Laparoscopic Radical Prostatectomy with a Remote Controlled Robot.

PURPOSE: Robotics in surgery is a recent innovation. This technology offers a number of attractive features in laparoscopy. It overcomes the difficulties with fixed port sites by restoring all 6 degrees of freedom at the instrument tips, provides new possibilities for miniaturization of surgical tasks and allows remote controlled surgery. We investigated the applicability of remote controlled robotic surgery to laparoscopic radical prostatectomy. MATERIALS AND METHODS: Our previous experience with laparoscopic prostatectomy served as a basis for adapting robotic surgery to this procedure. A surgeon at a different location who activated the tele-manipulators of the da Vinci∗ robotic system performed all steps of the intervention. A scrub nurse and second surgeon who stood at patient side had limited roles to port and instrument placement, exposure of the operative field, assistance in hemostasis and removal of the operative specimen. Our patient was a 63-year-old man presenting with a T1c tumor discovered on 1 positive sextant biopsy with a 3+3 Gleason score and 7 ng./ml. preoperative serum prostate specific antigen. RESULTS: The robot provided an ergonomic surgical environment and remarkable dexterity enhancement. Operating time was 420 minutes, and the hospital stay lasted 4 days. The bladder catheter was removed 3 days postoperatively, and 1 week later the patient was fully continent. Pathological examination showed a pT3a tumor with negative margins. CONCLUSIONS: Robotically assisted laparoscopic radical prostatectomy is feasible. This new technology enhances surgical dexterity. Further developments in this field may have new applications in laparoscopic tele-surgery.

Occupational exposure to polycyclic aromatic hydrocarbons influenced neither the frequency nor the spectrum of FGFR3 mutations in bladder urothelial carcinoma.

Occupational exposure to polycyclic aromatic hydrocarbons (PAH) is associated with an increased risk of urothelial carcinoma (UC). FGFR3 is found mutated in about 70% of Ta tumors, which represent the major group at diagnosis. The influence of PAH on FGFR3 mutations and whether it is related to the emergence or shaping of these mutations is not yet known. We investigated the influence of occupational PAH on the frequency and spectrum of FGFR3 mutations. We included on 170 primary urothelial tumors from five hospitals from France. Patients (median age, 64 yr) were interviewed to gather data on occupational exposure to PAH, revealing 104 non- and possibly PAH exposed patients, 66 probably and definitely exposed patients. Tumors were classified as follows: 75 pTa, 52 pT1, and 43 > or =pT2. Tumor grades were as follows: 6 low malignant potential neoplasms (LMPN) and 41 low-grade and 123 high-grade carcinomas. The SnaPshot method was used to screen for the following FGFR3 mutations: R248C, S249C, G372C, Y375C, A393E, K652E, K652Q, K652M, and K652T. Occupational PAH exposure was not associated with a particular stage or grade of tumors. Thirty-nine percent of the tumors harbored FGFR3 mutations. After adjustment for smoking, occupational exposure to PAH did not influence the frequency [OR, 1.10; 95% CI, 0.78-1.52], or spectrum of FGFR3 mutations. Occupational exposure to PAH influenced neither the frequency nor the spectrum of FGFR3 mutations and there was no direct relationship between these mutations and this occupational hazard.

The expression of Twist has an impact on survival in human bladder cancer and is influenced by the smoking status.

