Outcomes of an enhanced recovery after radical cystectomy program in a prospective multicenter study: compliance and key components for success.

OBJECTIVE: To investigate the effect of an Enhanced Recovery After Surgery (ERAS) program on complications and length of stay (LOS) after radical cystectomy (RC) and to assess if the number and type of components of ERAS play a key role on the decrease of surgical morbidity. MATERIALS AND METHODS: We analyzed the data of 277 patients prospectively recruited in 11 hospitals undergoing RC initially managed according to local practice (Group I) and later within an ERAS program (Group II). Two main outcomes were defined: 90-day complications rate and LOS. As secondary variables we studied 90-day mortality, 30-day readmission and transfusion rate. RESULTS: Patients in Group II had a higher use of ERAS measures (98.6%) than those in Group I (78.2%) (p < 0.05). Patients in Groups I and II experienced similar complications (70.5% vs. 66%, p = 0.42). LOS was not different between Groups I and II (12.5 and 14 days, respectively, p = 0.59). The risk of having any complication decreases for patients having more than 15 ERAS measures adopted [RR = 0.815; 95% confidence interval (CI) 0.667-0.996; p = 0.045]. Avoidance of transfusion and nasogastric tube, prevention of ileus, early ambulation and a fast uptake of a regular diet are independently associated with the absence of complications. CONCLUSIONS: Complications and LOS after RC were not modified by the introduction of an ERAS program. We hypothesize that at least 15 measures should be applied to maximize the benefit of ERAS.

Validation of the prostate health index in a predictive model of prostate cancer. / Validación del índice de salud prostática en un modelo predictivo de cáncer de próstata.

OBJECTIVES: To validate and analyse the clinical usefulness of a predictive model of prostate cancer that incorporates the biomarker «[-2] pro prostate-specific antigen¼ using the prostate health index (PHI) in decision making for performing prostate biopsies. MATERIAL AND METHODS: We isolated serum from 197 men with an indication for prostate biopsy to determine the total prostate-specific antigen (tPSA), the free PSA fraction (fPSA) and the [-2] proPSA (p2PSA). The PHI was calculated as p2PSA/fPSA×√tPSA. We created 2 predictive models that incorporated clinical variables along with tPSA or PHI. The performance of PHI was assessed with a discriminant analysis using receiver operating characteristic curves, internal calibration and decision curves. RESULTS: The areas under the curve for the tPSA and PHI models were 0.71 and 0.85, respectively. The PHI model showed a better ability to discriminate and better calibration for predicting prostate cancer but not for predicting a Gleason score in the biopsy ≥7. The decision curves showed a greater net benefit with the PHI model for diagnosing prostate cancer when the probability threshold was 15-35% and greater savings (20%) in the number of biopsies. CONCLUSIONS: The incorporation of p2PSA through PHI in predictive models of prostate cancer improves the accuracy of the risk stratification and helps in the decision-making process for performing prostate biopsies.

Do we need new high-risk criteria for surgically treated renal cancer patients to improve the outcome of future clinical trials in the adjuvant setting? Results of a comprehensive analysis based on the multicenter CORONA database.

BACKGROUND: Since there is still an unmet need for potent adjuvant strategies for renal cancer patients with high progression risk after surgery, several targeted therapies are currently evaluated in this setting. We analyzed whether inclusion criteria of contemporary trials (ARISER, ASSURE, SORCE, EVEREST, PROTECT, S-TRAC, ATLAS) correctly identify high-risk patients. METHODS: The study group comprised 8873 patients of the international CORONA-database after surgery for non-metastatic renal cancer without any adjuvant treatment. Patients were divided into potentially eligible high-risk and assumable low-risk patients who didn't meet inclusion criteria of contemporary adjuvant clinical trials. The ability of various inclusion criteria for disease-free survival (DFS) prediction was evaluated by Harrell's c-index. RESULTS: During a median follow-up of 53 months 15.2% of patients experienced recurrence (5-year-DFS 84%). By application of trial inclusion criteria, 24% (S-TRAC) to 47% (SORCE) of patients would have been eligible for enrollment. Actual recurrence rates of eligible patients ranged between 29% (SORCE) and 37% (S-TRAC) opposed to <10% in excluded patients. Highest Hazard Ratio for selection criteria was proven for the SORCE-trial (HR 6.42; p < 0.001), while ASSURE and EVEREST reached the highest c-index for DFS prediction (both 0.73). In a separate multivariate Cox-model, two risk-groups were identified with a maximum difference in 5-year-DFS (94% vs. 61%). CONCLUSION: Results of contemporary adjuvant clinical trials will not be comparable as inclusion criteria differ significantly. Risk assessment according to our model might improve patient selection in clinical trials by defining a high-risk group (28% of all patients) with a 5-year-recurrence rate of almost 40%.

