Francesco Paolo Selvaggi

4–Year Follow–Up Results of a European Prospective Randomized Study on Neoadjuvant Hormonal Therapy prior to Radical Prostatectomy in T2–3N0M0 Prostate Cancer

Objectives: To evaluate the long–term effects of 3–month neoadjuvant hormonal treatment in patients treated by radical prostatectomy for locally confined prostate cancer.Methods: We report the results of 402 patients (220 with a clinical T2 tumor and 182 with a clinical T3 tumor) of whom 192 randomly received neoadjuvant total androgen deprivation using a LHRH analogue (goserelin) plus flutamide for a period of 3 months and 210 underwent radical prostatectomy only.Results: ‘Clinical downstaging’ was seen in 30% of cases in the neoadjuvantly treated group (NEO). ‘Pathological downstaging’ occurred in 7 and 15% of cases in the direct radical prostatectomy (DP) group and the NEO group, respectively (p<0.01). In patients with clinical T2 as well as in patients with clinical T3 tumors, a significant difference in the number of positive margins was shown in favor of the NEO group (cT2, p<0.01; cT3, p = 0.01). This advantage, although there was a trend in favor of the NEO group, specifically in cT2 tumors, did not translate in a significantly better PSA progression rate (p = 0.18). However, when evaluating the local control rate in cT2 tumors, we observed local recurrence in 3 of 102 (3%) patients in the NEO group versus 12 of 114 (11%) patients in the DP group. The difference is statistically significant (p = 0.03). In the cT3 group, this difference was not statistically significant (NEO group: 15 of 87 (17%), and DP group: 21 of 95 (22%) patients; p = 0.41).Conclusions: In this study, the clinical revelance of pathological downstaging and the lower percentage of patients with positive margins in the neoadjuvantly treated group with a clinical T2 tumor is not confirmed by a lower PSA progression rate. However, this study indicates that there may be a trend that this advantage in favor of the NEO group directly translates into a better local control rate in clinical T2 tumors. Better local control in cT2 tumors is only going to be of relevance if subsequently you can show that there is a better survival for these patients. Unfortunately, this article reports a study which is not yet mature enough to show relevant information. Presently, neoadjuvant therapy should not be given outside clinical research settings.

Therapeutic Targeting of Classical and Lectin Pathways of Complement Protects from Ischemia-Reperfusion-Induced Renal Damage

Ischemia-reperfusion injury is the major cause of delayed graft function in transplanted kidneys, an early event significantly affecting long-term graft function and survival. Several studies in rodents suggest that the alternative pathway of the complement system plays a pivotal role in renal ischemia-reperfusion injury. However, limited information is currently available from humans and larger animals. Here we demonstrated that 30 minutes of ischemia resulted in the induction of C4d/C1q, C4d/MLB, and MBL/MASP-2 deposits in a swine model of ischemia-reperfusion injury. The infusion of C1-inhibitor led to a significant reduction in peritubular capillary and glomerular C4d and C5b-9 deposition. Moreover, complement-inhibiting treatment significantly reduced the numbers of infiltrating CD163(+), SWC3a(+), CD4a(+), and CD8a(+) cells. C1-inhibitor administration led to significant inhibition of tubular damage and tubular epithelial cells apoptosis. Interestingly, we report that focal C4d-deposition colocalizes with C1q and MBL at the peritubular and glomerular capillary levels also in patients with delayed graft function. In conclusion, we demonstrated the activation and a pathogenic role of classical and lectin pathways of complement in a swine model of ischemia-reperfusion-induced renal damage. Therefore, inhibition of these two pathways might represent a novel therapeutic approach in the prevention of delayed graft function in kidney transplant recipients.

Ischemia-Reperfusion Induces Glomerular and Tubular Activation of Proinflammatory and Antiapoptotic Pathways: Differential Modulation by Rapamycin

Ischemia-reperfusion (I-R) injury in transplanted kidney, a key pathogenic event of delayed graft function (DGF), is characterized by tubular cell apoptosis and interstitial inflammation. Akt-mammalian target of rapamycin-S6k and NF-kappaB-inducing kinase (NIK)-NF-kappaB axis are the two main signaling pathways regulating cell survival and inflammation. Rapamycin, an immunosuppressive drug inhibiting the Akt axis, is associated with a prolonged DGF. The aim of this study was to evaluate Akt and NF-kappaB axis activation in patients who had DGF and received or not rapamycin and in a pig model of I-R and the role of coagulation priming in this setting. In graft biopsies from patients who were not receiving rapamycin, phosphorylated Akt increased in proximal tubular, interstitial, and mesangial cells with a clear nuclear translocation. The same pattern of activation was observed for S6k and NIK. However, in rapamycin-treated patients, a significant reduction of S6k but not Akt and NIK activation was observed. A time-dependent activation of phosphatidylinositol 3-kinase, Akt, S6k, and NIK was observed in the experimental model with the same pattern reported for transplant recipients who did not receive rapamycin. Extensive interstitial and glomerular fibrin deposition was observed both in pig kidneys upon reperfusion and in DGF human biopsies. It is interesting that the activation of both Akt and NIK-NF-kappaB pathways was induced by thrombin in cultured proximal tubular cells. In conclusion, the data suggest that (1) coagulation may play a pathogenic role in I-R injury; (2) the Akt axis is activated after I-R, and its inhibition may explain the prolonged DGF observed in rapamycin-treated patients; and (3) NIK activation in I-R and DGF represents a proinflammatory, rapamycin-insensitive signal, potentially leading to progressive graft injury.

Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer

From March 1987 to December 1990, 373 patients with stage C and D prostate cancer were randomized to receive either goserelin acetate alone or goserelin acetate plus flutamide. At a median follow-up time of 24 months, there was no significant difference in the response rate, progression-free and overall survival between the two treatment groups. In particular, median time to progression was 18 months in the goserelin arm and 24 months in the combined treatment arm (P = 0.09). However, median time to progression in stage D patients was 12 months in both treatment groups. Median time to death was 32 and 34 months, respectively. The combination regimen produced a more rapid normalisation of prostatic acid phosphatase levels and a prompt relief of bone pain. However, significantly more patients in the combination arm experienced treatment-related side-effects such as diarrhoea and increases in transaminase levels. The concurrent use of goserelin acetate and flutamide does not seem to significantly improve the results that can be achieved with goserelin acetate alone.

Patient and Partner Satisfaction after AMS Inflatable Penile Prosthesis Implant

INTRODUCTION The implantation of penile prostheses is an effective option for treating erectile dysfunction (ED), and nowadays it is used to treat those cases where pharmacological agents have not provided a useful result. AIMS The primary aim of the present study was to verify the patient and their partners satisfaction, in 80 patients who underwent AMS CX 700 prostheses implant in a single center, by the same surgeon, in the period between 2004 and 2008. METHODS In the period between March 2004 and May 2008, 80 penile prostheses implantations have been performed. Any information regarding patients has been retrospectively collected consulting their case histories stored in our archive. Each patient was followed postoperatively, and surgical complications were recorded. MAIN OUTCOME MEASURE All the patients entered in this study were contacted by phone by a single operator who asked for their consent to collect information regarding their operation, the use of the prostheses, and the couple satisfaction. Once the consent was obtained, a nine-point questionnaire was administered. RESULTS Seventy-six patients (97%) affirmed to use penile prostheses frequently. Fifty-four patients (69%) and 70 partners (90%) affirmed that they never had problems with the use of the prosthesis and they considered themselves satisfied. Sixty-two patients (79%) answered that this therapeutic method has led to evident improvements in their sexual life. Sixty-two patients (79%) gave a score equal or major than seven and sixty-four partners (82%) gave a score equal or major than seven. All but two patients (97%) reported they would suggest this treatment to other people. CONCLUSIONS Penile prosthetic surgery constitutes a valid therapeutic alternative, capable of modifying the prognosis and the course of ED. This consideration is emphasized by the high rate of patients and partners satisfaction emerged in our series and in literature.

Serum sarcosine increases the accuracy of prostate cancer detection in patients with total serum PSA less than 4.0 ng/ml

Sarcosine is reported to be a differential metabolite that is greatly increased during prostate cancer (PCa) progression. In this study, we assessed the role of serum sarcosine as a biomarker for PCa, as well as any association between sarcosine levels and clinical–pathological parameters.

GEMCITABINE PLUS CISPLATIN FOR ADVANCED TRANSITIONAL CELL CARCINOMA OF THE URINARY TRACT: A PHASE II MULTICENTER TRIAL

PURPOSE We determined the activity and toxicity of gemcitabine plus cisplatin in patients with inoperable or metastatic transitional cell carcinoma of the urinary tract. MATERIALS AND METHODS A total of 54 patients with transitional cell carcinoma, measurable disease and Eastern Cooperative Oncology Group performance status 2 or greater were enrolled in this multicenter phase II trial. Previous adjuvant or neoadjuvant therapy for locally advanced disease was acceptable if it had been completed more than 1 year before study entry. Every 4 weeks patients received 1,000 mg./m.2 gemcitabine intravenously on days 1, 8 and 15, and 70 mg./m.2 cisplatin intravenously on day 2. RESULTS All patients were evaluable for response and toxicity. Notably only 7 of the 54 patients (13%) previously received chemotherapy in an adjuvant or neoadjuvant setting. Overall we observed 26 objective responses (48%), of which 15% were complete. Median time to progression was 23 weeks and median survival was 54 weeks. Treatment was well tolerated. The main toxicities were leukopenia (grade 3 in 28% and grade 4 in 11% of patients), anemia (grade 3 in 34% and grade 4 in 6%) and thrombocytopenia (grade 3 in 14% and grade 4 in 6%). Other relevant side effects were nausea and vomiting in 20% of cases, fever in 24%, alopecia in 22%, renal failure in 7.4% and mucositis in 2%. CONCLUSIONS Combined cisplatin plus gemcitabine is highly active in advanced transitional cell carcinoma of the urinary tract with manageable toxicity. The response rate, time to treatment failure and overall survival appeared to be comparable to those achieved with combined methotrexate, vinblastine, doxorubicin and cisplatin. Conversely toxicity appeared lower. Evaluation of this regimen in randomized studies with methotrexate, vinblastine, doxorubicin and cisplatin is strongly suggested.