OBJECTIVES: Twist is considered as transcription factor that regulates epithelial mesenchymal transition (EMT) by at least inhibition of E-cadherin expression. EMT is a key event in the tumor invasion process. The purpose of this study is to investigate the expression of Twist but also those of E- and N-cadherin in human primary bladder tumor and to evaluate its prognostic value. As smoking cigarettes is a strong bladder cancer risk factor, we tried to evaluate the impact of the tobacco status on these molecular abnormalities. MATERIALS AND METHODS: To delineate on the oncogenic role for Twist in human bladder cancer, we evaluated the E- and N-cadherin but also Twist expression (n = 70) by immunohistochemistry. We evaluated the prognostic value of these expressions. Moreover, we tried to correlate these protein expressions to the smoking status of the patients. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. RESULTS: Of the 70 bladder tumors, 28 (40%) cases were positive for Twist expression, 16 (23%) cases were negative for E-cadherin expression, and 12 (17%) were positive for N-cadherin expression. When categorized into negative vs. positive expression, Twist was associated with the stage (P = 0.001), the grade (P < 0.001), the progression (P = 0.02), and the E-cadherin expression (P = 0.01). Moreover, positive Twist expression clearly predicted poorer PFS (P = 0.02). In the multivariate analysis, both positive Twist expression and loss of E-cadherin expression were independent prognostic factors for PFS (P = 0.046 and P = 0.001, respectively) and only loss of E-cadherin expression for the OS (P < 0.001). We also demonstrated that almost 60% (16/28) of patients with Twist-positive expression were current smokers at the time of the diagnosis, corroborating the fact that smoking modulates the expression of EMT markers including Twist. CONCLUSION: Positive Twist expression may be a useful prognostic marker for patients with bladder cancer. Its expression seems to be correlated to the tobacco status of the patients.

The striated urethral sphincter of the pig shows morphological and functional characteristics essential for the evaluation of treatments for sphincter insufficiency.

PURPOSE: New treatments are currently under investigation for intrinsic sphincter insufficiency. However, animal models in which to study the resting urethral tone generated by the striated urethral sphincter are still lacking. We describe the striated urethral sphincter in the pig. We investigated its participation in resting urethral tone with the aim of developing new tools for evaluating therapies for sphincter insufficiency. MATERIALS AND METHODS: A total of 15 female pigs were used in this study. Anatomy of the striated urethral sphincter was described via transpubic and endoscopic approaches. Participation of the striated urethral sphincter in resting urethral tone was assessed by analysis of urethral pressure profilometry (maximum urethral closure pressure, functional urethral length and area under the curve) before and after curare injection or by destruction of the striated urethral sphincter by endoscopic electrocautery. Serial urethral cross sections were immunostained for slow/fast myosin and digitalized for 3-dimensional reconstructions to determine striated urethral sphincter volume. RESULTS: The striated urethral sphincter was Omega-shaped and it encircled the distal third of the urethra. A mean peak intraurethral pressure +/- SEM of 58.9 +/- 13.4 cm H(2)O was noted in front of the striated urethral sphincter. Curare injection and endoscopic injury decreased maximum urethral closure pressure by 48.4% and 51.1%, functional urethral length by 10.3% and 15.3%, and area under the curve by 47% and 64%, respectively. The striated urethral sphincter consisted of 52% slow and 48% fast myofibers. Its mean volume was 0.87 cm. CONCLUSIONS: The striated urethral sphincter of the female pig shows the morphological and functional features of a tonic muscle. Methods of measuring resting urethral tone generated by the striated urethral sphincter represent original tools for evaluating therapies for intrinsic sphincter insufficiency.

Regional copy number-independent deregulation of transcription in cancer.

Genetic and epigenetic alterations have been identified that lead to transcriptional deregulation in cancers. Genetic mechanisms may affect single genes or regions containing several neighboring genes, as has been shown for DNA copy number changes. It was recently reported that epigenetic suppression of gene expression can also extend to a whole region; this is known as long-range epigenetic silencing. Various techniques are available for identifying regional genetic alterations, but no large-scale analysis has yet been carried out to obtain an overview of regional epigenetic alterations. We carried out an exhaustive search for regions susceptible to such mechanisms using a combination of transcriptome correlation map analysis and array CGH data for a series of bladder carcinomas. We validated one candidate region experimentally, demonstrating histone methylation leading to the loss of expression of neighboring genes without DNA methylation.

Saturation biopsy protocol enhances prediction of pT3 and surgical margin status on prostatectomy specimen.

