Muscle-invasive Cancer Research Articles

Beyond Cisplatin – I

Roughly 25% of patients at diagnosis of urothelial cancer (UC) have at least muscle invasive disease [1] and about half of these have extravesical extension or more advanced disease at that time. Additionally 10–15% of patients who initially have non-muscle invasive UC will subsequently develop muscle invasive or more advanced cancer. The outlook for patients with advanced or metastatic UC, particularly those who do not respond to Cisplatin-based combination chemotherapy regimens is very poor. Moreover, except in adjuvant and neoadjuvant settings, despite objective response rates to Cisplatin based combination therapies of about 50% [2] median survival is only about 15 months and time to progression far briefer, with 5 year survival only being about 15% [3]. Additionally, because of comorbidities and frailty, many patients with advanced UC cannot receive these Cisplatin containing regimens. Relapsing patients respond poorly to additional treatments with median survival of usually <10 months [4]. However two “new” approaches have appeared on the horizon to treat such patients which take advantage of great advances in molecular biology over the past 15 years which give some reason for optimism. The first is targeted molecular therapies which are tied to our increased understanding of urothelial cancer’s molecular and genetic makeup (as illustrated by The Cancer Genome Atlas [TCGA]) [5], and the second, is the emergence of immune checkpoint inhibitors as viable options for systemic treatment of UC. We will focus on the former in this Paper Alert, and will review new articles on the immune modulators in a later edition.

Molecular Subtypes of Non-muscle Invasive Bladder Cancer

In this issue of Cancer Cell, Hedegaard etal. report a comprehensive multi-center transcriptional analysis of non-muscle invasive urothelial bladder cancer. They describe three molecular subtypes similar to those seen in other cohorts, as well as a unique CIS signature associated with risk of progression to muscle invasive cancer.

Systemic therapy in muscle-invasive and metastatic bladder cancer: current trends and future promises.

Bladder urothelial cancers remain an important urologic cancer with limited treatment options in the locally advanced and metastatic setting. While neoadjuvant chemotherapy for locally advanced muscle-invasive cancers has shown overall survival benefit, clinical uptake in practice have lagged behind. Controversies surrounding adjuvant chemotherapy use are also ongoing. Systemic therapies for metastatic bladder cancer have largely used platinum-based therapies without effective standard second-line therapy options for those who fail, although vinflunine is approved in Europe as a second-line therapy based on a Phase III trial, and most recently, atezolizumab, a checkpoint inhibitor, was approved by the US FDA. Given increasing recognition of mutational signatures expressed in urothelial carcinomas, several promising agents with use of VEGF-targeted therapies, HER2-directed agents and immunotherapies with PD-1/PD-L1 antibodies in various settings are discussed herein.

Prognostic Significance of Neutrophilic Infiltration in Benign Lymph Nodes in Patients with Muscle-invasive Bladder Cancer

BackgroundPreclinical studies suggest that signal transducer and activator of transcription 3 (STAT3)-mediated recruitment of neutrophils to premetastatic tissue occurs prior to metastatic progression. ObjectiveWe sought to determine if neutrophilic infiltration in benign nodal tissue is associated with poor clinical outcome in patients with muscle-invasive bladder cancer. Design, setting, and participantsFormalin-fixed, paraffin-embedded tissue was secured from 55 patients with muscle-invasive bladder cancer who had undergone cystectomy at our institution. Sections of benign lymph nodes were obtained and stained with primary antibodies against 3-fucosyl-N-acetyl-lactosamine, phosphorylated STAT3, and interleukin-17, the latter being a key mediator of neutrophil infiltration and STAT3 activation. Outcome measurements and statistical analysisThe Kaplan–Meier method was used to interrogate differences in overall survival (OS) in patients with high versus low biomarker expression. Cohorts stratified by receipt and nonreceipt of neoadjuvant chemotherapy were separately explored. Results and limitationsOf the 55 patients examined, 19 patients (35%) had no prior neoadjuvant chemotherapy. Amongst these patients, median OS was improved in patients with low 3-fucosyl-N-acetyl-lactosamine+ cell counts (196 mo vs 37 mo; p=0.0062) and low phosphorylated STAT3+ cell counts (278 mo vs 106 mo; p=0.025). In the same cohort, a trend towards improved OS in patients with low interleukin-17+ cell count was observed (not reached vs 117 mo; p=0.18). No differences in OS were noted in biomarker-based subgroups amongst patients that had received prior neoadjuvant chemotherapy. ConclusionsThe results herein support the hypothesis that bladder cancer metastasis may be driven by STAT3-mediated neutrophilic infiltration in premetastatic sites. Validation of these findings using tissues derived from a phase 3 surgical trial (Southwest Oncology Group 1011) is currently underway. Patient summaryLymph node metastases occur in up to 25% of patients with muscle-invasive cancer and it represents one of the most frequent sites of bladder cancer metastasis. This report provides preliminary evidence that neutrophil levels in benign lymph nodes may predict clinical outcome.

