High magnification cystoscopy in the primary diagnosis of bladder tumors.

Purpose of reviewIn bladder cancer, discrimination between benign and malignant tissue may remain tricky with current endoscopic tools. On the basis of our recent experience with high-magnification cystoscopy, compared with other tools such as optical coherence tomography or confocal laser endomicroscopy, it is suggested here that this discrimination may well be feasible endoscopically. The clinical potential of these systems that are being developed as complementary tools to the current endoscopic equipment is reviewed.Recent findingsAt present, white-light cystoscopy, either assisted by fluorescence cystoscopy or narrow-band imaging, is proposed for the global cystoscopic examination of bladder cancer patients. Both techniques compete to help to reduce the recurrence rate by improving exophytic tumor detection, and the extent of carcinoma in situ and high-grade dysplasia. All of which are important prognosis factors for disease progression. In addition, recent findings on neoangiogenesis that accompanies early stage bladder cancer show that this may also be an important observable switch in bladder cancerogenesis, as it is found very early in tumor development. The high magnification cystoscopy as a complementary tool to fluorescence cystoscopy allows classification of the vessel patterns on fluorescence positive sites, and thus facilitates the discrimination between cancerous and noncancerous lesions. This information may be useful to reduce the false positive rate of fluorescence cystoscopy.SummaryEmerging technologies aiming at a real-time in-situ discrimination between benign and malignant tissue during endoscopic bladder exploration is a promising development for the monitoring of bladder cancer patients.

Histopathology and prognosis of de novo bladder tumors following solid organ transplantation.

BACKGROUND: Patients following solid organ transplantation have an increased risk of developing de novo bladder tumors, but their biology is poorly characterized. METHODS: We studied 1743 patients who underwent a transurethral resection of a newly diagnosed bladder tumor at a single institution. The histopathology, treatment, recurrence-free survival and overall survival were evaluated and compared between transplant and non-transplant patients. RESULTS: We identified 74 transplant patients who developed a de novo bladder tumor after a median post-transplantation interval of 62 months. The tumor was malignant in 29 patients (39 %). The most common benign lesion was nephrogenic adenoma (84 %), which neither coexisted with nor developed into malignant tumors during follow-up. Compared with non-transplant patients (n = 1669), transplant patients were significantly younger (median 55 vs 69 years, P < 0.001) and had a 9.0-fold higher odds of benign tumors (P < 0.001), while there were no differences in pathology among patients with urothelial carcinoma of the bladder (UCB). In a multivariable analysis for non-muscle-invasive UCB that was adjusted for the risk group, patients with a transplant had a 1.8-fold increased risk of recurrence (P = 0.048). Four of five transplant patients did not respond to Bacillus Calmette-Guérin instillations. There were no differences in overall survival after radical cystectomy (P = 0.87). CONCLUSIONS: The majority of bladder tumors in transplant patients are benign, and they neither coexist with nor develop into malignant tumors. Transplant patients with non-muscle-invasive UCB show an increased risk of disease recurrence, while those treated with radical cystectomy have similar outcomes to patients without a transplant.

Intravaginal and subcutaneous immunization induced vaccine specific CD8 T cells and tumor regression in the bladder.

PURPOSE: Vaccines targeting tumor associated antigens are in development for bladder cancer. Most of these cancers are nonmuscle invasive at diagnosis and confined in the mucosa and submucosa. However, to our knowledge how vaccination may induce the regression of tumors at such mucosal sites has not been examined previously. We compared different immunization routes for the ability to induce vaccine specific antitumor CD8 T cells in the bladder and bladder tumor regression in mice. MATERIALS AND METHODS: In the absence of a murine bladder tumor model expressing a tumor antigen relevant for human use we established an orthotopic model expressing the HPV-16 tumor antigen E7 as a model. We used an adjuvant E7 polypeptide to induce CD8 T cell mediated tumor regression. RESULTS: Subcutaneous and intravaginal but not intranasal vaccination induced a high number of TetE7(+)CD8(+) T cells in the bladder as well as bladder tumor regression. The entry of vaccine specific T cells in the bladder was not the only key since persistent regression of established bladder tumors by intravaginal or subcutaneous immunization was associated with tumor infiltration of total CD4 and CD8 T cells. This resulted in an increase in TetE7(+)CD8(+) T cells and a decrease in T regulatory cells, leading to an increased number of effector interferon-γ secreting vaccine specific CD8 T cells in the regressing bladder tumor. CONCLUSIONS: These data show that immunization routes should be tailored to each mucosal tumor site. Subcutaneous or intravaginal vaccination may be of additional value to treat patients with bladder cancer.

