPE OOSCC with pathologically determined nodal status. Five out of 28 methylation markers (OCLN, CDKN2A, MGMT, MLH1 and DAPK1) were frequently differentially methylated in OOSCC. Of these, MGMT methylation was associated with pN0 status (P = 0.02) and with lower immunoexpression (P = 0.02). DAPK1 methylation was associated with pN+ status (P = 0.008) but did not associate with protein expression. In conclusion, out of 28 candidate genes, two (7%) showed a predictive value for the pN status. Both genes, DAPK1 and MGMT, have predictive value for nodal metastasis in a clinical group of OOSCC. Therefore DNA methylation markers are capable of contributing to diagnosis and treatment selection in OOSCC. To efficiently identify additional new methylation markers, genome-wide methods are needed. PMID:26213212

  4. HIF1-Alpha Expression Predicts Survival of Patients with Squamous Cell Carcinoma of the Oral Cavity

    PubMed Central

    dos Santos, Marcelo; Mercante, Ana Maria da Cunha; Louro, Iúri Drumond; Gonçalves, Antônio José; de Carvalho, Marcos Brasilino; da Silva, Eloiza Helena Tajara; da Silva, Adriana Madeira Álvares

    2012-01-01

    Background Oral squamous cell carcinoma is an important cause of death and morbidity wordwide and effective prognostic markers are still to be discovered. HIF1α protein is associated with hypoxia response and neovascularization, essential conditions for solid tumors survival. The relationship between HIF1α expression, tumor progression and treatment response in head and neck cancer is still poorly understood. Patients and Methods In this study, we investigated HIF1α expression by immunohistochemistry in tissue microarrays and its relationship with clinical findings, histopathological results and survival of 66 patients with squamous cell carcinoma of the lower mouth. Results Our results demonstrated that high HIF1α expression is associated with local disease-free survival, independently from the choice of treatment. Furthermore, high expression of HIF1α in patients treated with postoperative radiotherapy was associated with survival, therefore being a novel prognostic marker in squamous cell carcinoma of the mouth. Additionally, our results showed that MVD was associated with HIF1α expression and local disease relapse. Conclusion These findings suggest that HIF1α expression can be used as a prognostic marker and predictor of postoperative radiotherapy response, helping the oncologist choose the best treatment for each patient. PMID:23028863

  5. Urothelial bladder cancer with cavitary lung metastases.

    PubMed

    Kurian, Anil; Lee, Jason; Born, Abraham

    2011-01-01

    Transitional cell carcinoma (TCC) of the bladder tends to remain superficial; however, in 5% to 20% of cases, it progresses to muscle invasion and, more rarely, can metastasize. TCC of the bladder primarily spreads via regional lymphatics. The most common sites of distant metastases of TCC are the liver, lung, mediastinum and bone. Longterm survival of patients with metastatic bladder cancer is rare. Patterns of pulmonary metastasis include multiple nodules, a solitary mass or interstitial micronodule. When multiple nodules are present, they are round and well-circumscribed, without calcification or cavitation. An unusual case of rapidly metastatic TCC to the lung causing large cavitary masses and nodules is presented. Imaging performed after the patient began chemotherapy revealed widespread necrosis of the metastatic cavitary masses causing moderate volume hemoptysis. PMID:21766082

  6. Chromosomal damage in urothelial cells from Egyptians with chronic Schistosoma haematobium infections.

    PubMed

    Rosin, M P; Anwar, W

    1992-02-20

    The most common cancer in Egypt is urinary-bladder carcinoma, which is strongly associated with infection with Schistosoma haematobium. The object of this study was to determine whether infection with this parasite resulted in an increase in chromosomal breakage in the urothelium. Urine samples were collected from 37 Egyptian farmers with S. haematobium ova in their urine and from 32 non-infected males attending the same village clinic. The urine was centrifuged and the urothelial cells present in the sediment were assayed for the presence of micronuclei, a quantitative indicator of chromosomal breakage. Micronucleus frequencies were significantly higher in the infected group (mean frequency, 0.97 +/- 0.12%) than among controls (mean frequency, 0.12 +/- 0.04%, p less than 0.001). There was a trend towards an increase in micronucleus frequencies in infected individuals who smoked (10 of the 37 subjects) compared with those who were non-smokers, although this effect was not significant (p = 0.12). Bladder infection was associated with a 6.8-fold increase in micronucleus frequencies among non-smokers. In a pilot study, 11 patients were treated with praziquantel, an anti-schistosomal agent. Mean micronucleus frequencies were reduced significantly (before treatment, 1.27 +/- 0.16%; after treatment, 0.30 +/- 0.16%, p less than 0.001), thus supporting a direct involvement of the infection in increased chromosomal breakage in the urothelium.

  7. Nomograms for predicting long-term survival in patients with non-metastatic nasopharyngeal carcinoma in an endemic area

    PubMed Central

    Meng, Xiang-Qi; Guo, Xiang; Qian, Chao-Nan; Wu, Pei-Hong; Huang, Pei-Yu

    2016-01-01

    Purpose Nomogram for predicting more than a 5-year survival for non-metastatic nasopharyngeal carcinoma (NPC) was lacking. This study aimed to develop the new nomograms to predict long-term survival in these patients. Results The median follow-up time for training set and test set was 95.2 months and 133.3 months, respectively. The significant predictors for death were age, gender, body mass index (BMI), T stage, N stage, lactate dehydrogenase (LDH), and radiotherapy techniques. For predicting recurrence, age, gender, T stage, LDH, and radiotherapy techniques were significant predictors, whereas age, gender, BMI, T stage, N stage and LDH were significant predictors for distant metastasis. The calibration curves showed the good agreements between nomogram-predicted and actual survival. The c-indices for predicting death, recurrence, and distant metastases between nomograms and the TNM staging system were 0.767 VS.0.686 (P<0.001), 0.655 VS.0.585 (P<0.001), and 0.881 VS.0.754 (P<0.001), respectively. These results were further confirmed in the test set. Methods On the basis of a retrospective study of 1593 patients (training set) who received radiotherapy alone or concurrent chemoradiotherapy from 2000 to 2004, significant predictors were identified and incorporated to build the nomograms. The calibration curves of nomogram-predicted survival versus the actual survival were plotted and reviewed. Bootstrap validation was performed to calculate the concordance index (c-index). These models were further validated in an independent prospective trial (test set, n=400). Conclusion The established nomograms suggest more-accurate long-term prediction for patients with non-metastatic NPC. PMID:27102440

  8. MCAM and LAMA4 are highly enriched in tumor blood vessels of renal cell carcinoma and predict patient outcome

    PubMed Central

    Wragg, Joseph W; Finnity, Jonathan P; Anderson, Jane A; Ferguson, Henry JM; Porfiri, Emilio; Bhatt, Rupesh I; Murray, Paul G; Heath, Victoria L; Bicknell, Roy

    2016-01-01

    The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma (CRC), or colorectal liver metastasis (CRM). We identified a panel of genes consistently upregulated by tumor blood vessels of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and CRC blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in CRC. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting. PMID:26921326

  9. Predictive Value of Antiviral Effects in the Development of Hepatocellular Carcinoma in the General Korean Population with Chronic Hepatitis B

    PubMed Central

    Shim, Jae-Jun; Oh, In Hwan; Kim, Sang Bae; Kim, Jung Wook; Lee, Chang Kyun; Jang, Jae Young; Lee, Ju-Seog; Kim, Byung-Ho

    2016-01-01

    Background/Aims The benefit of oral antiviral therapy in preventing hepatocellular carcinoma (HCC) in the general population is not well understood. We used a novel prediction method to estimate the risk of HCC in the Korean population based on various treatment guidelines. Methods The 5-year risk of HCC following antiviral therapy was calculated using an HCC risk prediction model. A virtual cohort that represented Koreans (>40 years old) with chronic hepatitis B virus (HBV) infection was established using the fifth National Health and Nutrition Examination Survey. The antiviral indications tested were the Korean National Health Insurance (NHI) and European Association for the Study of the Liver (EASL) guidelines as well as a new extended indication (serum HBV DNA >2,000 IU/mL regardless of serum aminotransferase level). Results A total of 993,872 subjects were infected with HBV in the general Korean population. Over a 5-year period, 2,725 HCC cases were predicted per 100,000 persons (0.55%/yr). When the cohort was treated based on the Korean NHI, the EASL, and the newly extended indications, HCC risks decreased to 2,531 (−7.1%), 2,089 (−23.3%), and 1,122 (−58.8%) cases per 100,000 persons, respectively (p<0.0001). Conclusions Simulated risk prediction suggests that extending of oral antiviral indication may reduce the HCC risk in the general population. PMID:27282260

  10. The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma.

    PubMed

    Ma, Kai; Cao, Baoping; Guo, Mingzhou

    2016-01-01

    Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC). Tobacco smoking and alcohol consumption are two major risk factors for ESCC, and both tobacco and alcohol were found to induce methylation changes in ESCC. Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression. DNA methylation may occur in the key components of cancer-related signaling pathways. Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-β, and NF-κB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382. Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17. CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC. FHIT methylation is associated with poor prognosis in ESCC. Aberrant DNA methylation changes may serve as diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies. PMID:27110300

  11. Vinflunine treatment in patients with metastatic urothelial cancer: A Nordic retrospective multicenter analysis

    PubMed Central

    Holmsten, Karin; Dohn, Line; Jensen, Niels Viggo; Shah, Carl-Henrik; Jäderling, Fredrik; Pappot, Helle; Ullén, Anders

    2016-01-01

    In 2009, vinflunine was introduced as a second-line treatment to be used after the failure of platinum therapy in patients with metastatic urothelial carcinoma (mUC). The present study investigated the administered vinflunine to patients with mUC in standard clinical practice with the aim of evaluating treatment patterns, response, survival parameters and side-effects. Data were collected retrospectively from the first 100 mUC patients treated with vinflunine at three Nordic cancer centers associated with the Nordic Urothelial Cancer Oncology Group. The overall response rate was 23% and complete response was observed in one patient. The median progression-free survival (mPFS) and median overall survival (mOS) were 2.8 (range, 0.5–34.3) and 6.3 (range, 0.3–39.7) months, respectively. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 was present in 20% of the patients, and those patients exhibited significantly shorter mOS (4.1 vs. 7.0 months, P=0.001) and a significantly higher degree of grade 3/4 toxicity (P=0.026) compared with ECOG PS 0–1 patients. Furthermore, patients without visceral metastases had significantly longer mOS than patients with visceral metastases (10.6 vs. 6.0 months, P=0.008). The median number of cycles of vinflunine was 3 (range, 1–28). The current data confirms that vinflunine is an active agent for second-line treatment in an unselected clinical cohort of patients with mUC. ECOG PS and presence of visceral metastases were significant prognostic parameters. In particular, patients with ECOG PS 2 receiving vinflunine had a shorter mOS and a higher frequency of severe toxicity, and, thus, should be treated with caution. Furthermore, the present study observed large inter-individual differences in radiological response and OS, indicating the need for further development of improved patient selection tools to optimize vinflunine treatment in platinum-refractory mUC patients. PMID:27446429

  12. The phosphorylation status of VASP at serine 322 can be predictive for aggressiveness of invasive ductal carcinoma

    PubMed Central

    Borges, Sahra; Geiger, Xochiquetzal; Storz, Peter

    2015-01-01

    Vasodilator-stimulated phosphoprotein (VASP) signaling is critical for dynamic actin reorganization processes that define the motile phenotype of cells. Here we show that VASP is generally highly expressed in normal breast tissue and breast cancer. We also show that the phosphorylation status of VASP at S322 can be predictive for breast cancer progression to an aggressive phenotype. Our data indicate that phosphorylation at S322 is gradually decreased from normal breast to DCIS, luminal/ER+, HER2+ and basal-like/TN phenotypes. Similarly, the expression levels of PKD2, the kinase that phosphorylates VASP at this site, are decreased in invasive ductal carcinoma samples of all three groups. Overall, the phosphorylation status of this residue may serve as an indicator of aggressiveness of breast tumors. PMID:26336132

  13. Role of CT Perfusion in Monitoring and Prediction of Response to Therapy of Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Preda, Lorenzo; Moscatelli, Marco Elvio Manlio; Cossu Rocca, Maria

    2014-01-01

    This review aims to summarize the technique and clinical applications of CT perfusion (CTp) of head and neck cancer. The most common pathologic type (90%) of head and neck cancer is squamous cell carcinoma (HNSCC): its diagnostic workup relies on CT and MRI, as they provide an accurate staging for the disease by determining tumour volume, assessing its extension, and detecting of lymph node metastases. Compared with conventional CT and MRI, CTp allows for obtaining measures of tumour vascular physiology and functional behaviour, and it has been demonstrated to be a feasible and useful tool in predicting local outcomes in patients undergoing radiation therapy and chemotherapy and may help monitor both treatments. PMID:25140324

  14. The phosphorylation status of VASP at serine 322 can be predictive for aggressiveness of invasive ductal carcinoma.

    PubMed

    Döppler, Heike; Bastea, Ligia; Borges, Sahra; Geiger, Xochiquetzal; Storz, Peter

    2015-10-01

    Vasodilator-stimulated phosphoprotein (VASP) signaling is critical for dynamic actin reorganization processes that define the motile phenotype of cells. Here we show that VASP is generally highly expressed in normal breast tissue and breast cancer. We also show that the phosphorylation status of VASP at S322 can be predictive for breast cancer progression to an aggressive phenotype. Our data indicate that phosphorylation at S322 is gradually decreased from normal breast to DCIS, luminal/ER+, HER2+ and basal-like/TN phenotypes. Similarly, the expression levels of PKD2, the kinase that phosphorylates VASP at this site, are decreased in invasive ductal carcinoma samples of all three groups. Overall, the phosphorylation status of this residue may serve as an indicator of aggressiveness of breast tumors. PMID:26336132

  15. An Encapsulation of Gene Signatures for Hepatocellular Carcinoma, MicroRNA-132 Predicted Target Genes and the Corresponding Overlaps

    PubMed Central

    Chen, Gang; Ren, Fanghui; Liang, Haiwei; Dang, Yiwu; Rong, Minhua

    2016-01-01

    Objectives Previous studies have demonstrated that microRNA-132 plays a vital part in and is actively associated with several cancers, with its tumor-suppressive role in hepatocellular carcinoma confirmed. The current study employed multiple bioinformatics techniques to establish gene signatures for hepatocellular carcinoma, microRNA-132 predicted target genes and the corresponding overlaps. Methods Various assays were performed to explore the role and cellular functions of miR-132 in HCC and a successive panel of tasks was completed, including NLP analysis, miR-132 target genes prediction, comprehensive analyses (gene ontology analysis, pathway analysis, network analysis and connectivity analysis), and analytical integration. Later, HCC-related and miR-132-related potential targets, pathways, networks and highlighted hub genes were revealed as well as those of the overlapped section. Results MiR-132 was effective in both impeding cell growth and boosting apoptosis in HCC cell lines. A total of fifty-nine genes were obtained from the analytical integration, which were considered to be both HCC- and miR-132-related. Moreover, four specific pathways were unveiled in the network analysis of the overlaps, i.e. adherens junction, VEGF signaling pathway, neurotrophin signaling pathway, and MAPK signaling pathway. Conclusions The tumor-suppressive role of miR-132 in HCC has been further confirmed by in vitro experiments. Gene signatures in the study identified the potential molecular mechanisms of HCC, miR-132 and their established associations, which might be effective for diagnosis, individualized treatments and prognosis of HCC patients. However, combined detections of miR-132 with other bio-indicators in clinical practice and further in vitro experiments are needed. PMID:27467251

  16. Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation.

    PubMed

    Dumoff, Kimberly L; Chu, Christina S; Harris, Eleanor E; Holtz, David; Xu, Xiaowei; Zhang, Paul J; Acs, Geza

    2006-05-01

    Lymphatic invasion and nodal metastasis are predictors of poor outcome in cervix carcinoma. We have recently found that low podoplanin immunoreactivity in cervix carcinoma correlated with the presence of lymphatic invasion and nodal metastasis. In the current study, we examined whether podoplanin expression in pretreatment cervical biopsies can predict the presence lymphatic invasion, nodal metastasis, and outcome in advanced-stage tumors treated by nonsurgical means. Podoplanin expression was analyzed by immunohistochemistry in 48 cervical biopsies and corresponding hysterectomy specimens of early-stage invasive squamous cell carcinoma and in 74 pretreatment biopsies from advanced-stage tumors treated with primary radiation. We found a highly significant correlation between podoplanin expression obtained in biopsy and corresponding hysterectomy materials (r = 0.8962, P < 0.0001). Low podoplanin expression showed a significant correlation with lymphatic invasion (P < 0.0001) and nodal metastasis (P = 0.0058). Low podoplanin expression in pretreatment biopsy material showed a significant correlation with poor disease-free (P = 0.0009) and overall (P = 0.0002) survival in advanced-stage tumors. Our results suggest that in advanced-stage cervix carcinomas treated by radiation, when traditional prognostic indicators are not available and treatment decisions are based on biopsy material and clinical staging parameters, examination of podoplanin expression in pretreatment biopsy material may be a useful marker to predict lymphatic metastasis and patient outcome. Prospective studies involving larger numbers of patients are needed to further evaluate the clinical utility of examination of podoplanin expression in patients with cervix carcinoma.

  17. ISG15 predicts poor prognosis and promotes cancer stem cell phenotype in nasopharyngeal carcinoma

    PubMed Central

    Han, Ping; Wang, Hong-Bo; Liang, Fa-Ya; Feng, Guo-Kai; Zhou, Ai-Jun; Cai, Mu-Yan; Zhong, Qian; Zeng, Mu-Sheng; Huang, Xiao-Ming

    2016-01-01

    Interferon-stimulated gene 15 (ISG15), the first identified ubiquitin-like protein, is known for its anti-viral capacity. However, its role in tumorigenesis remains controversial. Here, using RNA-seq profiling analysis, we identified ISG15 as a differentially expressed gene in nasopharyngeal carcinoma (NPC) and validated its overexpression in NPC samples and cells. High ISG15 levels in NPC tissues were correlated with more frequent local recurrence and shorter overall survival and disease-free survival. ISG15 overexpression promoted a cancer stem cell phenotype in NPC cells, including increased colony and tumorsphere formation abilities, pluripotency-associated genes expression, and in vivo tumorigenicity. By contrast, knockdown of ISG15 attenuated stemness characteristics in NPC cells. Furthermore, overexpression of ISG15 increased NPC cell resistance to radiation and cisplatin (DDP) treatment. Our study demonstrates a protumor role of ISG15, and suggests that ISG15 is a prognostic predictor and a potential therapeutic target for NPC. PMID:26919245

  18. A possible role of microRNAs as predictive markers for the recurrence of hepatocellular carcinoma after liver transplantation.