A 21-samples saturation biopsy procedure (SBP) was developed in order to improve prostate cancer detection rate. Out of 650 patients who underwent this protocol, 150 had a clinically localized prostate cancer and underwent a radical prostatectomy. The number of cores positive for tumor was assessed in the SBP, and also in the sextant component of the SBP (SC) and in the non-sextant component of the SBP (NSC). Numbers of cores positive for tumor on SBP, SC, and NSC were significantly higher in pT3 group versus pT2 (P < 0.001 each) and in positive surgical margins (PSM) group versus no PSM (P < 0.001 each). When comparing area under the curve obtained from SBP with those obtained from NSC and SC, the SBP showed higher accuracy than the NSC and the SC for the prediction of pT3 and PSM. On multivariate analyses, SC and NSC were independent predictors of pT3 and PSM on radical prostatectomy.

The effect of ofloxacin on bacillus calmette-guerin induced toxicity in patients with superficial bladder cancer: results of a randomized, prospective, double-blind, placebo controlled, multicenter study.

PURPOSE: We determined whether prophylaxis with ofloxacin could decrease the toxicity of bacillus Calmette-Guerin for transitional cell carcinoma of the bladder. We also investigated the impact of ofloxacin on bacillus Calmette-Guerin antitumor efficacy. MATERIALS AND METHODS: In this randomized, double-blind, multicenter study 115 patients with primary or recurrent superficial bladder cancer (Ta/T1, CIS, G1-G3) and no prior bacillus Calmette-Guerin treatment were randomized to induction treatment with intravesical bacillus Calmette-Guerin (6 plus 3 instillations) plus 200 mg ofloxacin in group 1 or plus placebo in group 2. Adverse events were assessed using a detailed grid of classification for bacillus Calmette-Guerin related adverse events. Mean patient age +/- SD was 65.6 +/- 10.4 years in the 57 group 1 patients and 65.7 +/- 8.7 years in the 58 in group 2. Median followup was 369 and 374 days in groups 1 and 2, respectively. RESULTS: Ofloxacin significantly decreased by 18.5% the incidence of class II or higher moderate and severe adverse events between instillations 4 and 6. The percent of class III adverse events was significantly decreased by ofloxacin between instillations 1 and 9. Although ofloxacin decreased adverse events involving the lower urinary tract, it did not prevent class I adverse events. Compliance with full bacillus Calmette-Guerin treatment was also improved. Of patients in group 1, 80.7% received 9 instillations compared with 65.5% in group 2 (p = 0.092). At 12 months recurrence and progression rates in group 1 and 2 were 12.7% and 17.2%, and 5.5% and 1.7%, respectively. CONCLUSIONS: Prophylactic ofloxacin decreased the incidence of moderate to severe adverse events associated with bacillus Calmette-Guerin intravesical therapy, particularly class III events, which are primarily associated with patient dropout. Compliance with induction and maintenance therapy may be improved by adjuvant ofloxacin therapy. However, long-term comparative studies with other preventive strategies must be done to confirm these initial findings with compliance and recurrence-free survival as the primary end points.

[Complications of retroperitoneal laparoscopy based on a series of 500 cases]. / Complications de la laparoscopie rétropéritonéale: experience aprés 500 cas.

OBJECTIVE: To evaluate the complications of retroperitoneal laparoscopy for upper urinary tract surgery. METHODS: From 1994 to 2003, 500 retroperitoneal laparoscopy procedures were performed: 143 radical nephrectomies, 104 simple nephrectomies, 95 adrenalectomies, 47 ureteropelvic junction plasties, 44 partial nephrectomies, 22 nephroureterectomies, 20 cyst resections, 9 diverticulectomies, 8 lymphadenectomies, 4 pyelotomies and 4 ureteric procedures. The standardized technique uses 5 trocars. RESULTS: There were 23 conversions (4.60%): 5 for retroperitoneal adhesions, 11 for intraoperative bleeding, 7 for technical impossibility. 14 patients (2.8%) required surgical revision: 5 urinomas and 2 urocutaneous fistulas treated by ureteric drainage, 2 deep abscesses, 2 cases of secondary bleeding, 2 colostomies for gastrointestinal fistula after colonic injury, 1 incisional hernia on a trocar orifice. There were postoperative 2 deaths (0.4%) due to septic shock and haemorrhagic shock. 21 patients (4.2%) presented medical postoperative complications: haematoma, hyperthermia, phlebitis and pulmonary infections. 15 patients (3%) were transfused. The most frequent complications occurred after partial nephrectomies and the most serious complications occurred after radical nephrectomies. CONCLUSION: The complication rate is low. Retroperitoneal laparoscopy allows reproducible and effective upper urinary tract surgery, but it is not recommended in patients with a history of retroperitoneal surgery.

