Giorgio Gandaglia

A Systematic Review of the Association Between Erectile Dysfunction and Cardiovascular Disease

CONTEXT Erectile dysfunction (ED) is considered a vascular impairment that shares many risk factors with cardiovascular disease (CVD). A correlation between ED and CVD has been hypothesized, and ED has been proposed as an early marker of symptomatic CVD. OBJECTIVE To analyze the relationship between ED and CVD, evaluating the pathophysiologic links between these conditions, and to identify which patients would benefit from cardiologic assessment when presenting with ED. EVIDENCE ACQUISITION A systematic literature review searching Medline, Embase, and Web of Science databases was performed. The search strategy included the terms erectile dysfunction, cardiovascular disease, coronary artery disease, risk factors, pathophysiology, atherosclerosis, low androgen levels, inflammation, screening, and phosphodiesterase type 5 inhibitors alone or in combination. We limited our search to studies published between January 2005 and May 2013. EVIDENCE SYNTHESIS Several studies reported an association between ED and CVD. The link between these conditions might reside in the interaction between androgens, chronic inflammation, and cardiovascular risk factors that determines endothelial dysfunction and atherosclerosis, resulting in disorders of penile and coronary circulation. Because penile artery size is smaller compared with coronary arteries, the same level of endothelial dysfunction causes a more significant reduction of blood flow in erectile tissues compared with that in coronary circulation. Thus ED could be an indicator of systemic endothelial dysfunction. From a clinical standpoint, because ED may precede CVD, it can be used as an early marker to identify men at higher risk of CVD events. ED patients at high risk of CVD should undergo detailed cardiologic assessment and receive intensive treatment of risk factors. CONCLUSIONS ED and CVD should be regarded as two different manifestations of the same systemic disorder. ED usually precedes CVD onset, and it might be considered an early marker of symptomatic CVD.

Long-term Outcomes of Salvage Lymph Node Dissection for Clinically Recurrent Prostate Cancer: Results of a Single-institution Series with a Minimum Follow-up of 5 Years

BACKGROUND Prostate cancer (PCa) patients with lymph node recurrence after radical prostatectomy (RP) are usually managed with androgen-deprivation therapy. Despite the absence of prospective randomized studies, salvage lymph node dissection (LND) has been proposed as an alternative treatment option. OBJECTIVE To examine long-term outcomes of salvage LND in patients with nodal recurrent PCa documented by 11C-choline positron emission tomography/computed tomography (PET/CT) scan. DESIGN, SETTING, AND PARTICIPANTS Overall, 59 patients affected by biochemical recurrence (BCR) with 11C-choline PET/CT scan with pathologic activity treated between 2002 and 2008 were included. INTERVENTION Pelvic and/or retroperitoneal salvage LND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES Biochemical response (BR) was defined as prostate-specific antigen (PSA) <0.2 ng/ml at 40 d after surgery. BCR for those who achieved BR was defined as a PSA >0.2 ng/ml. Clinical recurrence (CR) was defined as a positive PET/CT scan after salvage LND in the presence of a rising PSA. Kaplan-Meier curves assessed time to BCR, CR, and cancer-specific mortality (CSM). Cox regression analyses were fitted to assess predictors of CR. RESULTS AND LIMITATIONS Median follow-up after salvage LND was 81.1 mo. Overall, 35 patients (59.3%) achieved BR. The 8-yr BCR-free survival rate in patients with complete BR was 23%. Overall, the 8-yr CR- and CSM-free survival rates were 38% and 81%, respectively. In multivariable analyses evaluating preoperative variables, PSA at salvage LND represented the only predictor of CR (p=0.03). When postoperative variables were considered, BR and the presence of retroperitoneal lymph node metastases were significantly associated with the risk of CR (all p ≤ 0.04). Our study is limited by the lack of a control group. CONCLUSIONS Salvage LND may represent a therapeutic option for patients with BCR after RP and nodal pathologic uptake at 11C-choline PET/CT scan. Although most patients progressed to BCR after salvage LND, roughly 40% of them experienced CR-free survival. PATIENT SUMMARY Salvage lymph node dissection may represent a therapeutic option for selected patients with nodal recurrence after radical prostatectomy. Roughly 40% of men did not show any further clinical recurrence at long-term follow-up after surgery.