The association between metabolic syndrome and prostate cancer: Effect on its aggressiveness and progression.

OBJECTIVES: To evaluate the impact of metabolic syndrome and its individual components on prostate biopsy findings, the radical prostatectomy specimen and on biochemical recurrence. MATERIAL AND METHODS: An observational study was conducted of 1319 men who underwent prostate biopsy between January 2007 and December 2011. The impact on the biopsy findings, the radical prostatectomy specimen and biochemical recurrence was evaluated using logistic regression and Cox regression. RESULTS: Of the 1319 patients, 275 (21%) had metabolic syndrome, and 517 prostate cancers were diagnosed. A greater percentage of metabolic syndrome was found among patients with prostate cancer than among patients without prostate cancer (25% vs. 18%; P=.002). Poorer results were found in the radical prostatectomy specimens (Gleason score ≥ 7, P<.001; stage ≥ T2c, P<.001; positive surgical margins, P<.001), and there was a greater percentage of biochemical recurrence in patients with metabolic syndrome than in those without metabolic syndrome (24% vs. 13%; P=.003). Metabolic syndrome behaved as an independent predictive factor of finding a Gleason score ≥ 7 for the specimen, as well as for finding a specimen stage ≥ T2c. Metabolic syndrome was also able to independently predict a greater rate of biochemical recurrence (OR: 3.6, P<.001; OR: 3.2, P=.03; HR: 1.7; respectively). CONCLUSIONS: Metabolic syndrome is associated with poorer findings in the radical prostatectomy specimens and is an independent prognostic factor of biochemical recurrence.

Evolution of the patient characteristics of candidates for radical prostatectomy and the results obtained with the technique.

OBJECTIVES: To evaluate the oncological profile and risk of biochemical recurrence of patients with prostate cancer who underwent radical prostatectomy based on the time period in which the patients were operated. To evaluate the differences in prostate-specific antigen (PSA) at diagnosis of patients with or without biochemical recurrence based on these time periods. MATERIAL AND METHODS: Observation carried forward study of a cohort of 972 radical prostatectomies performed during 3 time periods (1994-2000, 2001-2006, 2007-2011). The importance of PSA at diagnosis on the time periods and on biochemical recurrence was assessed using a generalized linear model. The independent predictive behavior of biochemical recurrence was analyzed using Cox regression. RESULTS: The median follow-up was 38 (16-76) months. PSA levels at diagnosis were higher in the period 1994-2000 (12.97ng/mL, P<.001). Seventy-two percent of the patients from the period 2007-2011 were diagnosed as clinical stage T1c (P<.001), compared with 55% from the period 1994-2000. The percentage of extracapsular extension in the specimen decreased from 27% to 18% from the period 1994-2000 to the period 2007-2011 (p<.001). The percentage of patients with biochemical recurrence went from 38% to 14% from the first to the third period (P>.001). The difference between PSA levels at diagnosis for the patients with or without biochemical recurrence was independent of the period (P=.84). The period during which surgery was performed was not an independent predictive factor for biochemical recurrence (P=.09). CONCLUSIONS: Patients from the 2007-2011 period had less extracapsular disease in the radical prostatectomy. The period was not an independent predictive factor for biochemical recurrence.

Prostate anatomy in motheaten viable (me(v)) mice with mutations in the protein tyrosine phosphatase SHP-1.