    PubMed

    Liese, Juliane; Peveling-Oberhag, Jan; Doering, Claudia; Schnitzbauer, Andreas A; Herrmann, Eva; Zangos, Stephan; Hansmann, Martin L; Moench, Christian; Welker, Martin W; Zeuzem, Stefan; Bechstein, Wolf O; Ulrich, Frank

    2016-03-01

    With favourable 5-year survival rates up to 75%, liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). Nonetheless, tumour recurrence after LT remains a challenge. The aim of this retrospective study was to develop a predictive score for tumour recurrence after LT by combining clinical parameters with HCC biomarkers (microRNA). A microRNA (miRNA) microarray analysis was used to compare miRNA expression patterns in tissue samples of 40 patients with and without HCC recurrence after LT. In a screening cohort (n = 18), the miRNA analysis identified significant differences in the expression of 13 miRNAs in patients with tumour recurrence. Using the most significant miRNAs in this screening cohort, we could develop a predictive score, which combined the expression levels of miR-214, miR-3187 and the Milan criteria, and we could define low- and high-risk groups for tumour recurrence and death. The above score was evaluated in a second and independent cohort (n = 22). In contrast to the Milan criteria alone, this score was significantly associated with tumour recurrence. Our analysis indicated that the use of a specific miRNA expression pattern in combination with a limited tumour burden as defined by the Milan criteria may lead to a more accurate prediction of tumour recurrence.

  19. A Novel and Validated Inflammation-Based Score (IBS) Predicts Survival in Patients With Hepatocellular Carcinoma Following Curative Surgical Resection

    PubMed Central

    Fu, Yi-Peng; Ni, Xiao-Chun; Yi, Yong; Cai, Xiao-Yan; He, Hong-Wei; Wang, Jia-Xing; Lu, Zhu-Feng; Han, Xu; Cao, Ya; Zhou, Jian; Fan, Jia; Qiu, Shuang-Jian

    2016-01-01

    Abstract As chronic inflammation is involved in the pathogenesis and progression of hepatocellular carcinoma (HCC), we investigated the prognostic accuracy of a cluster of inflammatory scores, including the Glasgow Prognostic Score, modified Glasgow Prognostic Score, platelet to lymphocyte ratio, Prognostic Nutritional Index, Prognostic Index, and a novel Inflammation-Based Score (IBS) integrated preoperative and postoperative neutrophil to lymphocyte ratio in 2 independent cohorts. Further, we aimed to formulate an effective prognostic nomogram for HCC after hepatectomy. Prognostic value of inflammatory scores and Barcelona Clinic Liver Cancer (BCLC) stage were studied in a training cohort of 772 patients with HCC underwent hepatectomy. Independent predictors of survival identified in multivariate analysis were validated in an independent set of 349 patients with an overall similar clinical feature. In both training and validation cohorts, IBS, microscopic vascular invasion, and BCLC stage emerged as independent factors of overall survival (OS) and recurrence-free survival (RFS). The predictive capacity of the IBS in both OS and RFS appeared superior to that of the other inflammatory scores in terms of C-index. Additionally, the formulated nomogram comprised IBS resulted in more accurate prognostic prediction compared with BCLC stage alone. IBS is a novel and validated prognostic indicator of HCC after curative resection, and a robust HCC nomogram including IBS was developed to predict survival for patients after hepatectomy. PMID:26886627

  20. Predictive Value of Estimated Tumor Volume Measured by Ultrasonography for Occult Central Lymph Node Metastasis in Papillary Thyroid Carcinoma.

    PubMed

    Park, Ki Nam; Kang, Kyung Yoon; Hong, Hyun Sook; Jeong, Han-Shin; Lee, Seung Won

    2015-11-01

    The clinical and prognostic value of tumor volume in various solid tumors has been investigated. However, there have been few studies on the clinical impact of tumor volume in papillary thyroid carcinoma (PTC). This study was performed to investigate the predictive value of estimated tumor volume measured by ultrasonography for occult central neck metastasis (OCNM) of PTC. A total of 264 patients with clinically node-negative PTC on ultrasonography and computed tomography who underwent total thyroidectomy in conjunction with at least ipsilateral prophylactic central neck dissection were enrolled in this study. Tumor volume was derived with the formula used to calculate ellipsoids from two orthogonal scans during 2-D ultrasonography at initial aspiration biopsy. We retrospectively evaluated demographic characteristics, pre-operative ultrasonographic features (tumor size, volume and multifocality) and pathologic results. The OCNM rate was 35.6%; estimated tumor volume was used to predict OCNM (p = 0.035). At 0.385 mL, sensitivity and specificity were 51.1% and 66.5%, and the area under the curve for OCNM detection was 0.610. In multivariate analysis, tumor volume, but not size, was an independent predictive factor for OCNM (odds ratio = 1.83, p = 0.029). The other factors were extrathyroidal extension (odds ratio = 2.39, p = 0.004) and male gender (odds ratio = 3.90, p < 0.001). The estimated tumor volume of PTC measured by ultrasonography could be a pre-operative predictor of OCNM.

  1. Clonal, Self-Renewing and Differentiating Human and Porcine Urothelial Cells, a Novel Stem Cell Population

    PubMed Central

    Larsson, Hans M.; Gorostidi, Francois; Hubbell, Jeffrey A.; Barrandon, Yann; Frey, Peter

    2014-01-01

    Although urothelial progenitor-like cells have been described in the human urinary tract, the existence of stem cells remains to be proven. Using a culture system that favors clonogenic epithelial cell growth, we evaluated and characterized clonal human urothelial cells. We isolated human urothelial cells that were clonogenic, capable of self-renewal and could develop into fully differentiated urothelium once re-implanted into the subcapsular space of nude mice. In addition to final urothelial cell differentiation, spontaneous formation of bladder-like microstructures was observed. By examining an epithelial stem cell signature marker, we found p63 to correlate with the self-renewal capacity of the isolated human urothelial clonal populations. Since a clinically relevant, long-term model for functional reconstitution of human cells does not exist, we sought to establish a culture method for porcine urothelial cells in a clinically relevant porcine model. We isolated cells from porcine ureter, urethra and bladder that were clonogenic and capable of self-renewal and differentiation into fully mature urothelium. In conclusion, we could isolate human and porcine cell populations, behaving as urothelial stem cells and showing clonogenicity, self-renewal and, once re-implanted, morphological differentiation. PMID:24587183

  2. Dynamic Change in p63 Protein Expression during Implantation of Urothelial Cancer Clusters12

    PubMed Central

    Yoshida, Takahiro; Okuyama, Hiroaki; Nakayama, Masashi; Endo, Hiroko; Tomita, Yasuhiko; Nonomura, Norio; Nishimura, Kazuo; Inoue, Masahiro

    2015-01-01

    Although the dissemination of urothelial cancer cells is supposed to be a major cause of the multicentricity of urothelial tumors, the mechanism of implantation has not been well investigated. Here, we found that cancer cell clusters from the urine of patients with urothelial cancer retain the ability to survive, grow, and adhere. By using cell lines and primary cells collected from multiple patients, we demonstrate that △ Np63α protein in cancer cell clusters was rapidly decreased through proteasomal degradation when clusters were attached to the matrix, leading to downregulation of E-cadherin and upregulation of N-cadherin. Decreased △ Np63α protein level in urothelial cancer cell clusters was involved in the clearance of the urothelium. Our data provide the first evidence that clusters of urothelial cancer cells exhibit dynamic changes in △ Np63α expression during attachment to the matrix, and decreased △ Np63α protein plays a critical role in the interaction between cancer cell clusters and the urothelium. Thus, because △ Np63α might be involved in the process of intraluminal dissemination of urothelial cancer cells, blocking the degradation of △ Np63α could be a target of therapy to prevent the dissemination of urothelial cancer. PMID:26297435

  3. Overexpression of WWP1 Promotes tumorigenesis and predicts unfavorable prognosis in patients with hepatocellular carcinoma

    PubMed Central

    Pan, Qiu-Zhong; Pan, Ke; Weng, De-Sheng; Wang, Qi-Jing; Zhao, Jing-Jing; He, Jia; Liu, Qing; Jiang, Shan-Shan; Chen, Chang-Long; Zhang, Hong-Xia; Xia, Jian-Chuan

    2015-01-01

    WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) has been speculated to play important roles in the development of several kinds of cancers. However, the role of WWP1 in hepatocellular carcinoma(HCC) is not clear. In the present study, we investigated the expression and prognostic role of WWP1 in primary hepatocellular carcinoma (HCC) using cell lines and 149 archived HCC samples. Correlation between the functions of WWP1 in HCC was also explored. We used human HCC cell lines (BEL-7402, SMMC-7721, Hep-G2, Hep-3B, SK-hep1 and Huh7) and a normal hepatocyte cell line (LO2) along with HCC samples from patients who had undergone resection for HCC previously at our hospital. A battery of methods (real-time quantitative polymerase chain reaction; western blotting; immunohistochemical analyses; cell proliferation and colony formation assays; cell migration and cell invasion assays) were employed to assess various aspects of WWP1. We found that WWP1 expression was upregulated aberrantly at mRNA and protein levels in human primary HCC tissues. Amplified expression of WWP1 was highly correlated with poor outcome. Silencing of WWP1 expression by siRNA inhibited the proliferation, colony formation, migration and invasion of HCC cells in vitro, and resulted in significant apoptosis and cycle arrest in HCC cells. Our findings suggest that WWP1 might have an oncogenic role in human primary HCC, and that it could be used as a prognostic marker as well as a potential molecular target for the treatment of HCC. PMID:26506518

  4. Immunohistochemical Determination of p53 Protein Overexpression for Predicting p53 Gene Mutations in Hepatocellular Carcinoma: A Meta-Analysis

    PubMed Central

    Deng, Miao; Liu, Dechun; Ma, Qingyong; Feng, Xiaoshan

    2016-01-01

    Background Whether increased expression of the tumor suppressor protein p53 indicates a p53 gene mutation in hepatocellular carcinoma (HCC) remains unclear. We conducted a meta-analysis to determine whether p53 protein overexpression detected by immunohistochemistry (IHC) offers a diagnostic prediction for p53 gene mutations in HCC patients. Methods Systematic literature searches were conducted with an end date of December 2015. A meta-analysis was performed to estimate the diagnostic accuracy of IHC-determined p53 protein overexpression in the prediction of p53 gene mutations in HCC. Sensitivity, subgroup, and publication bias analyses were also conducted. Results Thirty-six studies were included in the meta-analysis. The results showed that the overall sensitivity and specificity for IHC-determined p53 overexpression in the diagnostic prediction of p53 mutations in HCC were 0.83 (95% CI: 0.80–0.86) and 0.74 (95% CI: 0.71–0.76), respectively. The summary positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.65 (95% CI: 2.21–3.18) and 0.36 (95% CI: 0.26–0.50), respectively. The diagnostic odds ratio (DOR) of IHC-determined p53 overexpression in predicting p53 mutations ranged from 0.56 to 105.00 (pooled, 9.77; 95% CI: 6.35–15.02), with significant heterogeneity between the included studies (I2 = 40.7%, P = 0.0067). Moreover, subgroup and sensitivity analyses did not alter the results of the meta-analysis. However, potential publication bias was present in the current meta-analysis. Conclusion The upregulation of the tumor suppressor protein p53 was indeed linked to p53 gene mutations. IHC determination of p53 overexpression can predict p53 gene mutations in HCC patients. PMID:27428001

  5. Hexavalent chromium induces chromosome instability in human urothelial cells.

    PubMed

    Wise, Sandra S; Holmes, Amie L; Liou, Louis; Adam, Rosalyn M; Wise, John Pierce

    2016-04-01

    Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of hexavalent chromium (Cr(VI)) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Cr(VI) induced a concentration- and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer, specifically, and may be a mechanism for metal-induced bladder cancer, in general. PMID:26908176

  6. Hexavalent chromium induces chromosome instability in human urothelial cells.

    PubMed

    Wise, Sandra S; Holmes, Amie L; Liou, Louis; Adam, Rosalyn M; Wise, John Pierce

    2016-04-01

    Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of hexavalent chromium (Cr(VI)) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Cr(VI) induced a concentration- and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer, specifically, and may be a mechanism for metal-induced bladder cancer, in general.

  7. Polycomb Repressor Complex 1 Member, BMI1 Contributes to Urothelial Tumorigenesis through p16-Independent Mechanisms1

    PubMed Central

    De Faveri, Lia E.; Hurst, Carolyn D.; Roulson, Jo-An; Wood, Henry; Sanchez-Carbayo, Marta; Knowles, Margaret A.; Chapman, Emma J.

    2015-01-01

    Urothelial carcinoma (UC) causes significant morbidity and remains the most expensive cancer to treat because of the need for repeated resections and lifelong monitoring for patients with non–muscle-invasive bladder cancer (NMIBC). Novel therapeutics and stratification approaches are needed to improve the outlook for both NMIBC and muscle-invasive bladder cancer. We investigated the expression and effects of B Lymphoma Mo-MLV Insertion Region 1 (BMI1) in UC. BMI1 was found to be overexpressed in most UC cell lines and primary tumors by quantitative real-time polymerase chain reaction and immunohistochemistry. In contrast to some previous reports, no association with tumor stage or grade was observed in two independent tumor panels. Furthermore, upregulation of BMI1 was detected in premalignant bladder lesions, suggesting a role early in tumorigenesis. BMI1 is not located within a common region of genomic amplification in UC. The CDKN2A locus (which encodes the p16 tumor suppressor gene) is a transcriptional target of BMI1 in some cellular contexts. In UC cell lines and primary tissues, no correlation between BMI1 and p16 expression was observed. Retroviral-mediated overexpression of BMI1 immortalized normal human urothelial cells (NHUC) in vitro and was associated with induction of telomerase activity, bypass of senescence, and repression of differentiation. The effects of BMI1 on gene expression were identified by expression microarray analysis of NHUC-BMI1. Metacore analysis of the gene expression profile implicated downstream effects of BMI1 on α4/β1 integrin-mediated adhesion, cytoskeleton remodeling, and CREB1-mediated transcription. PMID:26500029

  8. Prediction of Pathologic Grade and Prognosis in Mucoepidermoid Carcinoma of the Lung Using 18F-FDG PET/CT

    PubMed Central

    Park, Byungjoon; Kim, Hong Kwan; Choi, Yong Soo; Kim, Jhingook; Zo, Jae Il; Choi, Joon Young

    2015-01-01

    Objective The maximum standardized uptake value (SUVmax) of pulmonary mucoepidermoid carcinoma (PMEC) in fluorine-18fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was evaluated as a preoperative predictor of pathologic grade and survival rate. Materials and Methods Twenty-three patients who underwent preoperative PET/CT and complete resection for PMEC were enrolled. The optimal cut-off SUVmax for tumor grade was calculated as 6.5 by receiver operating characteristic curve. The patients were divided into a high SUV group (n = 7) and a low SUV group (n = 16). Clinicopathologic features were compared between the groups by χ2 test and overall survival was determined by Kaplan-Meier analysis. Results The mean SUVmax was 15.4 ± 11.5 in the high SUV group and 3.9 ± 1.3 in the low SUV group. All patients except one from the low SUV group had low grade tumors and all had no nodal metastasis. The sensitivity and specificity of SUVmax from PET/CT for predicting tumor grade was 85.7% and 93.8%, respectively. During the follow-up period (mean, 48.6 ± 38.7 months), four patients from the high SUV group experienced cancer recurrence, and one died of cancer. In contrast, none of the low SUV group had recurrence or mortality. Five-year overall survival rate was significantly higher in the low SUV group (100% vs. 71.4%, p = 0.031). Conclusion Pulmonary mucoepidermoid carcinoma patients with high SUVmax in PET/CT had higher tumor grade, more frequent lymph node metastasis and worse long-term outcome. Therefore, PMEC patients with high uptake on PET/CT imaging might require aggressive mediastinal lymph node dissection and adjuvant therapies. PMID:26175595

  9. HPV Genotypes Predict Survival Benefits From Concurrent Chemotherapy and Radiation Therapy in Advanced Squamous Cell Carcinoma of the Cervix

    SciTech Connect

    Wang, Chun-Chieh; Lai, Chyong-Huey; Huang, Yi-Ting; Chao, Angel; Chou, Hung-Hsueh; Hong, Ji-Hong

    2012-11-15

    Purpose: To study the prognostic value of human papillomavirus (HPV) genotypes in patients with advanced cervical cancer treated with radiation therapy (RT) alone or concurrent chemoradiation therapy (CCRT). Methods and Materials: Between August 1993 and May 2000, 327 patients with advanced squamous cell carcinoma of the cervix (International Federation of Gynecology and Obstetrics stage III/IVA or stage IIB with positive lymph nodes) were eligible for this study. HPV genotypes were determined using the Easychip Registered-Sign HPV genechip. Outcomes were analyzed using Kaplan-Meier survival analysis and the Cox proportional hazards model. Results: We detected 22 HPV genotypes in 323 (98.8%) patients. The leading 4 types were HPV16, 58, 18, and 33. The 5-year overall and disease-specific survival estimates for the entire cohort were 41.9% and 51.4%, respectively. CCRT improved the 5-year disease-specific survival by an absolute 9.8%, but this was not statistically significant (P=.089). There was a significant improvement in disease-specific survival in the CCRT group for HPV18-positive (60.9% vs 30.4%, P=.019) and HPV58-positive (69.3% vs 48.9%, P=.026) patients compared with the RT alone group. In contrast, the differences in survival with CCRT compared with RT alone in the HPV16-positive and HPV-33 positive subgroups were not statistically significant (P=.86 and P=.53, respectively). An improved disease-specific survival was observed for CCRT treated patients infected with both HPV16 and HPV18, but these differenced also were not statistically significant. Conclusions: The HPV genotype may be a useful predictive factor for the effect of CCRT in patients with advanced squamous cell carcinoma of the cervix. Verifying these results in prospective trials could have an impact on tailoring future treatment based on HPV genotype.

