Bladder Tumor Recurrence Research Articles

Could basic research shed light on false positivity in photodynamic diagnosis?

Accumulating evidence has suggested that photodynamic diagnosis (PDD) using new optical imaging agents (5-aminolevlinic acid [5-ALA] or hexaminolevulinate [Hexvix]) has an advantage detecting the flat tumor of the bladder, especially carcinoma in situ, or tiny papillary tumors, which might be overlooked by conventional white-light cystoscopy.1 Recent randomized controlled trials have shown that PDD-assisted transurethral resection of bladder tumors (TURBT) yields better clinical outcomes in terms of progression-free survival than conventional TURBT.2 Most readers might have simple questions about PDD. How does is the red fluorescence imaging generated from cancer tissue? How is the optical imaging agent administered, and accumulated specifically, if true, in the tumor? Are there any adverse effects (AE) including photosensitivity? Intravesically or orally administered 5-ALA is uptaken to cells by active transport and incorporated into mitochondria. As ferrochelatase, a key enzyme of final process of heme synthesis, is inherently absent in tumor cells, an intermediary metabolite (protoporphirin IX [PPIX]) is specifically accumulated in tumor cells. Dysfunction of the transporter gene, which acts as a efflux pump of PPIX in tumor cells, might accelerate the specific accumulation of the agent.3 Regarding AE of 5-ALA, no severe photosensitivity, which is a common and severe AE of the conventional optical imaging photosensitizer, have been reported. As 5-ALA is not approved by Japan, a multi-institutional prospective phase I/II study is in progress as the investigator initiated clinical trial. One of the drawbacks of PDD, however, is a relatively higher false positive rate. Although red fluorescence is theoretically generated only from tumor cells, false positive fluorescence is often encountered in the clinical setting, leading to lowering specificity to 50–60% in the literature. Why does false red fluorescence take place? One of the possible reasons is an optical artifact as a result of tangential observation. Artifact is often observed at the bladder neck and prostatic urethra. Other possibilities have been reported to result from cystitis, squamous metaplasia, mild to moderate dysplasia, or hyperplasia. Can all false positivity be ignored as a non-cancerous phenomenon? It is well known that urothelial tumor is chronologically or spatially multifocal as a result of harboring either a field defect, or dissemination of the clonally-selected cancer cell. Non-random gene alterations have been reported to occur frequently at chromosomes 7, 9 and 17, and those alterations strongly affect patient outcome in bladder cancer. We hypothesized that false positive bladder mucosa might harbor premalignant lesion (Fig. 1).4 Lengauer et al. postulated the concept of chromosomal instability, which is evaluated by a higher aberrant fraction of the copy number, a non-modal fraction of the copy number distribution in each chromosome.5 The aberrant fraction of chromosome 9 by fluorescence in situ hybridization analysis was significantly higher in false positive fluorescent mucosa than that in the non-fluorescent counterpart. Array comparative genomic hybridization using established bladder cancer cell lines showed 9p24.1 to be a commonly deleted region for fluorescent positive cell lines.4 Hartmann et al. reported that the deletion of p53 was highly associated with chromosome 9 alterations in the flat urothelial lesions detected by fluorescent cystoscopy.6 Other investigators reported a close association between chromosome 9 alterations and fluorescent mucosa. A phase III randomized controlled trial proved that PDD-guided transurethral resection, with the resection of all visible fluorescent mucosae, yielded a statistically higher progression-free survival than did conventional transurethral resection.2 The study suggests that an incomplete resection, or ignoring the fluorescent mucosa with PDD except for optical artifacts, might thus leave a potential source for bladder tumor recurrence. Case presentation. 56 years, Male 2003/10/31 First presentation, Pathology: TCC, G2, pTa. 2006/4/26 Recurrence. (a) Representative case of positive of photodynamic diagnosis. Normal looking mucosa by white-light (conventional) cystoscopy. (b) Photodynamic diagnosis showing irregular red fluorescence, (c) Molecular cytogenetic by fluorescence in situ hybridization analysis showing a higher variant fraction of chromosome 9. Arrow: chromosome 9 monosomy. The pathological diagnosis was mild dysplasia. Could basic research shed light on false positivity of PDD? Yes, such false positive mucosa by PDD might be a potential reason for exploring the mechanism of oncogenesis in urothelial cancer. None declared.

