Bladder Cancer
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Bladder cancer is a disease in which malignant cells arise in the bladder. Symptoms can include blood in the urine, pain during urination, increased frequency of passing urine, or feeling the need to urinate but with nothing coming out. The bulk of bladder cancers are histlogically classed as transitional cell carcinomas which arise in the uroepithelium (lining of the bladder). Other types include squamous cell carcinomas, and adenocarcinomas. Treatment will depend on how far the tumour has invaded the surrounding tissues, and if it has spread to other parts of the body. World-wide about 260,000 people are diagnosed with bladder cancer each year.

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Molecular Biology of Bladder Cancer
Urinary System Cancers

Information Patients and the Public (16 links)

Information for Health Professionals / Researchers (8 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Batsi O, Giannopoulou I, Nesseris I, et al.
Immunohistochemical evaluation of CXCL12-CXCR4 axis and VEGFR3 expression in primary urothelial cancer and its recurrence.
Anticancer Res. 2014; 34(7):3537-42 [PubMed] Related Publications
AIM: The aim of this study was to investigate the expression of CXC chemokine ligand-12 (CXCL12), CXC chemokine receptor 4 CXCR4 and of vascular endothelial growth factor receptor 3 (VEGFR3) in primary urothelial bladder carcinoma and their recurrence in relation to grade and pT status.
MATERIALS AND METHODS: Immunohistochemistry was applied to 67 primary tumor (PC) sections and their recurrenct tumors (RC).
RESULTS: The expression of CXCL12 both in PC and in RC was positively associated with tumor grade (p<0.0001 and p<0.0001, respectively) and pT stage (p=0.001 and p=0.007, respectively). The expression of CXCR4 in both PC and RC was also positively related to grade (p=0.001 and p<0.0001, respectively) and pT stage (p=0.008 and p=0.005, respectively). We compared the expression of CXCL12 and CXCR4 in PC related to RC and found that both were more intense in RC than in PC (p<0.0001 and p<0.0001, respectively). In PC and in RC there was no association between the expression of VEGFR3 with tumor grade and pT stage.
CONCLUSION: CXCL12 and CXCR4 expression was related to adverse prognostic markers in urothelial bladder carcinoma through their association with grade and pT stage both in PC and RC. The CXCL12-CXCR4 axis may influence the expression of VEGFR3 in urothelial bladder carcinoma and promote tumor recurrence.

Jian W, Levitt JM, Lerner SP, Sonpavde G
The preclinical activity of lenalidomide in indolent urothelial carcinoma.
Anticancer Res. 2014; 34(7):3383-9 [PubMed] Related Publications
BACKGROUND: Lenalidomide is an IMiD® immunomodulatory drug, which may warrant evaluation in urothelial carcinoma (UC).
MATERIALS AND METHODS: The in vitro and in vivo activity of lenalidomide was evaluated in human and murine UC cell lines. Tumors were evaluated by immunohistochemistry for (CD31), cleaved caspase-3 (CC3) and CD3+/CD20+ lymphocyte infiltration. Cereblon, a molecular target of lenalidomide was analyzed by immunohistochemistry.
RESULTS: Significant pro-apoptotic activity, and reduction of cell viability was seen at low micromolar concentrations of lenalidomide against indolent human RT4 UC cells in vitro. Cereblon expression was quantitatively lower in sensitive RT4 cells compared to resistant 5637 cells. In RT4 xenografts, lenalidomide significantly reduced tumor size and CD31 expression, and increased expression of CC3 (p<0.05). Cereblon expression increased in lenalidomide-treated RT4 xenografts (p<0.05).
CONCLUSION: Lenalidomide demonstrated preclinical activity against superficially-invasive low-grade UC cells attributable to direct tumor cell apoptosis and anti-angiogenic activity. Clinical trials are warranted in patients with indolent UC.

Related: Angiogenesis Inhibitors Apoptosis Angiogenesis and Cancer Thalidomide Lenalidomide

Feng Y, Kang Y, He Y, et al.
microRNA-99a acts as a tumor suppressor and is down-regulated in bladder cancer.
BMC Urol. 2014; 14:50 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Increasing evidences have documented that microRNAs (miRNAs) act as oncogenes or tumor suppressors in a variety types of cancer. The discovery of tumor associated miRNAs in serum of patients gives rise to extensive investigation of circulating miRNAs in many human cancers which support the use of plasma/serum miRNAs as noninvasive means of cancer detection. However, the aberrant expression of miRNAs and the circulating miRNAs in bladder cancer are less reported.
METHODS: We used Taqman probe stem-loop real-time PCR to accurately measure the levels of miR-99a in bladder cancer cell lines, 100 pairs of bladder cancer tissues, the adjacent non-neoplastic tissues and plasma collected from bladder cancer patients or control patients. miR-99a mimics were re-introduced into bladder cancer cells to investigate its role on regulating cell proliferation which was measured by CCK-8 assay and cell cycle analysis.
RESULTS: miR-99a was significantly down-regulated in bladder cancer tissues, and even the lower expression of miR-99a was correlative with the more aggressive phenotypes of bladder cancer. Meanwhile, enforced expression of miR-99a can inhibit the cell proliferation of bladder cancer cells. Furthermore, investigation of the expression of miR-99a in plasma of bladder cancer patients showed that miR-99a was also decreased in plasma of bladder cancer patients. The results strongly supported miR-99a as the potential diagnostic marker of bladder cancer.
CONCLUSIONS: Our data indicated that miR-99a might act as a tumor suppressor in bladder cancer and was significantly down-regulated in development of bladder cancer.