Detection of functional antigen-specific T cells from urine of non-muscle invasive bladder cancer patients.

To gain further insights into the role of T lymphocytes in immune responses against bladder tumors, we developed a method that monitors the presence of functional antigen-specific T cells in the urine of non-muscle invasive bladder cancer patients. As relatively few immune cells can usually be recovered from urine, we examined different isolation/amplification protocols and took advantage of patients treated with weekly intravesical instillations of Bacillus Calmette-Guérin, resulting in large amounts of immune cells into urine. Our findings demonstrate that, upon in vitro amplification, antigen-specific T cells can be detected by an interferon γ (IFNγ)-specific ELISPOT assay.

Small Cell Carcinoma of the Urinary Bladder: A Retrospective, Multicenter Rare Cancer Network Study of 107 Patients.

PURPOSE: Small cell carcinomas of the bladder (SCCB) account for fewer than 1% of all urinary bladder tumors. There is no consensus regarding the optimal treatment for SCCB. METHODS AND MATERIALS: Fifteen academic Rare Cancer Network medical centers contributed SCCB cases. The eligibility criteria were as follows: pure or mixed SCC; local, locoregional, and metastatic stages; and age ≥18 years. The overall survival (OS) and disease-free survival (DFS) were calculated from the date of diagnosis according to the Kaplan-Meier method. The log-rank and Wilcoxon tests were used to analyze survival as functions of clinical and therapeutic factors. RESULTS: The study included 107 patients (mean [±standard deviation, SD] age, 69.6 [±10.6] years; mean follow-up time, 4.4 years) with primary bladder SCC, with 66% of these patients having pure SCC. Seventy-two percent and 12% of the patients presented with T2-4N0M0 and T2-4N1-3M0 stages, respectively, and 16% presented with synchronous metastases. The most frequent curative treatments were radical surgery and chemotherapy, sequential chemotherapy and radiation therapy, and radical surgery alone. The median (interquartile range, IQR) OS and DFS times were 12.9 months (IQR, 7-32 months) and 9 months (IQR, 5-23 months), respectively. The metastatic, T2-4N0M0, and T2-4N1-3M0 groups differed significantly (P=.001) in terms of median OS and DFS. In a multivariate analysis, impaired creatinine clearance (OS and DFS), clinical stage (OS and DFS), a Karnofsky performance status <80 (OS), and pure SCC histology (OS) were independent and significant adverse prognostic factors. In the patients with nonmetastatic disease, the type of treatment (ie radical surgery with or without adjuvant chemotherapy vs conservative treatment) did not significantly influence OS or DFS (P=.7). CONCLUSIONS: The prognosis for SCCB remains poor. The finding that radical cystectomy did not influence DFS or OS in the patients with nonmetastatic disease suggests that conservative treatment is appropriate in this situation.