Abstract 4023: Genome-wide analysis of CpG island methylation identified OTX1, OSR1 and ONECUT2 as biomarkers for recurrent bladder cancer detection in voided urine

Abstract Cancers of the urinary bladder (BC) present as muscle-invasive (MIBC) or non-muscle invasive (NMIBC). Major problems with NMIBC are that 70% of the tumors will recur and 10-20% will eventually progress to MIBC. Therefore the patients are monitored by cystoscopy every 3-6 months after transurethral resection of the tumor in order to spot potential recurrences. DNA methylation has been shown to contribute to the pathogenesis cancer and may serve as useful biomarker. Recent studies showed promising urine methylation biomarkers for BC, but none of these were specifically tested for detection of recurrent BCs which are often smaller and hence more difficult to detect than primary tumors. Therefore we aimed to develop an assay specific for the diagnosis of recurrent bladder tumors in voided urine. From our earlier genome-wide study, we selected 8 candidate CGIs (CpG islands) methylated in BC to screen for the detection of recurrent bladder tumors in voided urine. We first screened these 8 CGIs on an independent set of 50 FFPE bladder tumors and 70 urines from age matched individuals without any history of BC as controls using BS-SNaPshot (Bisulfite specific single nucleotide primer extension assay). Subsequently, the 8 CGIs were investigated in a test set of 100 preTUR (before Trans Urethral Resection) urines associated with a concomitant recurrent tumor. We analyzed the sensitivity, specificity, AUC (area under the curve), PPV and NPV of all the individual markers and five best combinations. We then validated this on a separate cohort of 100 preTUR urines samples. Single marker OTX1 identified recurrent bladder tumors in voided urine with a sensitivity of 71% at a specificity of 90% with an AUC of 0.85 (CI: 0.80-0.91, P<0.0001). A 3 gene methylation panel OTX1, ONECUT2 and OSR1 showed a sensitivity of 73% at a specificity of 90% with an AUC of 0.86 (CI: 0.80-0.91, P< 0.0001). Combining this 3-gene panel methylation assay with FGFR3 (fibroblast growth factor receptor 3) mutation assay achieved a sensitivity of 78% at a specificity of 90% with an AUC of 0.87 (CI: 0.82-0.93, P< 0.0001). This panel of markers showed a sensitivity of 100% in detecting bladder tumor tissue DNA. These markers were also investigated on 40 urines collected from patients who are recurrence free for a period of longer than 6 months. A total of 9/40 (22%) urines were positive in these recurrence free patients. The lower specificity of these samples could be due to the anticipatory effect that has been attributed to urine tests, i.e. urines test sees the tumor earlier than cystocopy. We also observed that multiple tumors from a patient are highly concordant in their methylation percentage, which underlines the usefulness of the markers. In summary the panel biomarkers that are identified will be able to detect the recurrent bladder tumors in voided urine, thereby helping in surveillance of patients with bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4023. doi:1538-7445.AM2012-4023