  10. Low Expression of Mucin-4 Predicts Poor Prognosis in Patients With Clear-Cell Renal Cell Carcinoma

    PubMed Central

    Fu, Hangcheng; Liu, Yidong; Xu, Le; Chang, Yuan; Zhou, Lin; Zhang, Weijuan; Yang, Yuanfeng; Xu, Jiejie

    2016-01-01

    Abstract Mucin-4 (MUC4), a member of membrane-bound mucins, has been reported to exert a large variety of distinctive roles in tumorigenesis of different cancers. MUC4 is aberrantly expressed in clear-cell renal cell carcinoma (ccRCC) but its prognostic value is still unveiled. This study aims to assess the clinical significance of MUC4 expression in patients with ccRCC. The expression of MUC4 was assessed by immunohistochemistry in 198 patients with ccRCC who underwent nephrectomy retrospectively in 2003 and 2004. Sixty-seven patients died before the last follow-up in the cohort. Kaplan–Meier method with log-rank test was applied to compare survival curves. Univariate and multivariate Cox regression models were applied to evaluate the prognostic value of MUC4 expression in overall survival (OS). The predictive nomogram was constructed based on the independent prognostic factors. The calibration was built to evaluate the predictive accuracy of nomogram. In patients with ccRCC, MUC4 expression, which was determined to be an independent prognostic indicator for OS (hazard ratio [HR] 3.891; P < 0.001), was negatively associated with tumor size (P = 0.036), Fuhrman grade (P = 0.044), and OS (P < 0.001). The prognostic accuracy of TNM stage, UCLA Integrated Scoring System (UISS), and Mayo clinic stage, size, grade, and necrosis score (SSIGN) prognostic models was improved when MUC4 expression was added. The independent prognostic factors, pT stage, distant metastases, Fuhrman grade, sarcomatoid, and MUC4 expression were integrated to establish a predictive nomogram with high predictive accuracy. MUC4 expression is an independent prognostic factor for OS in patients with ccRCC. PMID:27124015

  11. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation

    PubMed Central

    Cillo, Umberto; Giuliani, Tommaso; Polacco, Marina; Herrero Manley, Luz Maria; Crivellari, Gino; Vitale, Alessandro

    2016-01-01

    Morphological criteria have always been considered the benchmark for selecting hepatocellular carcinoma (HCC) patients for liver transplantation (LT). These criteria, which are often inappropriate to express the tumor’s biological behavior and aggressiveness, offer only a static view of the disease burden and are frequently unable to correctly stratify the tumor recurrence risk after LT. Alpha-fetoprotein (AFP) and its progression as well as AFP-mRNA, AFP-L3%, des-γ-carboxyprothrombin, inflammatory markers and other serological tests appear to be correlated with post-transplant outcomes. Several other markers for patient selection including functional imaging studies such as 18F-FDG-PET imaging, histological evaluation of tumor grade, tissue-specific biomarkers, and molecular signatures have been outlined in the literature. HCC growth rate and response to pre-transplant therapies can further contribute to the transplant evaluation process of HCC patients. While AFP, its progression, and HCC response to pre-transplant therapy have already been used as a part of an integrated prognostic model for selecting patients, the utility of other markers in the transplant setting is still under investigation. This article intends to review the data in the literature concerning predictors that could be included in an integrated LT selection model and to evaluate the importance of biological aggressiveness in the evaluation process of these patients. PMID:26755873

  12. Low cytoplasmic casein kinase 1 epsilon expression predicts poor prognosis in patients with hepatocellular carcinoma.

    PubMed

    Lin, Shu-Hui; Yeh, Chung-Min; Hsieh, Ming-Ju; Lin, Yueh-Min; Chen, Mei-Wen; Chen, Chih-Jung; Lin, Cheng-Yu; Hung, Hsiao-Fang; Yeh, Kun-Tu; Yang, Shun-Fa

    2016-03-01

    Casein kinase 1 epsilon (CK1ε) is a member of the casein kinase 1 (CK1) family, which comprises highly conserved and ubiquitous serine/threonine protein kinases. Recent studies have demonstrated that CK1ε plays a role in human cancers; however, the role of CK1ε in hepatocellular carcinoma (HCC) remains unclear. The study used immunohistochemistry to examine CK1ε expression in 230 HCC specimens by tissue microarray (TMA) and assessed the effect of CK1ε knockdown on migration of human hepatoma cells in vitro. The immunohistochemical analyses showed that low CK1ε expression was significantly correlated with tumor differentiation (p = 0.008), T classification (p = 0.016), tumor vascular invasion (p = 0.002), and cancer stage (p = 0.010). The univariate and multivariate analyses showed that patients with low CK1ε expression had a considerably lower OS rate than that of the patients with high CK1ε expression (p = 0.041, hazard ratio = 1.4; p = 0.039, hazard ratio = 1.4). Moreover, CK1ε small interfering RNA (siRNA) treatment exerted an invasion-promoting effect in human hepatoma cells. In conclusion, our data indicated that low CK1ε expression is correlated with a low survival rate and CK1ε may play a role as a tumor suppressor in hepatocarcinogenesis. PMID:26482619

  13. Expression of dystroglycan correlates with tumor grade and predicts survival in renal cell carcinoma.

    PubMed

    Sgambato, Alessandro; Camerini, Andrea; Amoroso, Domenico; Genovese, Giannicola; De Luca, Filomena; Cecchi, Massimo; Migaldi, Mario; Rettino, Alessandro; Valsuani, Chiara; Tartarelli, Gianna; Donati, Sara; Siclari, Olimpia; Rossi, Giulio; Cittadini, Achille

    2007-12-01

    The dystroglycan (DG) complex is a transmembrane glycoprotein that forms a continuous link from the extracellular matrix to the actin cytoskeleton. Deregulated expression of DG has been reported in a variety of human malignancies and related to tumor aggressiveness. In this study expression of the DG subunit was evaluated by immunostaining in a series of renal epithelial cancers and its relation with traditional prognostic indicators and with the clinical outcome of the patients was evaluated. alphaDG expression was undetectable in a significant fraction of tumors (54%). In renal cell carcinomas (RCC) loss of alpha-DG staining correlated with higher tumor grade (p = 0.02) but not with tumor stage nor tumor size. In clear cell RCC patients loss of alphaDG staining correlated with an increased risk of recurrence (p = 0.002 by log-rank test) and death (p = 0.004) also when patients with lower grade or stage tumors were analyzed separately. In a multivariate analysis loss of DG staining confirmed to be and independent predictor of shorter disease-free (p = 0.001; RR = 4.9) and overall (p = 0.009; RR = 4.9) survival stronger than tumor grade and size. These findings demonstrate that loss of alphaDG expression, which correspond to loss of a functional DG complex, is a frequent event in human renal tumorigenesis and is an independent predictor of early recurrence and death for patients with clear cell RCC.

  14. Novel Pretreatment Scoring Incorporating C-reactive Protein to Predict Overall Survival in Advanced Hepatocellular Carcinoma with Sorafenib Treatment

    PubMed Central

    Nakanishi, Hiroyuki; Kurosaki, Masayuki; Tsuchiya, Kaoru; Yasui, Yutaka; Higuchi, Mayu; Yoshida, Tsubasa; Komiyama, Yasuyuki; Takaura, Kenta; Hayashi, Tsuguru; Kuwabara, Konomi; Nakakuki, Natsuko; Takada, Hitomi; Ueda, Masako; Tamaki, Nobuharu; Suzuki, Shoko; Itakura, Jun; Takahashi, Yuka; Izumi, Namiki

    2016-01-01

    Objectives This study aimed to build a prediction score of prognosis for patients with advanced hepatocellular carcinoma (HCC) after sorafenib treatment. Methods A total of 165 patients with advanced HCC who were treated with sorafenib were analyzed. Readily available baseline factors were used to establish a scoring system for the prediction of survival. Results The median survival time (MST) was 14.2 months. The independent prognostic factors were C-reactive protein (CRP) <1.0 mg/dL [hazard ratio (HR) =0.51], albumin >3.5 g/dL (HR =0.55), alpha-fetoprotein <200 ng/mL (HR =0.45), and a lack of major vascular invasion (HR =0.39). Each of these factors had a score of 1, and after classifying the patients into five groups, the total scores ranged from 0 to 4. Higher scores were linked to significantly longer survival (p<0.0001). Twenty-nine patients (17.6%) with a score of 4 had a MST as long as 36.5 months, whereas MST was as short as 2.4 and 3.7 months for seven (4.2%) and 22 (13.3%) patients with scores of 0 and 1, respectively. Conclusions A novel prognostic scoring system, which includes the CRP level, has the ability to stratify the prognosis of patients with advanced stage HCC after treatment with sorafenib. PMID:27781198

  15. Body mass index and cholesterol level predict surgical outcome in patients with hepatocellular carcinoma in Taiwan - a cohort study

    PubMed Central

    Tsai, Tung-Hu; Chiang, Hsin-Yu; Ting, Chin-Tsung

    2016-01-01

    Curative surgical resection (CSR) remains the most effective therapeutic intervention for patients with hepatocellular carcinoma (HCC); however, frequent post-surgical recurrence leads to high cancer related mortality. This study aimed to clarify the role of body mass index (BMI) and serum cholesterol level in predicting post-surgical outcomes in HCC patients after CSR. A total of 484 HCC patients including 213 BMIhigh and 271 BMIlow patients were included. Overall survival (OS) and recurrence-free survival (RFS) rates were examined in patients with differential BMI and serum cholesterol level. The analysis showed that significant different 1-, 3- and 5-year cumulative OS rates (P-value=0.015) and RFS rate (P-value=0.010) between BMIlow and BMIhigh patients. Further analysis in groups with differential serum cholesterol levels among BMIlow and BMIhigh patients indicated that the BMIlow/Chollow patients exhibited the significant lower cumulative OS and RFS rates in comparison with the remaining subjects (P-value=0.007 and 0.039 for OS and RFS rates, respectively). In conclusion, the coexistence of low BMI and low serum cholesterol level could serve as prognostic factors to predict post-operative outcomes in HCC patients undergoing surgical hepatectomy. PMID:27027345

  16. Blood Neutrophil-to-Lymphocyte Ratio Predicts Tumor Recurrence in Patients with Hepatocellular Carcinoma within Milan Criteria after Hepatectomy

    PubMed Central

    Hu, Xu-Guang; Mao, Wei; Park, Yong-Keun; Xu, Wei-Guang; Kim, Bong-Wan

    2016-01-01

    Purpose The systemic inflammation biomarker, Neutrophil-to-Lymphocyte Ratio (NLR), has been reported as one of the adverse prognostic factors for hepatocellular carcinoma (HCC) patient. The purpose of this study was to evaluate whether NLR could predict the risk of recurrence and death for the HCC patient, according to Milan criteria after hepatectomy. Materials and Methods Retrospective analysis was performed on a database of HCC patients who underwent hepatectomy between March 2001 and December 2011. The cutoff value of NLR was decided by receiver operating characteristic (ROC) curve analysis. Univariate and multivariate regression analyses were performed to identify predictive factors of recurrence and death. Results A total of 213 patients were included in the present study. The median follow-up period was 48 months. One hundred and seven patients were experienced tumor recurrence; forty of them recurred within 12 months (early recurrence). NLR ≥1.505, albumin ≤3.75 g/dL, microvascular invasion and high grade of cirrhosis were found to be independent factors for adverse recurrence-free survival in multivariate regression analysis. And NLR ≥1.945 was also found as a prognosis factor for early recurrence by univariate regression analysis. Conclusion Elevated preoperative NLR can be easily obtained and reliable biomarker for assessing the tumor recurrence and early recurrence of Milan criteria HCC after the initial hepatectomy. PMID:27401641

  17. Prediction and prophylaxis of hepatocellular carcinoma occurrence and postoperative recurrence in chronic hepatitis B virus-infected subjects.

    PubMed

    Du, Yan; Han, Xue; Ding, Yi-Bo; Yin, Jian-Hua; Cao, Guang-Wen

    2016-08-01

    Hepatocellular carcinoma (HCC) is one of the most common and highly fatal malignancies worldwide. Chronic infection with hepatitis B virus (HBV) is a major cause of HCC. High HBV replication rate and related non-resolving inflammation are the major risk factors of HCC occurrence and postoperative recurrence. Early prophylactic options are effective in reducing HCC occurrence and improving survival. Therefore, it is important to identify HBV-infected patients who are at a higher risk of developing HCC and HBV-HCC patients who are more likely to relapse after surgery, thus providing them with more precise prophylactic strategies. Several prediction models of HCC occurrence have been constructed, with satisfactory predictive accuracy and discriminatory ability. However, there is a lack of consensus for their clinical implementation. Several staging systems have been proposed for HCC prognosis. However, the accuracy of these staging systems based on demographic characteristics and clinical measurements needs to be further improved, possibly by systematically incorporating viral and inflammatory factors. Since antiviral treatments are effective in promoting liver function reserve, reducing HCC occurrence and prolonging postoperative survival in some HBV-infected subjects, it is very important to identify subgroups of HBV-infected patients who would most benefit from antiviral treatment. PMID:27547000

  18. Systemic and intratumoral balances between monocytes/macrophages and lymphocytes predict prognosis in hepatocellular carcinoma patients after surgery.

    PubMed

    Liao, Rui; Jiang, Ning; Tang, Zhuo-Wei; Li, De Wei; Huang, Ping; Luo, Shi-Qiao; Gong, Jian-Ping; Du, Cheng-You

    2016-05-24

    The peripheral neutrophil-monocyte/lymphocyte ratio (NMLR) and intratumoral CD16/CD8 ratio (iMLR) may have prognostic value in hepatocellular carcinoma (HCC) patients after curative resection. In this study, the circulating NMLR was examined 387 HCC patients who underwent curative resection between 2006 and 2009. Intratumoral levels of CD4, CD8, CD16 and CD68 and the CD16/CD8 ratio were determined immunohistologically. The prognostic values of clinicopathological parameters, including NMLR and iMLR, were evaluated. NMLR was predictive of overall survival (OS) and recurrence-free survival (RFS) when patients in the training cohort (n = 256) were separated into high (> 1.2) and low (≤ 1.2) NMLR subgroups. NMLR was also an independent predictor of low alpha-fetoprotein (AFP) expression and early recurrence. High NMLR was associated with increases in clinicopathological variables, including alanine aminotransferase (ALT), tumor number, tumor size and BCLC stage. In addition, iMLR strongly predicted risk of recurrence and patient survival, and was positively correlated with NMLR. These findings were confirmed in an independent validation patient cohort (n = 131). Peripheral NMLR and iMLR may thus be useful prognostic markers, and anti-inflammatory treatment may be beneficial in HCC patients after curative hepatectomy.

  19. Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation.

    PubMed

    Lai, Ming-chun; Yang, Zhe; Zhou, Lin; Zhu, Qian-qian; Xie, Hai-yang; Zhang, Feng; Wu, Li-ming; Chen, Lei-ming; Zheng, Shu-sen

    2012-09-01

    Metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a long non-coding RNA (lncRNA), is up-regulated in many solid tumors and associated with cancer metastasis and recurrence. However, its role in hepatocellular carcinoma (HCC) remains poorly understood. In the present study, we evaluated the expression of MALAT1 by quantitative real-time PCR in 9 liver cancer cell lines and 112 HCC cases including 60 cases who received liver transplantation (LT) with complete follow-up data. Moreover, small interfering RNA (siRNA) was used to inhibit MALAT1 expression to investigate its biological role in tumor progression. We found that MALAT1 was up-regulated in both cell lines and clinical tissue samples. Patients with high expression level of MALAT1 had a significantly increased risk of tumor recurrence after LT, particularly in patients who exceeded the Milan criteria. On multivariate analysis, MALAT1 was an independent prognostic factor for predicting HCC recurrence (hazard ratio, 3.280, P = 0.003).In addition, inhibition of MALAT1 in HepG2 cells could effectively reduce cell viability, motility, invasiveness, and increase the sensitivity to apoptosis. Our data suggest that lncRNA MALAT1 play an important role in tumor progression and could be a novel biomarker for predicting tumor recurrence after LT and serve as a promising therapeutic target.

  20. Cyclooxygenase-2 expression is associated with initiation of hepatocellular carcinoma, while prostaglandin receptor-1 expression predicts survival

    PubMed Central

    Yang, Hao-Jie; Jiang, Jing-Hang; Yang, Yu-Ting; Yang, Xiang-Di; Guo, Zhe; Qi, Ya-Peng; Zeng, Feng-Hua; Zhang, Ke-Lan; Chen, Neng-Zhi; Xiang, Bang-De; Li, Le-Qun

    2016-01-01

    AIM To determine whether cyclooxygenase-2 (COX-2) and prostaglandin E1 receptor (EP1) contribute to disease and whether they help predict prognosis. METHODS We retrospectively reviewed the records of 116 patients with hepatocellular carcinoma (HCC) who underwent surgery between 2008 and 2011 at our hospital. Expression of COX-2 and EP1 receptor was examined by immunohistochemistry of formalin-fixed, paraffin-embedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined. RESULTS Factors associated with poor overall survival (OS) were alpha-fetoprotein > 400 ng/mL, tumor size ≥ 5 cm, and high EP1 receptor expression, but not high COX-2 expression. Disease-free survival was not significantly different between patients with low or high levels of COX-2 or EP1. COX-2 immunoreactivity was significantly higher in well-differentiated HCC tissues (Edmondson grade I-II) than in poorly differentiated tissues (Edmondson grade III-IV) (P = 0.003). EP1 receptor immunoreactivity was significantly higher in poorly differentiated tissue than in well-differentiated tissue (P = 0.001). CONCLUSION COX-2 expression appears to be linked to early HCC events (initiation), while EP1 receptor expression may participate in tumor progression and predict survival.

  1. Predictive Factors of Downstaging of Hepatocellular Carcinoma Beyond the Milan Criteria Treated with Intra-arterial Therapies

    SciTech Connect

    Bova, Valentina; Miraglia, Roberto Maruzzelli, Luigi; Vizzini, Giovanni Battista; Luca, Angelo

    2013-04-15

    This study was designed to analyze the clinical results in patients suitable for liver transplantation with hepatocellular carcinoma (HCC) who exceeded Milan criteria, which underwent intra-arterial therapies (IAT), to determine predictive factors of successful downstaging. A total of 277 consecutive patients with cirrhosis and HCC were treated by IAT (transarterial oily chemoembolization, transarterial chemoembolization, transarterial embolization) in a single center. Eighty patients exceed the Milan criteria. Patients with infiltrative HCC, hypovascular HCC, and portal vein thrombosis were excluded, with a final study population of 48 patients. Tumor response to IAT was evaluated with CT and/or MRI according to modified RECIST criteria. Successful downstaging was defined as a reduction in the number and size of viable tumors to within the Milan criteria, and serum alpha-fetoprotein (AFP) <100 ng/mL, for at least 6 months. Nineteen patients (39 %) had their tumors successfully downstaged; 29 patients (61 %) did not. Multivariate analysis showed that AFP level <100 ng/mL and 3-year calculated survival probability using the Metroticket calculator were the only independent predictors of successful downstaging (p < 0.023 and p < 0.049 respectively). Biological characteristics of HCC as AFP levels <100 ng/mL and high 3-year calculated survival probability may predict a good response to downstage after IAT.