Impact of Adjuvant Radiotherapy on Survival of Patients With Node-Positive Prostate Cancer

PURPOSE The role of adjuvant radiotherapy (aRT) in treating patients with pN1 prostate cancer is controversial. We tested the hypothesis that the impact of aRT on cancer-specific mortality (CSM) in these individuals is related to tumor characteristics. METHODS We evaluated 1,107 patients with pN1 prostate cancer treated with radical prostatectomy and anatomically extended pelvic lymph node dissection between 1988 and 2010 at two tertiary care centers. All patients received adjuvant hormonal therapy with or without aRT. Regression tree analysis stratified patients into risk groups on the basis of their tumor characteristics and the corresponding CSM rate. Cox regression analysis tested the relationship between aRT and CSM rate, as well as overall mortality (OM) rate in each risk group separately. RESULTS Overall, 35% of patients received aRT. At multivariable analysis, aRT was associated with more favorable CSM rate (hazard ratio [HR], 0.37; P < .001). However, when patients were stratified into risk groups, only two groups of men benefited from aRT: (1) patients with positive lymph node (PLN) count ≤ 2, Gleason score 7 to 10, pT3b/pT4 stage, or positive surgical margins (HR, 0.30; P = .002); and (2) patients with PLN count of 3 to 4 (HR, 0.21; P = .02), regardless of other tumor characteristics. These results were confirmed when OM was examined as an end point. CONCLUSION The beneficial impact of aRT on survival in patients with pN1 prostate cancer is highly influenced by tumor characteristics. Men with low-volume nodal disease (≤ two PLNs) in the presence of intermediate- to high-grade, non-specimen-confined disease and those with intermediate-volume nodal disease (three to four PLNs) represent the ideal candidates for aRT after surgery.

Comparative Effectiveness of Robot-Assisted and Open Radical Prostatectomy in the Postdissemination Era

PURPOSE Given the lack of randomized trials comparing robot-assisted radical prostatectomy (RARP) and open radical prostatectomy (ORP), we sought to re-examine the outcomes of these techniques using a cohort of patients treated in the postdissemination era. PATIENTS AND METHODS Overall, data from 5,915 patients with prostate cancer treated with RARP or ORP within the SEER-Medicare linked database diagnosed between October 2008 and December 2009 were abstracted. Postoperative complications, blood transfusions, prolonged length of stay (pLOS), readmission, additional cancer therapies, and costs of care within the first year after surgery were compared between the two surgical approaches. To decrease the effect of unmeasured confounders, instrumental variable analysis was performed. Multivariable logistic regression analyses were then performed. RESULTS Overall, 2,439 patients (41.2%) and 3,476 patients (58.8%) underwent ORP and RARP, respectively. In multivariable analyses, patients undergoing RARP had similar odds of overall complications, readmission, and additional cancer therapies compared with patients undergoing ORP. However, RARP was associated with a higher probability of experiencing 30- and 90-day genitourinary and miscellaneous medical complications (all P ≤ .02). Additionally, RARP led to a lower risk of experiencing blood transfusion and of having a pLOS (all P < .001). Finally, first-year reimbursements were greater for patients undergoing RARP compared with ORP (P < .001). CONCLUSION RARP and ORP have comparable rates of complications and additional cancer therapies, even in the postdissemination era. Although RARP was associated with lower risk of blood transfusions and a slightly shorter length of stay, these benefits do not translate to a decrease in expenditures.

More Extensive Pelvic Lymph Node Dissection Improves Survival in Patients with Node-positive Prostate Cancer