OBJECTIVE: To study prostate and seminal vesicle anatomy in viable motheaten (mev) with mutations in PTPN6 gene leading to a severe reduction in the activity of protein tyrosine phosphatase SHP-1. Homozygous mev mice exhibit multiple anomalies that include immunodeficiencies, increased proliferation of macrophage, neutrophil, and erythrocyte progenitors, decreased bone density and sterility. MATERIAL AND METHOD: We analyzed macro- and microscopic anatomy of the seminal vesicle and prostate macro- and microscopic anatomy of 5 mev/mev and 8 wt/wt adult 7 week old mice. Computerized morphometric analysis was performed to measure the relative changes appearing in the epithelial volume of the different prostatic lobes. RESULTS: All mice studied revealed normal genital organs (penis, testis, epididymis, vas deferens) and bladder. The seminal vesicle was absent in all mev/mev individuals analyzed, being normal and very noticeable in wt/wt mice. The different glands that compose the prostatic complex (anterior, ventral and dorso-lateral prostate) were atrophied in mev/mev mice: anterior prostate 0.4 times, ventral 0.19 times, dorsal 0.35 times and lateral 0.28 times those of the respective regions in wt/wt mice. Microscopically, mev/mev mice revealed scarce and large prostatic ducts, acini severely atrophic with empty lumen and scarce loose epithelial component forming tufts and infoldings, and hyperplastic changes in fibromuscular stroma. CONCLUSIONS: The prostate of mev/mev mice exhibits signs of aberrant differentiation and the resulting phenotype may be related to the loss of function of SHP-1. Prostatic anomalies in these mice affect, together with defects in sperm maduration, for their sterility. These data suggest SHP-1 plays an important role in prostate epithelial morphogenesis.

Impact of p53, MIB-1 and PECAM-1 expression on the prognosis of urothelial carcinoma of the renal pelvis.

OBJECTIVE: Determine whether the overexpression p53, MIB-1 and PECAM-1 of protein levels is of interest in predicting the prognosis of transitional cell carcinoma of the upper urinary tract (TCC-UUT) with the primary seat in the renal pelvis. MATERIAL AND METHOD: A univariate and multivariate analysis was conducted for prognosis prediction in a series of 82 patients with TCC-UUT of the renal pelvis who had no metastases at diagnosis (N0/Nx M0) and were treated exclusively with nephroureterectomy. We assessed clinicopathological parameters (age, gender, tumor grade and extent, histological variety, growth pattern, vascular invasion, infiltration of the renal parenchyma, tumor necrosis) and the immunohistochemical expression of p53, MIB-1 (ki-67) and PECAM-1 (CD31) in sections performed with tissue microarray (TMA). RESULTS: A total of 47.6% of the patients had high-grade lesions according to the USIP-WHO classification. The growth pattern was flat in 15.85%. The distribution by T category was: 3.7% pTa, 51.2% pT1, 11% pT2, 29.3% pT3 and 4.9% pT4. The mean follow-up was 46.8+38.5 (range, 4-172) months. The median survival was reached at 57 (95% CI 44-63) months. The univariate analysis revealed that survival in these patients is associated with tumor size (P=.028), histological variety (P<.0001), growth pattern (P<.0001), grade (P<.0001), pT (P=.01), vascular invasion (P=.025), necrosis (P=.004) and overexpression of p53 (P=.0006), PECAM-1 (P=.0036) and MIB-1 (P=.0038). The Cox regression model showed that high-grade (HR, 4.2; 95% CI 1.28-13.79; P=.018), flat growth pattern (HR, 2.52; 95% CI 1.05-6.03; P=.038) and p53 overexpression (HR, 2.8; 95% CI 1.22-6.44; P=.015) were independent predictors. CONCLUSION: Histological grade, tumor growth pattern and p53 overexpression were established as the primary predictors of prognosis for primary TCC-UUT of the renal pelvis. The independent value of MIB-1 observed in other studies was not reproduced in this study.

[Postoperative prognosis of chromophobic renal cell carcinoma: comparative analysis of the multinational CORONA database]. / Die postoperative Prognose des chromophoben Nierenzellkarzinoms : Eine vergleichende Analyse anhand der multinationalen CORONA-Datenbank.