Renal Function Preserved in Bladder-sparing Treatment for Muscle-Invasive Cancer

Renal Function Preserved in Bladder-sparing Treatment for Muscle-Invasive Cancer

Clinical Evaluation of Cisplatin Sensitivity of Germline Polymorphisms in Neoadjuvant Chemotherapy for Urothelial Cancer

BackgroundLevel 1 evidence has demonstrated increased overall survival with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive urothelial cancer. Usage remains low, however, in part because neoadjuvant chemotherapy will not be effective for every patient. To identify the patients most likely to benefit, we evaluated germline pharmacogenomic markers for association with neoadjuvant chemotherapy sensitivity in 2 large cohorts of patients with urothelial cancer. Patients and MethodsPatients receiving neoadjuvant cisplatin-based chemotherapy for muscle-invasive urothelial cancer were eligible. Nine germline single nucleotide polymorphisms (SNPs) potentially conferring platinum sensitivity were tested for an association with a complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (<pT2). ResultsThe data from 205 patients were analyzed—59 patients were included in the discovery set and 146 in an independent replication cohort—from 3 institutions. The stage pT0 (26%) and < pT2 (50%) rates were consistent across the discovery and replication populations. Using a multivariate recessive genetic model, rs244898 in RARS (odds ratio, 6.8; 95% confidence interval, 1.8-28.9; P = .006) and rs7937567 in GALNTL4 (odds ratio, 4.8; 95% confidence interval, 1.1-22.6; P = .04) were associated with pT0 in the discovery set. Despite these large effects, neither were associated with achievement of pT0 in the replication set. A third SNP, rs10964552, was associated with stage < pT2 in the discovery set but also failed to replicate. ConclusionGermline SNPs previously associated with platinum sensitivity were not associated with the neoadjuvant chemotherapy response in a large replication cohort of patients with urothelial cancer. These results emphasize the need for replication when evaluating pharmacogenomic markers and demonstrate that multi-institutional efforts are feasible and will be necessary to achieve advances in urothelial cancer pharmacogenomics.

Rôle de la chimiothérapie dans le cancer de la vessie

The management of bladder cancer, initially exclusively surgical, was recently improved by the development of chemotherapy. Chemotherapy can thus be proposed as bladder instillations in order to prevent recurrences of non-muscle-invasive cancer (NMIC), and systemically in case of muscle-invasive cancer (MIC). Chemotherapy can then be administered prior to surgery (neoadjuvant), as a complement to surgery (adjuvant), as an alternative to surgery as part of a multimodality treatment, and alone in palliative intent in case of metastatic cancer. Renal function and general health status of the patient help the decision-making and the choice of the chemotherapy regimen, which should be validated during a multidisciplinary meeting and presented to the patient during a dedicated medical and paramedical appointment.

Significance of the interval between first and second transurethral resection on recurrence and progression rates in patients with high-risk non-muscle-invasive bladder cancer treated with maintenance intravesical Bacillus Calmette-Guérin.

To evaluate the effect of the interval between the initial and second transurethral resection (TUR) on the outcome of patients with high-risk non-muscle-invasive bladder cancer (NMIBC) treated with maintenance intravesical Bacillus Calmette-Guérin (BCG) therapy. We reviewed the data of patients from 10 centres treated for high-risk NMIBC between 2005 and 2012. Patients without a diagnosis of muscle-invasive cancer on second TUR performed ≤90days after a complete first TUR, and received at least 1year of maintenance BCG were included in this study. The interval between first and second TUR in addition to other parameters were recorded. Multivariate logistic regression analysis was used to identify predictors of recurrence and progression. In all, 242 patients were included. The mean (sd, range) follow-up was 29.4 (22.2, 12-96)months. The 3-year recurrence- and progression-free survival rates of patients who underwent second TUR between 14 and 42days and 43-90days were 73.6% vs 46.2% (P < 0.001) and 89.1% vs 79.1% (P = 0.006), respectively. On multivariate analysis, the interval to second TUR was found to be a predictor of both recurrence [odds ratio (OR) 3.598, 95% confidence interval (CI) 1.885-8.137; P = 0.001] and progression (OR 2.144, 95% CI 1.447-5.137; P = 0.003). The interval between first and second TUR should be ≤42days in order to attain lower recurrence and progression rates. To our knowledge, this is the first study demonstrating the effect of the interval between first and second TUR on patient outcomes.