Development of novel immunotherapies against bladder cancer

Le cancer de la vessie est le deuxième cancer urologique le plus fréquent dans le monde. La plupart des patients (75%) sont initialement diagnostiqués avec un cancer non musculo- invasif. Après résection trans-urétrale, ie traitement standard pour ce type de lésion chez les patients présentant un risque important de récidive/progression consiste en une série d'instillations intravésicales du Bacille de Calmette-Guerin (i.e. le vaccin BCG). Cependant cette "BCG thérapie" est associée à des effets secondaires non négligeables et s'avère inefficace dans 30% des cas, des limitations donc importantes qui soulignent la nécessité de développer des stratégies thérapeutiques alternatives. L'utilisation d'antigènes associés aux tumeurs (TAA) comme vaccin, combinée à une application locale d'immunostimulants sur le site tumoral, est une approche prometteuse en vue de maximiser les réponses immunitaires anti-tumorales localement. Nous montrons que la bactérie vivante atténuée Ty21a, issue du vaccin Vivotif® contre la fièvre typhoïde, peut être utilisée comme immunostimulant intravésical (IVES), mais ce uniquement dans le cas où la bactérie est en phase exponentielle de croissance (Vivotif exp). En effet, l'instillation IVES de Vivotif exp à la suite d'une vaccination par un TAA, un antigène mineur d'histocompatibilité mâle H-Y (Uty), permet d'augmenter de 15 fois le nombre de cellules T CD8 totales et spécifiques de l'antigène dans la vessie. Le recrutement des cellules T est TLR4-dépendent, ce qui suggère un rôle des lipopolysaccharides du Vivotif exp. Par ailleurs, en comparaison avec le contenu bactérien de la capsule de Vivotif, les bactéries en phase exponentielle de croissance permettent également une augmentation préférentielle des chemokines C5/C5a, CXCL1, CXCL2 et CXCL5 dans la vessie, mais pas du nombre de cellules T exprimant les récepteurs apparentés (C5aR et CXCR2). De plus, combiner la vaccination Uty avec le Vivotif exp en IVES permet d'améliorer la survie des souris présentant une tumeur orthotopique de la vessie exprimant l'antigène Uty (lignée tumorale murine MB49). Puisque pour certains cancers, aucun TAA - du moins exprimé à tous les stades tumoraux - n'est identifié, il est nécessaire de développer d'autres approches non vaccinales. Dans une deuxième partie de ce travail de thèse, nous avons donc investigué deux stratégies permettant d'induire une destruction des cellules tumorales, la thérapie génique par gène de suicide, d'une part, et la thérapie photodynamique dans le proche infrarouge (NIR-PDT), d'autre part. Pour appliquer ces thérapies, nous avons utilisé comme vecteur sûr et non toxique une forme non réplicative du virus du « Human Papillomavirus » (HPV) capable de "pseudo-infecter" préférentiellement les souris présentant des tumeurs vésicales (MB49). L'utilisation de pseudovirions (PsV) HPV portant comme gène suicide la thymidine kinase, une enzyme du virus de l'herpès simplex, suivi d'un traitement par la prodrogue Ganciclovir, permet de tuer 90% des cellules MB49 in-vitro ainsi que de ralentir significativement le développement des tumeurs vésicales in-vivo. Par ailleurs, l'emploi de particules pseudo- virales HPV couplées à la phtalocyanine IR700, un pigment photosensible présentant un pouvoir cytotoxique une fois activé, permet de tuer, après application d'une lumière dans le proche infrarouge, quasi 100% des cellules MB49 in-vitro et, plus important, de régresser des tumeurs in-vivo. De façon générale, ce travail de thèse présente des approches thérapeutiques innovantes et prometteuses pour le traitement des patients avec un cancer non musculo-invasif de la vessie. -- Bladder cancer is the second most common urological malignancy in the world. At initial diagnosis, non-muscle invasive bladder cancer (NMIBC) accounts for 75% of bladder cancer. The standard of care of NMIBC consists of intravesical (IVES) treatments with Bacillus- Calmette-Guerin (BCG) following transurethral resections of the lesions. However, repeated BCG treatments are associated with significant side effects and treatment failure may occur in 30% of the cases, underlying the necessity of alternative therapeutic strategies. The use of tumor-associated antigens (TAA) as vaccines followed by the local application of immunostimulants where the tumor resides is a promising approach to increase anti-tumor immune responses locally. We show that live attenuated Ty21a bacteria used from the vivotif® vaccine against typhoid fever can efficiently be used as IVES immunostimulant, only if bacteria are grown to exponential phase (Vivotif exp). In this condition, IVES immunostimulation after TAA vaccination with a minor histocompatibility male antigen HY (Uty) resulted in more than 15-fold increase of both vaccine-specific and total CD8-T cells in the bladder. T cell recruitment was mediated by TLR-4 suggesting that it was mainly mediated by lipopolysaccharides of Vivotif exp. In addition, these bacteria, as compared to the bacterial content of the vivotif capsule preferentially increased C5/C5a, CXCL1, CXCL2 and CXCL5 chemokines, but not the numbers of T cells expressing the cognate receptors (C5aR and CXCR2). Combination of IVES Vivotif exp with Uty vaccination improved survival of mice with pre-established orthotopic Uty-expressing MB49 murine bladder tumors, as compared to vaccination alone. As known TAA are not identified in all cancers, or not expressed in all stages of the tumor, we further investigated two potent approaches able of initiating tumor-cell destruction, suicide-gene therapy and near-infrared (NIR) photodynamic therapy (PDT). Towards a safe and non-toxic application of these therapies, we used Human Papillomavirus (HPV) replication-defective vectors that were able to preferentially pseudo-infect MB49-tumor bearing mice. HPV pseudovirions (PsV) carrying the Herpex-Simplex virus thymidine kinase suicide-gene followed by treatment with the prodrug Ganciclovir resulted in 90% of MB49 cell-death in-vitro and was able to significantly reduce bladder tumor growth in-vivo. Furthermore, HPV virus-like particles coupled to a NIR phtalocyanine dye, IR700 in combination with specific NIR light led to almost 100% of MB49 cell-death in-vitro and more interestingly, to bladder tumors shrinkage in-vivo. Overall, in this thesis, we offer promising therapeutic approaches for application in NMIBC patients.