Clark BZ, Beriwal S, Dabbs DJ, Bhargava R
Semiquantitative GATA-3 immunoreactivity in breast, bladder, gynecologic tract, and other cytokeratin 7-positive carcinomas.
Am J Clin Pathol. 2014; 142(1):64-71 [PubMed] Related Publications
OBJECTIVES: To evaluate GATA-3 immunohistochemical expression semiquantitatively in breast, gynecologic, gastric, pancreatic-biliary tract, urothelial, and vulvar/cervical squamous cell carcinomas.
METHODS: GATA-3 expression was evaluated by immunohistochemistry in 198 invasive breast carcinomas on tissue microarrays. Tissue microarrays of other tissues included 144 gynecologic tumors, 28 bladder carcinomas, 63 cholangiocarcinomas, 20 pancreatic carcinomas, and 62 gastric carcinomas. Full tissue sections of 10 invasive squamous cell carcinomas were also stained. GATA-3 expression was semiquantitatively scored using an H-score method. H-score greater than 10 was considered a positive result.
RESULTS: Of 186 breast carcinomas, 95% were positive (mean H-score of 217). GATA-3 expression was uncommon in 139 nonsquamous gynecologic tumors, with often weak reactivity (mean H-score <50) seen in 18% of endocervical, 7% of endometrial, and 10% of ovarian tumors. Six (60%) of 10 squamous cell carcinomas expressed GATA-3 (mean H-score of 102). Of 22 urothelial carcinomas, 95% expressed GATA-3 (mean H-score of 170). A few cholangiocarcinomas (3%), pancreatic adenocarcinomas (10%), and gastric carcinomas (2%) weakly expressed GATA-3 (mean H-score <50).
CONCLUSIONS: Strong GATA-3 expression is a reliable marker of primary breast carcinoma in the appropriate clinical context. GATA-3 reactivity in around 70% of triple-negative breast carcinomas is also clinically useful. Significant reactivity in gynecologic squamous cell carcinomas suggests that GATA-3 alone cannot reliably distinguish these tumors from urothelial carcinoma.

Related: Breast Cancer GATA3 gene Gynacological Cancers

Moschini M, Suardi N, Pellucchi F, et al.
Impact of preoperative thrombocytosis on pathological outcomes and survival in patients treated with radical cystectomy for bladder carcinoma.
Anticancer Res. 2014; 34(6):3225-30 [PubMed] Related Publications
AIM: To investigate the impact of preoperative platelet count on pathological findings at the time of Radical Cystectomy for Bladder Cancer and postoperative cancer-specific and overall survival.
PATIENTS AND METHODS: A total of 906 consecutive patients treated with Radical Cystectomy for Bladder Cancer between 1995 and 2012 at a tertiary referral Center were included in the study. Thrombocytosis was defined as >400,000 platelets/μl, in agreement with the standard assumed by the central laboratory of our Institution. Univariable and multivariable logistic regression analyses were used to investigate the impact of preoperative platelet count on pathological stage. Univariate and multivariate Cox regression analyses were also adopted to predict both cancer-specific and overall survival.
RESULTS: The mean age at cystectomy was 67.25 years. The mean and median platelet counts were 242,100/μl and 227,500/μl. At a mean follow-up time of 41 months, the 2- and 5-year cancer-specific and overall survival were found to be 83.1% and 75.2% and 68.3 and 59.8%, respectively. At Univariable analysis, thrombocytosis count was significantly associated with adverse pathological disease stage (p ≤ 0.007) and lymph node invasion (p=0.05). Platelet count was significantly associated to patient survival at univariable analysis (Hazard Ratio=1.76 and 1.39 for overall survival and cancer specific survival, respectively; all p<0.05). At multivariate Cox regression analysis, platelet count was documented to be significantly related only to overall survival (Hazard Ratio=64,1.03-2.81; p=0.05).
CONCLUSION: Preoperative platelet count should be taken into account as a factor predictive of postoperative oncological outcomes after radical cystectomy for bladder cancer and patients should be counseled accordingly.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Mian C, Comploj E, Resnyak E, et al.
Long-term follow-up of intermediate-risk non-muscle invasive bladder cancer sub-classified by multi-coloured FISH.
Anticancer Res. 2014; 34(6):3067-71 [PubMed] Related Publications
AIM: To examine the long-term follow-up of patients with that previously underwent risk stratification based on multicolour FISH testing.
PATIENTS AND METHODS: On 81 patients with intermediate-risk urothelial carcinoma, a multicolour-FISH was performed. Patients were sub-divided into low- and high-risk groups based on chromosomal patterns. Univariate analysis, using Mantel-Cox log-rank test for disease-free, progression-free survival and overall survival, was employed to determine the prognostic significance of FISH analysis. Survival times were calculated according to the Kaplan-Meier product-limit method and multivariate analysis using Cox proportional hazards regression model.
RESULTS: The univariate Mantel-Cox log-rank test showed significant differences between the low-risk and the high-risk group for disease-free survival (p=0.005) and overall survival (p=0.038), but not for progression-free survival (p=0.129).
CONCLUSION: Our long-term follow-up data appear to be able to divide tumors into low and high risk groups for recurrence based on molecular/genetic changes observed with FISH.

