Ciro Imbimbo

Validation of the 2009 TNM Version in a Large Multi-Institutional Cohort of Patients Treated for Renal Cell Carcinoma: Are Further Improvements Needed?

BACKGROUND A new edition of the TNM was recently released that includes modifications for the staging system of kidney cancers. Specifically, T2 cancers were subclassified into T2a and T2b (< or =10 cm vs >10 cm), tumors with renal vein involvement or perinephric fat involvement were classified as T3a cancers, and those with adrenal involvement were classified as T4 cancers. OBJECTIVE Our aim was to validate the recently released edition of the TNM staging system for primary tumor classification in kidney cancer. DESIGN, SETTING, AND PARTICIPANTS Our multicenter retrospective study consisted of 5339 patients treated in 16 academic Italian centers. INTERVENTION Patients underwent either radical or partial nephrectomy. MEASUREMENTS Univariable and multivariable Cox regression models addressed cancer-specific survival (CSS) after surgery. RESULTS AND LIMITATIONS In the study, 1897 patients (35.5%) were classified as pT1a, 1453 (27%) as pT1b, 437 (8%) as pT2a, 153 (3%) as pT2b, 1059 (20%) as pT3a, 117 (2%) as pT3b, 26 (0.5%) as pT3c, and 197 (4%) as pT4. At a median follow-up of 42 mo, 786 (15%) had died of disease. In univariable analysis, patients with pT2b and pT3a tumors had similar CSS, as did patients with pT3c and pT4 tumors. Moreover, both pT3a and pT3b stages included patients with heterogeneous outcomes. In multivariable analysis, the novel classification of the primary tumor was a powerful independent predictor of CSS (p for trend <0.0001). However, the substratification of pT1 tumors did not retain an independent predictive role. The major limitations of the study are retrospective design, lack of central pathologic review, and the small number of patients included in some substages. CONCLUSIONS The recently released seventh edition of the primary tumor staging system for kidney tumors is a powerful predictor of CSS. However, some of the substages identified by the classification have overlapping prognoses, and other substages include patients with heterogeneous outcomes. The few modifications included in this edition may have not resolved the most critical issues in the previous version.

Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation

Hydrogen sulfide (H2S) is synthesized by 2 enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). l-Cysteine (l-Cys) acts as a natural substrate for the synthesis of H2S. Human penile tissue possesses both CBS and CSE, and tissue homogenates efficiently convert l-Cys to H2S. CBS and CSE are localized in the muscular trabeculae and the smooth-muscle component of the penile artery, whereas CSE but not CBS is also expressed in peripheral nerves. Exogenous H2S [sodium hydrogen sulfide (NaHS)] or l-Cys causes a concentration-dependent relaxation of strips of human corpus cavernosum. l-Cys relaxation is inhibited by the CBS inhibitor, aminoxyacetic acid (AOAA). Electrical field stimulation of human penile tissue, under resting conditions, causes an increase in tension that is significantly potentiated by either propargylglycine (PAG; CSE inhibitor) or AOAA. In rats, NaHS and l-Cys promote penile erection, and the response to l-Cys is blocked by PAG. Our data demonstrate that the l-Cys/H2S pathway mediates human corpus cavernosum smooth-muscle relaxation.

Combination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory Prostate Cancer: A Phase 2 Study

OBJECTIVE Although the taxanes represent the most active agents for the first-line treatment of metastatic hormone-refractory prostate cancer (HRPC), most patients eventually progress while receiving taxane-based treatments. No agents are approved for second-line therapy in HRPC, but common standard practice for the oncologists is to treat patients also after docetaxel failure. METHODS Twenty highly pretreated patients with HRPC received bevacizumab (10mg/kg) and docetaxel (60mg/m(2)) every 3 wk. All patients had bone metastases and eight had measurable lesions. RESULTS Eleven patients (55%) had major prostate-specific antigen (PSA) responses, and 3 (37.5%) had objective responses. Seven major PSA responses were recorded in the same patients who had reported a >50% PSA decrease after first-line docetaxel. However, four major PSA responses were observed in patients previously nonresponsive to docetaxel alone. The treatment was well tolerated. CONCLUSIONS Our results show that the combination of bevacizumab and docetaxel is active and well tolerated. Continued investigation of bevacizumab with cytotoxic chemotherapy is warranted in HRPC.