Forced diuresis improves the diagnostic accuracy of 18F-FDG PET in abdominopelvic malignancies.

Our aim was to evaluate the role of forced diuresis in improving the diagnostic accuracy of abdominopelvic (18)F-FDG PET. METHODS: Thirty-two patients were enrolled. Besides the presence of known intravesical tumors or undefined renal lesions on the initial PET scan, the inclusion criterion was the appearance of indeterminate or equivocal (18)F-FDG foci that extended along the course of the urinary tract and could not confidently be separated from urinary activity. For each patient, a second abdominopelvic PET study was performed after intravenous injection of 0.5 mg of furosemide per kilogram of body weight (maximum, 40 mg) coupled with parenteral infusion of physiologic saline. RESULTS: Forced diuresis coupled with parenteral hydration eliminated any significant (18)F-FDG activity from the lower urinary tract in 31 (97%) of 32 patients after the bladder had been voided 3 successive times. Twelve intravesical lesions were visualized with outstanding clarity, whereas radiologic suspicion of locally recurrent bladder tumors was ruled out in 3 patients. Among 14 indeterminate or equivocal extravesical foci, 7 were deemed of no clinical value because they disappeared after furosemide challenge, whereas 7 persisting foci were proven to be true-positive PET findings. The performance of (18)F-FDG PET in characterizing 3 renal-space-occupying lesions could not be improved by our protocol. CONCLUSION: Furosemide challenge has the potential to noninvasively resolve the inherent (18)F-FDG contrast handicap in the lower urinary tract.

