Tommaso Prayer-Galetti

Multi-Institutional Validation of a New Renal Cancer–Specific Survival Nomogram

PURPOSE We tested the hypothesis that the prediction of renal cancer-specific survival can be improved if traditional predictor variables are used within a prognostic nomogram. PATIENTS AND METHODS Two cohorts of patients treated with either radical or partial nephrectomy for renal cortical tumors were used: one (n = 2,530) for nomogram development and for internal validation (200 bootstrap resamples), and a second (n = 1,422) for external validation. Cox proportional hazards regression analyses modeled the 2002 TNM stages, tumor size, Fuhrman grade, histologic subtype, local symptoms, age, and sex. The accuracy of the nomogram was compared with an established staging scheme. RESULTS Cancer-specific mortality was observed in 598 (23.6%) patients, whereas 200 (7.9%) died as a result of other causes. Follow-up ranged from 0.1 to 286 months (median, 38.8 months). External validation of the nomogram at 1, 2, 5, and 10 years after nephrectomy revealed predictive accuracy of 87.8%, 89.2%, 86.7%, and 88.8%, respectively. Conversely, the alternative staging scheme predicting at 2 and 5 years was less accurate, as evidenced by 86.1% (P = .006) and 83.9% (P = .02) estimates. CONCLUSION The new nomogram is more contemporary, provides predictions that reach further in time and, compared with its alternative, which predicts at 2 and 5 years, generates 3.1% and 2.8% more accurate predictions, respectively.

Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers

Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.

Urinary incontinence after radical prostatectomy: incidence by definition, risk factors and temporal trend in a large series with a long-term follow-up

To investigate the incidence of urinary incontinence and its development over time, to compare the effects of alternative definitions on the incontinence rate and to explore risk factors for incontinence after radical retropubic prostatectomy (RRP) for clinically localized prostate cancer.

Prognostic Value of Renal Vein and Inferior Vena Cava Involvement in Renal Cell Carcinoma

BACKGROUND The prognostic significance of venous tumor thrombus extension in patients with renal cell carcinoma (RCC) is a matter of many controversies in the current literature. OBJECTIVE To evaluate the prognostic role of inferior vena cava (IVC) involvement in a large series of pT3b and pT3c RCCs. DESIGN, SETTING, AND PARTICIPANTS A total of 1192 patients from 13 European institutions underwent a radical nephrectomy for pT3b and pT3c RCC between 1982 and 2003. The patients were evaluated in a retrospective manner. Age, gender, clinical symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, TNM stage, tumor size, adrenal invasion, perinephric fat invasion, histological type, and Fuhrman grade were reviewed. The log-rank and Cox uni- and multivariate regression analyses were used to evaluate prognostic factors for overall survival. MEASUREMENTS Overall survival and prognostic factors for overall survival in patients with RCC extending to the renal vein (RV) or to the IVC. RESULTS AND LIMITATIONS The median follow-up was 61.4 mo (56.3-66.5 mo). The mean age was 63.2 yr. The mean tumor size was 8.9 cm. Group 1 (Gr 1) included 933 patients with a renal vein tumor thrombus (78.3%), Group 2 (Gr 2) included 196 patients with a subdiaphragmatic IVC tumor thrombus (16.4%), and Group 3 (Gr 3) included 63 patients with a supradiaphragmatic IVC tumor thrombus (5.3%). Median survival was 52 mo for Gr 1, 25.8 mo for Gr 2, and 18 mo for Gr 3. In univariate analysis, Gr 1 had a significantly better overall survival than Gr 2 (p<0.001) and Gr 3 (p<or=0.001). No significant difference in survival was noted between Gr 2 and Gr 3 (p=0.613). Prognostic factors for overall survival in univariate analysis were clinical symptoms (p<0.001), tumor size (p<0.001), perinephric fat invasion (p<0.001), Fuhrman grade (p<0.001), histological type (p=0.021), lymph node invasion (p<0.001), and distant metastasis (p<0.001). Independent prognostic factors in multivariate analysis were tumor size (p=0.013), perinephric fat invasion (p=0.003), lymph node invasion (p<0.001), distant metastasis (p<0.001), and IVC invasion (p=0.008). CONCLUSIONS The level of tumor thrombus in the IVC does not significantly affect long-term overall survival in patients with renal cell carcinoma. The overall survival was statistically different for patients with a tumor thrombus in the RV compared to those with IVC involvement. This has to be considered for the next revision of the TNM system, and the pT3b and pT3c stages have to be redesigned.