Phase II Study of Sorafenib in Patients With Sunitinib-Refractory Metastatic Renal Cell Cancer

PURPOSE No previous prospective trials have been reported with sorafenib in patients with sunitinib-refractory metastatic renal cell cancer (MRCC). We conducted a multicenter study to determine the activity and tolerability of sorafenib as second-line therapy after sunitinib progression in MRCC. PATIENTS AND METHODS Between January 2006 and September 2008, 52 patients were enrolled onto this single-arm phase II study. All patients received sorafenib 400 mg orally twice a day until disease progression or intolerable toxicity. The primary end point was objective response rate (complete or partial response) evaluated every 8 weeks by use of the Response Evaluation Criteria in Solid Tumors; secondary end points were toxicity, time to progression (TTP), and overall survival (OS). RESULTS All patients were included in response and safety analyses. Partial responses were observed in 9.6% of patients (five of 52 patients; 95% CI, 5% to 17%) after two cycles. Grade 1 to 2 fatigue, diarrhea, nausea/vomiting, rash, and neutropenia were the most common side effects, noted in 16 (30.8%), 19 (36.5%), 20 (38.5%), 19 (36.5%), and 20 patients (38.5%), respectively. The most common grade 3 toxicity was diarrhea, noted in six patients (11.5%). Median TTP was 16 weeks (range, 8 to 40 weeks), and median OS was 32 weeks (range, 16 to 64 weeks). CONCLUSION Although well tolerated, sorafenib shows limited efficacy in sunitinib-refractory MRCC. Further randomized trials comparing sorafenib with other drugs that target different biologic pathways are needed to define the best second-line treatment option in these patients.

A First Prospective, Randomized, Double-Blind, Placebo-Controlled Clinical Trial Evaluating Extracorporeal Shock Wave Therapy for the Treatment of Peyronie's Disease

BACKGROUND Extracorporeal shock wave therapy (ESWT) is a conservative therapy for patients with Peyronies disease (PD). OBJECTIVE To investigate the effects of ESWT in patients with PD. DESIGN, SETTING, AND PARTICIPANTS One hundred patients with a history of PD not >12 mo who had not had previous PD-related treatments were enrolled in a prospective, randomized, double-blind, placebo-controlled study. Patients were randomly allocated to either ESWT (n=50) or placebo (n=50). Erectile function (EF), pain during erection, plaque size, penile curvature, and quality of life (QoL) were assessed at baseline, at 12 wk, and at 24 wk follow-up. INTERVENTION Four weekly treatment sessions were administered. Each ESWT session consisted of 2000 focused shock waves. For the placebo group, a nonfunctioning transducer was employed. MEASUREMENTS EF was evaluated with the shortened version of the International Index of Erectile Function (IIEF-5), pain was evaluated with a visual analog scale (VAS; 0-10), plaque size was measured in cm(2), and penile curvature was measured in degrees. RESULTS AND LIMITATIONS After 12 wk, mean VAS score, mean IIEF-5 score, and mean QoL score ameliorated significantly in patients receiving ESWT. Mean plaque size and mean curvature degree were unchanged in the ESWT group, while a slight increase was reported in the placebo group (p-value not significant vs baseline). After 24 wk, mean IIEF-5 score and mean QoL score were stable in the ESWT group, while mean VAS score was significantly lower when compared with baseline in both groups. Interestingly, after 24 wk, mean plaque size and mean curvature degree were significantly higher in the placebo group when compared with both baseline and ESWT values. The main limitations were that the QoL questionnaire was not validated, ED was not etiologically characterized, and inclusion criteria were restricted. CONCLUSIONS In patients with PD, ESWT leads to pain resolution and ameliorates both EF and QoL.