BACKGROUND The role of extended pelvic lymph node dissection (ePLND) in treating prostate cancer (PCa) patients with lymph node invasion (LNI) remains controversial. OBJECTIVE The relationship between the number of removed lymph nodes (RLNs) and cancer-specific mortality (CSM) was tested in patients with LNI. DESIGN, SETTING, AND PARTICIPANTS We examined data of 315 pN1 PCa patients treated with radical prostatectomy (RP) and anatomically ePLND between 2000 and 2012 at one tertiary care centre. All patients received adjuvant hormonal therapy with or without adjuvant radiotherapy (aRT). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Univariable and multivariable Cox regression analyses tested the relationship between RLN number and CSM rate, after adjusting to all available covariates. Survival estimates were based on the multivariable model; patients were stratified according to RLN number using points of maximum separation. RESULTS AND LIMITATIONS The average number of RLNs was 20.8 (median: 19; interquartile range: 14-25). Mean and median follow-up were 63.1 and 54 mo, respectively. At 10-yr, the CSM-free survival rate was 74.7%, 85.9%, 92.4%, 96.0%, and 97.9% for patients with 8, 17, 26, 36, and 45 RLNs, respectively. By multivariable analyses, the number of RLNs independently predicted lower CSM rate (hazard ratio [HR]: 0.93; p=0.02). Other predictors of CSM were Gleason score 8-10 (HR: 3.3), number of positive nodes (HR: 1.2), and aRT treatment (HR: 0.26; all p ≤ 0.006). The study is limited by its retrospective nature. CONCLUSIONS In PCa patients with LNI, the removal of a higher number of LNs during RP was associated with improvement in cancer-specific survival rate. This implies that ePLND should be considered in all patients with a significant preoperative risk of harbouring LNI. PATIENT SUMMARY We found that removing more lymph nodes during prostate cancer surgery can significantly improve cancer-specific survival in patients with lymph node invasion.

The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH)

Several different stimuli may induce chronic prostatic inflammation, which in turn would lead to tissue damage and continuous wound healing, thus contributing to prostatic enlargement. Patients with chronic inflammation and benign prostatic hyperplasia (BPH) have been shown to have larger prostate volumes, more severe lower urinary tract symptoms (LUTS) and a higher probability of acute urinary retention than their counterparts without inflammation. Chronic inflammation could be a predictor of poor response to BPH medical treatment. Thus, the ability to identify patients with chronic inflammation would be crucial to prevent BPH progression and develop target therapies. Although the histological examination of prostatic tissue remains the only available method to diagnose chronic inflammation, different parameters, such as prostatic calcifications, prostate volume, LUTS severity, storage and prostatitis‐like symptoms, poor response to medical therapies and urinary biomarkers, have been shown to be correlated with chronic inflammation. The identification of patients with BPH and chronic inflammation might be crucial in order to develop target therapies to prevent BPH progression. In this context, clinical, imaging and laboratory parameters might be used alone or in combination to identify patients that harbour chronic prostatic inflammation.

Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy.

BACKGROUND Early salvage radiotherapy (eSRT) represents the only curative option for prostate cancer patients experiencing biochemical recurrence (BCR) for local recurrence after radical prostatectomy (RP). OBJECTIVE To develop and internally validate a novel nomogram predicting BCR after eSRT in patients treated with RP. DESIGN, SETTING, AND PARTICIPANTS Using a multi-institutional cohort, 472 node-negative patients who experienced BCR after RP were identified. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at prostate-specific antigen (PSA) ≤ 0.5 ng/ml. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS BCR after eSRT was defined as two consecutive PSA values ≥ 0.2 ng/ml. Uni- and multivariable Cox regression models predicting BCR after eSRT were fitted. Regression-based coefficients were used to develop a nomogram predicting the risk of 5-yr BCR after eSRT. The discrimination of the nomogram was quantified with the Harrell concordance index and the calibration plot method. Two hundred bootstrap resamples were used for internal validation. RESULTS AND LIMITATIONS Mean follow-up was 58 mo (median: 48 mo). Overall, 5-yr BCR-free survival rate after eSRT was 73.4%. In univariable analyses, pathologic stage, Gleason score, and positive surgical margins were associated with the risk of BCR after eSRT (all p ≤ 0.04). These results were confirmed in multivariable analysis, where all the previously mentioned covariates as well as pre-RT PSA were significantly associated with BCR after eSRT (all p ≤ 0.04). A coefficient-based nomogram demonstrated a bootstrap-corrected discrimination of 0.74. Our study is limited by its retrospective nature and use of BCR as an end point. CONCLUSIONS eSRT leads to excellent cancer control in patients with BCR for presumed local failure after RP. We developed the first nomogram to predict outcome after eSRT. Our model facilitates risk stratification and patient counselling regarding the use of secondary therapy for individuals experiencing BCR after RP. PATIENT SUMMARY Salvage radiotherapy leads to optimal cancer control in patients who experience recurrence after radical prostatectomy. We developed a novel tool to identify the best candidates for salvage treatment and to allow selection of patients to be considered for additional forms of therapy.

