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MeSH term: Urinary Bladder Neoplasms
US National Library of Medicine
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Showing publications with corresponding authors from the UK (Source: PubMed).
Chronic Infections of the Urinary Tract and Bladder Cancer Risk: a Systematic Review.
Asian Pac J Cancer Prev. 2016; 17(8):3805-7 [PubMed] Related Publications
Prospective Study Delivering Simultaneous Integrated High-dose Tumor Boost (≤70 Gy) With Image Guided Adaptive Radiation Therapy for Radical Treatment of Localized Muscle-Invasive Bladder Cancer.
Int J Radiat Oncol Biol Phys. 2016; 94(5):1022-30 [PubMed] Related Publications
METHODS AND MATERIALS: A library of 3 intensity modulated radiation therapy plans were created (small, medium, and large) from planning computed tomography (CT) scans performed at 30 and 60 minutes; treating the whole bladder to 52 Gy and the tumor to 70 Gy in 32 fractions. A "plan of the day" approach was used for treatment delivery. A post-treatment cone beam CT (CBCT) scan was acquired weekly to assess intrafraction filling and coverage.
RESULTS: A total of 18 patients completed treatment to 70 Gy. The plan and treatment for 1 patient was to 68 Gy. Also, 1 patient's plan was to 70 Gy but the patient was treated to a total dose of 65.6 Gy because dose-limiting toxicity occurred before dose escalation. A total of 734 CBCT scans were evaluated. Small, medium, and large plans were used in 36%, 48%, and 16% of cases, respectively. The mean ± standard deviation rate of intrafraction filling at the start of treatment (ie, week 1) was 4.0 ± 4.8 mL/min (range 0.1-19.4) and at end of radiation therapy (ie, week 5 or 6) was 1.1 ± 1.6 mL/min (range 0.01-7.5; P=.002). The mean D98 (dose received by 98% volume) of the tumor boost and bladder as assessed on the post-treatment CBCT scan was 97.07% ± 2.10% (range 89.0%-104%) and 99.97% ± 2.62% (range 96.4%-112.0%). At a median follow-up period of 19 months (range 4-33), no muscle-invasive recurrences had developed. Two patients experienced late toxicity (both grade 3 cystitis) at 5.3 months (now resolved) and 18 months after radiation therapy.
CONCLUSIONS: Image guided adaptive radiation therapy using intensity modulated radiation therapy to deliver a simultaneous integrated tumor boost to 70 Gy is feasible, with acceptable toxicity, and will be evaluated in a randomized trial.
Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer.
PLoS One. 2016; 11(2):e0149756 [PubMed] Free Access to Full Article Related Publications
METHODS: DNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+) and 91 bladder cancer patients post-TURBT (89 cancer-free).
RESULTS: Despite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity) and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity).
CONCLUSION: This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer.
The potential of MRI-guided online adaptive re-optimisation in radiotherapy of urinary bladder cancer.
Radiother Oncol. 2016; 118(1):154-9 [PubMed] Related Publications
MATERIALS AND METHODS: Nine bladder cancer patients treated in a phase II trial of plan selection underwent 6-7 weekly repeat MRI series, each with volumetric scans acquired over a 10 min period. Adaptive re-planning on the 0 min MRI scans was performed using density override, simulating a hypo-fractionated schedule. Target coverage was evaluated on the 10 min scan to quantify the impact of intra-fractional motion.
RESULTS: MRIGARTanIso reduced the course-averaged PTV by median 304 cc compared to plan selection. Bladder shifts affected target coverage in individual fractions for all strategies. Two patients had a v95% of the bladder below 98% for MRIGARTiso. MRIGARTiso decreased the bowel V25 with 15-46 cc compared to MRIGARTpop.
CONCLUSION: Online re-optimised ART has a considerable normal tissue sparing potential. MRIGART with online corrections for target shift during a treatment fraction should be considered in ART for bladder cancer.
Significant Role of Lifetime Cigarette Smoking in Worsening Bladder Cancer and Upper Tract Urothelial Carcinoma Prognosis: A Meta-Analysis.