Immunotherapies for uro-genital cancers

Les cancers du col utérin et de la vessie prennent tous deux leur origine dans les sites muqueux et peuvent évoluer lentement de lésions superficielles (lésions squameuses intra-épithéliales de bas à haut grade (HSIL) et carcinomes in situ du col utérin (CIS); ou tumeurs non musculo-invasives de la vessie (NMIBC)) à des cancers invasifs plus avancés. L'éthiologie de ces deux cancers est néanmoins très différente. Le cancer du col utérin est, à l'échelle mondiale, le deuxième cancer le plus mortel chez la femme. Ce cancer résulte de l'infection des cellules basales de l'épithélium stratifié du col utérin par le papillomavirus humain à haut risque (HPV). Les vaccins prophylactiques récemment développés contre le HPV (Gardasil® et Cervarix®) sont des moyens de prévention efficaces lorsqu'ils sont administrés chez les jeunes filles qui ne sont pas encore sexuellement actives; cependant ces vaccins ne permettent pas la régression des lésions déjà existantes. Malgré un développement actif, les vaccins thérapeutiques ciblant les oncogènes viraux E6/E7 n'ont montré qu'une faible efficacité clinique jusqu'à présent. Nous avons récemment démontré qu'une immunisation sous-cutanée (s.c.) était capable de faire régresser les petites tumeurs génitales chez 90% des souris, mais chez seulement 20% des souris présentant de plus grandes tumeurs. Dans cette étude, nous avons développé une nouvelle stratégie où la vaccination est associée à une application locale (intra-vaginale (IVAG)) d'agonistes de TLR. Celle-ci induit une augmentation des cellules T CD8 totales ainsi que T CD8 spécifiques au vaccin, mais pas des cellules T CD4. L'attraction sélective des cellules T CD8 est permise par leur expression des récepteurs de chemokines CCR5 et CXCR3 ainsi que par les ligants E-selectin. La vaccination, suivie de l'application IVAG de CpG, a conduit, chez 75% des souris, à la régression de grandes tumeurs établies. Le cancer de la vessie est le deuxième cancer urologique le plus fréquente. La plupart des tumeurs sont diagnostiquées comme NMIBC et sont restreintes à la muqueuse de la vessie, avec une forte propension à la récurrence et/ou progression après une résection locale. Afin de développer des vaccins contre les antigènes associés à la tumeur (TAA), il est nécessaire de trouver un moyen d'induire une réponse immunitaire CD8 spécifique dans la vessie. Pour ce faire, nous avons comparé différentes voies d'immunisation, en utilisant un vaccin composé d'adjuvants et de l'oncogène de HPV (E7) comme modèle. Les vaccinations s.c. et IVAG ont toutes deux induit un nombre similaire de cellules T CD8 spécifiques du vaccin dans la vessie, alors que l'immunisation intra-nasale fut inefficace. Les voies s.c. et IVAG ont induit des cellules T CD8 spécifiques du vaccin exprimant principalement aL-, a4- et le ligand d'E-selectin, suggérant que ces intégrines/sélectines sont responsables de la relocalisation des cellules T dans la vessie. Une unique immunisation avec E7 a permis une protection tumorale complète lors d'une étude prophylactique, indépendemment de la voie d'immunisation. Dans une étude thérapeutique, seules les vaccinations s.c. et IVAG ont efficacement conduit, chez environ 50% des souris, à la régression de tumeurs de la vessie établies, alors que l'immunisation intra-nasale n'a eu aucun effet. La régression de la tumeur est correlée avec l'infiltration dans la tumeur des cellules T CD8 spécifiques au vaccin et la diminution des cellules T régulatrices (Tregs). Afin d'augmenter l'efficacité de l'immunisation avec le TAA, nous avons testé une vaccination suivie de l'instillation d'agonistes de TLR3 et TLR9, ou d'un vaccin Salmonella Typhi (Ty21a). Cette stratégie a entraîné une augmentation des cellules T CD8 effectrices spécifiques du vaccin dans la vessie, bien qu'à différentes échelles. Ty21a étant l'immunostimulant le plus efficace, il mérite d'être étudié de manière plus approfondie dans le contexte du NMIBC. - Both cervical and bladder cancer originates in mucosal sites and can slowly progress from superficial lesions (low to high-grade squamous intra-epithelial lesions (HSIL) and carcinoma in situ (CIS) in the cervix; or non-muscle invasive tumors in the bladder (NMIBC)), to more advanced invasive cancers. The etiology of these two cancers is however very different. Cervical cancer is the second most common cause of cancer death in women worldwide. This cancer results from the infection of the basal cells of the stratified epithelium of the cervix by high-risk human papillomavirus (HPV). The recent availability of prophylactic vaccines (Gardasil® and Cervarix®) against HPV is an effective strategy to prevent this cancer when administered to young girls before sexual activity; however, these vaccines do not induce regression of established lesions. Despite active development, therapeutic vaccines targeting viral oncogenes E6/E7 had limited clinical efficacy to date. We recently reported that subcutaneous (s.c.) immunization was able to regress small genital tumors in 90% of the mice, but only 20% of mice had regression of larger tumors. Here, we developed a new strategy where vaccination is combined with the local (intravaginal (IVAG)) application of TLR agonists. This new strategy induced an increase of both total and vaccine-specific CD8 T cells in cervix-vagina, but not CD4 T cells. The selective attraction of CD8 T cells is mediated by the expression of CCR5 and CXCR3 chemokine receptors and E-selectin ligands in these cells. Vaccination followed by IVAG application of CpG resulted in tumor regression of large established tumors in 75% of the mice. Bladder cancer is the second most common urological malignancy. Most tumors are diagnosed as NMIBC, and are restricted to the mucosal bladder with a high propensity to recur and/or progress after local resection. Aiming to develop vaccines against tumor associated antigens (TAA) it is necessary to investigate how to target vaccine-specific T-cell immune responses to the bladder. Here we thus compared using an adjuvanted HPV oncogene (E7) vaccine, as a model, different routes of immunization. Both s.c. and IVAG vaccination induced similar number of vaccine-specific CD8 T-cells in the bladder, whereas intranasal (i.n.) immunization was ineffective. S.c. and IVAG routes induced predominantly aL-, a4- and E-selectin ligand-expressing vaccine-specific CD8 T-cells suggesting that these integrin/selectin are responsible for T-cell homing to the bladder. A single E7 immunization conferred full tumor protection in a prophylactic setting, irrespective of the immunization route. In a therapeutic setting, only ivag and s.c. vaccination efficiently regressed established bladder-tumors in ca. 50 % of mice, whereas i.n. immunization had no effect. Tumor regression correlated with vaccine- specific CD8 T cell tumor-infiltration and decrease of regulatory T cells (Tregs). To increase efficacy of TAA immunization, we tested vaccination followed by the local instillation of TLR3 or TLR9 agonist or of a Salmonella Typhi vaccine (Ty21a). This strategy resulted in an increase of vaccine-specific effector CD8 T cells in the bladder, although at different magnitudes. Ty21a being the most efficient, it deserves further investigation in the context of NMIBC. We further tested another strategy to improve therapies of NMIBC. In the murine MB49 bladder tumor model, we replaced the intravesical (ives) BCG therapy by another vaccine strain the Salmonella Ty21a. Ives Ty21a induced bladder tumor regression at least as efficiently as BCG. Ty21a bacteria did not infect nor survive neither in healthy nor in tumor-bearing bladders, suggesting its safety. Moreover, Ty21a induced a transient inflammatory response in healthy bladders, mainly through infiltration of neutrophils and macrophages that rapidly returned to basal levels, confirming its potential safety. The tumor regression was associated to a robust infiltration of immune cells, and secretion of cytokines in urines. Infection of murine tumor cell lines by Ty21a resulted in cell apoptosis. The infection of both murine and human urothelial cell lines induced secretion of in vitro inflammatory cytokines. Ty21a may be an attractive alternative for the ives treatment of NMIBC after transurethral resection and thus deserves more investigation.