1274 NONINVASIVE TEST FOR DIAGNOSIS AND AGGRESSIVENESS ASSESSMENT OF BLADDER CANCER: VALIDATION STUDY

You have accessJournal of UrologyBladder Cancer: Detection and Screening1 Apr 20121274 NONINVASIVE TEST FOR DIAGNOSIS AND AGGRESSIVENESS ASSESSMENT OF BLADDER CANCER: VALIDATION STUDY Lourdes Mengual, Maria J. Ribal, Juan J. Lozano, Mercedes Ingelmo-Torres, Moises Burset, Pedro L. Fernandez, and Antonio Alcaraz Lourdes MengualLourdes Mengual Barcelona, Spain More articles by this author , Maria J. RibalMaria J. Ribal Barcelona, Spain More articles by this author , Juan J. LozanoJuan J. Lozano Barcelona, Spain More articles by this author , Mercedes Ingelmo-TorresMercedes Ingelmo-Torres Barcelona, Spain More articles by this author , Moises BursetMoises Burset Barcelona, Spain More articles by this author , Pedro L. FernandezPedro L. Fernandez Barcelona, Spain More articles by this author , and Antonio AlcarazAntonio Alcaraz Barcelona, Spain More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1606AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cystoscopy and cytology, the standard methods used to detect and monitor bladder urothelial cell carcinoma (UCC), are invasive or present low sensitivity. The objective of the present work was to validate the performance of our previously reported noninvasive test for bladder cancer diagnosis and prediction of disease aggressiveness based on the gene expression patterns of urine, in an independent set of samples. METHODS The previously reported 12+2 gene expression signature was validated using an independent set of 207 urines; 96 urines from patients subjected to transurethral resection of the bladder for a primary or recurrent bladder tumour and with histologically confirmed tumours ( 35 Ta, 35 T1, 21 T2-T4, 4 Tis and 1 Tx) and 111 control urine samples from patients with non neoplasic urological disease. For the prediction of UCC tumour aggressiveness, tumour samples were grouped as high grade (HG, n=63) and low grade (LG, n=32). RNA was extracted from urine samples and was reverse transcribed and pre-amplified using standard protocols. Subsequently, target cDNAs were amplified in singleplex reactions using TaqMan Arrays. Data normalization was carried out with the geometric average of the measured CT of the two reference genes (GUSB and PPIA). Logistic regression was used to assess the performance of the 12+2 gene signature in the independent validation set of samples. RESULTS The SN and SP of the signature in the validation set were 80% and 86%, respectively (AUC: 0.914). As in the training set of samples, SN increases through the UCC risk groups, being lower in low risk non muscle invasive bladder cancer and achieving 100% in muscle invasive bladder cancer. The overall SN and SP for discriminating urine from HG and LG UCC patients in the validation set of samples was 75% and 75%, respectively (AUC: 0.83). The overall accuracy for diagnosis and prognosis in the independent validation set was 84% and 75%, respectively. CONCLUSIONS This validation study strongly supports the feasibility of using a urine-based gene expression signature as an accurate tool in the assessment of bladder cancer. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e516 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lourdes Mengual Barcelona, Spain More articles by this author Maria J. Ribal Barcelona, Spain More articles by this author Juan J. Lozano Barcelona, Spain More articles by this author Mercedes Ingelmo-Torres Barcelona, Spain More articles by this author Moises Burset Barcelona, Spain More articles by this author Pedro L. Fernandez Barcelona, Spain More articles by this author Antonio Alcaraz Barcelona, Spain More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Efficacy of postoperative three-dimensional conformal radiotherapy in transitional cell carcinoma of the renal pelvis or ureter

Objective To evaluate the role of postoperative three-dimensional conformalradiotherapy (3DCRT) in transitional cell carcinoma of the renal pelvis or ureter. Methods Weretrospectively reviewed a series of 103 patients with transitional cell carcinoma of the renal pelvis or ureter.All patients received surgery without distant metastases and had T3 or T4 disease, or grade 3 disease if T2.No patient received chemotherapy. Thirty-seven patients received three-dimensional conformal radiotherapy(3DCRT) following surgery. Sixty-six patients received surgery alone. The local control rates and survivalrates were calculated by Kaplan-Meier method and compared by Logrank test in univariate analysis. Coxregression was used for multivariate analysis. Results The follow-up rates were 89％ and 92％ in surgeryalone and 3DCRT groups. The number of patients who had minimal followed-up time of 5 years were 33 ,37in surgery alone and 3DCRT groups. The 1-,3-, and 5-year local control rates were 89％ vs. 94％ , 74％vs. 90％ , and 72％ vs. 90％ in surgery alone and 3DCRT groups, respectively ( X2 = 3. 90 , P = 0. 048) .The 1-,3-, and 5-year bladder tumor-free survival rates were 87％ vs. 94％ , 60％ vs. 79％ , and 57％ vs.79％ in surgery alone and 3DCRT groups, respectively ( X2 = 4. 50, P = 0. 037) . The 1-,3-, and 5-yearoverall survival rates were 90％ vs. 84％ , 71％ vs. 65％ , and 65％ vs. 62％ in surgery alone and 3DCRTgroups, respectively ( X2 = 0. 32, P = 0. 573 ) . Univariate and multivariate analyses showed that T stage,lymph node metastasis , positive surgical margin were correlated with overall survival rate ( x2 =7. 91 ,64. 69 ,40. 20 and 5. 08 , 17. 23 , 8. 22 , P = 0. 005 ,0. 000 ,0. 000 and 0. 024 , 0. 000 , 0. 004 ) . Conclusions 3DCRTmay improve local control and reduce tumor recurrence in bladder in patients with locally advancedtransitional cell carcinoma of the renal pelvis or ureter. However, 3DCRT does not improve overall survivalin this group of patients. Key words: Renal pelvis ureter neoplasms/surgery; Renal pelvis ureter neoplasms/three-dimensional conformal radiotherapy; Prognosis