J Urol. 2016; 195(4 Pt 1):872-9 [PubMed] Related Publications
MATERIALS AND METHODS: A total of 24 studies, comprising data from 13,114 patients with bladder cancer and 2,259 patients with upper tract urothelial carcinoma, were included in this meta-analysis. Publication bias was addressed through Egger's test, and the heterogeneity among studies was assessed by the I(2) test statistic and subgroup analyses.
RESULTS: Current smokers at diagnosis are at increased risk for local recurrence in nonmuscle invasive bladder cancer (HR 1.27, 95% CI 1.09-1.46) and smokers with muscle invasive bladder cancer have an increased risk of dying of bladder cancer (HR 1.23, 95% CI 1.02-1.44). In the upper tract urothelial carcinoma population smokers have an increased risk of recurrence in the operative bed (HR 1.57, 95% CI 1.19-1.95) and of death from upper tract urothelial carcinoma (HR 1.53, 95% CI 1.13-1.92). We did not identify significant heterogeneity among included studies.
CONCLUSIONS: The body of evidence is limited due to the absence of prospective studies. However, the results from this meta-analysis unambiguously support the hypothesis that lifetime cigarette smokers are at increased risk for a more malignant type of urothelial carcinoma associated with a worse prognosis.
Methylation of HOXA9 and ISL1 Predicts Patient Outcome in High-Grade Non-Invasive Bladder Cancer.
PLoS One. 2015; 10(9):e0137003 [PubMed] Free Access to Full Article Related Publications
METHODS: Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases.
RESULTS: The ISL1 genes' promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM).
CONCLUSIONS: In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC.
Real-life Experience: Early Recurrence With Hexvix Photodynamic Diagnosis-assisted Transurethral Resection of Bladder Tumour vs Good-quality White Light TURBT in New Non-muscle-invasive Bladder Cancer.
Urology. 2015; 86(2):327-31 [PubMed] Related Publications
METHODS: A prospective controlled study was conducted commencing with a planned prospective cohort of patients with new tumors undergoing white-light TURBT in 2007-2008. Previously defined principles of GQ-WLTURBT for standardization and comparison of TURBT techniques, which are (1) cystoscopic mapping using a bladder diagram, (2) documented complete resection of the tumor, (3) resection performed or supervised by an experienced surgeon, (4) presence of detrusor muscle in the specimen, and (5) patient receiving mitomycin C within 24 hours of the resection, were applied. This was followed by a prospective cohort of new patients undergoing PDD-TURBT in 2009-2011. Only patients with new non-muscle-invasive bladder cancer (NMIBC) deemed to have had complete first TURBT were included for analysis. Tumor features and findings at first check cystoscopy and early re-TURBT (in high-risk NMIBC) were evaluated. Early recurrence (for calculating recurrence rate at first follow-up cystoscopy) was defined as pathologically confirmed tumor on early re-TURBT or recurrence at the first check cystoscopy. Comparison was analyzed between GQ-WLTURBT and good-quality PDD-TURBT (GQ-PDDTURBT).
RESULTS: A total of 808 patients were evaluated. The overall RRFFCs for GQ-WLTURBT and GQ-PDDTURBT were 30.9% and 13.6%, respectively (odds ratio = 2.9; 95% CI = 1.6-5.0; P <.001), with statistically significant lower recurrence rates in low- and intermediate-risk NMIBC after GQ-PDDTURBT.
CONCLUSION: Hexvix PDD-assisted TURBT is associated with a significantly lower risk of early recurrence compared with GQ-WLTURBT in a real-life clinical setting.
68Ga-DOTATATE PET/MR Imaging of Urinary Bladder Paraganglioma.
Clin Nucl Med. 2015; 40(8):692-4 [PubMed] Related Publications
Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer.
Cancer. 2015; 121(15):2586-93 [PubMed] Related Publications
METHODS: Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC.
RESULTS: In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P = .77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P = .48).
CONCLUSIONS: Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice.