Incidental Detection beyond Pathological Factors as Prognostic Predictor of Renal Cell Carcinoma

PURPOSE To evaluate the prognostic significance of different detection modalities of renal cell carcinoma (RCC) in a large cohort of patients who had been previously submitted to surgery in two teaching hospitals in Italy. MATERIALS AND METHODS We reviewed the clinical records of 1446 patients who had been submitted to surgical treatment for RCC at the Departments of Urology of Padua (n=747) and Verona (n=699) from 1976 to 2000. Patients were classified into two groups according to the detection mode: symptomatic and incidental. The cancer-specific survival probability was estimated according to the Kaplan-Meier method. In order to compare the survival curves the log rank test was used. The predictive independent value of the variables was examined using the Cox proportional hazards model. RESULTS Six hundred and thirty patients (43.6%) were treated for incidental RCC and 816 (56.4%) for symptomatic RCC. In the incidental group, the size (p<0.001), the pathological stage (p<0.001) and the nuclear grading (p<0.001) of tumors were lower than those causing symptoms. The 5-year and 10-year cancer-specific survival probability were 84% and 75% in the incidental group, and 66% and 54.5% in the symptomatic group (p<0.0001), respectively. At a multivariate analysis, the mode of detection was an independent predictive variable (H.R. 1.559), as well as pathological stage (H.R. 1.809), nuclear grading (H.R. 1.411), size <or=4 cm (H.R. 1.667), and venous involvement (H.R. 1.526). CONCLUSION In patients with RCC, the detection modality can predict the cancer-specific survival rate independently of tumor pathological stage and grading.

Gene expression, localization, and characterization of endothelin A and B receptors in the human adrenal cortex.

Compelling evidence indicates that the endothelium-derived potent vasoconstrictor endothelin-1 (ET-1) stimulates aldosterone secretion by interacting with specific receptors. Although two different ET-1 receptors have been identified and cloned, the receptor subtype involved in mediating aldosterone secretion is still unknown. Accordingly, we wished to investigate whether the genes of ET-1 and of its receptors A and B are expressed in the normal human adrenal cortex. We designed specific primers for ET-1 and the ETA and ETB receptors genes and developed a reverse transcription polymerase chain reaction (RT-PCR) with chemiluminescent quantitation of the cDNA. In addition, we carried out 125I ET-1 displacement studies with cold ET-1, ET-3 and the specific ETA and ETB ligands BQ123 and sarafotoxin 6C. Localization of each receptor subtype was also investigated by autoradiography. Binding experiments were first individually analyzed by Scatchard and Hofstee plot and then coanalyzed by the nonlinear iterative curve fitting program Ligand. Histologically normal adrenal cortex tissue, obtained from kidney cancer patients (n = 7), and an aldosterone-producing adenoma (APA), which is histogenetically derived from the zona glomerulosa (ZG) cells, were studied. Results showed that the ET-1, ETA and ETB mRNA can be detected by RT-PCR in all adrenal cortices as well as in the APA. The best fitting of the 125I ET-1 displacement binding data was consistently provided by a two-site model both in the normal adrenal cortex (F = 22.1, P < 0.0001) and in the APA (F = 18.4, P < 0.0001). In the former the density (Bmax) of the ETA and ETB subtype was 2.6 +/- 0.5 pmol/mg protein (m +/- SEM) and 1.19 +/- 0.6, respectively. The dissociation constant (Kd) of ET-1, ET-3, S6C, and BQ-123 for each receptor subtype resulted to be within the range reported for human tissue for the ETA and ETB receptors. In the APA tissue the Bmax tended to be lower (1.33 and 0.8 pmol/mg protein, for the ETA and ETB, respectively) but the Kd were similar. Autoradiographic studies confirmed the presence of both receptor subtypes on the ZG as well as on APA cells. Thus, the genes of ET-1 and both its receptor subtypes ETA and ETB are actively transcribed in the human adrenal cortex. Furthermore, both receptor subtypes are translated into proteins in ZG and APA cells.