MP45-05 TO DISEASE: THE POTENTIAL OF AVOIDING CYSTECTOMIES THROUGH MIRNA PROFILES IN CELL-FREE URINE

INTRODUCTION AND OBJECTIVES: Neoadjuvant chemotherapy prior to radical cystectomy has been shown to confer a survival advantage in patients with muscle-invasive bladder cancer. When combined with maximal endoscopic resection of visible tumor, 38% of patients can be rendered pathologic stage 0 (pT0) at the time of cystectomy. Previous studies have shown differential expression of microRNA (miRNA) in the cell-free urine of patients with muscle invasive and non-muscle invasive bladder cancer. We aimed to identify miRNA in the urine of patients with a history of invasive bladder cancer and differentiating patients with a complete response to therapy from those with persistent disease. METHODS: Total RNA was isolated from cell-free urine of patients undergoing cystectomy for muscle-invasive cancer (pT0, pT1, and >pT2), cT0 patients on active surveillance with a history of muscle invasive disease, as well as healthy control samples (HC) from patients with no history of cancer. Patient samples were divided into four groups: HC (n1⁄413), pT0/cT0 (n1⁄417), pT1 (n1⁄49) and pT2 (n1⁄423), consistent with the pathologic tumor stage of the specimen at the time of TURBT or surgery. Pooled RNA isolates from each group were profiled via PCR array of 751 miRNA (Exiqon). MiRNA expression levels were validated on individual samples by qRT-PCR. RESULTS: The number of miRNA detected within each group correlated with the severity of disease where 391 miRNAs were detected in the pT2 group, 137 in the pT1 group, 124 in the pT0/cT0 group, and 73 among the HCs. Hierarchical cluster analysis revealed two main branches; one consisting of the HC and pT0/cT0 pools and the other comprised of the pT1 and pT2 pools. Additionally, 32 miRNA were expressed in the pT1 and pT2 pools, and not detected in the pT0/ cT0 and HC pools. qRT-PCR confirmed differential expression of several miRNA distinguishing the two clustered groups (p<0.05). CONCLUSIONS: This study identified miRNA in cell-free urine differentiating patients with evidence of bladder cancer from those without evidence of disease (pT0/cT0). This miRNA profile may aid in the development of a noninvasive method of confirming response to neoadjuvant therapies, and may provide an adjunct to expectant management and surveillance strategies for the treatment of bladder cancer.

MP11-15 DEVELOPMENT OF A TARGETED GADOLINIUM CONTRAST FOR NONINVASIVE OF MAGNETIC RESONANCE (MR) IMAGING OF NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyImaging/Radiology: Uroradiology II1 Apr 2015MP11-15 DEVELOPMENT OF A TARGETED GADOLINIUM CONTRAST FOR NONINVASIVE OF MAGNETIC RESONANCE (MR) IMAGING OF NON-MUSCLE INVASIVE BLADDER CANCER Joel Slaton, Carole Davis, Nataliya Smith, Debbie Saunders, Paul Hauser, Robert Hurst, and Rheal Towner Joel SlatonJoel Slaton More articles by this author , Carole DavisCarole Davis More articles by this author , Nataliya SmithNataliya Smith More articles by this author , Debbie SaundersDebbie Saunders More articles by this author , Paul HauserPaul Hauser More articles by this author , Robert HurstRobert Hurst More articles by this author , and Rheal TownerRheal Towner More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.396AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Development of methods to noninvasively detect bladder cancer and eliminate cystoscopy remains the golden ring of urology research. While muscle invasive cancer is relatively easily imaged with standard CT and MRI technology, the ability to image non-muscle invasive bladder cancer (NMIBC) in a noninvasive manner remains a challenge. We report our experience with a tumor-targeted gadolinium contrast agent for MR imaging NMIBC. METHODS The peptide ligand (CSNRDARRC) has previously been reported as having strong specificity for urothelial cancer. The peptide linked to a FITC was tested against a panel of human and rodent malignant and benign urothelial cell lines and imaged fluorescently. The peptide ligand was then conjugated to Gadolinium-DOTA (Gd). The linked Gd-ligand was studied in vitro against urothelial cell lines and compared to a scrambled peptide linked to Gd and visualized with MRI. The linked Gd-ligandide ligand was delivered intravesically into a murine model of non-muscle invasive bladder cancer for 90 minutes and then washed clear with saline and then imaged with MR. This approach was repeated using a intravenous (IV)delivery and renal filtering into the bladder to image the surface cancer. Intravenous delivery was also used to image the same tumor growing in the subcutis of the mouse. RESULTS The FITC-ligand reproducibly bound to the surface of the various cancer lines but no to the benign immortalized urothelial and nonurothelial cell lines increasing fluorescence in cells 2.5-fold. The ligand-linked Gd was bound to the cancer cell growing in vitro increasing “MR signal” by 300% compared to scramble peptide-linked Gd. Intravesically delivered ligand-linked Gd successfully bound to the surface tumor and allowed for easy imaging for up to 6 hours after infusion. Similar results were found when the ligand-linked Gd was delivered intravenously and imaged 12–24 hour later. CONCLUSIONS Cancer targeted Gd can be delivered intravesically and intravenously to allow for enhanced MR imaging of superficial bladder cancer. This approach may be first step toward MR-based noninvasive surveillance of the bladder for recurrent non-muscle invasive cancer. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e125 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joel Slaton More articles by this author Carole Davis More articles by this author Nataliya Smith More articles by this author Debbie Saunders More articles by this author Paul Hauser More articles by this author Robert Hurst More articles by this author Rheal Towner More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Adjuvant Cisplatin-Based Chemotherapy for High-Risk Bladder Cancer