BACKGROUND: The chromophobe subtype represents the third most common histological subtype of renal cell carcinoma (chRCC). Due to the rarity of this subtype only one publication regarding the specific analysis of clinical and histopathological criteria as well as survival analysis of more than 200 patients with chRCC is known to date. MATERIALS AND METHODS: A total of 6,234 RCC patients from 11 centres who were treated by (partial) nephrectomy are contained in the database of this multinational study. Of the patients 259 were diagnosed with chRCC (4.2 %) and thus formed the study group for this retrospective investigation. These subjects were compared to 4,994 patients with a clear cell subtype (80.1 %) with respect to clinical and histopathological criteria. The independent influence of the chromophobe subtype regarding tumor-specific survival and overall survival was determined using analysis by Cox proportional hazards regression models. The median follow-up was 59 months (interquartile range 29-106 months). RESULTS: The chRCC patients were significantly younger (60 vs. 63.2 years, p < 0.001), more often female (50 vs. 41 %, p = 0.005) and showed simultaneous distant metastases to a lesser extent (3.5 vs. 7.1 %, p = 0.023) compared to patients with a clear cell subtype. Despite a comparable median tumor size a ≥ pT3 tumor stage was diagnosed in only 24.7 % of the patients compared to of 30.5 % in patients with a clear cell subtype (p = 0.047). In addition to the clinical criteria of age, sex and distant metastases, the histological variables pTN stage, grade and tumor size showed a significant influence on tumor-specific and overall survival. However, in the multivariable Cox regression analysis no independent effect on tumor-specific mortality (HR 0.88, p = 0.515) and overall mortality (HR 1.00, p = 0.998) due to the histological subtype was found (c-index 0.86 and 0.77, respectively). CONCLUSIONS: Patients with chRCC and clear cell RCC differ significantly concerning the distribution of clinical and histopathological criteria. Patients with chRCC present with less advanced tumors which leads to better tumor-specific survival rates in general; however, this advantage could not be verified after adjustment for the established risk factors.

The role of matrix metalloproteinase MMP-9 and TIMP-2 tissue inhibitor of metalloproteinases as serum markers of bladder cancer.

INTRODUCTION: The diagnosis and molecular staging of bladder cancer based on the detection of gelatinases mRNA (MMP-2 and MMP-9) in peripheral blood circulating and mononuclear cells have shown promising results. We analyze if the determination of the corresponding protein synthesis products makes it possible to diagnose and characterize patients with bladder cancer. MATERIAL AND METHOD: Quantification of the serum levels of MMP-2, MMP-9 and TIMP-2 in a series of 42 individuals (31 patients with bladder cancer in different stages and 11 healthy controls) using the ELISA technique was carried out. The determinations were compared between cases and controls (Mann-Whitney U) and between different groups of tumors (Mann-Whitney U or Kruskal-Wallis), according to the clinical-pathological characteristics (age, gender, T category, M category or grade). Diagnostic yield of these markers was evaluated by analysis of the ROC curves. RESULTS: There is a correlation between the determinations of MMP-2 and TIMP-2 (R=.699; P>.0001) and MMP-9 and TIMP-2 (R=.305; P=.049). Patients with bladder cancer have higher levels of MMP-9 (p<0.0001) and TIMP-2 (P=.047) than the controls. Furthermore, the MMP-9/TIMP-2 ratio is also superior in cancer patients (P<.001). Differences were not detected between cancer and controls regarding age (P=.64) or gender (P=.64). Differences were also not detected regarding MMP-2 (P=.35) or MMP-2/TIMP-2 rate (P=.45). Within the cancer patient population, the MMP-2 and MMP-9 values differ according to T category (P=.022 and P=.038, respectively) and those of the TIMP-2 according to M category (P=.036). ROC curve analysis showed that both MMP-9 and the MMP-9/TIMP-2 ratio discriminate patients with cancer and controls, with equivalent diagnostic accuracy (ABC 0.953) and cut offs of 3.93 ng/mL (S 90%; Sp 81%) and 0.053 ng/mL (S 96%; Sp 84%), respectively. CONCLUSIONS: The results obtained suggest that both serum MMP-9 and TIMP-2 would have an application in the prediction of the development and progression of bladder cancer, and a potential utility as clinical markers of the disease. Multicenter, prospective studies that confirm their preliminary results are necessary.

The study of DNA methylation in urological cancer: present and future.