Metastatic primary adenocarcinoma of the bladder in a twenty-five years old woman.

Primary adenocarcinoma of the bladder is a rare tumor. The classification between primary vesical and urachal is debated. We present the case of a young female who presented clinicopathological features of a metastatic urachal adenocarcinoma, but the histological result revealed primary adenocarcinoma of the bladder contrary to expectancy. To the best of our knowledge this is the first reported case of a metastatic adenocarcinoma of the bladder in a 25 years old female. This case emphasizes the challenge for urologists to recognize and manage this aggressive tumor in the setting described.

Clinical evaluation of a method for detecting superficial surgical transitional cell carcinoma of the bladder by light-induced fluorescence of protoporphyrin IX following the topical application of 5-aminolevulinic acid: preliminary results.

BACKGROUND AND OBJECTIVE: In bladder cancer, conventional white light endoscopic examination of the bladder does not provide adequate information about the presence of "flat" urothelial lesions such as carcinoma in situ. In the present investigation, we examine a new technique for the photodetection of such lesions by the imaging of protoporphyrin IX (PpIX) fluorescence following topical application of 5-aminolevulinic acid (ALA). STUDY DESIGN/MATERIALS AND METHODS: Several hours after bladder instillation of an aqueous solution of ALA in 34 patients, a Krypton ion laser or a filtered Xenon arc-lamp was used to excite PpIX fluorescence. Tissue samples for histological analysis were taken while observing the bladder wall either by means of a video camera, or by direct endoscopic observation. RESULTS: A good correlation was found between the PpIX fluorescence and the histopathological diagnosis. On a total of 215 biopsies, 143 in fluorescent and 72 in nonfluorescent areas, all visible tumors on white light cytoscopy appeared in a bright red fluorescence with the photodetection technique. In addition, this method permitted to discover 47 unsuspected carcinomatous lesions on white light observation, among which 40% were carcinoma in situ. CONCLUSION: PpIX fluorescence induced by instillation into the bladder of 5-ALA is an efficient method of mapping the mucosa in bladder carcinoma.

Invasive bladder carcinoma: a pilot study of conservative treatment with accelerated radiotherapy and concomitant cisplatin.