Homologous Mutation to Human BRAF V600E Is Common in Naturally Occurring Canine Bladder Cancer--Evidence for a Relevant Model System and Urine-Based Diagnostic Test.
Mol Cancer Res. 2015; 13(6):993-1002 [PubMed] Free Access to Full Article Related Publications
IMPLICATIONS: This study demonstrates the activating BRAF mutation (V600E), which is found in multiple human cancers, is a driver of canine InvTCC, and highlights a urine-based test for quick diagnosis.
Protein interactome of muscle invasive bladder cancer.
PLoS One. 2015; 10(1):e0116404 [PubMed] Free Access to Full Article Related Publications
Management of Node-Positive Bladder Cancer After Neoadjuvant Chemotherapy and Radical Cystectomy: A Survey of Current UK Practice.
Clin Genitourin Cancer. 2015; 13(3):e153-8 [PubMed] Related Publications
MATERIALS AND METHODS: An electronic survey was sent to UK pelvic cancer centers regarding: (1) choice of NAC regimen; (2) indications for reimaging; (3) choice and indication of adjuvant chemotherapy (AC) for patients with nodal disease after NAC and RC; (4) choice and indication of chemotherapy regimen if disease continues to progress in patients with advanced bladder cancer; and (5) guidelines used by those surveyed.
RESULTS: Consultant uro-oncologists from 77% of UK pelvic cancer centers responded, who treated a median of 13 patients per year with NAC before RC. Three cycles of gemcitabine and cisplatin was the most common NAC regimen, with 93% and 67% respondents giving it for downstaging of cN1- and cN2- and 3-positive patients, respectively. Forty-five percent would not give AC after NAC and RC in patients with positive lymph nodes. The patient's performance status, followed by response to NAC were key factors in dictating the use of AC. In the presence of disease progression, 46% of participants would use a taxane. Fifty-two percent of responders do not follow any guidelines.
CONCLUSION: In the United Kingdom, the treatment of patients with nodal disease after NAC and RC is variable. There is little evidence on which to base the management of such patients. The creation of national and international guidelines might help clinicians to optimize care for these patients.
Fruits, vegetables, and bladder cancer risk: a systematic review and meta-analysis.
Cancer Med. 2015; 4(1):136-46 [PubMed] Free Access to Full Article Related Publications
Cisplatin-based first-line therapy for advanced urothelial carcinoma after previous perioperative cisplatin-based therapy.
Clin Genitourin Cancer. 2015; 13(2):178-84 [PubMed] Free Access to Full Article Related Publications
PATIENTS AND METHODS: Data were collected for patients who received cisplatin-based first-line therapy for advanced UC after previous perioperative cisplatin-based therapy. Cox proportional hazards models were used to investigate the prognostic ability of visceral metastasis, ECOG PS, TFPC, anemia, leukocytosis, and albumin on overall survival (OS).
RESULTS: Data were available for 41 patients from 8 institutions including 31 men (75.6%). The median age was 61 (range, 41-77) years, most received gemcitabine plus cisplatin (n = 26; 63.4%), and the median number of cycles was 4 (range, 1-8). The median OS was 68 weeks (95% confidence interval [CI], 48.0-81.0). Multivariable Cox regression analysis results showed an independent prognostic effect on OS for PS > 0 versus 0 (hazard ratio [HR], 4.56 [95% CI, 1.66-12.52]; P = .003) and TFPC ≥ 78 weeks versus < 78 weeks (HR, 0.48 [95% CI, 0.21-1.07]; P = .072). The prognostic model for OS was internally validated with c-index = 0.68. Patients with TFPC < 52 weeks, 52 to 104 weeks, and ≥ 104 weeks had median survival of 42, 70, and 162 weeks, respectively.
CONCLUSION: Longer TFPC ≥ 78 weeks and ECOG PS = 0 were independently prognostic for better survival with cisplatin-based first-line chemotherapy for advanced UC after previous perioperative cisplatin-based chemotherapy. The data support using TFPC ≥ 52 weeks to rechallenge with cisplatin-based first-line chemotherapy for metastatic disease.