National Practice Patterns for Immediate Postoperative Instillation of Chemotherapy in Nonmuscle Invasive Bladder Cancer

We assessed the use of intravesical postoperative chemotherapy among United States urologists in patients with nonmuscle invasive bladder cancer. A national sample of United States based urologists (259) retrospectively assessed their practice patterns involving intravesical postoperative chemotherapy after transurethral resection in patients with nonmuscle invasive bladder cancer. These urologists reviewed the medical records of their last 4 patients with nonmuscle invasive bladder cancer, and completed a case report form for specific demographic, pathological and treatment information. Selection criteria included the pathological and patient factors of histologically confirmed diagnosis of nonmuscle invasive bladder cancer-transitional cell carcinoma, completion of initial treatment plan with ongoing observation, candidate for or recipient of intravesical therapy, and no ongoing initial intravesical induction therapy. Overall the participation rate among those sampled was 61%. Of the 1,010 eligible patients with nonmuscle invasive bladder cancer 59.6% received instillation therapy during the initial treatment, of whom 28.4% (16.9% of patients overall) received intravesical postoperative chemotherapy. Primary, low risk patients most often received intravesical postoperative chemotherapy and 90.4% of the time patients received immediate instillation within 12 hours of surgery. However, of the urologists surveyed 66% never used intravesical postoperative chemotherapy, 17% used intravesical postoperative chemotherapy half (50%) of the time and only 2% used intravesical postoperative chemotherapy all (100%) of the time. Wide variation in the use of intravesical postoperative chemotherapy exists among urologists in the United States. The reason for the great diversity in the use of intravesical postoperative chemotherapy is speculative. However, physician awareness, physician bias, recurrence risk, and local pharmacy and hospital practice factors are all likely contributing factors.

Simultaneous transurethral resection of a bladder tumor and benign prostatic hyperplasia: Four case reports and literature review

To evaluate the recurrence of a bladder tumor on the prostate fossa and bladder neck in patients undergoing simultaneous transurethral resection of a bladder tumor (TUR-BT) and benign prostatic hyperplasia (BPH) in our hospital, we retrospectively studied four patients who underwent simultaneous TUR-BT and transurethral resection of the prostate (TUR-P) in 2001 to 2004. The pathology was confirmed histologically to be transitional cell carcinoma of the bladder tissue or atypia cells and BPH. Two patients had bladder tumor recurrence at 18 and 33 months during the postoperative follow-up period (10–36 months, with a mean of 18.5 months). One at the bladder neck recurred 33 months postoperatively, and the other in the trigone area, near the bladder neck, recurred after 18 months. After another TUR-BT, there were no more recurrences in these two patients. No tumor progressed to the invasive stage. Tumor recurrence on simultaneous TUR-BT and TUR-P patients is a key issue of concern. We present a brief history of the four patients and a literature review. We concluded that conducting the two procedures simultaneously is clinically feasible for selected patients.

Phase I trial of sorafenib with concurrent radiotherapy (RT) in patients with invasive bladder cancer treated with bladder-sparing intent: A Spanish Oncology Genitourinary Group study.