Related: FISH

Li JR, Cheng CL, Yang WJ, et al.
FIP-gts potentiate autophagic cell death against cisplatin-resistant urothelial cancer cells.
Anticancer Res. 2014; 34(6):2973-83 [PubMed] Related Publications
BACKGROUND: Urothelial cancer (UC) is a common cancer among males. Once metastatic or chemoresistant diseases develop, there is little effective treatment available. A fungal immunomodulatory protein, ganoderma tsugae (FIP-gts) possesses antitumor activity against solid tumors and inhibits telomerase activity. FIP-gts induces autophagy in cancer cells and may provide an alternative pathway against chemo-resistance.
MATERIALS AND METHODS: Two UC cell lines were used to investigate the cytotoxicity effects and the autophagy regulation of FIP-gts using flow cytometry, acidic vesicular organelles (AVO) staining and western blotting.
RESULTS: MTT assay showed that FIP-gts and bafilomycin-A1 (Baf-A1) and or chloroquine (CQ) could enhance a significantly synergistic cytotoxicity. The treatment of UC cell lines with FIP-gts activated LC-3 II formation and AVO positive staining on western blot and flow cytometry. Interestingly, FIP-gts and Baf-A1 combined treatment was found to lead to enhancement of apoptosis along with inhibition of autophagy in parental and resistant UC cells.
CONCLUSION: FIP-gts may have the potential to be utilized as a therapeutic adjuvant for the treatment of resistant UC cancer down-regulating Beclin-1 to activate autophagic cell death.

Related: Apoptosis Cisplatin

Karavitakis M, Msaouel P, Michalopoulos V, Koutsilieris M
Pattern of somatostatin receptors expression in normal and bladder cancer tissue samples.
Anticancer Res. 2014; 34(6):2937-42 [PubMed] Related Publications
BACKGROUND/AIM: Known risks factors for bladder cancer progression and recurrence are limited regarding their prognostic ability. Therefore identification of molecular determinants of disease progression could provide with more specific prognostic information and could be translated into new approaches for biomarker development. In the present study we evaluated, the expression patterns of somatostatin receptors 1-5 (SSTRs) in normal and tumor bladder tissues.
MATERIALS AND METHODS: The expression of SSTR1-5 was characterized in 45 normal and bladder cancer tissue samples using reverse transcriptase-polymerase chain reaction (RT-PCR).
RESULTS: SSTR1 was expressed in 24 samples, SSTR2 in 15, SSTR3 in 23, SSTR4 in 16 and SSTR5 in all but one sample. Bladder cancer tissue samples expressed lower levels of SSTR3. Co-expression of SSTRs was associated with superficial disease.
CONCLUSION: Our results demonstrate, for the first time, that there is expression of SSTR in normal and bladder cancer urothelium. Further studies are required to evaluate the prognostic and therapeutic significance of these findings.

Allchorne P, Lamb BW, Kinsella J, et al.
Initial experience of intravesical gemcitabine for patients with high-risk superficial transitional cell carcinoma of the bladder following BCG failure.
Urol Nurs. 2014 Mar-Apr; 34(2):95-9 [PubMed] Related Publications
This study reports the use of intravesical gemcitabine in managing patients with high-risk bladder cancer, refractory to Bacillus Calmette-Guerin (BCG). Patients were given gemcitibine; treatment response was evaluated by fluorescence-cystoscopy biopsy and urine cytology. Time to reoccurrence increased with instillation time.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Gemcitabine

Dai J, Caldamone AA, Ellermeier CJ, Ellsworth P
A case report and review of transitional cell carcinoma in children.
Urol Nurs. 2014 Mar-Apr; 34(2):75-82 [PubMed] Related Publications
Transitional cell carcinoma (TCC) is a rare cause of hematuria in children. This type of urothelial bladder tumor is typically low grade and carries a good prognosis. In this article, a case report is presented along with a review of the literature on TCC in children.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Honeycutt J, Hammam O, Fu CL, Hsieh MH
Controversies and challenges in research on urogenital schistosomiasis-associated bladder cancer.
Trends Parasitol. 2014; 30(7):324-32 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Urogenital schistosomiasis, infection with Schistosoma haematobium, is linked to increased risk for the development of bladder cancer, but the importance of various mechanisms responsible for this association remains unclear, in part, owing to lack of sufficient and appropriate animal models. New advances in the study of this parasite, bladder regenerative processes, and human schistosomal bladder cancers may shed new light on the complex biological processes that connect S. haematobium infection to bladder carcinogenesis.

Cormio L, Sanguedolce F, Massenio P, et al.
Osseous metaplasia within a urothelial bladder cancer nodal metastasis: a case report.
Anal Quant Cytopathol Histpathol. 2014; 36(2):117-9 [PubMed] Related Publications
BACKGROUND: Osseous metaplasia within bladder cancer is extremely rare and, to our knowledge, has not been previously reported within a urothelial bladder carcinoma (UBC) nodal metastasis.
CASE: A 78-year-old man underwent radical cystoprostatectomy because of high-grade pT2 UBC. Pathology revealed a high-grade pT4aN2 UBC with osseous metaplasia into a massively metastatic lymph node but not into the primary bladder tumor.
CONCLUSION: Based independently on its location, this finding warrants a careful differential diagnosis with sarcomatoid bladder tumors and is likely to be a marker of tumor aggressiveness, thus recommending aggressive treatment.