  2. Prediction and prophylaxis of hepatocellular carcinoma occurrence and postoperative recurrence in chronic hepatitis B virus-infected subjects

    PubMed Central

    Du, Yan; Han, Xue; Ding, Yi-Bo; Yin, Jian-Hua; Cao, Guang-Wen

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most common and highly fatal malignancies worldwide. Chronic infection with hepatitis B virus (HBV) is a major cause of HCC. High HBV replication rate and related non-resolving inflammation are the major risk factors of HCC occurrence and postoperative recurrence. Early prophylactic options are effective in reducing HCC occurrence and improving survival. Therefore, it is important to identify HBV-infected patients who are at a higher risk of developing HCC and HBV-HCC patients who are more likely to relapse after surgery, thus providing them with more precise prophylactic strategies. Several prediction models of HCC occurrence have been constructed, with satisfactory predictive accuracy and discriminatory ability. However, there is a lack of consensus for their clinical implementation. Several staging systems have been proposed for HCC prognosis. However, the accuracy of these staging systems based on demographic characteristics and clinical measurements needs to be further improved, possibly by systematically incorporating viral and inflammatory factors. Since antiviral treatments are effective in promoting liver function reserve, reducing HCC occurrence and prolonging postoperative survival in some HBV-infected subjects, it is very important to identify subgroups of HBV-infected patients who would most benefit from antiviral treatment. PMID:27547000

  3. Atezolizumab in Treating Patients With Recurrent BCG-Unresponsive Non-muscle Invasive Bladder Cancer

    ClinicalTrials.gov

    2016-09-12

    Recurrent Bladder Urothelial Carcinoma; Stage 0a Bladder Urothelial Carcinoma; Stage 0is Bladder Urothelial Carcinoma; Stage I Bladder Cancer With Carcinoma In Situ; Stage I Bladder Urothelial Carcinoma

  4. The 1973 WHO Classification Is More Suitable than the 2004 WHO Classification for Predicting Prognosis in Non-Muscle-Invasive Bladder Cancer

    PubMed Central

    Xu, Ke; Tan, Jun; Sun, Chuanyu; Gou, Yuancheng; Tong, Shijun; Xia, Guowei; Fang, Zujun; Ding, Qiang

    2012-01-01

    Background Predicting the recurrence and progression of Non-muscle-invasive bladder cancer(NMIBC) is critical for urologist. Histological grade provides significant prognostic information, especially for prediction of progression. Currently, the 1973 and the 2004 WHO classification co-exist. Which system is better for predicting rumor recurrence and progression still a matter for debate. Methodology/Principal Findings 348 patients diagnosed with Non-muscle invasive bladder cancer were enrolled in our retrospective study. Paraffin sections were assessed by an experienced urological pathologist according to both the 1973 and 2004 WHO classifications. Tumor recurrence and progression was followed-up in all patients. During follow-up, corresponding 5-year recurrence-free survival rates of G1, G2 and G3 were 82.1%, 55.9%, 32.1% and the 5-year progression-free survival rates were 95.9%, 84.4% and 43.3%, respectively. The 5-year recurrence-free survival rates of papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade papillary urothelial carcinoma(LGPUC) and high-grade papillary urothelial carcinoma (HGPUC) were 69.8%, 67.1% and 42.0% respectively and the 5-year progression-free survival rates were 100%, 90.9% and 54.8% respectively. In multivariate analysis, the 1973 WHO classification significantly associated with both tumor recurrence and progression(p = 0.010 and p = 0.022, respectively); the 2004 WHO classification correlated with tumor progression(p = 0.019), while was not proved to be a variable that can predict the risk of recurrence(p = 0.547). Kaplan-Meier plots showed that both the 1973 WHO and the 2004 WHO classifications were significantly associated with progression-free survival (p<0.0001, log-rank test). For prediction of recurrence, significant differences were observed between the tumor grades classified using the 1973 WHO grading system (p<0.0001, log-rank test), while a significant overlap was observed between

  5. Transarterial Chemoembolization for Hepatocellular Carcinomas with Central Bile Duct Invasion: Safety, Prognosis, and Predictive Factors

    SciTech Connect

    Choi, Jin Woo; Chung, Jin Wook; Cho, Yun Ku; Kim, Yoon Jun; Yoon, Jung-Hwan; Kim, Hyo-Cheol; Jae, Hwan Jun

    2015-08-15

    PurposeTo assess the safety and effectiveness of transarterial chemoembolization (TACE) of patients who have hepatocellular carcinomas (HCCs) with central bile duct invasion.Materials and MethodsThe institutional review board approved this retrospective study and waived informed consent. Fifty-three patients, initially treated with TACE for HCCs with central bile duct invasion from January 1999 to September 2012, were included. Clinical, laboratory, and survival data were reviewed. Complications and hospitalization length were evaluated using the χ{sup 2} test, Fisher’s exact test, and logistic regression analysis. Survival was analyzed using the Kaplan–Meier method with log-rank test and Cox proportional hazard model.ResultsSeven patients experienced TACE-related major complications (severe post-embolization syndrome in 3, non-fatal sepsis in 3, and secondary bacterial peritonitis in 1). The overall major complication rate was 13.2 %, but there were no permanent adverse sequelae or deaths within 30 days. Serum total bilirubin ≥3.0 mg/dL was the only significant risk factor for long hospitalization [hazard ratio (HR) = 4.341, p = .022]. The median survival was 12.2 months. Extrahepatic metastasis (HR = 6.145, p < .001), international normalized ratio (PT-INR) ≥1.20 (HR = 4.564, p < .001), vascular invasion (HR = 3.484, p = .001), and intermediate tumor enhancement (HR = 2.417, p = .019) were significantly associated with shorter survival.ConclusionTACE can be a safe and effective treatment for patients who have HCCs with central bile duct invasion. In particular, long-term survival can be expected if patients have strongly enhancing tumors without poor prognostic factors such as extrahepatic metastasis, PT-INR prolongation, and vascular invasion.

  6. Activating JAK1 mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma.

    PubMed

    Yang, Shuqun; Luo, Chonglin; Gu, Qingyang; Xu, Qiang; Wang, Guan; Sun, Hongye; Qian, Ziliang; Tan, Yexiong; Qin, Yuxin; Shen, Yuhong; Xu, Xiaowei; Chen, Shu-Hui; Chan, Chi-Chung; Wang, Hongyang; Mao, Mao; Fang, Douglas D

    2016-02-01

    Hepatocellular carcinoma (HCC) is the fifth most common type of cancers worldwide. However, current therapeutic approaches for this epidemic disease are limited, and its 5-year survival rate hasn't been improved in the past decades. Patient-derived xenograft (PDX) tumor models have become an excellent in vivo system for understanding of disease biology and drug discovery. In order to identify new therapeutic targets for HCC, whole-exome sequencing (WES) was performed on more than 60 HCC PDX models. Among them, four models exhibited protein-altering mutations in JAK1 (Janus Kinase 1) gene. To explore the transforming capability, these mutations were then introduced into HEK293FT and Ba/F3 cells. The results demonstrated that JAK1S703I mutation was able to activate JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway and drive cell proliferation in the absence of cytokine stimulation in vitro. Furthermore,the sensitivity to the treatment of a JAK1/2 inhibitor, ruxolitinib, was observed in JAK1S703I mutant PDX model, but not in other non-activating mutant or wild type models. Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib-treated tumor tissues was significantly suppressed. Collectively, our results suggested that JAK1S703I is an activating mutation for JAK-STAT signaling pathway in vitro and in vivo, and JAK-STAT pathway might represent a new therapeutic approach for HCC treatment. Monotherapy using a more potent and specific JAK1 inhibitor and combinatory therapy should be further explored in JAK1 mutant PDX models. PMID:26701727

  7. JNK1 activation predicts the prognostic outcome of the human hepatocellular carcinoma

    PubMed Central

    Chang, Qingshan; Chen, Jianguo; Beezhold, Kevin J; Castranova, Vince; Shi, Xianglin; Chen, Fei

    2009-01-01

    Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with an extremely poor prognosis. The classification of HCC based on the molecular signature is not well-established. Results In the present study, we reported HCC signature genes based on the JNK1 activation status in 31 HCC specimens relative to the matched distal noncancerous liver tissue from 31 patients. The HCCs with high JNK1 (H-JNK1) and low JNK1 (L-JNK1) were sub-grouped. Two different signature gene sets for both H-JNK1 and L-JNK1 HCC were identified through gene expression profiling. A striking overlap of signature genes was observed between the H-JNK1 HCC and the hepatoblastoma or hepatoblastoma-type HCC. Many established biomarkers for hepatic progenitor cells were over-expressed in H-JNK1 HCC, including AFP, TACSTD1, KRT19, KRT7, THY1, and PROM1. In addition, the majority of the most up-regulated genes were those associated with metastasis and earlier recurrence, whereas the genes for normal liver function were substantially down-regulated in H-JNK1 HCC tissue. A Kaplan-Meier plot demonstrated that the survival of the patients with H-JNK1 HCC was severely impaired. Conclusion Accordingly, we believe that the H-JNK1 HCC may originate from hepatic progenitor cells and is associated with poorer prognosis. The status of JNK1 activation in HCC tissue, thus, might be a new biomarker for HCC prognosis and therapeutic targeting. PMID:19686584

  8. Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma.

    PubMed

    Lian, Yi-Fan; Yuan, Jing; Cui, Qian; Feng, Qi-Sheng; Xu, Miao; Bei, Jin-Xin; Zeng, Yi-Xin; Feng, Lin

    2016-01-01

    Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC. PMID:27030985

  9. Over-Expression of CD200 Predicts Poor Prognosis in Cutaneous Squamous Cell Carcinoma

    PubMed Central

    Li, Li; Tian, YanLi; Shi, ChengFang; Zhang, Hua; Zhou, Zhi

    2016-01-01

    Background CD200 is reported to be involved in tumor progression and can serve as a prognostic marker in several cancers. The purpose of this study was to evaluate the prognostic significance of CD200 in cutaneous squamous cell carcinoma (CSCC). Material/Methods The relative mRNA and protein expression of CD200 in the tumor tissues and corresponding normal tissues of 102 CSCC patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis, respectively. The chi-square test was used to analyze the association between CD200 expression and clinical features of CSCC patients. In addition, the overall survival of the patients according to the expression level of CD200 was estimated by Kaplan-Meier analysis and the prognostic significance of the gene was analyzed by Cox regression analysis. Results Increased expression of CD200 was detected in the tumor tissues compared with the corresponding normal tissues both at mRNA and protein level. And CD200 expression level was associated with tumor differentiation grade (P=0.041) and clinical stage (P=0.004). Patients with high expression level of CD200 had a shorter overall survival than those with low expression (31.3 months vs. 41.9 months) and there was a significant difference between them (log-rank test, P<0.001). Cox regression analysis indicated that CD200 could be an independent marker for the prognosis of CSCC. Conclusions CD200 is up-regulated and may be a novel biomarker for the prognosis in CSCC, and it may be a potential therapeutic target for CSCC. PMID:27035797

  10. Overexpression of MutSα Complex Proteins Predicts Poor Prognosis in Oral Squamous Cell Carcinoma

    PubMed Central

    Wagner, Vivian Petersen; Webber, Liana Preto; Salvadori, Gabriela; Meurer, Luise; Fonseca, Felipe Paiva; Castilho, Rogério Moraes; Squarize, Cristiane Helena; Vargas, Pablo Agustin; Martins, Manoela Domingues

    2016-01-01

    Abstract The DNA mismatch repair (MMR) system is responsible for the detection and correction of errors created during DNA replication, thereby avoiding the incorporation of mutations in dividing cells. The prognostic value of alterations in MMR system has not previously been analyzed in oral squamous cell carcinoma (OSCC). The study comprised 115 cases of OSCC diagnosed between 1996 and 2010. The specimens collected were constructed into tissue microarray blocks. Immunohistochemical staining for MutSα complex proteins hMSH2 and hMSH6 was performed. The slides were subsequently scanned into high-resolution images, and nuclear staining of hMSH2 and hMSH6 was analyzed using the Nuclear V9 algorithm. Univariable and multivariable Cox proportional hazard regression models were performed to evaluate the prognostic value of hMSH2 and hMSH6 in OSCC. All cases in the present cohort were positive for hMSH2 and hMSH6 and a direct correlation was found between the expression of the proteins (P < 0.05). The mean number of positive cells for hMSH2 and hMSH6 was 64.44 ± 15.21 and 31.46 ± 22.38, respectively. These values were used as cutoff points to determine high protein expression. Cases with high expression of both proteins simultaneously were classified as having high MutSα complex expression. In the multivariable analysis, high expression of the MutSα complex was an independent prognostic factor for poor overall survival (hazard ratio: 2.75, P = 0.02). This study provides a first insight of the prognostic value of alterations in MMR system in OSCC. We found that MutSα complex may constitute a molecular marker for the poor prognosis of OSCC. PMID:27258499

  11. Activating JAK1 mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma.

    PubMed

    Yang, Shuqun; Luo, Chonglin; Gu, Qingyang; Xu, Qiang; Wang, Guan; Sun, Hongye; Qian, Ziliang; Tan, Yexiong; Qin, Yuxin; Shen, Yuhong; Xu, Xiaowei; Chen, Shu-Hui; Chan, Chi-Chung; Wang, Hongyang; Mao, Mao; Fang, Douglas D

    2016-02-01

    Hepatocellular carcinoma (HCC) is the fifth most common type of cancers worldwide. However, current therapeutic approaches for this epidemic disease are limited, and its 5-year survival rate hasn't been improved in the past decades. Patient-derived xenograft (PDX) tumor models have become an excellent in vivo system for understanding of disease biology and drug discovery. In order to identify new therapeutic targets for HCC, whole-exome sequencing (WES) was performed on more than 60 HCC PDX models. Among them, four models exhibited protein-altering mutations in JAK1 (Janus Kinase 1) gene. To explore the transforming capability, these mutations were then introduced into HEK293FT and Ba/F3 cells. The results demonstrated that JAK1S703I mutation was able to activate JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway and drive cell proliferation in the absence of cytokine stimulation in vitro. Furthermore,the sensitivity to the treatment of a JAK1/2 inhibitor, ruxolitinib, was observed in JAK1S703I mutant PDX model, but not in other non-activating mutant or wild type models. Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib-treated tumor tissues was significantly suppressed. Collectively, our results suggested that JAK1S703I is an activating mutation for JAK-STAT signaling pathway in vitro and in vivo, and JAK-STAT pathway might represent a new therapeutic approach for HCC treatment. Monotherapy using a more potent and specific JAK1 inhibitor and combinatory therapy should be further explored in JAK1 mutant PDX models.

  12. Activating JAK1 mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma

    PubMed Central

    Yang, Shuqun; Luo, Chonglin; Gu, Qingyang; Xu, Qiang; Wang, Guan; Sun, Hongye; Qian, Ziliang; Tan, Yexiong; Qin, Yuxin; Shen, Yuhong; Xu, Xiaowei; Chen, Shu-Hui; Chan, Chi-Chung; Wang, Hongyang; Mao, Mao; Fang, Douglas D.

    2016-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common type of cancers worldwide. However, current therapeutic approaches for this epidemic disease are limited, and its 5-year survival rate hasn't been improved in the past decades. Patient-derived xenograft (PDX) tumor models have become an excellent in vivo system for understanding of disease biology and drug discovery. In order to identify new therapeutic targets for HCC, whole-exome sequencing (WES) was performed on more than 60 HCC PDX models. Among them, four models exhibited protein-altering mutations in JAK1 (Janus Kinase 1) gene. To explore the transforming capability, these mutations were then introduced into HEK293FT and Ba/F3 cells. The results demonstrated that JAK1S703I mutation was able to activate JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway and drive cell proliferation in the absence of cytokine stimulation in vitro. Furthermore, the sensitivity to the treatment of a JAK1/2 inhibitor, ruxolitinib, was observed in JAK1S703I mutant PDX model, but not in other non-activating mutant or wild type models. Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib-treated tumor tissues was significantly suppressed. Collectively, our results suggested that JAK1S703I is an activating mutation for JAK-STAT signaling pathway in vitro and in vivo, and JAK-STAT pathway might represent a new therapeutic approach for HCC treatment. Monotherapy using a more potent and specific JAK1 inhibitor and combinatory therapy should be further explored in JAK1 mutant PDX models. PMID:26701727

  13. Low CDX1 expression predicts a poor prognosis for hepatocellular carcinoma patients after hepatectomy.

    PubMed

    Zheng, Hao; Yang, Yuan; Wang, Meng-Chao; Yuan, Sheng-Xian; Tian, Tao; Han, Jun; Ni, Jun-Sheng; Wang, Jian; Xing, Hao; Zhou, Wei-Ping

    2016-09-01

    The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC·In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P = 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection. PMID:27566019

  14. Genetic Variation in the PNPLA3 Gene and Hepatocellular Carcinoma in USA: Risk and Prognosis Prediction

    PubMed Central

    Hassan, Manal M.; Kaseb, Ahmed; Etzel, Carol J.; El-Serag, Hashem; Spitz, Margaret R.; Chang, Ping; Hale, Katherine S.; Liu, Mei; Rashid, Asif; Shama, Mohamed; Abbruzzese, James L.; Loyer, Evelyne M.; Kaur, Harmeet; Hassabo, Hesham M.; Vauthey, Jean-Nicolas; Wray, Curtis J.; Hassan, Basmah S.; Patt, Yehuda Z.; Hawk, Ernest; Soliman, Khalid M.; Li, Donghui

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case–control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68–6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13–71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05–5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26–3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3. PMID:23776098

  15. Prediction of Neck Dissection Requirement After Definitive Radiotherapy for Head-and-Neck Squamous Cell Carcinoma

    SciTech Connect

    Thariat, Juliette; Ahamad, Anesa; Williams, Michelle D.; Myers, Jeffrey N.; El-Naggar, Adel K.; Ginsberg, Lawrence E.; Rosenthal, David I.; Glisson, Bonnie S.; Weber, Randal S.; Garden, Adam S.

    2012-03-01

    Background: This analysis was undertaken to assess the need for planned neck dissection in patients with a complete response (CR) of involved nodes after irradiation and to determine the benefit of a neck dissection in those with less than CR by tumor site. Methods: Our cohort included 880 patients with T1-4, N1-3M0 squamous cell carcinoma of the oropharynx, larynx, or hypopharynx who received treatment between 1994 and 2004. Survival curves were calculated by the Kaplan-Meier Method, comparisons of rates with the log-rank test and prognostic factors by Cox's proportional hazard model. Results: Nodal CR occurred in 377 (43%) patients, of whom 365 patients did not undergo nodal dissection. The 5-year actuarial regional control rate of patients with CR was 92%. Two hundred sixty-eight of the remaining patients (53%) underwent neck dissections. The 5-year actuarial regional control rate for patients without a CR was 84%. Those who had a neck dissection fared better with 5-year actuarial regional control rates of 90% and 76% for those operated and those not operated (p < 0.001). Variables associated with poorer regional control rates included higher T and N stage, non-oropharynx cancers, non-CR, both clinical and pathological. Conclusions: With 92% 5-year neck control rate without neck dissection after CR, there is little justification for systematic neck dissection. The addition of a neck dissection resulted in higher neck control after partial response though patients with viable tumor on pathology specimens had poorer outcomes. The identification of that subgroup that benefits from additional treatment remains a challenge.

  16. Prediction of Neck Dissection Requirement After Definitive Radiotherapy for Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Thariat, Juliette; Ang, K. Kian; Allen, Pamela K.; Ahamad, Anesa; Williams, Michelle D.; Myers, Jeffrey N.; El-Naggar, Adel K.; Ginsberg, Lawrence E.; Rosenthal, David I.; Glisson, Bonnie S.; Morrison, William H.; Weber, Randal S.; Garden, Adam S.