Level 1 evidence supports the role of cisplatin-based neoadjuvant chemotherapy for patients undergoing cystectomy for muscle-invasive transitional cell cancer of the bladder. However, the use of adjuvant chemotherapy remains attractive to many clinicians given that patients are often referred following cystectomy. To evaluate the effectiveness of adjuvant versus deferred cisplatin-based chemotherapy following cystectomy, European investigators conducted an intergroup, phase III, randomized, open-label study involving …

Editorial Comment

The report by Byler et al 1 Byler T.K. Reeder J. Nsouli I. Incidental computed tomographic bladder wall abnormalities: harbinger or herring?. Urol. 2015; 85: 288-291 Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar on the incidence of transitional cell carcinoma of the bladder in patients with incidental radiologic finding of bladder wall thickening on computerized tomography (CT) scan in the absence of hematuria and gross or microscopic or positive urine cytology is significant and timely. The results are sobering. More than 15% of these patients have bladder cancer, and nearly 9% have high-grade or muscle invasive cancer. Worth noting that in none of the study patients with radiologic finding of focal thickening in the bladder (n = 15) had any type of bladder cancer. On the other hand, patients with diffuse thickening of the bladder wall or intraluminal mass had 31.5% (6 of 19) incidence of bladder cancer, and of these, 15.7% (3 of 19) were high-grade or muscle-invasive cancers. Incidental Computed Tomographic Bladder Wall Abnormalities: Harbinger or Herring?UrologyVol. 85Issue 2PreviewTo evaluate the outcomes of incidental radiographically identified bladder wall abnormalities in the absence of other urologic indications for evaluation. Full-Text PDF ReplyUrologyVol. 85Issue 2PreviewWe appreciate the interest and the comments regarding our work. With widespread use of imaging, incidental findings and evaluation of these findings has become more common in numerous disciplines. This series seeks to give evidence to the workup involved for incidental thickened bladder wall after exclusion of established “high-risk” patients. These high-risk patients include those with hematuria, bladder cancer, or previous radiation. Our survey of patients yielded unexpected results. Our initial thoughts were that the elimination of cystoscopy from this evaluation could save time, morbidity, and money. Full-Text PDF

Molecular Assessment of Non-Muscle Invasive and Muscle Invasive Bladder Tumors: Mapping of Putative Urothelial Stem Cells and Toll-Like Receptors (TLR) Signaling