Franco R, Zappavigna S, Gigantino V, et al.
Urotensin II receptor determines prognosis of bladder cancer regulating cell motility/invasion.
J Exp Clin Cancer Res. 2014; 33:48 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Non Muscle Invasive Bladder Transitional Cancer (NMIBC) and Muscle Invasive Bladder Transitional Cancer (MIBC)/invasive have different gene profile and clinical course. NMIBC prognosis is not completely predictable, since the relapse rate is higher than 20%, even in the form of MIBC. The aim of this study is to evaluate if UTR expression can discriminate between NMIBC and MIBC and predict the risk of relapses in NMIBCs.
METHODS: We have investigated upon urotensin-II (UII) receptor (UTR) expression in vivo in 159 patients affected by NMIBC. The biological role of UTR was also investigated in vitro. UTR expression was evaluated in a tissue-micro-array, consisting of normal, NMIBC and invasive bTCC samples.
RESULTS: UTR discriminated between NMIBC and MIBC and showed a significant correlation between low UTR expression and shorter disease free survival in NMIBC. The superagonist UPG84 induced growth suppression at nM concentrations on 3/4 cell lines. Bladder cancer cell treatment with the antagonist urantide or the knock-down of UTR with a specific shRNA significantly blocked both the motility and invasion of bladder cancer cells.
CONCLUSIONS: The evaluation of UTR expression can discriminate between NMIBC at high and low risk of relapse. Moreover, our data suggest that UTR is involved in the regulation of motility, invasion and proliferation of bladder cancer cells. High UTR expression is an independent prognostic factor of good prognosis for NMIBC regulating motility and invasion of bladder cancer cells.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Andersson G, Wennersten C, Gaber A, et al.
Reduced expression of ezrin in urothelial bladder cancer signifies more advanced tumours and an impaired survival: validatory study of two independent patient cohorts.
BMC Urol. 2014; 14:36 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with tumour progression and poor prognosis in patients with T1G3 urothelial cell carcinoma of the bladder treated with non-maintenance Bacillus Calmette-Guérin (n = 92), and the associations with adverse clinicopathological factors have been validated in another, unselected, cohort (n = 104). In the present study, we examined the prognostic significance of ezrin expression in urothelial bladder cancer in a total number of 442 tumours from two independent patient cohorts.
METHODS: Immunohistochemical expression of ezrin was evaluated in tissue microarrays with tumours from one retrospective cohort of bladder cancer (n = 110; cohort I) and one population-based cohort (n = 342; cohort II). Classification regression tree analysis was applied for selection of prognostic cutoff. Kaplan-Meier analysis, log rank test and Cox regression proportional hazards' modeling were used to evaluate the impact of ezrin on 5-year overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS).
RESULTS: Ezrin expression could be evaluated in tumours from 100 and 342 cases, respectively. In both cohorts, reduced membranous ezrin expression was significantly associated with more advanced T-stage (p < 0.001), high grade tumours (p < 0.001), female sex (p = 0.040 and p = 0.013), and membranous expression of podocalyxin-like protein (p < 0.001 and p = 0.009). Moreover, reduced ezrin expression was associated with a significantly reduced 5-year OS in both cohorts (HR = 3.09 95% CI 1.71-5.58 and HR = 2.15(1.51-3.06), and with DSS in cohort II (HR = 2.77, 95% CI 1.78-4.31). This association also remained significant in adjusted analysis in Cohort I (HR1.99, 95% CI 1.05-3.77) but not in Cohort II. In pTa and pT1 tumours in cohort II, there was no significant association between ezrin expression and time to progression.
CONCLUSIONS: The results from this study validate previous findings of reduced membranous ezrin expression in urothelial bladder cancer being associated with unfavourable clinicopathological characteristics and an impaired survival. The utility of ezrin as a prognostic biomarker in transurethral resection specimens merits further investigation.

Haghighitalab A, Matin MM, Bahrami AR, et al.
In vitro investigation of anticancer, cell-cycle-inhibitory, and apoptosis-inducing effects of diversin, a natural prenylated coumarin, on bladder carcinoma cells.
Z Naturforsch C. 2014 Mar-Apr; 69(3-4):99-109 [PubMed] Related Publications
Chemotherapy is one of the main strategies for reducing the rate of cancer progression or, in some cases, curing the tumour. Since a great number of chemotherapeutic agents are cytotoxic compounds, i. e. similarly affect normal and neoplastic cells, application of antitumour drugs is preferred in cancer management and therapy. In this study, the cytotoxicity of diversin was evaluated in 5637 cells, a transitional cell carcinoma (TCC) subline (bladder carcinoma), and normal human fibroblast cells using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Chromatin condensation and DNA damage induced by diversin were also determined by means of 4',6-diamidino-2-phenylindole (DAPI) staining and the comet assay, respectively. In addition, the mechanism of action of diversin was studied in more detail by the caspase 3 colourimetric assay and flow cytometry-based cell-cycle analyses (PI staining). Our results revealed that diversin has considerable cytotoxic effects in 5637 cells, but not on HFF3 (human foreskin fibroblast) and HDF1 (human dermal fibroblast) cells. Further studies showed that diversin exerts its cytotoxicity via induction of chromatin condensation, DNA damage, and activation of caspase 3 in 5637 cells. In addition, flow cytometric analyses revealed that 5637 cells are mostly arrested at the G2 phase of the cell cycle in the presence of diversin.