270 Background: Preclinical studies suggest enhanced radiation-induced cell death when VEGFR inhibitor therapies are combined with RT. Methods: Patients with localized muscle invasive urothelial carcinoma of the bladder in clinical stage T2-3 N0 M0, who were not eligible or rejected radical cystectomy, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety and identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of sorafenib and RT. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Treatment consisted of TUR, followed by normofractionated (2 Gy/day) external-beam RT with high-energy photons, 46 Gy to minor pelvis and 66 Gy to bladder, combined with sorafenib given po continuously. Sorafenib was started two weeks before RT and was administered for 12 weeks, finishing 4 weeks after RT. Dose levels 1, 2 and 3 corresponded to sorafenib 200 mg qd, 200 mg bid and 800 mg bid. Pathological response was assessed by post-treatment TUR. Results: Ten patients were included: median age 71 years (44-84); gender 7M: 3F. Patients were treated at 3 dose levels, the MTD was reached at level 3 and the RD was: sorafenib 200 mg bid with RT. Two DLTs occurred, both at the third dose level: diarrhea grade 3 and digestive bleeding grade 3 with secondary anemia and hemodynamic angor in a patient with previous small bowel angiodysplasia. The most frequent toxicity was diarrhea. Other grade 1-2 toxicities included rash, fatigue, hand-foot syndrome, hypertension, dysuria and urinary frequency. One patient developed late radiation cystitis. Pathological complete response was achieved in 8 of 9 patients evaluated. Salvage cystectomy has been performed in one patient due to recurrent superficial bladder tumor. After a median follow up of 30 months, 6 patients remain disease-free with intact bladder. Conclusions: The combination of sorafenib and RT appears to be feasible and safe allowing long-term bladder preservation in selected patients. A phase II study to assess the activity of this promising combination is warranted.

1041 Safety and efficacy of an active surveillance program in recurrent non-muscle invasive bladder tumors. Results of an extended series

1041 Safety and efficacy of an active surveillance program in recurrent non-muscle invasive bladder tumors. Results of an extended series

Clinical Significance of Bladder Urothelial Thickening and Enhancement Revealed on MDCT Urography After Transurethral Resection of Tumor

To assess multidetector-row computed tomographic (MDCT) urography for detection of recurrence of bladder tumor after transurethral resection (TUR), and to assess significance of the MDCT findings like urothelial enhancement or thickening as a recurrence. A total of 216 MDCT urography examinations were performed for 100 patients undergoing follow-up after TURs were reviewed by 2 radiologists, according to MDCT findings (urothelial enhancement or thickening) and location (TUR site or distant sites of transitional cell carcinoma). Multidetector-row CT urography was confirmed by cystoscopy and urine cytologic examination. Analyses of per-MDCT urography and per-lesion basis were performed, assessing receiver operating characteristic analysis for combining excretory phases to noncontrast and portal venous phases. Fifty-two MDCT findings were positive, and 164 MDCT findings were negative. Of the 52 positive MDCT urography, 19 were true positive 33 were false positive. Of the 60 separate lesions, 25 lesions were true positive. Both urothelial enhancement and thickening were revealed in 19 lesions, urothelial enhancement in 4 lesions, and urothelial thickenings in 2 lesions. Nineteen lesions were revealed in TUR site, and 6 lesions were revealed in distant site of transitional cell carcinoma. For MDCT urography combining excretory phases to noncontrast and portal venous phases, a substantial agreement between radiologists was revealed (area under the curve; 0.910 ± 0.035, 0.749 ± 0.055; 8.3%; kappa score of 0.65). Multidetector-row CT urography has efficacy in detecting recurrence of bladder tumor in patients undergoing follow-up after TUR.

Hyperbaric oxygen therapy (HBOT ) in case of hemorrhagic cystitis after radiotherapy