OBJECTIVES: We have synthesized the principal advances in the field of the study of epigenetics and specifically DNA methylation regarding the diagnosis of urological neoplasms. ACQUISITION OF EVIDENCE: Review of the literature (PubMed, MEDLINE and Cochrane) on the study of DNA methylation in urological neoplasms (prostate cancer, bladder cancer, renal cancer and testicular cancer), considering all the studies published up to January 2013. SYNTHESIS OF EVIDENCE: It was possible to determine the state of methylation of many genes in our tumor samples. When these were compared with healthy tissue samples, it was possible to define the specific aberrant methylation patterns for each type of tumor. The study and definition of specific abnormal methylation patterns of each type of tumor is a tool having potential utility for diagnosis, evaluation, prediction of prognosis and treatment of the different forms of genitourinary cancer. The analysis of gene methylation in urine after micturition or post-prostatic massage urine, semen, in the wash plasma or fluid from prostatic biopsies may allow early detection of bladder, prostate, renal and testicular cancer. In each one of the neoplasms, an epigenetic signature that may be detected in the DNA has been identified, obtained from very scarce or not at all invasive specimens, with potential in the diagnosis and evaluation of prognosis. Validation of these studies will confirm the accuracy, effectiveness and reproducibility of the results available up to now. Criteria have still not been developed that determine if a gene panel provides sufficient information in the health care practice to guide an unequivocal diagnosis or therapeutic conduct. More studies are needed to compare sensitivity, specificity, positive and negative predictive value of the test in each case. Multicenter studies analyzing the real reproducibility of these results in a clinical setting also do not exist. CONCLUSIONS: The study of aberrant DNA methylation in biological specimens of patients has an enormous potential for the early diagnosis and screening of genitourinary neoplasms. A larger number of studies is needed to be able to define the series of genes that would mean unequivocal signatures of malignancy. This methodology also has potential when defining prognostic groups and potential of response to different therapies.

[Variability of the urological clinical practice in prostate cancer in Spain]. / Variabilidad de la práctica clínica urológica en cáncer de próstata en España.

OBJECTIVES: Study the opinion of the Spanish urologists regarding the main points in the diagnosis, prevention, quality of life and treatment of prostate cancer. MATERIAL AND METHODS: An anonymous questionnaire was administered to 290 specialists who represented the urological professional group involved in the management of prostate cancer in Spain. The following were considered in their definition: grade of professional experience, work setting, contractual relation with patient and academic character of the center. The statistical analysis was based on the study of relative frequencies for qualitative variables. The results were interpreted in 2009-10 and the final report of them was done in 2011. RESULTS: Response rate collected and correctly transcribed from the forms was 96.9% (n=281). This accounts for 10-15% of the national group. Median age was 47.7 (29-69) years and 92% were men. Mean years of professional experience were 19.1 (1-43). Responses collected regarding 153 questions were analyzed. These dealt with: a) How the diagnosis of the disease was carried out in the setting of the surveyed; b) The opinions given on the disease prevention; c) Treatment of the localized treatment; d) Treatment of the advanced disease; and e) The definition of the fields of interest for the professional. CONCLUSION: This survey showed important variability in some points of clinical practice in regards to the recommendations of the experts. It also shows the principal concerns of the professional, defines opportunities for training improvements and detects needs in the national urological group.

[Effectiveness and tolerability of zoledronic acid in the treatment of metastatic prostate cancer]. / Efectividad y tolerabilidad del acido zoledrónico en el tratamiento del cancer de próstata metastásico.