Related: Apoptosis

Pendse AA, Edgerly CH, Fedoriw Y
Hemolytic anemia and metastatic carcinoma: case report and literature review.
Lab Med. 2014; 45(2):132-5 [PubMed] Related Publications
Hemolytic anemia can complicate the development of a variety of solid tumors and hematologic malignancies. Although patients may have an established diagnosis with documented metastases, microangiopathic hemolytic anemia (MAHA) can be a presenting feature of an occult malignancy. Prompt diagnosis is essential because conditions that mimic the symptoms of MAHA, including thrombotic thrombocytopenic purpura, have different prognoses and therapeutic options. Although the exact pathogenesis is not yet delineated, we present herein a case of cancer-associated MAHA and discuss the known pathways that can contribute to the initiation and propagation of hemolytic anemia in patients with cancer. The patient is a 69-year-old woman with breast carcinoma that had metastasized to her rectum, urinary bladder, and brain. She eventually developed progressive decline in her functional status, with intermittent epistaxis and melena. The results of laboratory studies revealed hemolytic anemia and thrombocytopenia; results of a bone-marrow biopsy confirmed the involvement by metastatic carcinoma. The patient received red blood cell and platelet transfusions and was discharged to hospice care after clinical stabilization. She died soon thereafter.

Related: Breast Cancer

Hooda MN, Siddique FH, Nabi S, et al.
Clinicopathologic features and treatment outcome of urinary bladder neoplasm.
Mymensingh Med J. 2014; 23(2):341-4 [PubMed] Related Publications
More than ninety percent of bladder neoplasm is Transitional Cell Carcinoma (TCC). About 85% of patients present with symptom of painless haematuria. However haematuria is quite often intermittent so that a negative result has little meaning in ruling out the presence of bladder cancer. The present study was conducted to observe the natural history of different clinicopathologic stages of bladder cancer after transurethral resection bladder tumor (TURBT), either intravescical chemotherapy (IVC) or immunotherapy with BCG and of other forms of therapy like radio-chemotherapy (RCT) and radical surgery in few cases. A consecutive series of 52 cases with different grades and stages of bladder cancer patients were studied. Those who were noncompliant with surgery were sent for RCT. The age range of the patients was 34 to 75 with mean 53 year. Macroscopic haematuria, flank pain, microscopic haematuria, bladder irritability was found in 43(82.7%), 06(11.5%), 03(5.8%), 32(61.5%) cases respectively and coincidental ureteral TCC with hydronephrosis was found in 04(7.7%) cases for whom radical nephreureterectomy and cystectomy with ileal conduit was done. Amongst the other muscle invasive tumor only three cases were compliant to do radical surgery; rest were advised to consult with oncologist for possible RCT. Superficial bladder cancer was 19(36.5%) and invasive bladder cancer was 33(63.5%). TURBT and IVT were offered for all superficial bladder tumors. Of them 06(31.5%) patients showed recurrence during the study period. More recurrences occur in IVC group (35.7%) than immunotherapy with BCG group (20%) Re-TURBT and stage wise treatment was offered to them. All recurrent cases were G-3 tumor and were multifocal. Recurrence rate is about 30%. Screening program and structured referral system should be developed to have early diagnosis for prompt treatment and best prognosis.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Choi JW, Kim Y, Lee JH, Kim YS
Prognostic significance of lactate/proton symporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder.
Urology. 2014; 84(1):245.e9-15 [PubMed] Related Publications
OBJECTIVE: To investigate the prognostic significance of lactate/proton monocarboxylate transporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder (UCB).
METHODS: We examined the expressions of MCT1, MCT4, and CD147 proteins in a total of 360 cases of UCB by immunohistochemistry. The immunohistochemical expressions were quantified using an ImageJ-based analysis program.
RESULTS: MCT1, MCT4, and CD147 expressions were increased in 130 (36.1%), 168 (46.7%), and 228 (63.3%) UCB cases, respectively. Most tumor cells showed diffuse membranous staining, whereas normal urothelial cells showed negative or weak staining. High levels of MCT1 expression correlated with high World Health Organization grade (P<.001), advanced tumor node metastasis (TNM) stage (P<.001), nonpapillary growth type (P<.001), and lymphatic tumor invasion (P=.010), whereas high levels of MCT4 expression did not significantly correlate with any of these variables. High CD147 expression was associated with high World Health Organization grade (P<.001), advanced tumor node metastatis stage (P<.001), and nonpapillary growth type (P=.003). Univariate analyses revealed that high MCT1 (P<.001) and CD147 (P=.029) expressions were associated with poor overall survival and that high MCT4 expression was correlated with poor recurrence-free survival (P=.036). Multivariate analyses revealed that high MCT1 and MCT4 expressions were independent prognostic factors for poor overall survival and poor recurrence-free survival, respectively, in UCB patients.
CONCLUSION: Our results indicate that increased MCT1, MCT4, and CD147 expressions have prognostic implications in UCB and suggest their roles in urothelial cancer metabolism.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Kluth M, Reynolds K, Rink M, et al.
Reduced membranous MET expression is linked to bladder cancer progression.
Cancer Genet. 2014; 207(4):147-52 [PubMed] Related Publications
The MET protein is involved in the malignant progression of different tumors. This study aimed to analyze the relationship of MET expression with tumor phenotype and clinical outcome in bladder cancer and the role of gene amplification for MET overexpression. A bladder cancer tissue microarray containing 686 bladder cancers was analyzed by immunohistochemistry and by fluorescence in situ hybridization. MET immunostaining was seen in normal urothelium and was recorded in 459 of 560 analyzable urothelial carcinomas (82.0%). Low MET staining was associated with a more unfavorable tumor phenotype. MET staining was seen in 89.8% of 266 pTa, 81.1% of 132 pT1, and 69.4% of 160 pT2-4 cancers (P < 0.0001). MET staining was detectable in 92.4% of 66 grade 1, 85.6% of 257 grade 2, and 75.1% of 237 grade 3 cancers (P = 0.001). MET expression status was not associated with overall or tumor-specific survival in muscle-invasive cancers (pT2-4), tumor progression in pT1 cancers, or recurrences in pTa tumors. Only four of the analyzed tumors (0.8%) showed amplification of the MET gene. We conclude that MET is not overexpressed in urothelial cancer but rather downregulated in a fraction of cancers. Accordingly, rare amplification of the genomic area including the MET gene was not associated with MET protein overexpression.