IntroductionWe present the effect of hyperbaric oxygen therapy (HBOT) after radiotherapy for cancer in the pelvic cavity resulting in hematuria. Increasing the pressure of oxygen (PO2) in ischemic tissues favors the formation of new blood vessels and increases the secretion of collagen.Material and methodsWe evaluated 10 patients who were treated with HBOT from October 2006 to December 2010 due to persistent radiation damage to the lining of the bladder leading to recurrent hematuria. The study group was comprised of seven men and three women. In the case of cervical and endometrial cancers, 30 Gy of brachytherapy with 45-50 Gy of teleradiotherapy were used. In prostate cancer (PCa), we applied 50 Gy of teleradiotherapy with an additional dose of 20-24 Gy, and in the case of bladder cancer (BCa), 50 Gy of teleradiotherapy was applied with an additional dose of 16 Gy. HBOT consisted of 60 HBO2 treatments, in which patients were administered 100% oxygen at a pressure of 2.5 atm.ResultsThe group effect of total or partial resolution was observed in six patients. In one case, treatment was discontinued due to an increase in hematuria and the consequent suspicion of bladder tumor recurrence. While in and additional three cases, the treatment did not produce the desired result.ConclusionsTreatment of hemorrhagic cystitis is a difficult therapeutic challenge. One possible method is the implementation of HBOT. In very difficult cases, HBO2 treatment appears to be effective in giving more than half of patients a chance of getting better.

Probiotics, dendritic cells and bladder cancer

What's known on the subject? and What does the study add? The suppressor effect of probiotics on superficial bladder cancer is an observed phenomenon but the specific mechanism is poorly understood. The evidence strongly suggests natural killer (NK) cells are the anti-tumour effector cells involved and NK cell activity correlates with the observed anti-tumour effect in mice. It is also known that dendritic cells (DC) cells are responsible for the recruitment and mobilization of NK cells so therefore it may be inferred that DC cells are most likely to be the interphase point at which probiotics act. In support of this, purification of NK cells was associated with a decrease in NK cells activity. The current use of intravesical bacille Calmette-Guérin in the management of superficial bladder cancer is based on the effect of a localised immune response. In the same way, understanding the mechanism of action of probiotics and the role of DC may potentially offer another avenue via which the immune system may be manipulated to resist bladder cancer. Probiotic foods have been available in the UK since 1996 with the arrival of the fermented milk drink (Yakult) from Japan. The presence of live bacterial ingredients (usually lactobacilli species) may confer health benefits when present in sufficient numbers. The role of probiotics in colo-rectal cancer may be related in part to the suppression of harmful colonic bacteria but other immune mechanisms are involved. Anti-cancer effects outside the colon were suggested by a Japanese report of altered rates of bladder tumour recurrence after ingestion of a particular probiotic. Dendritic cells play a central role to the general regulation of the immune response that may be modified by probiotics. The addition of probiotics to the diet may confer benefit by altering rates of bladder tumour recurrence and also alter the response to immune mechanisms involved with the application of intravesical treatments (bacille Calmette-Guérin).

UP-01.197 Invasive Bladder Tumor Recurrence After Nephroureterectomy for Upper Urinary Tract Urothelial Carcinoma

Bladder tumor recurrence after nephroureterectomy (NUx) is important problem to affect patients' survival and quality of life. Recurrence rate is reported to be various between 15% and 60% and the rate of progression to invasive bladder tumor is rarely informed as far as we know. To evaluate bladder tumor recurrence including invasive tumor after NUx in patients with upper urinary tract urothelial carcinoma (UUT-UC), we analyzed potential risk factors and identified the prognosis.

NMP22 as a urine-based tumour marker for bladder cancer screening in a prospective cohort of chemical workers formerly exposed to aromatic amines: results of the UroScreen study

ObjectivesCancer of the urinary bladder ranks among the four leading cancers among men in Germany. Because bladder cancer can be successfully treated, patients will benefit from early detection. Due to...

UP-01.065 Randomized Biopsy in the Diagnosis and Treatment of Superficial Bladder Cancer

The combination of various pathological changes in visually intact urothelium ranging from dysplasia to carcinoma in situ, with invasive carcinoma of the bladder has been proved in many studies. This phenomenon associated with the multicentric origin of bladder tumors, explains the development of relapses and requires the use of radical surgical treatment for invasive bladder tumors. Later, it was proved that the superficial tumors can be combined with the microscopic changes in the mucous layer. On this basis, it was found that these lesions cause progression and recurrence of superficial bladder tumors. In order to determine the prognosis and treatment strategy it was proposed to use a randomized biopsy of cystoscopically unchanged urothelium with superficial bladder tumors. The objective of this study was to evaluate the role of randomized biopsies in the diagnosis and treatment of superficial bladder tumors.