From November 1992 to December 1997, 25 patients (inoperable or refusing cystectomy) were included in a prospective study to assess the feasibility, tolerance, and curative potential of accelerated radiotherapy (RT) and concomitant cisplatin. Median age was 74 years (range 49-86). Stage distribution was as follows: 1 T1, 10 T2, 8 T3, and 6 T4. Two patients had clinically positive pelvic nodes. The goal was to deliver a total dose of 40 Gy to the whole pelvis and bladder in 4 weeks using a concomitant boost of 20 Gy to the tumor or to the whole bladder during the third and fourth weeks (total dose 60 Gy), with daily cisplatin (6 mg/m(2)) before RT for patients with creatinine clearance > 50 ml/min. All but one patient completed the RT protocol. Daily cisplatin was successfully delivered in 18 patients. One patient presented with grade III ototoxicity. Diarrhea was scored grade III in two and grade IV in two patients. Acute urinary toxicity was scored grade III in one patient. Posttreatment late effects included bladder grade II and grade III in two patients and one patient, respectively; large bowel grade III in one; urethral grade III in one; and femoral head radionecrosis in one. Four-year overall and disease-specific survival rates were 23% and 35%, respectively. The latter was 60% for patients with T2 tumors. The 4-year actuarial locoregional control rate for all patients was 61%. In summary, accelerated RT and concomitant cisplatin is feasible with acceptable tolerance even in relatively old patients. Although outcome was better for patients with low-stage tumors, local control and survival rates appeared similar to those of standard RT schedules for a similar patient population.

Image en fluorescence en endoscopie: contribution dans la prise en charge des tumeurs de vessie [Fluorescence guided endoscopy: improvement in the management of bladder cancer].

White-light cystoscopy and cytology are the standard tools to diagnose bladder cancer. White-light cystoscopy is excellent to detect macroscopic exophytic tumors, but its sensitivity is poor for flat tumors such as carcinoma in situ. Use of fluorescence cystoscopy during transurethral bladder resection improve tumor detection, particulary for carcinoma in situ. Fluorescence cystoscopy reduce residual tumor rate, especially for voluminous and multifocal tumors with consecutive lower recurrence. Fluorescence is now recommended to diagnose and treat bladder cancer.

Immunotherapeutic strategies for bladder cancer.

Bladder cancer is a common urologic malignancy with rising incidence in the elderly population. In most cases, bladder cancer is non-muscle-invasive at diagnosis and shows dramatically high recurrence rates, although current treatments often reduce the risk of disease progression. Immunotherapy using intravesical instillation of Bacillus Calmette-Guérin (BCG) remains the most effective therapy for patients with high risk tumors. However, BCG-therapy has important limitations including substantial adverse events and frequent treatment failure. Thus, it appears crucial to either improve or replace current therapy using new immunotherapeutic strategies. Here, we discuss the clinical trials that assessed therapeutic vaccination of bladder cancer patients using tumor associated antigens and we also argue for novel approaches arising from murine models. Vaccination routes to induce appropriate T-cell homing in the tumor site as well as the use of local immunostimulation to enhance recruitment of vaccine-induced T cells are discussed to highlight what we believe is a promising therapeutic vaccination strategy for patients with non-muscle-invasive bladder cancer.

Clinical assessment of fluorescence cytoscopy during transurethral bladder resection in superficial bladder cancer.

The prognosis of superficial bladder cancer in terms of recurrence and disease progression is related to bladder tumor multiplicity and the presence of concomitant "plane" tumors such as high-grade dysplasia and carcinoma in situ. This study in 33 patients aimed to demonstrate the role of fluorescence cystoscopy in transurethral resection of superficial bladder cancer. The method is based on the detection of protoporphyrin-IX-induced fluorescence in urothelial cancer cells by topical administration of 5-aminolevulinic acid. The sensitivity and the specificity of this procedure on apparently normal mucosa in superficial bladder cancer are estimated to be 82.9% and 81.3%, respectively. Thus, fluorescence cytoscopy is a simple and reliable method for mapping the bladder mucosa, especially in the case of multifocal bladder disease, and it facilitates the screening of occult dysplasia.

Positron Emission Tomography and Computer Tomography (PET/CT) in Prostate, Bladder, and Testicular Cancers.

Positron emission computed tomography (PET) is a functional, noninvasive method for imaging regional metabolic processes that is nowadays most often combined to morphological imaging with computed tomography (CT). Its use is based on the well-founded assumption that metabolic changes occur earlier in tumors than morphologic changes, adding another dimension to imaging. This article will review the established and investigational indications and radiopharmaceuticals for PET/CT imaging for prostate cancer, bladder cancer and testicular cancer, before presenting upcoming applications in radiation therapy.