Involvement of β3-adrenergic receptor activation via cyclic GMP- but not NO-dependent mechanisms in human corpus cavernosum function

The β3-adrenoreceptor plays a major role in lipolysis but the role and distribution of β3-receptors in other specific sites have not been extensively studied. β3-adrenergic receptors are present not only in adipose tissue but also in human gall bladder, colon, prostate, and skeletal muscle. Recently, β3-adrenergic receptor stimulation was shown to elicit vasorelaxation of rat aorta through the NO–cGMP signal transduction pathway. Here we show that β3-receptors are present in human corpus cavernosum and are localized mainly in smooth muscle cells. After activation by a selective β3-adrenergic receptor agonist, BRL 37344, there was a cGMP-dependent but NO-independent vasorelaxation that was selectively blocked by a specific β3-receptor antagonist. In addition, we report that the human corpus cavernosum exhibits basal β3-receptor-mediated vasorelaxant tone and that β3-receptor activity is linked to inhibition of the RhoA/Rho-kinase pathway. These observations indicate that β3-receptors may play a physiological role in mediating penile erection and, therefore, could represent a therapeutic target for treatment of erectile dysfunction.

Third-Line Sorafenib After Sequential Therapy With Sunitinib and mTOR Inhibitors in Metastatic Renal Cell Carcinoma

BACKGROUND Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined. OBJECTIVE To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective. DESIGN, SETTING, AND PARTICIPANTS One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib-everolimus or temsirolimus-sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment. MEASUREMENTS PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS). RESULTS AND LIMITATIONS Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3-6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6-10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data. CONCLUSIONS Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.

Variations of proline-rich kinase Pyk2 expression correlate with prostate cancer progression

Proline-rich kinase 2 (Pyk2), also known as CAKβ (cell adhesion kinase β), is a cytoplasmic tyrosine kinase that is structurally related to focal adhesion kinase. Pyk2 is expressed in different cell types including brain cells, fibroblasts, platelets, and other hemopoietic cells. Pyk2 is rapidly tyrosine phosphorylated in response to diverse extracellular signals acting via different post receptor pathways. We have investigated whether this protein kinase is functionally expressed in normal and neoplastic prostate tissues. In this study, we demonstrate that Pyk2 is expressed only in normal epithelial prostate tissue and in benign prostatic hyperplasia, whereas its expression progressively declines with an increasing grade of malignancy of prostate cancer.

Neurophysiologic evaluation of central-peripheral sensory and motor pudendal pathways in primary premature ejaculation

OBJECTIVES Pudendal nerve somatosensory evoked potentials (SEPs), the bulbocavernosus (BC) reflex, and BC perineal motor evoked potentials after transcranial magnetic cortical stimulation were performed in patients with primary premature ejaculation to investigate the somatic sensory and motor function of the genital area. METHODS Fourteen patients with primary premature ejaculation underwent psychological counseling, urologic physical examination, transrectal ultrasound examination, laboratory testing, and the Stamey test. The spinal and cortical pudendal nerve SEPs were performed by dorsal nerve stimulation at the penile shaft (DN-SEPs) in all patients and at the glans penis (GP-SEPs) in 3 of them. The BC reflex was obtained by stimulating the base of the penis. RESULTS The mean sensory threshold did not significantly differ between the patients and normal subjects. Cortical DN-SEPs were normal in all patients. The sensory central conduction time, calculated in 6 patients, was normal. The mean cortical DN-SEP amplitude was significantly smaller in patients than in controls. In 3 patients and in 3 controls who underwent both DN-SEP and GP-SEP testing, the glans penis sensory threshold was lower than the dorsal nerve threshold and the cortical GP-SEP latency was longer than the cortical DN-SEP latency. The BC reflex was normal in most patients. The BC motor evoked potentials were normal in all patients, but one. CONCLUSIONS We did not confirm either a faster conduction along the pudendal sensory pathway or a greater cortical representation of the sensory stimuli from the genital area in our patients. Moreover, we did not confirm hyperexcitability of the BC reflex in them. Our results suggest that the electrophysiologic approach is probably not sufficient to clarify the causes of primary premature ejaculation. A more integrated investigation could allow better results in this field.

Factors predicting continence recovery 1 month after radical prostatectomy: Results of a multicenter survey

Objectives:  To assess the factors associated with continence recovery 1 month after radical prostatectomy (RP) and to identify the correlation between these factors.