Nuclear cIAP1 overexpression is a tumor stage- and grade-independent predictor of poor prognosis in human bladder cancer patients

PurposeTo evaluate the tumor-related expression profile of cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein (cIAP2) in patients with bladder cell carcinoma (BCC) and to investigate its potential prognostic value. MethodsThe expression of cIAP1 and cIAP2 was examined immunohistochemically in archival bladder specimens from 32 normal controls and 102 consecutive patients who underwent surgical operations at our department from January 2004 through December 2005. Cytoplasm cIAP1 and cIAP2 expression was scored as 0 (negative), +1 (weak), +2 (medium), and +3 (strong). Nuclear cIAP1 expression was scored as 0 (0%), +1 (1%–25%), +2 (26%–50%), and +3 (>50%). Proliferation was determined by Ki67 staining as percentage of positive cells. ResultscIAP1 and cIAP2 expression were significantly increased in bladder cancer compared with normal bladder urothelium (cIAP1-C: P < 0.01, cIAP2-C: P = 0.017, cIAP1-N: P < 0.01). Nuclear staining of cIAP1 (cIAP1-N) was significantly associated with tumor stage (muscle invasive vs. non-muscle invasive, P = 0.03) and tumor grade (low vs. high, P = 0.01). Both the mean overall survival and mean recurrence-free survival were significantly decreased in the high cIAP1-N group compared to the low cIAP1-N group (low cIAP1-N: mean overall survival 62.7 months, high cIAP1-N: mean overall survival 45.6 months, P < 0.01; low cIAP1-N: mean recurrence-free survival 44.2 months, high cIAP1-N: mean recurrence-free survival 30.1 months, P < 0.01). cIAP1-N expression correlated strongly with KI67 expression (r = 0.744, P < 0.01). ConclusionNuclear cIAP-1 expression strongly correlated to bladder cancer stage, tumor grade, tumor recurrence and tumor related death. This marker expression was also appears to be a marker in bladder cancer prognosis.

Is Hand-Assisted Retroperitoneoscopic Nephroureterectomy Better Than Transurethral Bladder Cuff Incision-Assisted Nephroureterectomy?

To compare the perioperative and oncologic outcome between hand-assisted nephroureterectomy (HARNU) and transurethral bladder cuff incision-assisted nephroureterectomy (TUINU), which manage the bladder cuff with different methods. From January 2005 to December 2008, 325 patients with upper urinary tract urothelial carcinoma (UUT-UC) underwent nephroureterectomy at our institution. A total of 208 patients were enrolled in this retrospective study. A total of 208 patients, including 102 men and 106 women, were analyzed in this retrospective study. Ninety-eight patients underwent HARNU for UUT-UC, and110 patients underwent TUINU. The HARNU group has less operative time and hospital stay, and fewer postoperative ileus episodes. There were trends of less blood loss in the HARNU group. There were no statistical differences in the total bladder tumor recurrence, local recurrence, contralateral recurrence, distant metastasis, and cancer-specific survival between HARNU and TUINU. There was a significantly higher incidence of bladder tumor recurrence in TUINU group, however, than in the HARNU group (P=0.008) if the tumor was located at the low third of the ureter. There were more oncologic concerns about bladder tumor recurrence for the low third ureteral tumor in the TUINU group. In addition, the perioperative outcomes such as operative time, blood loss, hospital stay, and ileus rate were better in the HARNU group. Therefore, surgeons can manage UUT tumor with less oncologic concern and better perioperative results with HARNU.

Radiotherapy may improve overall survival of patients with T3/T4 transitional cell carcinoma of the renal pelvis or ureter and delay bladder tumour relapse