Urinary diversion: how experts divert.
Urology. 2015; 85(1):233-8 [PubMed] Related Publications
METHODS: Population-based data from the literature included all patients (n = 7608) treated in Sweden during the period 1964-2008, from Germany (n = 14,200) for the years 2008 and 2011, US patients (identified from National Inpatient Sample during 1998-2005, 35,370 patients and 2001-2008, 55,187 patients), and from Medicare (n = 22,600) for the years 1992, 1995, 1998, and 2001. After the International Consultation on Urologic Diseases-European Association of Urology International Consultation on Bladder Cancer 2012, the urinary diversion committee members disclosed data from their home institutions (n = 15,867), including the pioneering institutions and the leading urologic oncology centers. They are the coauthors of this report.
RESULTS: The receipt of continent urinary diversion in Sweden and the United States is <15%, whereas in the German high-volume setting, 30% of patients receive a neobladder. At leading urologic oncology centers, this rate is also 30%. At pioneering institutions up to 75% of patients receive an orthotopic reconstruction. Anal diversion is <1%. Continent cutaneous diversion is the second choice.
CONCLUSION: Enormous variations in urinary diversion exist for >2 decades. Increased attention in expanding the use of continent reconstruction may help to reduce these disparities for patients undergoing radical cystectomy for bladder cancer. Continent reconstruction should not be the exclusive domain of cystectomy centers. Efforts to increase rates of this complex reconstruction must concentrate on better definition of the quality-of-life impact, technique dissemination, and the centralization of radical cystectomy.
The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease.
Cancer Res. 2014; 74(20):5808-18 [PubMed] Free Access to Full Article Related Publications
Deoxycytidine kinase expression underpins response to gemcitabine in bladder cancer.
Clin Cancer Res. 2014; 20(21):5435-45 [PubMed] Free Access to Full Article Related Publications
EXPERIMENTAL DESIGN: Four bladder cancer cell lines were screened for radiosensitization by low-dose gemcitabine using clonogenic assay, and gemcitabine-resistant RT112gem and CALgem cells created by exposure to increasing gemcitabine doses. Four key gemcitabine-regulatory genes were knocked down by transient siRNA. Nude mice carrying CALgem subcutaneous xenografts were exposed to 100 mg/kg gemcitabine ± ionizing radiation (IR) and response assessed by tumor growth delay.
RESULTS: Gemcitabine was cytotoxic in the low nanomolar range (10-40 nmol/L) in four bladder cancer cell lines and radiosensitized all four lines. Sensitizer enhancement ratios at 10% survival were: RT112 1.42, CAL29 1.55, T24 1.63, and VMCUB1 1.47. Transient siRNA knockdown of deoxycytidine kinase (dCK) significantly reduced radiosensitization by gemcitabine (P = 0.02). RT112gem and CALgem cells displayed robust decreases of dCK mRNA and protein levels; reexpression of dCK restored gemcitabine sensitivity. However, CALgem xenografts responded better to combination gemcitabine/IR than either treatment alone (P < 0.001) with dCK strongly expressed in the tumor vasculature and stroma.
CONCLUSIONS: Gemcitabine resistance in bladder cancer cell lines was associated with decreased dCK expression, but gemcitabine-resistant xenografts were responsive to combination low-dose gemcitabine/IR. We propose that dCK activity in tumor vasculature renders it gemcitabine sensitive, which is sufficient to invoke a tumor response and permit tumor cell kill in gemcitabine-resistant tumors.
Alteration of cell-cell and cell-matrix adhesion in urothelial cells: an oncogenic mechanism for mutant FGFR3.
Mol Cancer Res. 2015; 13(1):138-48 [PubMed] Related Publications
IMPLICATIONS: The ability of mutant FGFR3 to drive transcriptional expression profiles involved in tumor cell adhesion suggests a mechanism for expansion of premalignant urothelial lesions.
Molecular markers for urothelial bladder cancer prognosis: toward implementation in clinical practice.