OBJECTIVES: To assess the effectiveness and tolerability of zoledronic acid in prostate cancer patients with bone metastases at the hormone-sensitive (HS) and hormone-independent (HI) stages. MATERIALS AND METHODS: A nationwide, observational, prospective, open and multi-centre trial was devised, with a total of 218 male patients diagnosed with prostate cancer at the HS stage (36%) or HI stage (64%) who were administered zoledronic acid (4 mg/IV/month for 6 months) in addition to their specific oncological treatment. Effectiveness was assessed by the following means: 1) Assessment of the improvement in pain and mobility; 2) Incidence and time to onset of skeletal-related events (SREs) and 3) Analysis of bone markers. Tolerability was assessed by means of registering the number and type of adverse effects. A satisfaction survey was carried out amongst the patients after the end of the trial. RESULTS: Out of the 218 patients, 170 (78%) were evaluable for effectiveness. A decrease in pain ratings at rest and during movement was observed in all patients, whether in the HS or HI groups (p < 0.0001). Improved mobility was observed likewise (p = 0.005), as was quality of life. The global incidence of skeletal events was 11.2%, with a time to onset of SREs of 10.7 months. There were no significant differences observed between HS vs. HI patients. Osteolysis markers (N-telopeptide) decreased significantly with the treatment across both the HS and HI groups. For safety reasons. 212 patients were evaluable (97.2%). The incidence of adverse drug reactions was 16% (34/212) and was found to be significantly higher in HS patients (22.4%) compared with HI patients (11.9%). Overall, the tolerability of zoledronic acid was good, with no significant morbidity in either group (HS and HI). 66% of the patients reported feeling satisfied or very satisfied. CONCLUSIONS: Zoledronic acid proved effective in the relief of pain, improving mobility and quality of life as well as reducing or delaying the occurrence of skeletal-related events in prostate cancer patients presenting metastatic bone disease, regardless of the phase, whether HS or HI, they found themselves in. Tolerability and patient satisfaction were rates as good.

Bicalutamide (Casodex) 150 mg plus standard care in early non-metastatic prostate cancer: results from Early Prostate Cancer Trial 24 at a median 7 years' follow-up.

Trial 24, one of three ongoing trials in the Early Prostate Cancer programme, is evaluating the efficacy and tolerability of bicalutamide (Casodex) 150 mg following standard care (radiotherapy, radical prostatectomy or watchful waiting) in patients with early, non-metastatic prostate cancer. At 7 years' median follow-up, addition of bicalutamide significantly improved objective progression-free survival (PFS) for patients with locally advanced disease, reducing the risk of progression by 34% versus standard care alone (hazard ratio 0.66; 95% confidence interval 0.55, 0.79; P<0.001). In localized disease, a significant difference in objective PFS was not found. There was no significant difference in overall survival.

Bicalutamide ('Casodex') 150 mg in addition to standard care in patients with nonmetastatic prostate cancer: updated results from a randomised double-blind phase III study (median follow-up 5.1 y) in the early prostate cancer programme.

Trial 24 is one of three placebo-controlled trials within the ongoing bicalutamide ('Casodex') Early Prostate Cancer (EPC) programme evaluating bicalutamide 150 mg/day in addition to radical prostatectomy, radiotherapy or watchful waiting for T1b-4, any N, M0 prostate cancer. In Trial 24, at 5.1 y median follow-up, the addition of bicalutamide significantly (P < 0.0001) improved objective progression-free survival (PFS) and prostate-specific antigen PFS compared with standard care alone. There was no significant difference in overall survival (P = 0.746). In the context of the whole EPC programme, long-term bicalutamide is not appropriate for localised disease, yet provides advantages in delaying disease progression in patients with locally advanced prostate cancer.

[Importance of heterotrimeric G proteins in prostate cancer molecular biology]. / Importancia de las proteínas G heterotriméricas en la biología molecular del cáncer de próstata.

OBJECTIVE: To deep in the knowledge of the involvement of G-protein alphas and alphai subunits in human prostate cancer. METHODS: Prostate tissue from 9 patients undergoing radical prostatectomy for prostate cancer and 5 controls undergoing cystoprostatectomy for bladder carcinoma. G-protein alphas and alphai subunits were studied for expression (mRNA by RT-PCR and protein by Western-blot), functionality (adenylyl cyclase activity, AC) and possibility of mutations (analysis with restriction enzymes and cDNA sequentiation). RESULTS: At mRNA level, the expression of alphas, alphai1, alphai2 y alphai3 was detected in healthy and cancerous tissues. At protein level, the expression of alphas y alphai1,2 diminished (25% and 40%, respectively) in prostate cancer. The expression of alphai3/0 also diminished, whereas that of beta subunit was not modified. Basal AC activity in adenocarcinoma membranes was 40% inferior to the control. Digestion with restriction enzymes Eag I or AlwN I did not allow to locate mutations in alphas. However, digestion at alphai2 level with BstU I enzyme served to observe a change of Gln205 (CAG triplet) to Pro (CCG). CONCLUSIONS: The functionality and expression of heterotrimeric G proteins are selectively modified in human prostate adenocarcinoma, occurring in addition some punctual mutation. The observed substitution of Gln205 by Pro may result in a low GTPase activity for alphai2 that, therefore, is stabilized in its active form.