Gefitinib inhibits the growth and invasion of urothelial carcinoma cell lines in which Akt and MAPK activation is dependent on constitutive epidermal growth factor receptor activation.

PURPOSE: Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC. EXPERIMENTAL DESIGN: Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC. RESULTS: Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens. CONCLUSIONS: Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders.

Characterization of ZAG protein expression in prostate cancer using a semi-automated microscope system.

OBJECTIVE: Zinc-alpha-2-glycoprotein 1 (ZAG) is a 41-kD secreted protein that is known to stimulate lipid degradation in adipocytes. The aim of this study was to determine how ZAG protein expression is associated with prostate cancer (PCa). MATERIALS AND METHODS: An immunohistochemistry analysis was performed on a 227 PCa tissue microarray cases. ZAG protein expression was assessed using a semi-automated cellular image analysis system. RESULTS: ZAG expression was associated with tumor stage (pT2 > pT3 > metastasis cases, P < 0.001), and was inversely associated with Gleason score on pathology (P = 0.01). ZAG intensity was predictive of biochemical recurrence (P = 0.002). On multivariate analysis including pT2 patients, the predictive factors of biochemical recurrence were ZAG expression (P = 0.016), Gleason score (P = 0.011), and surgical margin status (P = 0.047). CONCLUSIONS: This study characterized ZAG protein expression in PCa using a semi-automated system. ZAG expression level found to have an independent prognostic value for pT2 patients.

Tumor size improves the accuracy of TNM predictions in patients with renal cancer.

OBJECTIVES: Current staging for renal cancer (RC) does not directly rely on tumor size. We examined the increment in accuracy related to inclusion of pathologically determined tumor size in prediction of nodal metastases (N+), distant metastases (M+), and cancer-specific survival (CSS). METHODS: Partial or radical nephrectomy was performed in 2245 patients with clear cell histology. Pathologic stages were T1a in 566, T1b in 490, T2 in 303, T3 in 831, and T4 in 55 patients. Tumor size was 0.5-25 cm (mean, 6.8). Multivariate models relied on 1997 and 2002 TNM variables and addressed N+, M+ disease, and CCS. Their accuracy was compared according to either the presence or absence of tumor size. RESULTS: In all univariate and multivariate models, tumor size was a statistically significant predictor of all outcomes (p< or =0.001). In all multivariate models, tumor size added between 3.7% and 0.8% to predictive accuracy of either 1997 or 2002 TNM categories. CONCLUSIONS: Tumor size represents a highly significant, multivariate, and informative predictor of RC outcomes and may warrant inclusion in future TNM revisions.

Serum bioavailable testosterone: assayed or calculated?

BACKGROUND: Bioavailable testosterone (BT), circulating testosterone not bound to sex hormone-binding globulin (SHBG), is thought to easily penetrate cells. We compared BT measurements obtained by assays with those obtained by calculation with different testosterone association constants. METHODS: We obtained sera from 2 groups of hypogonadal men [group 1 (G1), 1421 samples; group 2 (G2), 170 samples] and a group of healthy men [group 3 (G3), 109 samples]. We added minute doses of [3H]testosterone to the sera, precipitated the SHBG-bound fraction of testosterone with ammonium sulfate (50% saturation), and then assayed serum BT (ABT) as %BT x total. Calculated BT (CBT) was determined with theoretical association constants of testosterone for SHBG (Ks = 1 x 10(9) L/mol) and albumin (Ka = 3.6 x 10(4) L/mol) and paired optimal Ks and Ka values obtained by use of Microsoft Excel software. RESULTS: CBT calculated with theoretical constants differed from ABT by >30% in 85.7% (G1), 84.1% (G2), and 77.9% (G3) of samples, and the mean CBT/ABT ratios were 1.57 (G1), 1.85 (G2), and 1.50 (G3) in spite of fairly good correlations. CBT calculated with paired optimal K(s) and K(a) differed from ABT by <30% in 87.4% (G1), 87.5% (G2), and 97.5% (G3) of samples, and mean CBT/ABT ratios were 0.95-1.04. CONCLUSIONS: To obtain CBT values as close as possible to ABT, optimal paired association constants determined for each studied population must be used instead of the theoretical association constants. Considering the uncertainty of calculating BT, however, use of the ammonium sulfate precipitation method for determining BT is advisable.

Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b.

Germinal activating mutations of FGFR3 are responsible for several forms of dwarfism due to the inhibitory effect of FGFR3 on bone growth. Surprisingly, identical somatic activating mutations have been found at the somatic level in tumours: at high frequency in benign epithelial tumours (seborrheic keratosis, urothelial papilloma) and in low-grade, low-stage urothelial carcinomas, and at a lower frequency in other types of urothelial carcinoma, in cervix carcinoma, and in haematological cancer, multiple myeloma. FGFR3 exists as two isoforms, FGFR3b and FGFR3c, differs in ligand specificity and tissue expression. FGFR3b is the main form in epithelial cells and derived tumours, whereas FGFR3c is the main form in mesenchyme-derived cells and multiple myeloma. Several lines of evidence suggest that mutated FGFR3c has transforming properties. Although mutated FGFR3b is mostly found in benign epithelial tumours or carcinomas of low malignant potential, we present evidence here that mutated FGFR3b is oncogenic. All bladder tumours presenting FGFR3 mutations expressed this receptor more strongly than normal urothelium or non-mutated tumours. NIH-3T3 cells transfected with a mutated form of FGFR3b--FGFR3b-S249C, the most common mutation in bladder tumours--presented a spindle-cell morphology, grew in soft agar and gave rise to tumours when xenografted into nude mice. We identified one line of 17 bladder cell lines tested (MGH-U3) that expressed a mutated form of FGFR3b, FGFR3b-Y375C. We showed using siRNA and SU5402, an FGFR inhibitor, that the tumour properties of MGH-U3 depended on mutated receptor activity. Thus, in two different models, mutated FGFR3b presents oncogenic properties.

What information are urologists extracting from prostate needle biopsy reports and what do they need for clinical management of prostate cancer?

OBJECTIVES: This survey-based study examines what information urologists are extracting from prostate needle biopsy reports, and what they need for clinical management of prostate cancer (PC) patients. METHODS: A questionnaire was used to investigate several topics related to PC biopsy reporting. Two different clinical situations were separately explored, depending on whether the urologist intended a curative or a palliative therapy. RESULTS: 110 of the 300 (37%) urologists responded to the questionnaire and returned anonymous responses. The mean age of respondents was 47.5 years old (range 27-66). On average, they performed 31 (range 0-182) radical prostatectomies per year. Before proposing a curative therapy, several biopsy parameters were requested by the majority of respondents, including number of positive biopsies (104/110 or 95%), Gleason score (103/110 or 94%), highest Gleason grade (94/110 or 85%), localization of positive biopsies (80/110 or 73%), length of tumor on biopsy (58/110 or 53%), presence of extraprostatic extension (66/110 or 60%). In a palliative situation, only three parameters were requested by the majority of respondents: Gleason score (101/110 or 92%), highest Gleason grade (67/110 or 61%) and number of positive biopsies (59/110 or 54%). In prostate needle biopsies harboring cancer on multiple cores from separately designated locations, 77% (68/88) of respondents used the highest Gleason score, regardless of the overall percentage involvement, to determine their treatment plan. PIN (Prostatic Intraepithelial Neoplasia) on biopsy without PC was considered sufficient to re-biopsy by 77% (85/110) of respondents. Thirty six percent (40/110) of the respondents considered ASAP (Atypical Small Acinar Proliferation) to be equivalent to PIN. There was no significant association between the demographic data and the type of information requested on the biopsy report. CONCLUSIONS: In this sample of 110 French and Belgian urologists there was high variability in the way clinicians use prostate needle biopsy pathology report. Results of this survey should improve communication between urologists and pathologists and should help evaluate what data should be included in routine pathology reports.