Purpose: The main objectives of this study were to characterize and compare the urothelial stem cells (healthy and cancer cells) and TLRs features in the urinary bladder of men without lesionsand with non-muscle-invasive and muscle invasive urothelial tumors. Materials and Methods: Thirty samples of the urinary bladder of 50 to 80-year-old men, with and without diagnosis of malignant urothelial lesions were used. The 30 samples were divided into 3 groups (n = 10 per group): Normal Group; Non-Muscle Invasive Bladder Cancer Group; Muscle Invasive Bladder Cancer Group. The samples were histopathologically and immunohistochemically analyzed. The study was conducted at teaching Hospital of the University of Campinas (UNICAMP). Results: The CD44 and CD133 immunoreactivities were significantly intense in the muscle-invasive cancer group when compared to the other groups. The ABCG2 biomarker demonstrated intense immunoreactivities in both non-muscle and muscle invasive groups, and absent immunoreactivity in the normal group. All groups showed weak CD117 immunoreactivity. Putative Healthy Stem Cells (CD44/CD133/ CD117+) occurred in all groups. Putative Cancer Stem Cells (CD44/CD133/ABCG2+) only occurred in the non-muscle and muscle invasive cancer groups. TLR2 immunoreactivity was significantly lower in the non-muscle invasive cancer group and absent in the muscle invasive cancer group. TLR4 immunoreactivity was significantly lower in both cancer groups. Conclusions: This study leads us to the conclusion that putative cancer stem cell occurrence was sensitive to the decreased in TLR2 and TLR4 immunoreactivities. Also, TLR2 and TLR4 demonstrated their involvement in the regulation of the different biomarkers for putative healthy and cancer urothelial stem cells, probably acting as negative regulators of urothelial carcinogenesis. Taken together data obtained suggest that use of TLRs agonists could be a promising alternative for the treatment of non-muscle and muscle invasive bladder tumors.

Timing of radical cystectomy in Central Europe - multicenter study on factors influencing the time from diagnosis to radical treatment of bladder cancer patients.

IntroductionTime that passes between an unfavourable diagnosis to a radical cystectomy (RC) affects oncological outcomes in patients with bladder cancer. Unsatisfactory survival of patients after RC in Central Europe can potentially result from this factor.Material and methodsThe aim of this study was to assess the time interval between transurethral resection of the bladder tumor (TURBT) and RC in Central Europe and to identify clinical factors of possible delays. 941 consecutive patients who underwent RC in nine Central European urological centers were enrolled into the study. After the TURBT–RC time was calculated, selected clinical and pathological parameters were tested as potential factors influencing the timing of RC.ResultsOn average, RCs were performed 73.8 days after TURBTs (median – 53, range 0–1587). In 238 patients (25.3%) the time exceeded 12 weeks. Patients with muscle–invasive cancer were operated earlier on than patients with nonmuscle–invasive cancer (67.6 vs.105.2 days, RR = 1.41, p = 0.00). In high volume centers (>30 RC per year) longer TURBT–RC intervals were observed (97.6 vs. 66.3 days, RR = 2.49, p = 0.00). Simultaneously, factors such as female sex (RR = 1.21), more advanced age of patient (>65 years, RR = 1.23), presence of concomitant CIS (RR = 2.43), grade of cancer cells (RR = 1.67) and final post–RC stage (RR = 1.51) had no statistically significant effect on the results (p >0.05).ConclusionsThe mean time interval between the diagnosis and radical treatment of patients with bladder cancer in Central Europe is adequate. However, there are still a relatively high number of patients waiting for radical cystectomy longer than 8 weeks. A lower stage of disease as well as a higher case load within of a hospital may delay the surgery.

MALDI imaging–based identification of prognostically relevant signals in bladder cancer using large-scale tissue microarrays

ObjectiveAlthough most patients with urinary bladder cancer present with noninvasive and low-malignant stages of the disease, about 20% eventually develop life-threatening metastatic tumors. This study was designed to evaluate the potential of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify molecular markers predicting the clinical course of bladder cancer. Materials and methodsWe employed MALDI-MSI to a bladder cancer tissue microarray including paraffin-embedded tissue samples from 697 patients with clinical follow-up data to search for prognostically relevant associations. ResultsAnalysis of our MALDI imaging data revealed 40 signals in the mass spectra (m/z signals) associated with epithelial structures. The presence of numerous m/z signals was statistically related to one or several phenotypical findings including tumor aggressiveness (stage, grade, or nodal status; 30 signals), solid (5 signals) or papillary (3 signals) growth patterns, and increased (6 signals) or decreased (12 signals) cell proliferation, as determined by Ki-67 immunohistochemistry. Two signals were linked with tumor recurrence in noninvasive (pTa category) tumors, of which one was also related to progression from pTa-category to pT1-category disease. The absence of one m/z signal was linked with decreased survival in the subset of 102 muscle-invasive cancers. ConclusionOur data demonstrate the suitability of combining MSI and large-scale tissue microarrays to simultaneously identify and validate clinically useful molecular markers in urinary bladder cancer.