Urol Oncol. 2014; 32(7):1078-87 [PubMed] Related Publications
METHODS AND MATERIALS: Immunohistochemistry, gene signatures, and FGFR3-based molecular grading were used as molecular examples focussing on prognostics and issues related to robustness of pathological and molecular assays.
RESULTS: The role of molecular markers to predict recurrence is limited, as clinical variables are currently more important. The prediction of progression and survival using molecular markers holds considerable promise. Despite a plethora of prognostic (clinical and molecular) marker studies, reproducibility of pathology and molecular assays has been understudied, and lack of reproducibility is probably the main reason that individual prediction of disease outcome is currently not reliable.
CONCLUSIONS: Molecular markers are promising to predict progression and survival, but not recurrence. However, none of these are used in the daily clinical routine because of reproducibility issues. Future studies should focus on reproducibility of marker assessment and consistency of study results by incorporating scoring systems to reduce heterogeneity of reporting. This may ultimately lead to incorporation of molecular markers in clinical practice.
Identification of differentially expressed long noncoding RNAs in bladder cancer.
Clin Cancer Res. 2014; 20(20):5311-21 [PubMed] Related Publications
EXPERIMENTAL DESIGN: The expression of 17,112 lncRNAs and 22,074 mRNAs was determined using microarrays in 83 normal and malignant urothelial (discovery) samples and selected RNAs with qPCR in 138 samples for validation. Significantly differentially expressed RNAs were identified and stratified according to tumor phenotype. siRNA knockdown, functional assays, and whole-genome transcriptomic profiling were used to identify potential roles of selected lncRNAs.
RESULTS: We observed upregulation of many lncRNAs in urothelial cancer that was distinct to corresponding, more balanced changes for mRNAs. In general, lncRNA expression reflected disease phenotype. We identified 32 lncRNAs with potential roles in disease progression. Focusing upon a promising candidate, we implicate upregulation of AB074278 in apoptosis avoidance and the maintenance of a proproliferative state in cancer through a potential interaction with EMP1, a tumor suppressor and a negative regulator of cell proliferation.
CONCLUSIONS: We report differential expression profiles for numerous lncRNA in urothelial cancer. We identify phenotype-specific expression and a potential mechanistic target to explain this observation. Further studies are required to validate lncRNAs as prognostic biomarkers in this disease.
Robotic or open radical cystectomy, which is safer? A systematic review and meta-analysis of comparative studies.
J Endourol. 2014; 28(10):1215-23 [PubMed] Related Publications
OBJECTIVES: To compare early surgical outcomes for RRC and open radical cystectomy (ORC) with an emphasis on complications and postoperative mortality rates.
FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases.
J Urol. 2015; 193(1):325-30 [PubMed] Related Publications
MATERIALS AND METHODS: We examined matched primary tumor and nodal metastases from 150 patients with bladder cancer clinically staged as N0M0. Four samples per patient were incorporated into a tissue microarray and FGFR3 expression was assessed by immunohistochemistry. FGFR3 expression was tested for an association with categorical clinical data using the Fisher exact test, and with overall and recurrence-free survival by Kaplan-Meier analysis.
RESULTS: Duplicate spots from primary tumors and lymph node metastases were highly concordant (OR 8.6 and 16.7, respectively, each p <0.001). Overall FGFR protein expression levels did not differ between primary and metastatic lesions (p = 0.78). Up-regulated expression was recorded in 53 of 106 evaluable primary tumor spots and 56 matched metastases. Concordance of FGFR3 expression levels in 79 matched primary tumor and metastasis specimens was high (OR 8.45, p <0.001). In 15 and 12 patients expression was up-regulated in only metastasis and in only the primary tumor, respectively. Overall and recurrence-free survival was not related to FGFR3 expression.
CONCLUSIONS: FGFR3 expression in matched primary and metastasized bladder cancer specimens showed good but not absolute concordance. Thus, in most patients primary tumor FGFR3 status can guide the selection of FGFR targeted therapy.