Regulation of mRNA and Protein Levels of β1 Integrin Variants in Human Prostate Carcinoma

Alterations of integrin expression levels in cancer cells correlate with changes in invasiveness, tumor progression, and metastatic potential. The beta1C integrin, an alternatively spliced form of the human beta1 integrin, has been shown to inhibit prostate cell proliferation. Furthermore, beta1C protein levels were found to be abundant in normal prostate glandular epithelium and down-regulated in prostatic adenocarcinoma. To gain further insights into the molecular mechanisms underlying abnormal cancer cell proliferation, we have studied beta1C and beta1 integrin expression at both mRNA and protein levels by Northern and immunoblotting analysis using freshly isolated neoplastic and normal human prostate tissue specimens. Steady-state mRNA levels were evaluated in 38 specimens: 33 prostatic adenocarcinomas exhibiting different Gleasons grade and five normal tissue specimens that did not show any histological manifestation of benign prostatic hypertrophy. Our results demonstrate that beta1C mRNA is expressed in normal prostate and is significantly down-regulated in neoplastic prostate specimens. In addition, using a probe that hybridizes with all beta1 variants, mRNA levels of beta1 are found reduced in neoplastic versus normal prostate tissues. We demonstrate that beta1C mRNA down-regulation does not correlate with either tumor grade or differentiation according to Gleasons grade and TNM system evaluation, and that beta1C mRNA levels are not affected by hormonal therapy. In parallel, beta1C protein levels were analyzed. As expected, beta1C is found to be expressed in normal prostate and dramatically reduced in neoplastic prostate tissues; in contrast, using an antibody to beta1 that recognizes all beta1 variants, the levels of beta1 are comparable in normal and neoplastic prostate, thus indicating a selective down-regulation of the beta1C protein in prostate carcinoma. These results demonstrate for the first time that beta1C and beta1 mRNA expression is down-regulated in prostate carcinoma, whereas only beta1C protein levels are reduced. Our data highlight a selective pressure to reduce the expression levels of beta1C, a very efficient inhibitor of cell proliferation, in prostate malignant transformation.

Current insights in renal cell cancer pathology

In recent years molecular biologists and pathologists have described new entities of renal cell cancer (RCC) with a totally different morphology and biology among the histotypes of renal carcinoma, but always referring to the same renal cancer disease. The evidence of a distinct biological behavior and long-term prognosis among these makes the correct pathological diagnosis of renal cancer critically important for the clinician. Advances in understanding of the pathogenesis, behavior, and importance of prognostic factors for RCC have paved the way for a revision of its classification and staging. We reviewed the role of histological classification, microscopic tumor necrosis, microscopic venous invasion, lymph node involvement and, particularly, pathological stage. In our series of patients who underwent renal surgery for neoplasm, a retrospective study established the predictive role of tumor size on recurrence rate, compared with other known prognostic factors, and we conclude that histological grade, pathological stage and tumor size remain relevant prognosticators in early stage RCC patients. In order to optimize the management of patients with RCC it is necessary to develop an interdisciplinary approach (surgeon, radiologist, pathologist, oncologist) and find new prognostic parameters at molecular and cellular levels. Many efforts are ongoing to integrate molecular data (from tissue microarrays) and clinical data (traditional prognosticators) into a molecular integrated staging system. In the postgenomic era, new tumor-associated antigens and molecules can be identified at the protein level using proteomics, providing a major opportunity for screening and finding novel targets that are the basis of new emerging therapies for RCC.

Nocturnal enuresis can be caused by absorptive hypercalciuria.

OBJECTIVE The aim of this study was to determine whether nocturnal enuresis (NE) can be caused by absorptive hypercalciuria. MATERIALS AND METHODS From 1981 to 1995, 406 patients with primary monosymptomatic nocturnal enuresis were studied. Up to 1989 (Group 1), urinary electrolytes and urinary creatinine were not evaluated, but since 1990 (Group 2) these tests have been performed routinely. In doing so, we noticed that in 8 patients in Group 2 and in 13 patients in Group 1 with persistent NE the urinary calcium and the urinary calcium/creatinine ratios were significantly high (p < 0.001). These patients were submitted to Paks test and parathyroid hormone (PTH) and antidiuretic hormone (ADH) measurements. RESULTS In all 21 patients, PTH and ADH levels were normal, while the Paks test showed absorptive hypercalciuria. They were given an appropriate diet. After 3 months, NE had ceased completely in 4 patients (19%); bedwetting episodes diminished and calciuria levels were found to be borderline in the remaining 17. A new urodynamic evaluation showed normal patterns in 12 and detrusor instability (DI) in 5. Patients with DI received oxybutinine: enuresis disappeared in all. The remaining 12 children with persistent NE and normal urodynamic findings and the child with DI and persistent NE empirically received DDAVP; enuresis ceased in all of them within 1 month and calciuria stabilized at normal levels. CONCLUSIONS This study revealed that absorptive hypercalciuria can be responsible for NE and can be treated with the combination of diet and DDAVP.