Reduced membranous MET expression is linked to bladder cancer progression

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.

The impact of real-time 3d imaging by ultra-high speed optical coherence tomography in urothelial carcinoma

BackgroundOptical coherence tomography (OCT) has become a promising diagnostic tool in many medical fields. In particular, noninvasive real-time optical biopsy of internal organs is one of the most attractive applications of OCT, enabling in situ diagnosis of carcinoma at an early stage. We used an ultra-high speed OCT system for real-time three-dimensional (3D) imaging of three excised specimens of advanced urothelial carcinoma (UC) and investigated the association of the images with results from histopathological examination.Case presentationsCase 1 was a 69-year-old man underwent radical cystectomy for muscle-invasive UC (pT2). Case 2 was a 53-year-old man underwent laparoscopic nephroureterectomy and partial cystectomy for left ureter carcinoma (pT2) and case 3 was a 77-year-old woman underwent radical cystectomy for advanced bladder carcinoma (pT3b). Real-time 3D OCT images of normal bladder wall and ureter showed three layers, including the urothelium, lamina propria, and muscularis layer. In contrast, normal structure was not seen in the muscle-invasive UC area or the scar tissue area.ConclusionsThis study highlighted a new diagnostic method with potential application for UC diagnosis. We will investigate more cases in the future and expect improvement in the diagnosing efficiency of carcinoma in situ or organ-confined muscle-invasive cancer by cystoscopy or ureteroscopy with ultra-high speed OCT.

High morbidity and mortality found for high‐risk, non–muscle‐invasive bladder cancer

High morbidity and mortality found for high‐risk, non–muscle‐invasive bladder cancer

Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS).

4530 Background: Neoadjuvant (NA) ddMVAC in patients (pts) with MI-UC is associated with significant pathologic response (PaR) and radiologic response (RaR). We examined the frequency of PaR and RaR as well as the level of serum and tissue biomarkers in correlation with DFS. Methods: Pts treated on phase II prospective study of NA ddMVAC (4 cycles) in MI-UC were evaluated for RaR (at least &gt;50% decrease in the primary tumor and nodes after chemotherapy, with delayed enhancement of residual disease) and PaR (p&lt;T1N0M0). Elevated serum tumor markers (CA125, C19-9 and ßHCG) at baseline and Day 1 of each cycle were documented. Expression level of baseline DNA ERCC1 protein in tumor biopsy tissues was determined by immunohistochemistry based on H-score &lt;0.1 (negative) vs. &gt;0.1 (positive). Fisher’s Exact test was used to evaluate association with response. Post-surgery DFS was estimated by the Kaplan-Meier method and compared between response and biomarker groups using the logrank test. Results: Of 39 pts (cT2:42%, cT3:42%, cT4:16%, and cN1:45%), 49% (90% CI 35-63) experienced PaR, and 62% (90% CI 47-75) achieved RaR after ddMVAC chemotherapy. Pts who achieved PaR experienced a DFS advantage, with 18-month DFS of 78% (95% CI 47-92) vs. 48% (95% CI 18-74) in those who did not (p=0.146). Those achieving RaR had a significantly longer DFS (p=0.006), with 18-month DFS of 87% (95% CI 57-97) vs. 29% (95% CI 5-60) in those who did not. Among 10 pts with any elevated serum tumor marker at baseline, only 2 pts showed normalization, both without a PaR. ERCC1(+) tumors were not associated with PaR, pT0 or RaR. DFS by ERCC1status was inconclusive due to limited sample size. 18-month DFS was 91% (95% CI 51-99) in ERCC1(+) tumors vs. 63% (95% CI 29-85) in ERCC1(-) tumors. Conclusions: ddMVAC achieves significant PaR and RaR in MI-UC pts that translates into a post-surgery DFS advantage. ERCC1(+) was not associated with response. More effective biomarkers of platinum response are needed to select pts most likely to benefit from NA therapy. Clinical trial information: NCT00808639.

Gene expression profiling in bladder cancer to identify potential therapeutic targets.

4518 Background: Characterization of gene expression patterns in bladder cancer (BC) allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Methods: Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Results: Hierarchical clustering defined signatures, which differentiated between cancer and normal, muscle-invasive or non-muscle invasive cancer and normal, g1 and g3. Pathways associated with cell cycle and proliferations were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer as compared to normal tissue. Conclusions: This study contributes to a growing body of work on gene expression signatures in BC. The data support an important role for osteopontin in BC, and identify several pathways worthy of further investigation. [Table: see text]