    2014-01-01

    BACKGROUND This analysis was undertaken to assess the need for planned neck dissection in patients with a complete response (CR) of involved nodes after irradiation, and to determine the benefit of a neck dissection in those with less than CR by tumor site. METHODS Our cohort included 880 patients with T1-4, N1-3M0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx who received treatment between 1994 and 2004. Survival curves were calculated by the Kaplan-Meier Method, comparisons of rates with the log-rank test and prognostic factors by Cox analyses. RESULTS Nodal CR occurred in 377 (43%) patients of whom 365 patients did not undergo nodal dissection. The 5-year actuarial regional control rate of patients with CR was 92%. Two hundred sixty-eight of the remaining patients (53%) underwent neck dissections. The 5-year actuarial regional control rate for patients without a CR was 84%. Those who had a neck dissection fared better with 5-year actuarial regional control rates of 90% and 76% for those operated and those not operated (p <.001). Variables associated with poorer regional control rates included higher T and N stage, non-oropharynx cancers, non-CR, both clinical and pathological. CONCLUSIONS With 92% 5-year neck control rate without neck dissection after CR, there is little justification for systematic neck dissection. The addition of a neck dissection resulted in higher neck control after partial response though patients with viable tumor on pathology specimens had poorer outcomes. The identification of that subgroup that benefits from additional treatment remains a challenge. PMID:22284033

  17. Histologic Assessment of Intratumoral Lymphoplasmacytic Infiltration Is Useful in Predicting Prognosis of Patients with Hepatocellular Carcinoma

    PubMed Central

    Hayashi, Akimasa; Shibahara, Junji; Misumi, Kento; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Kokudo, Norihiro; Fukayama, Masashi

    2016-01-01

    In the present study, we investigated the clinicopathologic significance of intratumoral lymphoplasmacytic infiltration in a large cohort of patients with solitary hepatocellular carcinoma (HCC). Based on examination of hematoxylin and eosin-stained sections, significant infiltration was defined as dense lymphoplasmacytic infiltration, either multifocal or diffuse, in 2 or more fields under low-power magnification. Of 544 cases, 216 (39.7%) were positive for significant infiltration (HCC-LI group), while 328 (60.3%) were negative (HCC-NLI group). There were no significant between-group differences in patient age, sex, or background etiology. The lower incidence of Child-Pugh stage B (P = 0.001) and lower level of indocyanine green retention rate at 15 minutes (P < 0.001) in the HCC-LI group indicated better liver function in this group. Histologically, tumors were significantly smaller in size in the HCC-LI group than in the HCC-NLI group (P < 0.001). In addition, prominent neutrophilic infiltration, interstitial fibrosis and tumor steatosis were significantly more frequent (P < 0.001) in the HCC-LI group, while tumor necrosis was significantly less frequent (P = 0.008). Kaplan-Meier analyses revealed that overall and recurrence-free survival were significantly better in the HCC-LI group (P < 0.001). Multivariate Cox regression analysis showed that intratumoral lymphoplasmacytic infiltration was independently prognostic of both overall and recurrence-free survival (P < 0.001), with absence of infiltration showing high Cox-hazard ratios for poor prognosis. In conclusion, intratumoral lymphoplasmacytic infiltration, as determined by assessment of hematoxylin and eosin-stained slides, was significantly associated with the clinical and pathologic features of HCC and has profound prognostic importance. PMID:27195977

  18. Urothelial bladder tumour in childhood: A report of two cases and a review.

    PubMed

    Rifat, Usama N; Hamadalla, Nader Y; Chiad Safi, Khalid C; Al Habash, Salwan S; Mohammed, Mustafa

    2015-06-01

    Urothelial bladder tumour in childhood is extremely rare, and almost all the reported cases have been low-grade tumours with a favourable outcome. Here we review 57 reports comprising 127 cases, and we report two new cases.

  19. Urothelial bladder tumour in childhood: A report of two cases and a review

    PubMed Central

    Rifat, Usama N.; Hamadalla, Nader Y.; Chiad Safi, Khalid C.; Al Habash, Salwan S.; Mohammed, Mustafa

    2014-01-01

    Urothelial bladder tumour in childhood is extremely rare, and almost all the reported cases have been low-grade tumours with a favourable outcome. Here we review 57 reports comprising 127 cases, and we report two new cases. PMID:26413332

  20. Circulating miR-21 as an independent predictive biomarker for chemoresistance in esophageal squamous cell carcinoma

    PubMed Central

    Komatsu, Shuhei; Ichikawa, Daisuke; Kawaguchi, Tsutomu; Miyamae, Mahito; Okajima, Wataru; Ohashi, Takuma; Imamura, Taisuke; Kiuchi, Jun; Konishi, Hirotaka; Shiozaki, Atsushi; Fujiwara, Hitoshi; Okamoto, Kazuma; Otsuji, Eigo

    2016-01-01

    Only a few studies indentified the significance of circulating microRNAs in blood as a predictive biomarker for chemoresistance in esophageal squamous cell carcinoma (ESCC). In this study, we tested whether oncogenic miR-21 promoted chemoresistance in ESCC and served as a biomarker for predicting chemoresistance in plasma of patients with ESCC. All consecutive patients underwent the preoperative chemotherapy regimen (JCOG9907 trial) with cisplatin plus 5-fluorouracil. As a result, pretreatment plasma concentrations of miR-21 were significantly higher in ESCC patients with a low histopathological response than in those with a high histopathological response (P = 0.0416). Multivariate analysis revealed that a high pretreatment plasma concentration of miR-21 was an independent risk factor of chemoresistance (p = 0.0150; Odds Ratio 9.95 (range: 1.56-63.4)). The expression of miR-21 was also significantly higher in pretreatment ESCC tissues with a low histopathological response than in those with a high histopathological response (P = 0.0409). In vitro, although the growth of KYSE 170 ESCC cells transfected with the control mimics was markedly inhibited by the 5-fluorouracil or cisplatin treatment, the inhibitory effects of 5-FU (P < 0.05) or cisplatin (P < 0.05) were significantly reduced in KYSE170 cells that overexpressed miR-21. Taken together, the overexpression of miR-21 contributed to chemoresistance and circulating miR-21 in plasma of patients with ESCC could be a useful biomarker for predicting chemoresistance. PMID:27508093

  1. Decreased Expression of SETD2 Predicts Unfavorable Prognosis in Patients With Nonmetastatic Clear-Cell Renal Cell Carcinoma

    PubMed Central

    Liu, Weisi; Fu, Qiang; An, Huimin; Chang, Yuan; Zhang, Weijuan; Zhu, Yu; Xu, Le; Xu, Jiejie

    2015-01-01

    Abstract DNA sequencing revealed that mutations in SETD2 occur in 3% to 12% of clear-cell renal cell carcinoma (ccRCC) cases and are associated with poor clinical outcome. In this study, we used an immunohistochemistry (IHC) assay to evaluate the impact of SETD2 loss, with expression of H3K36me3, a nonredundantly histone modification by SETD2, on recurrence and survival of nonmetastatic ccRCC patients after nephrectomy. SETD2 and H3K36me3 were assessed in 192 nonmetastatic ccRCC patients enrolled retrospectively from a single institution. Kaplan–Meier and Cox regression analysis were used to associate prespecified SETD2/H3K36me3 score with overall survival (OS) and recurrence-free survival (RFS). And a nomogram was constructed to predict OS at 10 years. Patients with low expression of SETD2 were prone to possess large tumor size and advanced pT stage. And low H3K36me3 expression was associated with larger tumor size. A prespecified combined score based on SETD2 and H3K36me3 expression remained an independent prognosticator for OS and RFS, which was associated with tumor size, pT stage, and sarcomatoid. Furthermore, using prespecified SETD2/H3K36me3 score could stratify nonmetastatic ccRCC patients into different risk subgroups, especially in patients dichotomized by pT stage and Fuhrman grade, respectively. Finally, the C-index for predicting OS increased from 0.727 to 0.747, after adding SETD2/H3K36me3 score to pT stage and Fuhrman grade. The combined score based on expression of SETD2 and H3K36me3 using IHC could predict poor clinical outcomes in nonmetastatic ccRCC patients, and it may benefit preoperative risk stratification and guide treatment planning in the future. PMID:26559293

  2. Polarized ATP distribution in urothelial mucosal and serosal space is differentially regulated by stretch and ectonucleotidases.

    PubMed

    Yu, Weiqun

    2015-11-15

    Purinergic signaling is a major pathway in regulating bladder function, and mechanical force stimulates urothelial ATP release, which plays an important role in bladder mechanotransduction. Although urothelial ATP release was first reported almost 20 years ago, the way in which release is regulated by mechanical force, and the presence of ATP-converting enzymes in regulating the availability of released ATP is still not well understood. Using a set of custom-designed Ussing chambers with the ability to manipulate mechanical forces applied on the urothelial tissue, we have demonstrated that it is stretch and not hydrostatic pressure that induces urothelial ATP release. The experiments reveal that urothelial ATP release is tightly controlled by stretch speed, magnitude, and direction. We have further shown that stretch-induced urothelial ATP release is insensitive to temperature (4°C). Interestingly, stretch-induced ATP release shows polarized distribution, with the ATP concentration in mucosal chamber (nanomolar level) about 10 times higher than the ATP concentration in serosal chamber (subnanomolar level). Furthermore, we have consistently observed differential ATP lifetime kinetics in the mucosal and serosal chambers, which is consistent with our immunofluorescent localization data, showing that ATP-converting enzymes ENTPD3 and alkaline phosphatase are expressed on urothelial basal surface, but not on the apical membrane. In summary, our data indicate that urothelial ATP release is finely regulated by stretch speed, magnitude, and direction, and extracellular ATP signaling is likely to be differentially regulated by ectonucleotidase, which results in temporally and spatially distinct ATP kinetics in response to mechanical stretch. PMID:26336160

  3. Plasma Epstein–Barr Viral Deoxyribonucleic Acid Predicts Worse Outcomes in Pediatric Nonmetastatic Nasopharyngeal Carcinoma Patients

    PubMed Central

    Shen, Ting; Tang, Lin-Quan; Gu, Wei-Guang; Luo, Dong-Hua; Chen, Qiu-Yan; Li, Pei-Jing; Mai, Dong-Mei; Mai, Hai-Qiang; Mo, Hao-Yuan

    2015-01-01

    Abstract To evaluate the clinical significance of pretreatment levels of plasma Epstein–Barr virus DNA (pEBV DNA) on prognoses in pediatric nasopharyngeal carcinoma (NPC) patients. Eighty-nine patients aged 21 years old or younger with nonmetastatic NPC were evaluated to determine the effect of pEBV DNA levels on progression-free survival (PFS), distant metastasis-free survival (DMFS), and overall survival (OS). Survival probabilities in patient groups that were segregated by clinical stage or pEBV DNA load (low or high) were compared. The median pretreatment concentrations of pEBV DNA were 3440 copies/mL in 35 patients with stage III disease and 14,900 copies/mL in 50 patients with stage IV disease (P = 0.059). The median concentration of pEBV DNA was 34,500 copies/mL in 17 patients with relapse, which was higher than the concentration in 72 patients without relapse, who had a median level of 4985 copies/mL (P = 0.057). Further study showed that pretreatment pEBV DNA load was an independent prognostic indicator in pediatric NPC patients. High pEBV DNA was associated with adverse clinical outcomes, including PFS [3-year PFS rate = 80.5% versus 95.8%, hazard ratio (HR) = 5.00, 95% confidence interval (CI) = 1.00–25.00; P = 0.050], DMFS (3-year DMFS rate = 80.5% versus 95.8%, HR = 5.20, 95% CI = 1.04–26.00; P = 0.045), and OS (3-year OS rate = 82.9% versus 95.8%, HR = 5.41, 95% CI = 1.08–27.22; P = 0.040). Pretreatment pEBV DNA load was an independent prognostic indicator for PFS, DMFS, and OS in pediatric patients with NPC. Prospective studies, however, are needed to validate these results. PMID:26683909

  4. Predictive value of EGFR overexpression and gene amplification on icotinib efficacy in patients with advanced esophageal squamous cell carcinoma

    PubMed Central

    Fan, Qingxia; Lu, Ping; Ma, Changwu; Liu, Wei; Liu, Ying; Li, Weiwei; Hu, Shaoxuan; Ling, Yun; Guo, Lei; Ying, Jianming; Huang, Jing

    2016-01-01

    This study aimed to search for a molecular marker for targeted epithelial growth factor receptor (EGFR) inhibitor Icotinib by analyzing protein expression and amplification of EGFR proto-oncogene in esophageal squamous cell carcinoma (ESCC) patients. Immunohistochemistry and fluorescence in situ hybridization (FISH) was used to assess EGFR expression and gene amplification status in 193 patients with ESCC. We also examined the association between EGFR overexpression and the efficacy of a novel EGFR TKI, icotinib, in 62 ESCC patients. Of the 193 patients, 95 (49.2%) patients showed EGFR overexpression (3+), and 47(24.4%) patients harbored EGFR FISH positivity. EGFR overexpression was significantly correlated with clinical stage and lymph node metastasis (p<0.05). In addition, EGFR overexpression was significantly correlated with EGFR FISH positivity (p<0.001). Among the 62 patients who received icotinib, the response rate was 17.6% for patients with high EGFR-expressing tumors, which was markedly higher than the rate (0%) for patients with low to moderate EGFR-expressing tumors (p=0.341). Furthermore, all cases responded to icotinib showed EGFR overexpression. In conclusion, our study suggests that EGFR overexpression might potentially be used in predicting the efficacy in patients treated with Icotinib. These data have implications for both clinical trial design and therapeutic strategies. PMID:27013591

  5. Incidence and predictive factors of benign renal lesions in Korean patients with preoperative imaging diagnoses of renal cell carcinoma.

    PubMed

    Park, Seo Yong; Jeon, Seong Soo; Lee, Seo Yeon; Jeong, Byong Chang; Seo, Seong Il; Lee, Hyun Moo; Choi, Han Yong

    2011-03-01

    The present study was performed to determine the incidence and predictive factors of benign renal lesions in Korean patients undergoing nephrectomy for presumed renal cell carcinoma on preoperative imaging. We analyzed the pathologic reports and medical records of 1,598 eligible patients with unilateral, nonmetastatic, and nonfamilial renal masses. Of the 1,598 renal masses, 114 (7.1%) were benign lesions, including angiomyolipoma in 47 (2.9%), oncocytoma in 23 (1.4%), and complicated cysts in 18 (1.1%) patients. On univariate analysis, the proportion of benign lesions was significantly higher in female patients, and in patients with smaller tumors, cystic renal masses, and without gross hematuria as a presenting symptom. When renal lesions were stratified by tumor size, the proportion of benign as opposed to malignant lesions decreased significantly as tumor size increased. On multivariate analysis, female gender, smaller tumor size, and cystic lesions were significantly associated with benign histological features. The findings in this large cohort of Korean patients show a lower incidence (7.1%) of benign renal lesions than those of previous Western reports. Female gender, cystic renal lesions, and smaller tumor size are independent predictors of benign histological features.

  6. Genomic imbalances in urothelial cancer: intratumor heterogeneity versus multifocality.

    PubMed

    Prat, Esther; Del Rey, Javier; Camps, Jordi; Ponsa, Immaculada; Lloreta, Josep; Egozcue, Josep; Gelabert, Antoni; Campillo, Mercedes; Miro, Rosa

    2008-09-01

    Comparative genomic hybridization and fluorescence in situ hybridization were used to define genetic changes associated with multifocal bladder cancer and to investigate whether the genetic relationship between synchronous urothelial tumors is similar to that observed within different parts of the same tumor. We investigated 8 synchronous urothelial tumors from 3 patients and macroscopically different parts of the same tumor from 2 other patients. The most frequent imbalances were gains of 1q, 2p, and 17q, and losses in 4q. The high number of chromosome imbalances detected in the present report confirms that a high level of chromosome instability could be characteristic of multicentric bladder tumors. Comparative genomic hybridization profiles obtained from independent tumors belonging to the same patient allowed us to elaborate cytogenetic pedigrees portraying the accumulation of chromosome alterations as a form of clonal evolution from a single precursor cell. The analysis of different macroscopic parts of the same tumor allowed us to detect chromosomal heterogeneity and to delineate intratumor clonal evolution. Some chromosome regions that appeared as a gain in one subpopulation were amplified in others indicating a genetic evolution process. Identical processes were observed in different tumors of the same patient. Expansion of chromosome gains and losses between different parts of the same tumor as well as in different tumors of the same patient was also observed. Our results not only provide further evidence of a clonal relationship between different synchronous bladder tumors but also show that the intratumor heterogeneity present in different subpopulations of the same tumor reproduces the behavior of independent synchronous tumors in a same patient. PMID:18382360

  7. Lab on chip microdevices for cellular mechanotransduction in urothelial cells

    NASA Astrophysics Data System (ADS)

    Maziz, A.; Guan, N.; Svennersten, K.; Hallén-Grufman, K.; Jager, Edwin W. H.

    2016-04-01

    Cellular mechanotransduction is crucial for physiological function in the lower urinary tract. The bladder is highly dependent on the ability to sense and process mechanical inputs, illustrated by the regulated filling and voiding of the bladder. However, the mechanisms by which the bladder integrates mechanical inputs, such as intravesicular pressure, and controls the smooth muscles, remain unknown. To date no tools exist that satisfactorily mimic in vitro the dynamic micromechanical events initiated e.g. by an emerging inflammatory process or a growing tumour mass in the urinary tract. More specifically, there is a need for tools to study these events on a single cell level or in a small population of cells. We have developed a micromechanical stimulation chip that can apply physiologically relevant mechanical stimuli to single cells to study mechanosensitive cells in the urinary tract. The chips comprise arrays of microactuators based on the electroactive polymer polypyrrole (PPy). PPy offers unique possibilities and is a good candidate to provide such physiological mechanical stimulation, since it is driven at low voltages, is biocompatible, and can be microfabricated. The PPy microactuators can provide mechanical stimulation at different strains and/or strain rates to single cells or clusters of cells, including controls, all integrated on one single chip, without the need to preprepare the cells. This paper reports initial results on the mechano-response of urothelial cells using the micromechanical stimulation chips. We show that urothelial cells are viable on our microdevices and do respond with intracellular Ca2+ increase when subjected to a micro-mechanical stimulation.