Related: FISH

de Haas RJ, Steyvers MJ, Fütterer JJ
Multiparametric MRI of the bladder: ready for clinical routine?
AJR Am J Roentgenol. 2014; 202(6):1187-95 [PubMed] Related Publications
OBJECTIVE: In this article, we describe the fundamentals of multiparametric MRI in bladder cancer and provide an overview of the currently available data concerning this new imaging technology. Urinary bladder cancer is a relatively common malignancy, especially in elderly patients. Treatment outcome and prognosis are strongly related to adequate local and regional tumor staging. Unfortunately, clinical understaging frequently occurs, which negatively influences prognosis. Therefore, advanced imaging techniques are needed to adequately stage bladder cancer patients. MRI is currently the best imaging technique for local and nodal staging in bladder cancer patients because of its superior soft-tissue contrast without exposure to ionizing radiation. Important improvements in MRI technology have led to the introduction of multiparametric MRI, combining anatomic and functional sequences.
CONCLUSION: The first results of multiparametric MRI seem promising, especially in detection, staging, and follow-up of bladder cancer. However, more studies are needed with larger study populations to define the exact place of multiparametric MRI in bladder cancer patients.

Wang HJ, Pui MH, Guo Y, et al.
Value of normalized apparent diffusion coefficient for estimating histological grade of vesical urothelial carcinoma.
Clin Radiol. 2014; 69(7):727-31 [PubMed] Related Publications
AIM: To compare the efficacy of apparent diffusion coefficient (ADC) and normalized ADC (nADC) for estimating the histological grade of vesical urothelial carcinoma and to identify an optimal reference for nADC calculation.
MATERIALS AND METHODS: Thirty patients with histologically confirmed vesical urothelial carcinomas underwent preoperative diffusion-weighted magnetic resonance imaging (DW-MRI) of the pelvis. nADC of the tumour was calculated as ADC (tumour)/ADC (reference) using urine in the bladder lumen, and the obturator internus and gluteus maximus muscles as reference. Receiver operating characteristic (ROC) curves were constructed and compared to identify an optimal reference for nADC calculation.
RESULTS: Both ADC and nADC of low-grade tumours (1.112 ± 0.159 × 10(-3) mm(2)/s, 0.403 ± 0.047 × 10(-3) mm(2)/s) were significantly (p < 0.001) higher than those of high-grade tumours (0.772 ± 0.091 × 10(-3) mm(2)/s, 0.276 ± 0.033 × 10(-3) mm(2)/s). The area under the nADC ROC curve using urine as reference was significantly (p = 0.000) larger (0.995) than those using obturator internus (0.960) and gluteus maximus (0.945).
CONCLUSIONS: nADC is superior to ADC for estimating the histological grade of bladder carcinoma using urine in the bladder lumen as an optimal reference for nADC calculation.

Choueiri TK, Jacobus S, Bellmunt J, et al.
Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.
J Clin Oncol. 2014; 32(18):1889-94 [PubMed] Related Publications
PURPOSE: In advanced urothelial cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer (MIUC).
PATIENTS AND METHODS: Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ≤ pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1.
RESULTS: Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% (80% CI, 38 to 61) achieved PaR of ≤ pT1N0M0, and we concluded this regimen was effective. High-grade (grade ≥ 3) toxicities were observed in 10% of patients, with no neutropenic fevers or treatment-related death. One-year DFS was 89% versus 67% for patients who achieved PaR compared with those who did not (hazard ratio [HR], 2.6; 95% CI, 0.8 to 8.1; P = .08) and 86% versus 62% for patients who achieved RaR compared with those who did not (HR, 4.1; 95% CI, 1.3 to 12.5; P = .009). We found no association between serum tumor markers or ERCC1 expression with response or survival.
CONCLUSION: In patients with MIUC, neoadjuvant ddMVAC was well tolerated and resulted in significant pathologic and radiologic downstaging.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Cisplatin Doxorubicin Methotrexate Vinblastine

Plimack ER, Hoffman-Censits JH, Viterbo R, et al.
Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity.
J Clin Oncol. 2014; 32(18):1895-901 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
PURPOSE: Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls.
PATIENTS AND METHODS: Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity.
RESULTS: Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non-muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity.
CONCLUSION: AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Cisplatin Doxorubicin Methotrexate Vinblastine

King K, Steggall M
Haematuria: from identification to treatment.
Br J Nurs. 2014 May 8-21; 23(9):S28-32 [PubMed] Related Publications
Haematuria has a prevalence of 0.1% to 2.6%. Potential diagnoses may include infection, kidney stones, trauma, exercise or spurious causes, such as foods, drugs or menstruation, and a tumour. Approximately 20% of patients with haematuria have a urological tumour, with a further 20% found to have a significant underlying pathology. Haematuria is subsequently known as the 'classic presentation' of bladder cancer with 70-80% of patients experiencing painless, gross (visible) haematuria. However, in all cases of visible haematuria, a tumour should be suspected until proven otherwise. A patient with visible haematuria requires urgent, stringent investigation, warranting specialist assessment and subsequent selective referral through a series of patient-centred investigations at a haematuria clinic. One-stop clinics have been shown to improve the patient experience in early diagnosis of potentially life-threatening conditions. Yet despite morbidity and mortality from bladder cancer increasing, the haematuria service has remained largely unchanged for several decades. This paper will discuss the tests and investigations that need to be undertaken in an individual with either visible or non-visible haematuria, and outline the care that is needed to support patients through the investigation process, with special focus on bladder tumour.