[Expression of p21ras in locally confined renal adenocarcinoma and its prognostic implications]. / Expresión de la proteína p21ras en el adenocarcinoma renal localmente confinado y sus implicaciones pronósticas.

OBJECTIVE: The p21ras protein is encoded by the three ras genes (H-, K- and N-ras) and participate in the regulation of normal cell growth and cell differentiation. The objective of this study is to determine the expression of this protein in locally confined renal cell carcinoma, as well as its relations with different histopathological variables and their prognostic implications. METHOD: 58 renal cell carcinomas, in pT1-T3a N0 M0 (TNM 1997) stages, treated by radical or partial nephrectomy with curative intention. We analysed different clinical and anatomopathological variables, as well as expression of p21ras in paraffinated tissue, using immunohistochemical techniques. RESULTS: The mean percentage of stained nuclei was 6.1%, with a range lying between 0 and 45%. We did not obtain statistically significant association between expression of p21ras and the tumour size (p = 0.698), the nuclear grade (p = 0.676) or the histopathological stage (p = 0.095). The survival analysis also did not show significant differences when we stratified the patients using the mean value of the sample as reference point (p = 0.134). CONCLUSIONS: Expression of p21ras was not demonstrated to be related to any of the histopathological variables analysed: size, grade and stage, or with survival. Therefore, this protein does not appear to be related to the evolution of renal cell carcinoma.

[Apoptosis in renal adenocarcinoma. Expression of bcl-2 in locally confined tumors]. / Apoptosis en el adenocarcinoma renal. Expresión de bcl-2 en tumores localmente confinados.

INTRODUCTION AND OBJECTIVE: Bcl-2 is a proto-oncogene known to be a negative regulator of apoptosis, whose expression conferring prolonged cell survival and contributing to tumorigenesis. Inconsistent results concerning bcl-2 expression and the frequency of apoptosis were noted in renal cell carcinoma. To investigate a possible role of bcl-2 protein in renal cell carcinomas, we analyzed its expression and relationship with clinical and pathological parameters, including prognostic impact. METHODS: 58 patients diagnosed of renal cell carcinoma stage pT1, pT2 and pT3a N0 M0 (TNM 1997) were treated by radical or partial nephrectomy. We analyzed clinical and pathological parameters including bcl-2 expression in paraffin-embedded tumor samples using immunohistochemical technique. RESULTS: Bcl-2 immunopositivity was detected in 44/58 of the samples in different grades of intensity. There was no correlation of nuclear grade, tumoral size, stage or recurrency with bcl-2 immunopositivity. Bcl-2 expression was not related to prognosis if we divided all cases into subgroups according of stain intensity. CONCLUSIONS: Bcl-2 expression was not related with any pathological parameters; size, nuclear grade and stage or prognostic.

Low expression of Galpha protein subunits in human prostate cancer.

PURPOSE: Because of increasing interest in G protein regulation of cell growth, differentiation and oncogenesis, we studied the functionality and expression of different G protein subunits in human prostate adenocarcinoma. MATERIALS AND METHODS: Surgical prostate specimens from control patients with bladder cancer and patients with prostate cancer were used. The functionality of alphas and alphai G protein subunits was evaluated by studying somatostatin or guanyl-5'-yl-imidotriphosphate regulation of forskolin stimulated adenylyl cyclase activity. The expression of alphas, alphai and beta subunits was studied by reverse transcriptase-polymerase chain reaction and immunoblot analysis. RESULTS: Adenylyl cyclase sensitivity to somatostatin inhibition decreased in prostate cancer. Low guanyl-5'-yl-imidotriphosphate doses inhibited forskolin stimulated adenylyl cyclase, whereas the opposite was true at high concentrations, evidencing the functionality of alphai and alphas, respectively, in normal and cancer tissue samples. Reverse transcriptase-polymerase chain reaction revealed RNA encoding for alphas and alphai1,2,3 subclasses in normal and pathological conditions. However, immunoblot analysis showed that the level of beta subunits was maintained, whereas that of alphas and alphai subunits decreased 30% to 40% after neoplastic transformation. The levels of alphas and alphai1,2 subunits correlated inversely with serum prostate specific antigen in patients with prostate cancer. CONCLUSIONS: The functionality and expression of G protein subunits are selectively modified in human prostate adenocarcinoma. Low alphas and alphai levels in prostate cancer suggest an important regulatory role of G proteins for cell proliferation and neoplastic transformation in the human prostate and they may have prognostic value.

Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression.

OBJECTIVES: To investigate the efficacy and tolerability of bicalutamide (Casodex) as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with localized or locally advanced (T1b-T4, any nodal status, M0) prostate cancer. METHODS: This was a multicenter, prospective, randomized, double-blind, placebo-controlled trial in Europe, South Africa, Australia, and Mexico and is part of the Casodex Early Prostate Cancer program. RESULTS: A total of 3603 men were randomized to receive bicalutamide (n = 1798) or placebo (n = 1805). The patient demographics were well balanced between the two groups. Prior therapy of curative intent had been given to 64% of the patients (prostatectomy [44%], radiotherapy [18%], and prostatectomy and radiotherapy [2%]) and 36% had been monitored with watchful waiting. After a median follow-up of 2.6 years and a median exposure to the study drug of 2.2 years, a significant 43% reduction in the risk of objective progression was observed for the bicalutamide group compared with the placebo group (hazard ratio 0.57, 95% confidence interval 0.48 to 0.69, P << 0.0001). The time to prostate-specific antigen doubling was significantly delayed for the bicalutamide group compared with the placebo group (hazard ratio 0.37, 95% confidence interval 0.32 to 0.43, P << 0.001). The survival data were immature, with 7.2% overall mortality. The most frequently reported adverse events with bicalutamide were gynecomastia alone (17.4%), breast pain alone (17.6%), and gynecomastia with breast pain (47.5%). CONCLUSIONS: Bicalutamide 150 mg daily as immediate therapy, alone or as adjuvant to treatment of curative intent, significantly reduced the risk of disease progression in patients with localized or locally advanced prostate cancer. Longer follow-up is underway to assess any benefit in overall survival.

Effects of the luteinising hormone-releasing hormone (LH-RH) agonist leuprolide on adenylyl cyclase regulation through G-protein coupled receptors in rat ventral prostate.

Luteinising hormone-releasing hormone (LH-RH) agonists are widely used for the therapy of advanced prostate cancer through the suppression of testosterone secretion. Furthermore, recent studies indicate the existence of prostate LH-RH receptors coupled to signalling pathways resulting in direct antiproliferative effects. In order to shed light on the mechanisms through which these compounds inhibit prostate cell growth, we investigated the effects of leuprolide (a LH-RH agonist) treatment of rats compared with the effects of surgical castration on the behaviour of G-protein coupled receptors acting through adenylyl cyclase in the ventral prostate. Important decreases of both plasma testosterone levels and ventral prostate weight were observed 5 weeks after subcutaneous (s.c.) injection of a leuprolide-depot preparation (1.5 mg/kg body weight (b.w.)) or 5 days after bilateral gonadectomy. However, leuprolide treatment increased the number of vasoactive intestinal peptide (VIP) receptors and the ability of this neuropeptide to stimulate adenylyl cyclase activity in prostate membranes, whereas surgical castration decreased both parameters. Moreover, leuprolide resulted in significant increases of prostate alpha(s) and alpha(i1-3) (but not alpha(i1) and beta) G-protein levels, while the four G-protein subunits were overexpressed after gonadectomy. The estimation of alpha(s) and alpha(i) activity by experiments with Gpp[NH]p and forskolin indicated a potentiation of the two arms of adenylyl cyclase regulation in leuprolide-treated rats. Present observations suggest that leuprolide treatment leads to an antimitogenic response by acting mainly through the activation of Gi proteins negatively coupled to adenylyl cyclase.