A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells.

Protocadherin-PC (PCDH-PC) is a gene on the human Y chromosome that is selectively expressed in apoptosis- and hormone-resistant human prostate cancer cells. The protein encoded by PCDH-PC is cytoplasmically localized and has a small serine-rich domain in its COOH terminus that is homologous to the beta-catenin binding site of classical cadherins. Variants of prostate cancer cells that express PCDH-PC have high levels of nuclear beta-catenin protein and increased wnt-signaling. In this study, we show that transfection of human prostate cancer cells (LNCaP) with PCDH-PC or culture of these cells in androgen-free medium (a condition that up-regulates PCDH-PC expression) activates wnt signaling as assessed by nuclear accumulation of beta-catenin, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes. Moreover, LNCaP cells transfected with PCDH-PC or grown in androgen-free medium transdifferentiate to neuroendocrine-like cells marked by elevated expression of neuron-specific enolase and chromogranin-A. Neuroendocrine transdifferentiation was also observed when LNCaP cells were transfected by stabilized beta-catenin. Increased wnt signaling and neuroendocrine transdifferentiation of LNCaP cells induced by culture in androgen-free medium was suppressed by short interfering RNAs that target PCDH-PC as well as by dominant-negative Tcf or short interfering RNA against beta-catenin, supporting the hypothesis that increased expression of PCDH-PC is driving neuroendocrine transdifferentiation by activating wnt signaling. These findings have significant implications for the process through which prostate cancers progress to hormone resistance in humans.

Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience.

PURPOSE: To analyze to what extent histologic subtype is of prognostic importance in renal cell carcinoma based on a large, international, multicenter experience. PATIENTS AND METHODS: Four thousand sixty-three patients from eight international centers were included in this retrospective study. Histologic subtype (1997 International Union Against Cancer [UICC] criteria of tumor response), age, sex, TNM stage, Fuhrman grade, tumor size, Eastern Cooperative Oncology Goup performance status (ECOG PS), and overall survival were determined in all cases. The prognostic values of clear cell, papillary, and chromophobe histologic features were assessed by uni- and multivariate analysis using the Kaplan-Meier method and Cox model, respectively. RESULTS: Clear cell, papillary, and chromophobe carcinomas accounted for 3,564 (87.7%), 396 (9.7%) and 103 (2.5%) cases, respectively. In univariate analysis, a trend toward a better survival was observed when clear cell, papillary, and chromophobe histologies were considered prognostic categories (log-rank P = .0007). However, in multivariate analysis, TNM stage, Fuhrman grade and ECOG PS, but not histology, were retained as independent prognostic variables (P < .001). CONCLUSION: The stratification in three main renal cell carcinoma histologic subtypes as defined by the 1997 UICC-American Joint Committee on Cancer consensus should not be considered a major prognostic variable comparable to TNM stage, Fuhrman grade and ECOG PS.

Evaluation of the antitumoral potential of different nitric oxide-donating non-steroidal anti-inflammatory drugs (NO-NSAIDs) on human urological tumor cell lines.

Our work aimed at identifying the antitumoral potential of new nitric oxide (NO)-releasing non-steroidal anti-inflammatory drug (NSAID) derivatives on human prostate and bladder carcinoma cell lines. Among all molecules tested, two sulindac derivatives, NCX 1102 ((Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl] methylene]-1H-indene-3-acetic acid 4-(nitrooxy)butyl ester) and NCX 1105 ((Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl] methylene]-1H-indene-3-acetic acid 6-(nitrooxymethyl)-2-methylpyrydyl ester hydrochloride), were the most cytotoxic compounds. In contrast to its parent molecule sulindac, cell cycle analysis showed that NCX 1102 led to cell accumulation in the G2-M transition stage in all cell lines, and induced apoptosis in five out of the six cell lines. Thus, NO-NSAIDs may be useful for the elaboration of new therapeutic strategies in the management of bladder and prostate cancer.