Cho SK, Emoto K, Su LJ, et al.
Functionalized gold nanorods for thermal ablation treatment of bladder cancer.
J Biomed Nanotechnol. 2014; 10(7):1267-76 [PubMed] Related Publications
Nanomaterial-directed, photothermal ablation is a practical future approach for the treatment of early-stage bladder cancer. Using a new PEGylation technique with bi-functional nitrophenyl carbonate PEG (bi-NPC-PEG) that promotes uniform suspension of the nanomaterial in solution, we have shown that gold nanorods conjugated to an anti-EGFR antibody (nano-alphaEGFR) bind effectively to EGFR-expressing bladder cancer cells. The subsequent application of infrared light, specifically tuned to the plasmon resonance of the nanorods used in this work, allows for the specific heating of nano-alphaEGFR to the point of localized cellular death. Such an approach, administering nano-alphaEGFR intravesically via a urinary catheter and infrared light via a modified cystoscope, represents a novel, future clinical application of this technology, which avoids the problem of systemic exposure and clearance of nanoparticles from body.

Köhler CU, Martin L, Bonberg N, et al.
Automated quantification of FISH signals in urinary cells enables the assessment of chromosomal aberration patterns characteristic for bladder cancer.
Biochem Biophys Res Commun. 2014; 448(4):467-72 [PubMed] Related Publications
Targeting the centromeres of chromosomes 3, 7, 17 (CEP3, 7, 17) and the 9p21-locus (LSI9p21) for diagnosing bladder cancer (BC) is time- and cost-intensive and requires a manual investigation of the sample by a well-trained investigator thus overall limiting its use in clinical diagnostics and large-scaled epidemiological studies. Here we introduce a new computer-assisted FISH spot analysis tool enabling an automated, objective and quantitative assessment of FISH patterns in the urinary sediment. Utilizing a controllable microscope workstation, the microscope software Scan^R was programmed to allow automatic batch-scanning of up to 32 samples and identifying quadruple FISH signals in DAPI-scanned nuclei of urinary sediments. The assay allowed a time- and cost-efficient, automated and objective assessment of CEP3, 7 and 17 FISH signals and facilitated the quantification of nuclei harboring specific FISH patterns in all cells of the urinary sediment. To explore the diagnostic capability of the developed tool, we analyzed the abundance of 51 different FISH patterns in a pilot set of urine specimens from 14 patients with BC and 21 population controls (PC). Herein, the results of the fully automated approach yielded a high degree of conformity when compared to those obtained by an expert-guided re-evaluation of archived scans. The best cancer-identifying pattern was characterized by a concurrent gain of CEP3, 7 and 17. Overall, our automated analysis refines current FISH protocols and encourages its use to establish reliable diagnostic cutoffs in future large-scale studies with well-characterized specimens-collectives.

Related: Chromosome 17 Chromosome 3 Chromosome 7 Chromosome 9 FISH

Mangrud OM, Gudlaugsson E, Skaland I, et al.
Prognostic comparison of proliferation markers and World Health Organization 1973/2004 grades in urothelial carcinomas of the urinary bladder.
Hum Pathol. 2014; 45(7):1496-503 [PubMed] Related Publications
European treatment guidelines of non-muscle-invasive urothelial carcinoma of the urinary bladder are strongly dependent on grade, but grading reproducibility is wanting. Protocolized proliferation features such as Mitotic Activity Index (MAI), Ki-67, and phosphohistone H3 are prognostic and reproducible. The objective of this population-based study was to compare proliferation biomarkers with each other and with World Health Organization (WHO) 1973/2004 grades with regard to prediction of stage progression. A total of 193 primary non-muscle-invasive urothelial carcinomas were analyzed using WHO73/04 grades and measurement of the proliferation markers mentioned above. Sensitivities, specificities, and positive and negative predictive values with confidence intervals (CIs) were estimated with regard to progression prediction. Kaplan-Meier survival curves were made, and the hazard ratio and Harrell's C-index with 95% CIs, P values, and adjusted C-index for stage progression or not of WHO73, WHO04, and the proliferation markers were calculated. The median follow-up time was 75 months (range, 1-127). A total of 111 patients (52%) experienced recurrence within 5 years, and 14 patients (7%) progressed. High values of MAI predicted stage progression with a positive predictive value of 0.22 (95% CI, 0.12-0.37). The positive predictive value of Ki-67 and phosphohistone H3 were 0.15 (both 95% CIs, 0.07-0.29) and comparable to that of the WHO04. The prognostic value of MAI was strongest, exceeding that of the other proliferation markers and the WHO grading systems. In conclusion, in non-muscle-invasive urinary bladder urothelial carcinomas, proliferation biomarkers have prognostic value, possibly exceeding that of the WHO classifications.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Kim SH, Yu A, Jung JH, et al.
Incidence and risk factors of 30-day early and 90-day late morbidity and mortality of radical cystectomy during a 13-year follow-up: a comparative propensity-score matched analysis of complications between neobladder and ileal conduit.
Jpn J Clin Oncol. 2014; 44(7):677-85 [PubMed] Related Publications
OBJECTIVE: We report on the short and late morbidity and mortality of ileal conduit and neobladder after radical cystectomy with their associated risk factors.
METHODS: We retrospectively collected data on 308 non-metastatic bladder cancer patients who underwent radical cystectomy with either ileal conduit or neobladder for a curative intent from January 1999 to December 2011. Post-operative morbidity and mortality of 30-day (early) and 90-day (late) complication with their risk factors were examined in association with different types of urinary diversion. A comparative analysis using propensity-score matching was performed with matching variables of age, sex, number of underlying diseases and pathologic T and N stages, lymph node dissection, operative time and time of surgical year for comparison of the early and late morbidities between ileal conduit and neobladder.
RESULTS: During the median follow-up of 46.6 months, early and late morbidities were 29.5% (n=91) and 19.8% (n=61), and complication-related mortalities were 2.2 and 6.6%, respectively. The type of urinary diversion significantly affected only the late complications (early: neobladder 57 vs. ileal conduit 47, P=0.096; late: neobladder 67 vs. ileal conduit 37, P<0.001). However, after propensity-score matching, no significant differences in early and late morbidities were observed between neobladder and ileal conduit. For risk factors of morbidity, number of removed lymph node states and hypertension were independently significant for both early and late complications (P<0.05).
CONCLUSIONS: The type of urinary diversion affected only late complication, however, results of the matching analysis showed no significant differences in early and late morbidities between neobladder and ileal conduit.