Loss of expression of the tumour suppressor gene AIMP3 predicts survival following radiotherapy in muscle-invasive bladder cancer.
Int J Cancer. 2015; 136(3):709-20 [PubMed] Related Publications
The Nrf2 transcription factor contributes to resistance to cisplatin in bladder cancer.
Urol Oncol. 2014; 32(6):806-14 [PubMed] Related Publications
MATERIALS AND METHODS: We first used bladder cancer cell lines, including a cisplatin-resistant RT112 subline (RT112-CP), to investigate Nrf2 expression and activation and its association with cisplatin response. We then undertook immunohistochemical analysis of a tissue microarray of archival bladder cancer radical cystectomy specimens to test the relevance of clinical Nrf2 expression to outcomes following either neoadjuvant chemotherapy and cystectomy or cystectomy alone.
RESULTS: Bladder cancer cell lines showed variable Nrf2 expression. Nrf2 expression was greater in RT112-CP cisplatin-resistant cells compared with that in parental RT112 cells. Nrf2 overexpression was functional in this model as it was associated with increased antioxidant response element reporter construct activity, Nrf2 target gene expression (metallothionein and glutathione reductase), and basal glutathione levels. Cisplatin resistance was associated with Nrf2 expression, and in RT112-CP cells, its depletion partially restored cisplatin sensitivity. We demonstrated increased cytoplasmic or nuclear Nrf2 expression or both in 32% of clinical bladder cancer samples compared with that in normal tissue samples. Expression of Nrf2 in bladder cancer following radical cystectomy was associated with unfavorable overall (median = 0.65 vs. 2.11 y, P = 0.045), bladder cancer-specific, and recurrence-free survival in those patients who also received neoadjuvant cisplatin-based chemotherapy but not in those treated with cystectomy alone.
CONCLUSIONS: Nrf2 overexpression in bladder cancer is associated with clinically relevant cisplatin resistance that is reversible in experimental models and should now be tested in prospective studies.
FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism.
Mol Cancer Res. 2014; 12(7):1042-54 [PubMed] Related Publications
IMPLICATIONS: Pharmacologic blockade of the molecular chaperone HSP90 represents a promising approach for treating bladder tumors driven by oncogenic gene rearrangements of FGFR3. Furthermore, UDP-glucuronosyltransferase enzyme expression may serve as a predictive factor for clinical response to resorcinol-based HSP90 inhibitors.
Defining and treating the spectrum of intermediate risk nonmuscle invasive bladder cancer.
J Urol. 2014; 192(2):305-15 [PubMed] Free Access to Full Article Related Publications
MATERIALS AND METHODS: The IBCG analyzed published clinical trials, meta-analyses and current clinical practice guidelines on intermediate risk nonmuscle invasive bladder cancer available as of September 2013. The definitions of intermediate risk, patient outcomes and guideline recommendations were considered, as were the limitations of the available literature and additional parameters that may be useful in guiding treatment decisions in intermediate risk patients.
RESULTS: Current definitions and management recommendations for intermediate risk nonmuscle invasive bladder cancer vary. The most simple and practical definition is that proposed by the IBCG and the AUA of multiple and/or recurrent low grade Ta tumors. The IBCG suggests that several factors should be considered in clinical decisions in intermediate risk disease, including number (greater than 1) and size (greater than 3 cm) of tumors, timing (recurrence within 1 year) and frequency (more than 1 per year) of recurrence, and previous treatment. In patients without these risk factors a single, immediate instillation of chemotherapy is advised. In those with 1 to 2 risk factors adjuvant intravesical therapy (intravesical chemotherapy or maintenance bacillus Calmette-Guérin) is recommended, and previous intravesical therapy should be considered when choosing between these adjuvant therapies. For those patients with 3 to 4 risk factors, maintenance bacillus Calmette-Guérin is recommended. It is also important that all intermediate risk patients are accurately risk stratified at initial diagnosis and during subsequent followup. This requires appropriate transurethral resection of the bladder tumor, vigilance to rule out carcinoma in situ or other potential high risk tumors, and review of histological material directly with the pathologist.