  8. Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck

    PubMed Central

    Handorf, Elizabeth; Nikonova, Anna; Dubyk, Cara; Peri, Suraj; Lango, Miriam; Ridge, John A.; Serebriiskii, Ilya G.; Burtness, Barbara; Golemis, Erica A.; Mehra, Ranee

    2015-01-01

    Locally advanced squamous cell carcinoma of the head and neck (SCCHN) that is not associated with human papillomavirus (HPV) has a poor prognosis in contrast to HPV-positive disease. To better understand the importance of RB1 activity in HPV-negative SCCHN, we investigated the prognostic value of inhibitory CDK4/6 phosphorylation of RB1 on threonine 356 (T356) in archival HPV-negative tumor specimens from patients who underwent surgical resection and adjuvant radiation. We benchmarked pT356RB1 to total RB1, Ki67, pT202/Y204ERK1/2, and TP53, as quantified by automatic quantitative analysis (AQUA), and correlated protein expression with tumor stage and grade. High expression of pT356RB1 but not total RB1 predicted reduced overall survival (OS; P = 0.0295), indicating the potential relevance of post-translational phosphorylation. Paired analysis of The Cancer Genome Atlas (TCGA) data for regulators of this RB1 phosphorylation identified loss or truncating mutation of negative regulator CDKN2A (p16) and elevated expression of the CDK4/6 activator CCND1 (cyclin D) as also predicting poor survival. Given that CDK4/6 inhibitors have been most effective in the context of functional RB1 and low expression or deletion of p16 in other tumor types, these data suggest such agents may merit evaluation in HPV-negative SCCHN, specifically in cases associated with high pT356RB1. PMID:26265441

  9. Upregulation of spondin-2 predicts poor survival of colorectal carcinoma patients

    PubMed Central

    Wang, Jie; Cui, Shu-Jian; Lou, Xiao-Min; Yan, Bing; Qiao, Jie; Jiang, Ying-Hua; Zhang, Li-Jun; Yang, Peng-Yuan; Liu, Feng

    2015-01-01

    Colorectal cancer (CRC) is the third and second most common cancer in males and females worldwide, respectively. Spondin-2 is a conserved secreted extracellular matrix protein and a candidate cancer biomarker. Here we found that Spondin-2 mRNA was upregulated in CRC tissues using quantitative RT-PCR and data-mining of public Oncomine microarray datasets. Spondin-2 protein was increased in CRC tissues, as revealed by immunohistochemistry analyses of two tissue microarrays containing 180 cases. Spondin-2 gene expression was significantly associated with CRC stage, T stage, M stage and Dukes stage, while its protein was associated with age and M stage. Kaplan-Meier analysis revealed that the upregulated Spondin-2 mRNA and protein predicted poor prognosis of CRC patients. Univariate and multivariate Cox regression analyses indicated that grade, recurrence, N stage and high Spondin-2 were independent predictors of overall survival of CRC patients. ELISA revealed that plasma Spondin-2 was upregulated in CRC and dropped after surgery. Receiver operating characteristic curve analysis demonstrated that plasma Spondin-2 has superior predictive performance for CRC with an area under the curve of 0.959 and the best sensitivity/specificity of 100%/90%. Furthermore, ectopic expression of Spondin-2 enhanced colon cancer cell proliferation. Spondin-2 could be an independent diagnostic and prognostic biomarker of colon cancer. PMID:25945835

  10. Development and Evaluation of a Prediction Model for Underestimated Invasive Breast Cancer in Women with Ductal Carcinoma In Situ at Stereotactic Large Core Needle Biopsy

    PubMed Central

    Diepstraten, Suzanne C. E.; van de Ven, Stephanie M. W. Y.; Pijnappel, Ruud M.; Peeters, Petra H. M.; van den Bosch, Maurice A. A. J.; Verkooijen, Helena M.; Elias, Sjoerd G.

    2013-01-01

    Background We aimed to develop a multivariable model for prediction of underestimated invasiveness in women with ductal carcinoma in situ at stereotactic large core needle biopsy, that can be used to select patients for sentinel node biopsy at primary surgery. Methods From the literature, we selected potential preoperative predictors of underestimated invasive breast cancer. Data of patients with nonpalpable breast lesions who were diagnosed with ductal carcinoma in situ at stereotactic large core needle biopsy, drawn from the prospective COBRA (Core Biopsy after RAdiological localization) and COBRA2000 cohort studies, were used to fit the multivariable model and assess its overall performance, discrimination, and calibration. Results 348 women with large core needle biopsy-proven ductal carcinoma in situ were available for analysis. In 100 (28.7%) patients invasive carcinoma was found at subsequent surgery. Nine predictors were included in the model. In the multivariable analysis, the predictors with the strongest association were lesion size (OR 1.12 per cm, 95% CI 0.98-1.28), number of cores retrieved at biopsy (OR per core 0.87, 95% CI 0.75-1.01), presence of lobular cancerization (OR 5.29, 95% CI 1.25-26.77), and microinvasion (OR 3.75, 95% CI 1.42-9.87). The overall performance of the multivariable model was poor with an explained variation of 9% (Nagelkerke’s R2), mediocre discrimination with area under the receiver operating characteristic curve of 0.66 (95% confidence interval 0.58-0.73), and fairly good calibration. Conclusion The evaluation of our multivariable prediction model in a large, clinically representative study population proves that routine clinical and pathological variables are not suitable to select patients with large core needle biopsy-proven ductal carcinoma in situ for sentinel node biopsy during primary surgery. PMID:24147085

  11. Model-guided therapy for hepatocellular carcinoma: a role for information technology in predictive, preventive and personalized medicine

    PubMed Central

    2014-01-01

    Predictive, preventive and personalized medicine (PPPM) may have the potential to eventually improve the nature of health care delivery. However, the tools required for a practical and comprehensive form of PPPM that is capable of handling the vast amounts of medical information that is currently available are currently lacking. This article reviews a rationale and method for combining and integrating diagnostic and therapeutic management with information technology (IT), in a manner that supports patients through their continuum of care. It is imperative that any program devised to explore and develop personalized health care delivery must be firmly rooted in clinically confirmed and accepted principles and technologies. Therefore, a use case, relating to hepatocellular carcinoma (HCC), was developed. The approach to the management of medical information we have taken is based on model theory and seeks to implement a form of model-guided therapy (MGT) that can be used as a decision support system in the treatment of patients with HCC. The IT structures to be utilized in MGT include a therapy imaging and model management system (TIMMS) and a digital patient model (DPM). The system that we propose will utilize patient modeling techniques to generate valid DPMs (which factor in age, physiologic condition, disease and co-morbidities, genetics, biomarkers and responses to previous treatments). We may, then, be able to develop a statistically valid methodology, on an individual basis, to predict certain diseases or conditions, to predict certain treatment outcomes, to prevent certain diseases or complications and to develop treatment regimens that are personalized for that particular patient. An IT system for predictive, preventive and personalized medicine (ITS-PM) for HCC is presented to provide a comprehensive system to provide unified access to general medical and patient-specific information for medical researchers and health care providers from different

  12. Genomic complexity of urothelial bladder cancer revealed in urinary cfDNA

    PubMed Central

    Togneri, Fiona S; Ward, Douglas G; Foster, Joseph M; Devall, Adam J; Wojtowicz, Paula; Alyas, Sofia; Vasques, Fabiana Ramos; Oumie, Assa; James, Nicholas D; Cheng, K K; Zeegers, Maurice P; Deshmukh, Nayneeta; O'Sullivan, Brendan; Taniere, Philippe; Spink, Karen G; McMullan, Dominic J; Griffiths, Mike; Bryan, Richard T

    2016-01-01

    Urothelial bladder cancers (UBCs) have heterogeneous clinical characteristics that are mirrored in their diverse genomic profiles. Genomic profiling of UBCs has the potential to benefit routine clinical practice by providing prognostic utility above and beyond conventional clinicopathological factors, and allowing for prediction and surveillance of treatment responses. Urinary DNAs representative of the tumour genome provide a promising resource as a liquid biopsy for non-invasive genomic profiling of UBCs. We compared the genomic profiles of urinary cellular DNA and cell-free DNA (cfDNA) from the urine with matched diagnostic formalin-fixed paraffin-embedded tumour DNAs for 23 well-characterised UBC patients. Our data show urinary DNAs to be highly representative of patient tumours, allowing for detection of recurrent clinically actionable genomic aberrations. Furthermore, a greater aberrant load (indicative of tumour genome) was observed in cfDNA over cellular DNA (P<0.001), resulting in a higher analytical sensitivity for detection of clinically actionable genomic aberrations (P<0.04) when using cfDNA. Thus, cfDNA extracted from the urine of UBC patients has a higher tumour genome burden and allows greater detection of key genomic biomarkers (90%) than cellular DNA from urine (61%) and provides a promising resource for robust whole-genome tumour profiling of UBC with potential to influence clinical decisions without invasive patient interventions. PMID:26757983

  13. MicroRNA-205 Targets Tight Junction-related Proteins during Urothelial Cellular Differentiation *

    PubMed Central

    Chung, Pei-Jung Katy; Chi, Lang-Ming; Chen, Chien-Lun; Liang, Chih-Lung; Lin, Chung-Tzu; Chang, Yu-Xun; Chen, Chun-Hsien; Chang, Yu-Sun

    2014-01-01

    The mammalian bladder urothelium classified as basal, intermediate, and terminally differentiated umbrella cells offers one of the most effective permeability barrier functions known to exist in nature because of the formation of apical uroplakin plaques and tight junctions. To improve our understanding of urothelial differentiation, we analyzed the microRNA (miRNA) expression profiles of mouse urinary tissues and by TaqMan miRNA analysis of microdissected urothelial layers and in situ miRNA-specific hybridization to determine the dependence of these miRNAs on the differentiation stage. Our in situ hybridization studies revealed that miR-205 was enriched in the undifferentiated basal and intermediate cell layers. We then used a quantitative proteomics approach to identify miR-205 target genes in primary cultured urothelial cells subjected to antagomir-mediated knockdown of specific miRNAs. Twenty-four genes were reproducibly regulated by miR-205; eleven of them were annotated as cell junction- and tight junction-related molecules. Western blot analysis demonstrated that antagomir-induced silencing of miR-205 in primary cultured urothelial cells elevated the expression levels of Tjp1, Cgnl1, and Cdc42. Ectopic expression of miR-205 in MDCK cells inhibited the expression of tight junction proteins and the formation of tight junctions. miR-205- knockdown urothelial cells showed alterations in keratin synthesis and increases of uroplakin Ia and Ib, which are the urothelial differentiation products. These results suggest that miR-205 may contribute a role in regulation of urothelial differentiation by modulating the expression of tight junction-related molecules. PMID:24912853

  14. Risk Factors and Post-Resection Independent Predictive Score for the Recurrence of Hepatitis B-Related Hepatocellular Carcinoma

    PubMed Central

    Poon, Ronnie Tung-Ping; Fong, Daniel Yee-Tak; Chui, Ada Hang-Wai; Seto, Wai-Kay; Fung, James Yan-Yue; Chan, Albert Chi-Yan; Yuen, John Chi-Hang; Tiu, Randal; Choi, Olivia; Lai, Ching-Lung; Yuen, Man-Fung

    2016-01-01

    Background Independent risk factors associated with hepatitis B (HBV)-related hepatocellular carcinoma (HCC) after resection remains unknown. An accurate risk score for HCC recurrence is lacking. Methods We prospectively followed up 200 patients who underwent liver resection for HBV-related HCC for at least 2 years. Demographic, biochemical, tumor, virological and anti-viral treatment factors were analyzed to identify independent risk factors associated with recurrence after resection and a risk score for HCC recurrence formulated. Results Two hundred patients (80% male) who underwent liver resection for HBV-related HCC were recruited. The median time of recurrence was 184 weeks (IQR 52–207 weeks) for the entire cohort and 100 patients (50%) developed HCC recurrence. Stepwise Cox regression analysis identified that one-month post resection HBV DNA >20,000 IU/mL (p = 0.019; relative risk (RR) 1.67; 95% confidence interval (C.I.): 1.09–2.57), the presence of lymphovascular permeation (p<0.001; RR 2.69; 95% C.I.: 1.75–4.12), microsatellite lesions (p<0.001; RR 2.86; 95% C.I.: 1.82–4.51), and AFP >100ng/mL before resection (p = 0.021; RR 1.63; 95% C.I.: 1.08–2.47) were independently associated with HCC recurrence. Antiviral treatment before resection (p = 0.024; RR 0.1; 95% C.I.: 0.01–0.74) was independently associated with reduced risk of HCC recurrence. A post-resection independent predictive score (PRIPS) was derived and validated with sensitivity of 75.3% and 60.6% and specificity of 55.7% and 79.2%, to predict the 1- and 3-year risks for the HCC recurrence respectively with the hazard ratio of 2.71 (95% C.I.: 2.12–3.48; p<0.001). The AUC for the 1- and 3-year prediction were 0.675 (95% C.I.: 0.6–0.78) and 0.746 (95% C.I.: 0.69–0.82) respectively. Conclusion Several tumor, virological and biochemical factors were associated with a higher cumulative risk of HCC recurrence after resection. PRIPS was derived for more accurate risk assessment

  15. Gemcitabine Hydrochloride and Eribulin Mesylate in Treating Patients With Bladder Cancer That is Advanced or Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-09-09

    Metastatic Ureteral Neoplasm; Metastatic Urethral Neoplasm; Stage III Bladder Urothelial Carcinoma; Stage III Ureter Cancer; Stage III Urethral Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Ureter Cancer; Stage IV Urethral Cancer; Ureter Urothelial Carcinoma; Urethral Urothelial Carcinoma

  16. Reduced Glucocorticoid Receptor Expression Predicts Bladder Tumor Recurrence and Progression

    PubMed Central

    Ishiguro, Hitoshi; Kawahara, Takashi; Zheng, Yichun; Netto, George J.; Miyamoto, Hiroshi

    2015-01-01

    Objectives To assess the levels of glucocorticoid receptor (GR) expression in bladder tumors because the status and its prognostic value remain largely unknown. Methods We immunohistochemically stained for GR in bladder tumor and matched non-neoplastic bladder tissue specimens. Results Overall, GR was positive in 129 (87%) of 149 urothelial tumors, which was significantly (P = .026) lower than in non-neoplastic urothelium (90 [96%] of 94). Forty-two (79%) of 53 low-grade tumors vs 45 (47%) of 96 high-grade carcinomas (P < .001) and 61 (73%) of 84 non–muscle-invasive (NMI) tumors vs 26 (40%) of 65 muscle-invasive (MI) carcinomas (P < .001) were moderately to strongly immunoreactive for GR. Kaplan-Meier and log-rank tests revealed that loss or weak positivity of GR significantly or marginally correlated with recurrence of NMI tumors (P = .025), progression of MI tumors (P = .082), and cancer-specific survival of MI tumors (P = .067). Multivariate analysis identified low GR expression as a strong predictor for recurrence of NMI tumors (P = .034). Conclusions GR expression was downregulated in bladder tumors compared with nonneoplastic bladder tumors and in high-grade/MI tumors compared with low-grade/NMI tumors. Decreased expression of GR, as an independent prognosticator, predicted recurrence of NMI tumors. These results support experimental evidence suggesting an inhibitory role of GR signals in bladder cancer outgrowth. PMID:25015855

  17. Role of Early Proctoscopy in Predicting Late Symptomatic Proctitis After External Radiation Therapy for Prostate Carcinoma

    SciTech Connect

    Campostrini, Franco; Musola, Renato; Marchiaro, Giuseppe; Lonardi, Federico; Verlato, Giuseppe

    2013-03-15

    Purpose: To determine whether acute radiation-proctitis, diagnosed by proctoscopy after radiation therapy for prostate cancer, can predict late clinical proctitis. Methods and Materials: A prospective study of 130 patients who underwent external radiation therapy (RT) for stage T1 to T4 prostate cancer between 1997 and 2008 was performed. Treatments were conventional (2-dimensional [2D]) in 61 patients and 3D conformal in 69, with a median target dose of 72 Gy (70-74 Gy). Within 1 week after RT, proctoscopy was performed to detect possible acute endoscopic proctitis (AEP). Acute clinical proctitis (ACP) and late clinical proctitis (LCP) were also evaluated. The median follow-up was 84 months (20-180 months). The influence of AEP and ACP on LCP occurrence was studied using the Cox model controlling for age, dose, prostatectomy, RT technique (2D vs 3D), and hormone therapy. Results: AEP was detected in 15 patients (11.5%) and ACP in 67 (51.5%); in 13 cases (10%) AEP and ACP occurred simultaneously. Thirty-five cases of LCP were recorded. The 5-year probability of developing LCP was highest in patients with AEP and ACP (77%, 95% confidence interval [CI] 53%-94%) and lowest in asymptomatic patients (14%, 95% CI 7%-26%; P<.001). Compared to asymptomatic patients, the 5-year probability also was slightly increased in patients with ACP only (26%, 95% CI 16%-40%; P=.052). In multivariable analysis, the combination of AEP and ACP was the main predictor of LCP: compared to asymptomatic patients, the hazard ratio was 5.6 (2.1-15.2) in patients with AEP plus ACP (P=.001) and 2.1 (0.9-4.9) in those with ACP only (P=.103). Conclusions: In patients with AEP and ACP, the risk of LCP was more than 5-fold increased compared to those who were asymptomatic, while a much smaller increase in risk occurred in patients with ACP only. Early proctoscopy can provide valuable information regarding the likelihood of late proctitis.

  18. Macrophage colony-stimulating factor expressed in non-cancer tissues provides predictive powers for recurrence in hepatocellular carcinoma

    PubMed Central

    Kono, Hiroshi; Fujii, Hideki; Furuya, Shinji; Hara, Michio; Hirayama, Kazuyoshi; Akazawa, Yoshihiro; Nakata, Yuuki; Tsuchiya, Masato; Hosomura, Naohiro; Sun, Chao

    2016-01-01

    AIM To investigate the role of macrophage colony-stimulating factor (M-CSF) in patients with hepatocellular carcinoma (HCC) after surgery. METHODS Expression of M-CSF, distribution of M2 macrophages (MΦs), and angiogenesis were assessed in the liver, including tumors and peritumoral liver tissues. The prognostic power of these factors was assessed. Mouse isolated hepatic MΦs or monocytes were cultured with media containing M-CSF. The concentration of vascular endothelial growth factor (VEGF) in media was assessed. Furthermore, the role of the M-CSF-matured hepatic MΦs on proliferation of the vascular endothelial cell (VEC) was investigated. RESULTS A strong correlation between the expressions of M-CSF and CD163 was observed in the peritumoral area. Also, groups with high density of M-CSF, CD163 or CD31 showed a significantly shorter time to recurrence (TTR) than low density groups. Multivariate analysis revealed the expression of M-CSF or hepatic M2MΦs in the peritumoral area as the most crucial factor responsible for shorter TTR. Moreover, the expression of M-CSF and hepatic M2MΦs in the peritumoral area had better predictable power of overall survival. Values of VEGF in culture media were significantly greater in the hepatic MΦs compared with the monocytes. Proliferation of the VEC was greatest in the cells co-cultured with hepatic MΦs when M-CSF was present in media. CONCLUSION M-CSF increases hepatocarcinogenesis, most likely by enhancing an angiogenic factor derived from hepatic MΦ and could be a useful target for therapy against HCC.

  19. Prognostic prediction and diagnostic role of intercellular adhesion molecule-1 (ICAM1) expression in clear cell renal cell carcinoma.