Zhang Z, Cao Z, Xu C, et al.
Solifenacin is able to improve the irritative symptoms after transurethral resection of bladder tumors.
Urology. 2014; 84(1):117-21 [PubMed] Related Publications
OBJECTIVE: To evaluate the efficacy and safety of solifenacin in the management of irritative symptoms after transurethral resection of bladder tumors (TURBTs) with subsequent intravesical chemotherapy.
METHODS: A total of 116 patients undergoing TURBT were randomly allocated into 2 groups, 58 patients in each group. Group 1 patients received solifenacin 5 mg, 6 hours before surgery and 5 mg per day, after surgery for 2 weeks, whereas group 2 patients received a placebo. Patients with low-risk non-muscle-invasive bladder cancer received immediate postoperative instillation of epirubicin. Patients with medium- or high-risk non-muscle-invasive bladder cancer received postoperative instillation twice within 2 weeks, once immediately following the operation and once on the eighth postoperative day. All patients completed bladder diaries before surgery, on the 1st, 7th, and 14th days after removal of the catheter with overactive bladder symptom scores completed preoperatively, and on the 7th and 14th days. Additionally, the incidence and severity of catheter-related bladder discomfort were recorded at 6, 12, 24, 48, and 72 hours after the surgery.
RESULTS: The incidence and the severity of catheter-related bladder discomfort in group 1, compared with group 2, were significantly reduced (P<.05). There was a significant difference in overactive bladder symptom scores between the 2 groups (5.67 vs 7.86; P<.001). Episodes of daytime, frequency, nocturia, urgency, and urge urinary incontinence in group 1 were also significantly lower than in group 2 (P<.05).
CONCLUSION: This study demonstrates that solifenacin can be beneficial for the management of irritative symptoms after TURBT with subsequent intravesical chemotherapy.

Paner GP, Annaiah C, Gulmann C, et al.
Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder.
Hum Pathol. 2014; 45(7):1473-82 [PubMed] Related Publications
Data on immunohistochemical expression of novel and traditional urothelial markers in the wide range of urothelial carcinoma variants have so far been very limited. In this study, whole tissue sections from 130 bladder urothelial carcinoma and variants were stained with a panel of novel and traditional immunomarkers supportive of urothelial lineage. The positivity rates were as follows: (a) urothelial carcinomas with or without divergent differentiation: GATA3 (50%), S-100P (86%), uroplakin III (20%), thrombomodulin (40%), cytokeratin 7 (CK7) (80%), CK20 (55%), p63 (87%), and high molecular weight cytokeratin (HMCK) (89%); (b) urothelial carcinoma variants (micropapillary, plasmacytoid, nested, clear cell, and microcystic): GATA3 (88%), S-100P (96%), uroplakin III (33%), thrombomodulin (49%), CK7 (95%), CK20 (61%), p63 (69%), and HMCK (96%); and (c) undifferentiated carcinomas (lymphoepithelioma-like carcinoma, small cell carcinoma, sarcomatoid carcinoma and carcinoma with rhabdoid and giant cells): GATA3 (28%), S-100P (31%), uroplakin III (0%), thrombomodulin (22%), CK7 (50%), CK20 (3%), p63 (50%), and HMCK (49%). In urothelial carcinoma with squamous differentiation, GATA3 expression was lower (20%) in contrast to p63 and S-100P. In urothelial carcinoma with glandular differentiation, GATA3 (50%) and p63 (60%) expression was lower than S-100P (100%). p63 expression was relatively lower in micropapillary (54%) and plasmacytoid (50%) variants compared with the other urothelial carcinoma variants. This study provides comprehensive data for novel and traditionally used markers to support urothelial lineage in urothelial carcinoma variants. Our findings show that GATA3, S-100P, CK7, CK20, HMCK, and p63, in the appropriate differential diagnostic setting, are useful to support urothelial lineage of variant morphologies.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

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