BackgroundSince transitional cell carcinoma (TCC) of the upper urinary tract is a relatively uncommon malignancy, the role of adjuvant radiotherapy is unknown.MethodsWe treated 133 patients with TCC of the renal pelvis or ureter at our institution between 1998 and 2008. The 67 patients who received external beam radiotherapy (EBRT) following surgery were assigned to the radiation group (RT). The clinical target volume included the renal fossa, the course of the ureter to the entire bladder, and the paracaval and para-aortic lymph nodes, which were at risk of harbouring metastatic disease in 53 patients. The tumour bed or residual tumour was targeted in 14 patients. The median radiation dose administered was 50 Gy. The 66 patients who received intravesical chemotherapy were assigned to the non-radiation group (non-RT).ResultsThe overall survival rates for the RT and non-RT groups were not significantly different (p = 0.198). However, there was a significant difference between the survival rates for these groups based on patients with T3/T4 stage cancer. A significant difference was observed in the bladder tumour relapse rate between the irradiated and non-irradiated bladder groups (p = 0.004). Multivariate analysis indicated that improved overall survival was associated with age < 60 years, T1 or T2 stage, absence of synchronous LN metastases, and EBRT. Acute gastrointestinal and bladder reactions were the most common symptoms, but mild non-severe (> grade 3) hematologic symptoms also occurred.ConclusionEBRT may improve overall survival for patients with T3/T4 cancer of the renal pelvis or ureter and delay bladder tumour recurrence in all patients.

Thérapie photodynamique et carcinomes urothéliaux

PurposePhotodynamic therapy (PDT) is an innovative therapeutic modality in urologic oncology. Material and methodsWe reviewed the current literature on principles and modalities of PDT in urothelial and penile oncology. ResultsPDT has been tested for the treatment recurrent superficial bladder tumors and in situ carcinoma. Carcinologic efficacy has been observed with first generation photosensitizer. The lack of selectivity for tumoral cells was responsible of serious adverse events. Development of selective photosensitizers has reduced the importance of side effects. Data concerning PDT for upper urinary tract urethra and carcinoma are still limited. ConclusionFirst PDT clinical applications in urothelial oncology have shown some effectiveness at the cost of significant morbidity. The development of selective photosensitizers should help to reduce side effects.

Bacillus Calmette‐Guerin immunotherapy of bladder cancer induces selection of human leukocyte antigen class I‐deficient tumor cells

Bacillus Calmette-Guerin (BCG) immunotherapy is a standard treatment for high-risk non-muscle-infiltrating bladder cancer patients. Although the outcomes are good, cancer relapse is observed in around 40% of patients. We present the comparative analysis of human leukocyte antigen (HLA) class I expression in recurrent bladder tumors in patients treated with mitomycin or BCG. HLA class I expression was analyzed by RT-Q-PCR and immunohistochemical techniques. Loss of heterozygosity (LOH) was determined by microsatellite amplification of markers in chromosome 6 and 15. More profound alterations in HLA class I expression were found in post-BCG recurrent tumors than in pre-BCG lesions, whereas mitomycin treatment did not change the HLA class I expression pattern. Post-BCG recurrent tumors also showed a higher incidence of structural defects underlying altered HLA class I expression. We hypothesize that the immunotherapy-activated immune system recognizes and eliminates tumor cells with reversible ("soft") HLA class I changes but not transformed cells with additional, irreversible ("hard") alterations. To our knowledge, this is the first clinical evidence of immunotherapy-induced immunoselection of HLA class I loss tumor variants in bladder cancer, although the study involved a small number of patients.

Implications of transcriptional factor, OCT-4, in human bladder malignancy and tumor recurrence

OCT-4, which is also known as POU5f1, is a key regulator of self-renewal in embryonic stem cells. The new cancer stem cell concept proposes that the expression of such genes is potentially correlated with tumorigenesis and can affect some aspects of the cancer behavior, such as recurrence or metastasis. This study investigated the association between OCT-4 expression in cancer tissues obtained by transurethral surgery and the clinical data to clarify the involvement of OCT-4 in human bladder malignancy. Immunohistochemical analysis demonstrated that a positive rate of OCT-4 expression was significantly associated with the higher-grade cancer (G2 and G3) in comparison with that of the lower grade (G1). In addition, positive OCT-4 expression was significantly associated with the intra-bladder tumor recurrence after the operation. The staining intensity of OCT-4 expression was also correlated with tumor recurrence. These data indicate that positive OCT-4 expression may be involved in the development of high-grade bladder cancer and with the bladder cancer recurrence. This is the first study showing a correlation between the expression of OCT-4 and bladder cancer recurrence. OCT-4 may be a valuable clinical marker for the progression of bladder cancer and may be an attractive therapeutic target for the development of new medicines for the treatment of malignancy.