    PubMed

    Shi, Xuebing; Jiang, Jifa; Ye, Xiaobing; Liu, Yanyan; Wu, Qiong; Wang, Lu

    2014-08-01

    The intercellular adhesion molecule-1 (ICAM1) has been reported to function in multiple malignancies, but its effect on clear cell renal cell carcinoma (ccRCC) hasn't been discussed yet. This study aimed to identify the potential role of ICAM1 in prognostic prediction and early diagnosis of ccRCC. ICAM1 expression was inspected by immunohistochemistry and correlated with clinicopathologic variables. Association between protein expression and cancer-specific survival (CSS) of ccRCC patients was evaluated and the value of area under the receiver operating characteristics (ROC) curve (AUC) was calculated to measure the protein's diagnostic accuracy. ICAM1 was positively immunostained in 83.2% of 173 ccRCC tissues, but negatively immunostained in all the para-cancerous normal epitheliums of renal tubules. High ICAM1 expression was significantly related to male sex (P = 0.00241), T3/T4 stage (P = 0.02249), non-N0M0 stage (P = 0.03797) and positive renal pelvis invasion (P = 0.04227). Kaplan-Meier survival analysis illustrated that high ICAM1 expression was significantly correlated to a decreased CSS (P = 0.00006). Multivariate Cox analysis indicated that ICAM1 was an independent predictor for CSS of patients (P = 0.00451). Furthermore, the AUC value of ICAM1 in diagnosing ccRCC was 0.916 (P < 0.00001). In conclusion, high ICAM1 expression on tumor cells indicates a poor outcome of patients and ICAM1 is likely to be an independent predictor for the prognosis of ccRCC. Moreover, ICAM1 has a high AUC value and may be a potential and useful diagnostic marker. PMID:24535541

  20. 1H Magnetic Resonance Spectroscopy Predicts Hepatocellular Carcinoma in a Subset of Patients With Liver Cirrhosis: A Randomized Trial.

    PubMed

    Wang, Dan; Li, Yuehua

    2015-07-01

    The goal of this study was to investigate the utility of H magnetic resonance spectroscopy (H-MRS) to quantify the differences in liver metabolites. Magnetic resonance spectroscopy was used as a means of predicting the probability of developing hepatocellular carcinoma (HCC) in patients with liver cirrhosis secondary to chronic hepatitis B.This study included 20 healthy volunteers, 20 patients with liver cirrhosis secondary to chronic hepatitis B (cirrhosis group), and 20 patients with small HCC secondary to cirrhosis liver parenchyma (HCC group). All patients underwent routine MRI and H-MRS scanning. LCModel software was used to quantify Cho (Choline), Lip (lipid), and Cho/Lip in the 3 groups, and a one-way ANOVA was used to compare the differences in these metabolites between groups.Choline levels were significantly different between the control and HCC group and between the cirrhosis group and the HCC group (all P < 0.001). There was also a significant difference in Lip levels between the control and cirrhosis group and the control and HCC groups (all P < 0.001). There were also differences in Cho/Lip between the control and cirrhosis groups, the control and HCC groups, and the cirrhosis and HCC groups (all P < 0.001).H-MRS followed by the analysis with LCModel can be used to measure changes in hepatic metabolite levels in patients with liver cirrhosis secondary to chronic hepatitis B and HCC. Thus, H-MRS may be helpful in monitoring HCC and liver cirrhosis development.

  1. Immunohistochemical Validation of Overexpressed Genes Identified by Global Expression Microarrays in Adrenocortical Carcinoma Reveals Potential Predictive and Prognostic Biomarkers

    PubMed Central

    Ip, Julian C.Y.; Pang, Tony C.Y.; Glover, Anthony R.; Soon, Patsy; Zhao, Jing Ting; Clarke, Stephen; Robinson, Bruce G.; Gill, Anthony J.

    2015-01-01

    Background. Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. The aim of this study was to identify novel protein signatures that would predict clinical outcomes in a large cohort of patients with ACC based on data from previous gene expression microarray studies. Materials and Methods. A tissue microarray was generated from the paraffin tissue blocks of 61 patients with clinical outcomes data. Selected protein biomarkers based on previous gene expression microarray profiling studies were selected, and immunohistochemistry staining was performed. Staining patterns were correlated with clinical outcomes, and a multivariate analysis was undertaken to identify potential biomarkers of prognosis. Results. Median overall survival was 45 months, with a 5-year overall survival rate of 44%. Median disease-free survival was 58 months, with a 5-year disease-free survival rate of 44%. The proliferation marker Ki-67 and DNA topoisomerase TOP2A were associated with significantly poorer overall and disease-free survival. The results also showed strong correlation between the transcriptional repressor EZH2 and TOP2A expression, suggesting a novel role for EZH2 as an additional marker of prognosis. In contrast, increased expression of the BARD1 protein, with its ubiquitin ligase function, was associated with significantly improved overall and disease-free survival, which has yet to be documented for ACC. Conclusion. We present novel biomarkers that assist in determining prognosis for patients with ACC. Ki-67, TOP2A, and EZH2 were all significantly associated with poorer outcomes, whereas BARD1 was associated with improved overall survival. It is hoped that these biomarkers may help tailor additional therapy and be potential targets for directed therapy. PMID:25657202

  2. CHD1L Protein is overexpressed in human ovarian carcinomas and is a novel predictive biomarker for patients survival

    PubMed Central

    2012-01-01

    Background Our recent studies suggested that the chromodomain helicase DNA binding protein 1-like (CHD1L) gene plays an oncogenic role in human hepatocellular carcinoma. However, the status of CHD1L protein expression in ovarian cancer and its clinical/prognostic significance are obscure. Methods In this study, immunohistochemistry (IHC) for CHD1L was performed on a tissue microarray (TMA) containing 102 primary ovarian carcinomas and 44 metastatic lesions (omental metastasis). Receiver-operator curve (ROC) analysis was used to evaluate patients’ survival status. Results There is an augmented tendency of CHD1L expression in ovarian carcinoma metastasis than in primary lesions (P<0.05). A significant association was found between positive expression of CHD1L and tumors histological type (P <0.05). By univariate survival analysis of the ovarian carcinoma cohorts, positive expression of CHD1L was significantly correlated with shortened patient survival (mean 66.7 months versus 97.4 months, P<0.05). Moreover, CHD1L expression was evaluated to be a significant and independent prognostic factor in multivariate analysis (P<0.05). Conclusions These findings provide evidence that positive expression of CHD1L protein is significantly correlated with the metastasis proceeding of ovarian carcinoma, and CHD1L protein expression, as examined by IHC, may act as a novel prognostic biomarker for patients with ovarian carcinoma. PMID:23020525

  3. Renal sparing treatment of upper tract malignant urothelial tumours using photodynamic therapy (PDT)-three case reports.

    PubMed

    Coombs, L M; Dixon, Kate

    2004-05-01

    Urothelial cancers of the upper urinary tract are usually treated by excision of the kidney, ureter and cuff of the bladder on the affected side. These three cases demonstrate the feasibility, safety and efficacy of photodynamic therapy as a renal sparing procedure for urothelial tumours. PMID:25048071

  4. Functional characterization of transient receptor potential channels in mouse urothelial cells.

    PubMed

    Everaerts, Wouter; Vriens, Joris; Owsianik, Grzegorz; Appendino, Giovanni; Voets, Thomas; De Ridder, Dirk; Nilius, Bernd

    2010-03-01

    The bladder urothelium is currently believed to be a sensory structure, contributing to mechano- and chemosensation in the bladder. Transient receptor potential (TRP) cation channels act as polymodal sensors and may underlie some of the receptive properties of urothelial cells. However, the exact TRP channel expression profile of urothelial cells is unclear. In this study, we have performed a systematic analysis of the molecular and functional expression of various TRP channels in mouse urothelium. Urothelial cells from control and trpv4-/- mice were isolated, cultured (12-48 h), and used for quantitative real-time PCR, immunocytochemistry, calcium imaging, and whole cell patch-clamp experiments. At the mRNA level, TRPV4, TRPV2, and TRPM7 were the most abundantly expressed TRP genes. Immunohistochemistry showed a clear expression of TRPV4 in the plasma membrane, whereas TRPV2 was more prominent in the cytoplasm. TRPM7 was detected in the plasma membrane as well as cytoplasmic vesicles. Calcium imaging and patch-clamp experiments using TRP channel agonists and antagonists provided evidence for the functional expression of TRPV4, TRPV2, and TRPM7 but not of TRPA1, TRPV1, and TRPM8. In conclusion, we have demonstrated functional expression of TRPV4, TRPV2, and TRPM7 in mouse urothelial cells. These channels may contribute to the (mechano)sensory function of the urothelial layer and represent potential targets for the treatment of bladder dysfunction. PMID:20015940

  5. Urinary BLCA1 is specific for urothelial cancer detection in Chinese ethnicity

    PubMed Central

    Wang, Lujia; Feng, Chenchen; Ding, Guanxiong; Jiang, Haowen; Ding, Qiang; Wu, Zhong

    2015-01-01

    Aim: To study the potential of BLCA1 for detection of urothelial cancer including urinary bladder cancer (UBC) and upper tract urothelial cancer (UTUC). Method: An antibody for BLCA1 was generated and indirect ELISA was used to detect urinary BLCA1 level. Clinicopathological parameters were studied for the association with BLCA1 level. Urine samples from UBC and UTUC patients, together with cases with other urological disorders were collected and tested. Results: Urinary BLCA1 level in UBC and UTUC patients were significantly higher than that in normal controls. This was also proven when urothelial cancers were grouped as a whole, where as the level did not differ between UBC and UTUC samples. BLCA1 was also significantly higher in urothelial cancer samples compared to other urological disorders such as patients with long-dwelling catheter, glandular cystitis, BPH and other benign conditions. Cut-off value at 0.0009 OD/μg yielded a sensitivity of 92.7% and a specificity of 92.9% for UBC. Conclusion: Urinary BLCA1 is a promising marker for urothelial cancers including UBC and UTUC with high sensitivity and specificity. PMID:26770501

  6. Characterizing and optimizing poly-l-lactide-co-ε-caprolactone membranes for urothelial tissue engineering

    PubMed Central

    Sartoneva, Reetta; Haaparanta, Anne-Marie; Lahdes-Vasama, Tuija; Mannerström, Bettina; Kellomäki, Minna; Salomäki, Minna; Sándor, George; Seppänen, Riitta; Miettinen, Susanna; Haimi, Suvi

    2012-01-01

    Different synthetic biomaterials such as polylactide (PLA), polycaprolactone and poly-l-lactide-co-ε-caprolactone (PLCL) have been studied for urothelial tissue engineering, with favourable results. The aim of this research was to further optimize the growth surface for human urothelial cells (hUCs) by comparing different PLCL-based membranes: smooth (s) and textured (t) PLCL and knitted PLA mesh with compression-moulded PLCL (cPLCL). The effects of topographical texturing on urothelial cell response and mechanical properties under hydrolysis were studied. The main finding was that both sPLCL and tPLCL supported hUC growth significantly better than cPLCL. Interestingly, tPLCL gave no significant advantage to hUC attachment or proliferation compared with sPLCL. However, during the 14 day assessment period, the majority of cells were viable and maintained phenotype on all the membranes studied. The material characterization exhibited potential mechanical characteristics of sPLCL and tPLCL for urothelial applications. Furthermore, the highest elongation of tPLCL supports the use of this kind of texturing. In conclusion, in light of our cell culture results and mechanical characterization, both sPLCL and tPLCL should be further studied for urothelial tissue engineering. PMID:22896571

  7. Second primary cancers in patients with urothelial cancers

    PubMed Central

    Altok, Muammer; Akdeniz, Fırat; Yıldız, Güner; Divrik, Rauf Taner

    2016-01-01

    Purpose To investigate the second primary cancers (SPCs) in patients with urothelial cancer (UC). Materials and Methods The records of 2,339 patients whose UC was diagnosed between January 1974 and December 2012 were reviewed. All data about characteristics of patients, of UC and, of SPC was, recorded digitally. We investigated the prevalence and the type of second or higher order cancers, and the factors associated with SPC. Results Total 260 patients (11.1%) had SPC, 14 had a third primary cancer and one had a fourth primary cancer. The most common SPC with UC was lung cancer (29.6%). Of all 260 with SPC, 64 (24.6%) had synchronous (within the 6 months) SPC, 120 (46.2%) had subsequent SPC and, 76 (29.2%) had antecedent SPC. The mean duration of SPC was 56 months in patients with subsequent SPC and 75.8 months in patients with antecedent SPC. The mean age at the time of diagnosis of UC was higher in patients with SPC. The ratio of male gender, body mass index, blood type, status of smoking and, occupational risk was similar in both groups. Total amount of smoking and the mean follow-up were higher in patients with SPC. Conclusions The majority of the patients with UC have long life expectancy. In patients with UC, the risk of having another cancer is quite higher than normal population. The physicians managing patients with UC should look for SPC. PMID:27617314

  8. Second primary cancers in patients with urothelial cancers

    PubMed Central

    Altok, Muammer; Akdeniz, Fırat; Yıldız, Güner; Divrik, Rauf Taner

    2016-01-01

    Purpose To investigate the second primary cancers (SPCs) in patients with urothelial cancer (UC). Materials and Methods The records of 2,339 patients whose UC was diagnosed between January 1974 and December 2012 were reviewed. All data about characteristics of patients, of UC and, of SPC was, recorded digitally. We investigated the prevalence and the type of second or higher order cancers, and the factors associated with SPC. Results Total 260 patients (11.1%) had SPC, 14 had a third primary cancer and one had a fourth primary cancer. The most common SPC with UC was lung cancer (29.6%). Of all 260 with SPC, 64 (24.6%) had synchronous (within the 6 months) SPC, 120 (46.2%) had subsequent SPC and, 76 (29.2%) had antecedent SPC. The mean duration of SPC was 56 months in patients with subsequent SPC and 75.8 months in patients with antecedent SPC. The mean age at the time of diagnosis of UC was higher in patients with SPC. The ratio of male gender, body mass index, blood type, status of smoking and, occupational risk was similar in both groups. Total amount of smoking and the mean follow-up were higher in patients with SPC. Conclusions The majority of the patients with UC have long life expectancy. In patients with UC, the risk of having another cancer is quite higher than normal population. The physicians managing patients with UC should look for SPC.

  9. Tryptase Activation of Immortalized Human Urothelial Cell Mitogen-Activated Protein Kinase

    PubMed Central

    Marentette, John O.; Hauser, Paul J.; Hurst, Robert E.; Klumpp, David J.; Rickard, Alice; McHowat, Jane

    2013-01-01

    The pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS) is multifactorial, but likely involves urothelial cell dysfunction and mast cell accumulation in the bladder wall. Activated mast cells in the bladder wall release several inflammatory mediators, including histamine and tryptase. We determined whether mitogen-activated protein (MAP) kinases are activated in response to tryptase stimulation of urothelial cells derived from human normal and IC/PBS bladders. Tryptase stimulation of normal urothelial cells resulted in a 2.5-fold increase in extracellular signal regulated kinase 1/2 (ERK 1/2). A 5.5-fold increase in ERK 1/2 activity was observed in urothelial cells isolated from IC/PBS bladders. No significant change in p38 MAP kinase was observed in tryptase-stimulated normal urothelial cells but a 2.5-fold increase was observed in cells isolated from IC/PBS bladders. Inhibition of ERK 1/2 with PD98059 or inhibition of p38 MAP kinase with SB203580 did not block tryptase-stimulated iPLA2 activation. Incubation with the membrane phospholipid-derived PLA2 hydrolysis product lysoplasmenylcholine increased ERK 1/2 activity, suggesting the iPLA2 activation is upstream of ERK 1/2. Real time measurements of impedance to evaluate wound healing of cell cultures indicated increased healing rates in normal and IC/PBS urothelial cells in the presence of tryptase, with inhibition of ERK 1/2 significantly decreasing the wound healing rate of IC/PBS urothelium. We conclude that activation of ERK 1/2 in response to tryptase stimulation may facilitate wound healing or cell motility in areas of inflammation in the bladder associated with IC/PBS. PMID:23922867

  10. Post-treatment serum lactic dehydrogenase as a predictive indicator for distant metastasis and survival of patients with nasopharyngeal carcinoma

    PubMed Central

    Dong, Bai-qiang; Xu, Yu-jin; Zheng, Yuan-da; Sun, Zhong-wen; Yang, Yang; Chen, Yuan-Yuan; Chen, Xiao-zhong; Chen, Ming

    2016-01-01

    Purpose To examine the function of serum lactic dehydrogenase (SLDH) level after intensity-modulated radiotherapy (IMRT) as a predictive factor for and loco-regional relapse free survival (LRFS), distant metastasis-free survival (DMFS), disease free survival (DFS), and overall survival(OS) among patients with in-situ nasopharyngeal carcinoma (NPC). Results Compared with the normal pt-SLDH group, elevated pt-SLDH demonstrated significant lower DMFS (46 versus 66 months, hazard ratio (HR) 4.07, 95% CI 2.43–6.80, p < 0.001), DFS (46 versus 63 months, HR 2.78, 95% CI 1.70–4.53, p < 0.001), and OS (54 versus 66 months, HR 2.93, 95% CI 1.65–5.23, p < 0.001). Distant metastasis were observed in 32.8% (20/61) patients with elevated pt-SLDH, and 8% (54/678) in normal SLDH (odds ratio (OR) 6.13, 95% CI 3.35–11.18, p < 0.001). COX regression showed that pt-SLDH was an independent prognostic factors for OS (HR 2.91, 95% CI 1.57–5.41, p < 0.001), DMFS (HR 4.21, 95% CI 2.51–7.07, p < 0.001), LRFS (HR 2.53, 95% CI 1.22–5.24, p < 0.001), and DFS (HR 2.81, 95% CI 1.72–4.59, p < 0.001). Materials and Methods The records of 739 in-situ NPC patients admitted to Zhejiang Cancer Hospital between January 2007 and May 2012 were retrospectively reviewed. The relationships between post-treatment SLDH (pt-SLDH) and LRFS, DMFS, DFS, and OS were analyzed. Conclusions Our finding indicated that elevated pt-SLDH could be a simple available prognostic indicator for distant metastasis and survival for in-situ NPC patients. PMID:27050275

  11. Soluble Serum αKlotho Is a Potential Predictive Marker of Disease Progression in Clear Cell Renal Cell Carcinoma.

    PubMed

    Gigante, Margherita; Lucarelli, Giuseppe; Divella, Chiara; Netti, Giuseppe Stefano; Pontrelli, Paola; Cafiero, Cesira; Grandaliano, Giuseppe; Castellano, Giuseppe; Rutigliano, Monica; Stallone, Giovanni; Bettocchi, Carlo; Ditonno, Pasquale; Gesualdo, Loreto; Battaglia, Michele; Ranieri, Elena

    2015-11-01

    Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, and clear cell RCC (ccRCC), that has a high metastatic index and high relapse rate, is the most common histological subtype. The identification of new biomarkers in ccRCC is fundamental for stratifying patients into prognostic risk groups and to guide therapy. The renoprotective antiaging gene, αKlotho, has recently been found to work as a tumor suppressor in different human cancers. Here, we evaluated αKlotho expression in tissue and serum of ccRCC patients and correlated it with disease progression. Tissue αKlotho expression was studied by quantitative RT-PCR and immunohistochemistry. In addition, soluble serum αKlotho levels were preoperatively measured in 160 patients who underwent nephrectomy for RCC with ELISA. Estimates of cancer-specific (CSS) and progression-free survival (PFS) were calculated according to the Kaplan-Meier method. Multivariate analysis was performed to identify the most significant variables for predicting CSS and PFS. αKlotho protein levels were significantly decreased in RCC tissues compared with normal tissues (P < 0.01) and the more advanced the disease, the more evident the down-regulation. This trend was also observed in serum samples. Statistically significant differences resulted between serum αKlotho levels and tumor size (P = 0.003), Fuhrman grade (P = 0.007), and clinical stage (P = 0.0004). CSS and PFS were significantly shorter in patients with lower levels of αKlotho (P < 0.0001 and P = 0.0004, respectively). At multivariate analysis low serum levels of αKlotho were independent adverse prognostic factors for CSS (HR = 2.11; P = 0.03) and PFS (HR = 2.18; P = 0.03).These results indicate that a decreased αKlotho expression is correlated with RCC progression, and suggest a key role of declining αKlotho in the onset of cancer metastasis. PMID:26559258