CONCLUSIONS: Intermediate risk disease is a heterogeneous category, and there is a paucity of independent studies comparing therapies and outcomes in subgroups of intermediate risk patients. The IBCG has proposed a management algorithm that considers tumor characteristics, timing and frequency of recurrence, and previous treatment. Subgroup analyses of intermediate risk subjects in pivotal EORTC trials and meta-analyses will be important to validate the proposed algorithm and support clear evidence-based recommendations for subgroups of intermediate risk patients.
Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11.
Clin Cancer Res. 2014; 20(7):1990-2000 [PubMed] Free Access to Full Article Related Publications
EXPERIMENTAL DESIGN: miRNA expression in paired cisplatin-resistant and -sensitive cell lines was measured. Dysregulated miRNAs were further studied for their ability to mediate resistance. The nature of the cisplatin-resistant phenotype was established by measurement of cisplatin/DNA adducts and intracellular glutathione (GSH). Candidate miRNAs were examined for their ability to (i) mediate resistance and (ii) alter the expression of a candidate target protein (SLC7A11); direct regulation of SLC7A11 was confirmed using a luciferase assay. SLC7A11 protein and mRNA, and miRNA-27a were quantified in patient tumor material.
RESULTS: A panel of miRNAs were found to be dysregulated in cisplatin-resistant cells. miRNA-27a was found to target the cystine/glutamate exchanger SLC7A11 and to contribute to cisplatin resistance through modulation of GSH biosynthesis. In patients, SLC7A11 expression was inversely related to miRNA-27a expression, and those tumors with high mRNA expression or high membrane staining for SLC7A11 experienced poorer clinical outcomes. Resistant cell lines were resensitized by restoring miRNA-27a expression or reducing SLC7A11 activity with siRNA or with sulfasalazine.
CONCLUSION: Our findings indicate that miRNA-27a negatively regulates SLC7A11 in cisplatin-resistant bladder cancer, and shows promise as a marker for patients likely to benefit from cisplatin-based chemotherapy. SLC7A11 inhibition with sulfasalazine may be a promising therapeutic approach to the treatment of cisplatin-resistant disease.
Assessment of the radiation-equivalent of chemotherapy contributions in 1-phase radio-chemotherapy treatment of muscle-invasive bladder cancer.
Int J Radiat Oncol Biol Phys. 2014; 88(4):927-32 [PubMed] Related Publications
METHODS AND MATERIALS: A standard logistic dose-response curve was fitted to data from radiation therapy-alone trials and then used as the platform from which to quantify the chemotherapy contribution in 1-phase radio-chemotherapy trials. Two possible mechanisms of chemotherapy effect were assumed (1) a fixed radiation-independent contribution to local control; or (2) a fixed degree of chemotherapy-induced radiosensitization. A combination of both mechanisms was also considered.
RESULTS: The respective best-fit values of the independent chemotherapy-induced complete response (CCR) and radiosensitization (s) coefficients were 0.40 (95% confidence interval -0.07 to 0.87) and 1.30 (95% confidence interval 0.86-1.70). Independent chemotherapy effect was slightly favored by the analysis, and the derived CCR value was consistent with reports of pathologic complete response rates seen in neoadjuvant chemotherapy-alone treatments of muscle-invasive bladder cancer. The radiation equivalent of the CCR was 36.3 Gy.
CONCLUSION: Although the data points in the analyzed radio-chemotherapy studies are widely dispersed (largely on account of the diverse range of chemotherapy schedules used), it is nonetheless possible to fit plausible-looking response curves. The methodology used here is based on a standard technique for analyzing dose-response in radiation therapy-alone studies and is capable of application to other mixed-modality treatment combinations involving radiation therapy.
Identification of mutations in distinct regions of p85 alpha in urothelial cancer.
PLoS One. 2013; 8(12):e84411 [PubMed] Free Access to Full Article Related Publications
Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging.
Cancer Res. 2014; 74(3):896-907 [PubMed] Related Publications
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