Incidence, survival and mortality rates of stage-specific bladder cancer in United States: A trend analysis

PURPOSE To examine the overall and stage-specific age-adjusted incidence, 5-year survival and mortality rates of bladder cancer (BCa) in the United States, between 1973 and 2009. MATERIALS AND METHODS A total of 148,315 BCa patients were identified in the Surveillance, Epidemiology and End Results database, between years 1973 and 2009. Incidence, mortality, and 5-year cancer-specific survival rates were calculated. Temporal trends were quantified using the estimated annual percentage change (EAPC) and linear regression models. All analyses were stratified according to disease stage, and further examined according to sex, race, and age groups. RESULTS Incidence rate of BCa increased from 21.0 to 25.5/100,000 person-years between 1973 and 2009. Stage-specific analyses revealed an increase incidence for localized stage: 15.4-20.2 (EAPC: +0.5%, p < 0.001) and distant stage: 0.5-0.8 (EAPC: +0.7%, p = 0.001). Stage-specific 5-year survival rates increased for all stages, except for distant disease. No significant changes in mortality were recorded among localized (EAPC: -0.2%, p = 0.1) and regional stage (EAPC: -0.1%, p = 0.5). An increase in mortality rates was observed among distant stage (EAPC: +1.0%, p = 0.005). Significant variations in incidence and mortality were recorded when estimates were stratified according to sex, race, and age groups. DISCUSSION Albeit statistically significant, virtually all changes in incidence and mortality were minor, and hardly of any clinical importance. Little or no change in BCa cancer control outcomes has been achieved during the study period.

Comparative effectiveness of robot-assisted versus open radical prostatectomy cancer control

BACKGROUND Robot-assisted radical prostatectomy (RARP) remains controversial, and no improvement in cancer control outcomes has been demonstrated over open radical prostatectomy (ORP). OBJECTIVE To examine population-based, comparative effectiveness of RARP versus ORP pertaining surgical margin status and use of additional cancer therapy. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective observational study of 5556 RARP and 7878 ORP cases from 2004 to 2009 from Surveillance Epidemiology and End Results-Medicare linked data. INTERVENTION RARP versus ORP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Propensity-based analyses were performed to minimize treatment selection biases. Generalized linear regression models were computed for comparison of RP surgical margin status and use of additional cancer therapy (radiation therapy [RT] or androgen deprivation therapy [ADT]) by surgical approach. RESULTS AND LIMITATIONS In the propensity-adjusted analysis, RARP was associated with fewer positive surgical margins (13.6% vs 18.3%; odds ratio [OR]: 0.70; 95% confidence interval [CI], 0.66-0.75), largely because of fewer RARP positive margins for intermediate-risk (15.0% vs 21.0%; OR: 0.66; 95% CI, 0.59-0.75) and high-risk (15.1% vs 20.6%; OR: 0.70; 95% CI, 0.63-0.77) disease. In addition, RARP was associated with less use of additional cancer therapy within 6 mo (4.5% vs 6.2%; OR: 0.75; 95% CI, 0.69-0.81), 12 mo (OR: 0.73; 95% CI, 0.62-0.86), and 24 mo (OR: 0.67; 95% CI, 0.57-0.78) of surgery. Limitations include the retrospective nature of the study and the absence of prostate-specific antigen levels to determine biochemical recurrence. CONCLUSIONS RARP is associated with improved surgical margin status relative to ORP for intermediate- and high-risk disease and less use of postprostatectomy ADT and RT. This has important implications for quality of life, health care delivery, and costs. PATIENT SUMMARY Robot-assisted radical prostatectomy (RP) versus open RP is associated with fewer positive margins and better early cancer control because of less use of additional androgen deprivation and radiation therapy within 2 yr of surgery.

Nerve-sparing approach during radical prostatectomy is strongly associated with the rate of postoperative urinary continence recovery

Urinary incontinence and erectile dysfunction are the most bothersome sequelae affecting health‐related quality of life in patients treated with radical prostatectomy for prostate cancer. While it has been widely reported that a nerve‐sparing approach significantly improves postoperative erectile function, the impact of neurovascular bundle preservation on urinary continence recovery is still a matter of controversy. Our study clearly demonstrates that patients treated with nerve‐sparing radical prostatectomy have higher chances of recovering full continence after surgery. The results indicate that, when technically and oncologically feasible, an attempt at a nerve‐sparing approach should be planned in order to increase the probability of achieving full continence after radical prostatectomy.