  12. Soluble Serum αKlotho Is a Potential Predictive Marker of Disease Progression in Clear Cell Renal Cell Carcinoma

    PubMed Central

    Gigante, Margherita; Lucarelli, Giuseppe; Divella, Chiara; Netti, Giuseppe Stefano; Pontrelli, Paola; Cafiero, Cesira; Grandaliano, Giuseppe; Castellano, Giuseppe; Rutigliano, Monica; Stallone, Giovanni; Bettocchi, Carlo; Ditonno, Pasquale; Gesualdo, Loreto; Battaglia, Michele; Ranieri, Elena

    2015-01-01

    Abstract Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, and clear cell RCC (ccRCC), that has a high metastatic index and high relapse rate, is the most common histological subtype. The identification of new biomarkers in ccRCC is fundamental for stratifying patients into prognostic risk groups and to guide therapy. The renoprotective antiaging gene, αKlotho, has recently been found to work as a tumor suppressor in different human cancers. Here, we evaluated αKlotho expression in tissue and serum of ccRCC patients and correlated it with disease progression. Tissue αKlotho expression was studied by quantitative RT-PCR and immunohistochemistry. In addition, soluble serum αKlotho levels were preoperatively measured in 160 patients who underwent nephrectomy for RCC with ELISA. Estimates of cancer-specific (CSS) and progression-free survival (PFS) were calculated according to the Kaplan–Meier method. Multivariate analysis was performed to identify the most significant variables for predicting CSS and PFS. αKlotho protein levels were significantly decreased in RCC tissues compared with normal tissues (P < 0.01) and the more advanced the disease, the more evident the down-regulation. This trend was also observed in serum samples. Statistically significant differences resulted between serum αKlotho levels and tumor size (P = 0.003), Fuhrman grade (P = 0.007), and clinical stage (P = 0.0004). CSS and PFS were significantly shorter in patients with lower levels of αKlotho (P < 0.0001 and P = 0.0004, respectively). At multivariate analysis low serum levels of αKlotho were independent adverse prognostic factors for CSS (HR = 2.11; P = 0.03) and PFS (HR = 2.18; P = 0.03). These results indicate that a decreased αKlotho expression is correlated with RCC progression, and suggest a key role of declining αKlotho in the onset of cancer metastasis. PMID:26559258

  13. Overexpression of Intrinsic Hypoxia Markers HIF1{alpha} and CA-IX Predict for Local Recurrence in Stage T1-T2 Glottic Laryngeal Carcinoma Treated With Radiotherapy

    SciTech Connect

    Schrijvers, M.L.; Laan, B.F.A.M. van der; Bock, G.H. de; Pattje, W.J.; Mastik, M.F.; Menkema, L.; Langendijk, J.A.; Kluin, P.M.; Schuuring, E.; Wal, J.E. van der

    2008-09-01

    Purpose: To examine the prognostic value of three endogenous hypoxia markers (hypoxia inducible factor 1 {alpha} subunit [HIF1{alpha}], carbonic anhydrase IX [CA-IX], and glucose transporter type 1 [GLUT-1]) on the clinical outcome in patients with early-stage glottic carcinoma primarily treated with radiotherapy (RT) and to determine the predictive hypoxic profile to choose the optimal treatment of early-stage laryngeal carcinoma. Methods and Materials: Immunohistochemistry for HIF1{alpha}, CA-IX, and GLUT-1 was performed on formalin-fixed, paraffin-embedded, pretreatment tissue samples of 91 glottic squamous cell carcinoma specimens. The patient group consisted only of those with early-stage (T1-T2) glottic carcinoma, and all patients were treated with RT only. Relative tumor staining was scored on the tissue samples. Receiver operating curve analysis was performed to determine the optimal cutoff value for each tumor marker. Cox regression analyses for the variables HIF1{alpha}, CA-IX, GLUT-1, gender, age, hemoglobin level, T category, N category, tobacco use, and alcohol use were performed with local control and overall survival as endpoints. Results: HIF1{alpha} overexpression in early-stage glottic carcinoma correlated significantly with worse local control (hazard ratio [HR], 3.05; p = 0.021) and overall survival (HR, 2.92; p = 0.016). CA-IX overexpression correlated significantly with worse local control (HR, 2.93; p = 0.020). GLUT-1 overexpression did not show any correlation with the clinical outcome parameters. Tumors with a nonhypoxic profile (defined as low HIF1{alpha} and low CA-IX expression) had significantly better local control (HR, 6.32; p 0.013). Conclusion: The results of our study have shown that early-stage glottic laryngeal carcinomas with low HIF1{alpha} and CA-IX expression are highly curable with RT. For this group, RT is a good treatment option. For tumors with HIF1{alpha} or CA-IX overexpression, hypoxic modification before RT or primary

  14. Immunohistochemical evaluation of global DNA methylation and histone acetylation in papillary urothelial neoplasm of low malignant potential.

    PubMed

    Barbisan, F; Mazzucchelli, R; Santinelli, A; Stramazzotti, D; Scarpelli, M; Lopez-Beltran, A; Cheng, L; Montironi, R

    2008-01-01

    A preceding study has shown that karyometry detected subvisual differences in chromatin organization status between non-recurrent and recurrent papillary urothelial neoplasm of low malignant potential (PUNLMP). The status of chromatin organization depends on epigenetic events, such as DNA methylation and histone acetylation. The aim of this study is to explore global DNA methylation and global histone acetylation in non-recurrent and recurrent PUNLMP. 5-methylcytosine (5MeC) and acetylated histone H3 lysine 9 (AcH3K9) were investigated by immunohistochemistry (IHC) in 20 PUNLMP cases (10 non-recurrent and 10 recurrent), in 5 cases of normal urothelium (NU) and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). For global DNA methylation, the mean percentage of positive nuclei in the cells adjacent to the stroma increased from NU (79%) through non-recurrent and recurrent PUNLMP (86% and 93%, respectively) to UC (97%). The percentages of positive nuclei in the intermediate cell layers and in the superficial cells in the four groups were similar to those adjacent to the stroma. The proportion of nuclei with weak-to-moderate intensity was far greater than that of those strongly stained and increased steadily from NU to UC. For global histone acetylation, the mean percentage of positive nuclei was highest in non-recurrent PUNLMP (i.e. 90%) and lowest in recurrent PUNLMP (i.e. 81%). In NU and UC the mean percentages of positive nuclei were 84% and 86%, respectively. The percentage of positive nuclei decreased from the cell layer adjacent to the stroma to the superficial cell layer. The proportion of nuclei with weak-to-moderate intensity was slightly greater than that of those strongly stained. In comparison with global DNA methylation, the proportion of strongly stained nuclei was much higher. In conclusion, there are differences in global DNA methylation and histone acetylation patterns between non-recurrent and recurrent PUNLMP. Further studies are needed to

  15. Quantification of dynamic contrast-enhanced ultrasound in HCC: prediction of response to a new combination therapy of sorafenib and panobinostat in advanced hepatocellular carcinoma.

    PubMed

    Knieling, Ferdinand; Waldner, Maximilian J; Goertz, Ruediger S; Strobel, Deike

    2012-01-01

    Here, we report the case of a patient, who showed an antitumour response to a new combination therapy of sorafenib and the histon deacetylase inhibitor panobinostat (LBH-589). D-CEUS (Dynamic contrast-enhanced ultrasonography) was able to predict response to the new therapy regime and may be an interesting tool in the early evaluation of response to therapy. It might be especially useful to differentiate between responders and non-responders of new-targeted pharmaceuticals like multikinase inhibitors in hepatocellular carcinomas. PMID:23257272

  16. Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness.

    PubMed

    Afonso, Julieta; Santos, Lúcio L; Morais, António; Amaro, Teresina; Longatto-Filho, Adhemar; Baltazar, Fátima

    2016-01-01

    Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance. However, the specific role of MCTs in the metabolic compartmentalization within bladder tumors, namely their preponderance on the tumor stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n = 111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells' compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance. PMID:26636903

  17. Clinical Model for Predicting Hepatocellular Carcinomas in Patients with Post-Sustained Virologic Responses of Chronic Hepatitis C: A Case Control Study

    PubMed Central

    Zeng, Qing-Lei; Li, Bing; Zhang, Xue-Xiu; Chen, Yan; Fu, Yan-Ling; Lv, Jun; Liu, Yan-Min; Yu, Zu-Jiang

    2016-01-01

    Background/Aims No clinical model exists to predict the occurrence of hepatocellular carcinoma in sustained virologic response-achieving (HCC after SVR) patients with chronic hepatitis C (CHC). Methods We performed a case-control study using a clinical database to research the risk factors for HCC after SVR. A predictive model based on risk factors was established, and the area under the receiver operating characteristic curve (AUC) was calculated. Results In the multivariate model, an initial diagnosis of compensated cirrhosis and post-SVR albumin reductions of 1 g/L were associated with 21.7-fold (95% CI, 4.2 to 112.3; p<0.001) and 1.3-fold (95% CI, 1.1 to 1.7; p=0.004) increases in the risk of HCC after SVR, respectively. A predictive model based on an initial diagnosis of compensated cirrhosis (yes, +1; no, 0) and post-SVR albumin ≤36.0 g/L (yes, +1; not, 0) predicted the occurrence of HCC after SVR with a cutoff value of >0, an AUC of 0.880, a sensitivity of 0.833, a specificity of 0.896, and a negative predictive value of 0.956. Conclusions An initial diagnosis of compensated cirrhosis combined with a post-SVR albumin value of ≤36.0 g/L predicts the occurrence of HCC after SVR in patients with CHC. PMID:27257023

  18. Small cell carcinoma of the urinary bladder--a new case report.

    PubMed

    Petrescu, Amelia; Berdan, Gabriela; Hulea, Ionela; Gaitanidis, Raluca; Ambert, V; Jinga, V; Damian, D; Codreanu, O; Andrei, F; Niculescu, L

    2007-01-01

    Primary pure small cell carcinoma of the urinary bladder is an extremely rare and highly aggressive tumor with an average five-year survival rate of less than 10% as cited by multiple case reports. It accounts for about 0.5-1% of all bladder tumors. We present the case of a 44-years-old man, smoker (10 cigarettes/day) hospitalized in the Department of Urology, from the "Prof. dr. Th. Burghele" Hospital, Bucharest, for one month intermittent hematuria. Ultrasonography showed a sessile tumoral mass, sized 37/30mm. Transurethral resection of the tumor mass was performed and tissue fragments were sent to the pathologic lab to establish the histologic type, the degree of differentiation and invasion. Fragments of the tumor were fixed in 10% formaldehyde, paraffin embedded and processed as standard technique; the sections were stained with HE, VG and immunohistochemically with: CROMO, EMA, NSE, CD56, NK1, p53 and betaHCG. The microscopic examination reveled a tumor proliferation composed of two distinct components: extensive small cells areas and foci of typical low grade (G2) papillary urothelial carcinoma. The small cell are uniformly, round, with increased nucleo-cytoplasmic ratio, eosinophyl cytoplasm, hyperchromatic nuclei, finely granular chromatin and inconspicuous nucleoli. Immunohistochemical stains showed diffuse positive staining of the small cell component for CROMO, EMA, NSE, CD56, NK1 and urothelial carcinoma component stained focally for betaHCG. The rate of cell proliferation was increased (p53 - 80% positive reaction). Conclusions. A diagnosis of small cell carcinoma coexisting with low-grade urothelial carcinoma was established. Because of aggressive behavior and distinct treatment, the pathologist should watch out for the presence of small cell carcinoma component. PMID:17914502

  19. Implications for Bidirectional Signaling Between Afferent Nerves and Urothelial Cells—ICI-RS 2014

    PubMed Central

    Kanai, Anthony; Fry, Christopher; Ikeda, Youko; Kullmann, Florenta Aura; Parsons, Brian; Birder, Lori

    2016-01-01

    Aims To present a synopsis of the presentations and discussions from Think Tank I, “Implications for afferent–urothelial bidirectional communication” of the 2014 International Consultation on Incontinence-Research Society (ICI-RS) meeting in Bristol, UK. Methods The participants presented what is new, currently understood or still unknown on afferent–urothelial signaling mechanisms. New avenues of research and experimental methodologies that are or could be employed were presented and discussed. Results It is clear that afferent–urothelial interactions are integral to the regulation of normal bladder function and that its disruption can have detrimental consequences. The urothelium is capable of releasing numerous signaling factors that can affect sensory neurons innervating the suburothelium. However, the understanding of how factors released from urothelial cells and afferent nerve terminals regulate one another is incomplete. Utilization of techniques such as viruses that genetically encode Ca2+ sensors, based on calmodulin and green fluorescent protein, has helped to address the cellular mechanisms involved. Additionally, the epithelial–neuronal interactions in the urethra may also play a significant role in lower urinary tract regulation and merit further investigation. Conclusion The signaling capabilities of the urothelium and afferent nerves are well documented, yet how these signals are integrated to regulate bladder function is unclear. There is unquestionably a need for expanded methodologies to further our understanding of lower urinary tract sensory mechanisms and their contribution to various pathologies. PMID:26872567

  20. Biomimetic urothelial tissue models for the in vitro evaluation of barrier physiology and bladder drug efficacy.

    PubMed

    Baker, Simon C; Shabir, Saqib; Southgate, Jennifer

    2014-07-01

    The bladder is an important tissue in which to evaluate xenobiotic drug interactions and toxicities due to the concentration of parent drug and hepatic/enteric-derived metabolites in the urine as a result of renal excretion. Breaching of the barrier provided by the bladder epithelial lining (the urothelium) can expose the underlying tissues to urine and cause harmful effects (e.g., cystitis or cancer). Human urothelium is most commonly represented in vitro as immortalized or established cancer-derived cell lines, but the compromised ability of such cells to undergo differentiation and barrier formation means that nonimmortalized, normal human urothelial (NHU) cells provide a more relevant cell culture system. The impressive capacity for urothelial self-renewal in vivo can be harnessed in vitro to generate experimentally-useful quantities of NHU cells, which can subsequently be differentiated to form a functional or "biomimetic" urothelium. When seeded onto permeable membranes, these barrier-forming human urothelial tissue models enable the modeling of serum and luminal (intravesical) exposure to drugs and metabolites, thus supporting efficacy/toxicity assessments. Biomimetic human urothelial constructs provide a potential step along the preclinical trail and may support the extrapolation from rodent in vivo data to determine human relevance. Early evidence is beginning to demonstrate that human urothelium in vitro can provide information that supersedes conventional rodent studies, but further validation is needed to support widespread adoption.

  1. Autocrine regulation of human urothelial cell proliferation and migration during regenerative responses in vitro

    SciTech Connect

    Varley, Claire; Hill, Gemma; Pellegrin, Stephanie; Shaw, Nicola J.; Selby, Peter J.; Trejdosiewicz, Ludwik K.; Southgate, Jennifer . E-mail: js35@york.ac.uk

    2005-05-15

    Regeneration of the urothelium is rapid and effective in order to maintain a barrier to urine following tissue injury. Whereas normal human urothelial (NHU) cells are mitotically quiescent and G0 arrested in situ, they rapidly enter the cell cycle upon seeding in primary culture and show reversible growth arrest at confluency. We have used this as a model to investigate the role of EGF receptor signaling in urothelial regeneration and wound-healing. Transcripts for HER-1, HER-2, and HER-3 were expressed by quiescent human urothelium in situ. Expression of HER-1 was upregulated in proliferating cultures, whereas HER-2 and HER-3 were more associated with a growth-arrested phenotype. NHU cells could be propagated in the absence of exogenous EGF, but autocrine signaling through HER-1 via the MAPK and PI3-kinase pathways was essential for proliferation and migration during urothelial wound repair. HB-EGF was expressed by urothelium in situ and HB-EGF, epiregulin, TGF-{alpha}, and amphiregulin were expressed by proliferating NHU cells. Urothelial wound repair in vitro was attenuated by neutralizing antibodies against HER-1 ligands, particularly amphiregulin. By contrast, the same ligands applied exogenously promoted migration, but inhibited proliferation, implying that HER-1 ligands provoke differential effects in NHU cells depending upon whether they are presented as soluble or juxtacrine ligands. We conclude that proliferation and migration during wound healing in NHU cells are mediated through an EGFR autocrine signalling loop and our results implicate amphiregulin as a key mediator.

  2. Genetic Variations in ABCG2 Gene Predict Breast Carcinoma Susceptibility and Clinical Outcomes after Treatment with Anthracycline-Based Chemotherapy

    PubMed Central

    Wu, Huizhe; Liu, Yong; Kang, Hui; Xiao, Qinghuan; Yao, Weifan; Zhao, Haishan; Wang, Enhua; Wei, Minjie

    2015-01-01

    The genetic variants of the ATP-binding cassette, subfamily G, member 2 (ABCG2) are known to be involved in developing cancer risk and interindividual differences in chemotherapeutic response. The polymorphisms in ABCG2 gene were genotyped by using PCR-RFLP assays. We found that ABCG2 G34A GA/AA genotype, C421A AA genotype, and haplotypes 34A-421C and 34G-421A were significantly associated with increased risk for developing breast carcinoma. Furthermore, ABCG2 C421A AA homozygote had a significant enhanced therapeutic response in patients with neoadjuvant anthracycline-based chemotherapy. Moreover, ABCG2 G34A AA genotype carriers displayed a longer OS in ER positive patients or PR positive patients after postoperative anthracycline-based chemotherapy. These results suggested that the ABCG2 polymorphisms might be a candidate pharmacogenomic factor to assess susceptibility and prognosis for breast carcinoma patients. PMID:26634205

  3. Tenascin-C and carcinoma cell invasion in oral and urinary bladder cancer.

    PubMed

    Berndt, Alexander; Richter, Petra; Kosmehl, Hartwig; Franz, Marcus

    2015-01-01

    Carcinoma invasion is a complex process regulated by genetic and epigenetic factors as well. A relevant supportive condition for cancer cell migration is the reorganization of the extracellular matrix (ECM), which is realized in an orchestrated multicellular manner including carcinoma cells and stromal fibroblasts. An important key player in the process of ECM reorganization is Tenascin-C (Tn-C). The molecule occurs as different isoforms generated by alternative splicing and de novo glycosylation. Large variants of Tn-C are abundantly re-expressed in the invasive front of many carcinom