The role of intermittent androgen deprivation in prostate cancer

Laurent Boccon-Gibod, Peter Hammerer*, Stephan Madersbacher†, Nicolas Mottet‡, Tommaso Prayer-Galetti¶ and Ulf Tunn§ Departments of Urology, Hopital Bichat, Paris, France, *Academic Hospital, Braunschweig, Germany, †/Andrology, Donauspital, Vienna, Austria; ‡Clinique Mutualiste, St Etienne, France, ¶Institute of Urology, University of Padua, Padua, Italy; and §Academic Hospital, Offenbach, Germany

Optimizing outcomes and quality of life in the hormonal treatment of prostate cancer

We review the effectiveness of androgen‐deprivation therapy (ADT) in the management of prostate cancer, and the effect that this treatment has on a patient’s quality of life (QoL), based on discussions held at a European symposium on the management of prostate cancer. The overall QoL is reduced in asymptomatic men, and there are known decreases in cognitive function, self‐esteem, libido and sexual function. Hot flashes are also a frequent problem. Prolonged ADT can lead to osteoporosis and subsequently fractures. Various effective methods exist to manage and minimize these side‐effects; some are specific to the side‐effect, whereas other more general methods include lifestyle changes, specific drugs and added hormonal manipulations. Intermittent ADT for patients taking luteinizing hormone‐releasing hormone agonists offers a promising method to reduce adverse effects, and possibly increases the time to androgen independence. Initial studies indicate that prostate‐specific antigen‐based progression with intermittent ADT is similar to that seen with continuous ADT, but there is a reduction in side‐effects, leading to an improvement in QoL.

Clinical and Pathological Characteristics of Patients Presenting with Biochemical Progression after Radical Retropubic Prostatectomy for Pathologically Organ-Confined Prostate Cancer

Introduction: To identify risk factors for biochemical failure after radical prostatectomy (RP) in men with pathologically organ-confined (OC) prostate cancer (PCa). Materials and Methods: Clinical and pathological features of 350 consecutive patients with pathologically OC PCa treated only with RP and bilateral pelvic lymphadenectomy were analyzed, retrospectively, to identify predictor parameters of prostate-specific antigen (PSA) failure (PSA ≧0.4 ng/ml). The median follow-up was 58.6 months (range: 3.9–183 months). All pathological specimens were step sectioned at 4-mm intervals. Kaplan-Meier progression-free survival rates and χ2 test were adopted for statistical analyses. Multivariate Cox proportional hazard regression models were used to test the association between pathological Gleason score and surgical margin status. Results: 67 patients (19.1%) failed at a median follow-up of 40.2 months (range 1.9–123.3). Age and preoperative PSA failed to reveal significance also in patients with serum PSA ≧20 ng/ml (p = 0.46). Patients with T3 clinical stage had a higher progression rate compared to T1C and T2 (43.5 vs. 27.8 and 17.3%, respectively) even if no high statistical significance was pointed out. Presence of perineural infiltration (p = 0.04) and prostatic apex infiltration (p = 0.74) in the prostatectomy specimens failed to reveal significance. A high pathological Gleason score (≧7; p = 0.0003) and surgical margin status (p < 0.0001) were shown to be the most powerful predictive parameters of biochemical progression. Conclusions: In patients with pathologically OC PCa the presence of a high pathological Gleason score and positive surgical margins appear to represent the most important factors for prediction of outcome following RP.

Total PSA, free PSA/total PSA ratio, and molecular PSA detection in prostate cancer: which is clinically effective and when?

OBJECTIVES To ascertain when the serum determination of the free prostate-specific antigen (PSA)/total PSA (fPSA/tPSA) ratio is clinically useful, and whether the identification of PSA or prostate-specific membrane antigen (PSM) mRNA in circulating cells has diagnostic advantages over the determination of their protein product. METHODS fPSA, tPSA, and the fPSA/tPSA ratio were determined in the sera of 50 men with benign nonprostatic urologic diseases (EPD), 112 patients with prostate cancer (PCa), and 218 with benign prostatic hyperplasia (BPH). mRNA was extracted from the circulating mononuclear cells of 13 EPD samples, 25 PCa samples, and 38 BPH samples. PSA and PSM mRNA signals were identified in these samples by means of reverse transcriptase-polymerase chain reaction. RESULTS Overall, at a fixed specificity of 95%, the sensitivity of tPSA was 19% and that of the fPSA/tPSA ratio was 40% in distinguishing PCa from BPH. The fPSA/tPSA ratio allowed the discrimination of PCa from BPH with satisfactory sensitivity and specificity when considering patients less than 60 years of age (100% and 95%, respectively). PSA and PSM mRNA were positive in 1 and 7 of 13 EPD samples, 6 and 13 of 25 PCa samples, and 6 and 17 of 38 BPH samples. The Gleason score did not correlate with tPSA, the fPSA/tPSA ratio, PSA mRNA, or PSM mRNA. CONCLUSIONS The serum determination of the fPSA/tPSA ratio is an excellent index of PCa for subjects younger than 60 years of age; the clinical utility of PSA mRNA identification in circulating cells needs to be validated by large follow-up studies, and the analysis of PSM mRNA seems to be of no clinical interest.