Alessandro Nini

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.

Tbr2-positive intermediate (basal) neuronal progenitors safeguard cerebral cortex expansion by controlling amplification of pallial glutamatergic neurons and attraction of subpallial GABAergic interneurons

Little is known about how, during its formidable expansion in development and evolution, the cerebral cortex is able to maintain the correct balance between excitatory and inhibitory neurons. In fact, while the former are born within the cortical primordium, the latter originate outward in the ventral pallium. Therefore, it remains to be addressed how these two neuronal populations might coordinate their relative amounts in order to build a functional cortical network. Here, we show that Tbr2-positive cortical intermediate (basal) neuronal progenitors (INPs) dictate the migratory route and control the amount of subpallial GABAergic interneurons in the subventricular zone (SVZ) through a non-cell-autonomous mechanism. In fact, Tbr2 interneuron attractive activity is moderated by Cxcl12 chemokine signaling, whose forced expression in the Tbr2 mutants can rescue, to some extent, SVZ cell migration. We thus propose that INPs are able to control simultaneously the increase of glutamatergic and GABAergic neuronal pools, thereby creating a simple way to intrinsically balance their relative accumulation.

Performance Characteristics of Computed Tomography in Detecting Lymph Node Metastases in Contemporary Patients with Prostate Cancer Treated with Extended Pelvic Lymph Node Dissection

BACKGROUND Computed tomography (CT) is a commonly used noninvasive procedure for prostate cancer (PCa) staging. All previous studies addressing the ability of CT scan to predict lymph node invasion (LNI) were based on historical patients treated with limited pelvic lymph node dissection (PLND). OBJECTIVE Assess the value of CT in predicting LNI in contemporary PCa patients treated with extended PLND (ePLND). DESIGN, SETTING, AND PARTICIPANTS We evaluated 1541 patients undergoing radical prostatectomy and ePLND between 2003 and 2010 at a single center. All patients were preoperatively staged using abdominopelvic CT scan. All lymph nodes with a short axis diameter ≥ 10 mm were considered suspicious for metastatic involvement. INTERVENTION All patients underwent preoperative CT scan, radical retropubic prostatectomy, and ePLND, regardless of PCa features at diagnosis. MEASUREMENTS The performance characteristics of CT scan were tested in the overall patient population, as well as according to the National Comprehensive Cancer Network (NCCN) classification and according to the risk of LNI derived from a nomogram developed on an ePLND series. Logistic regression models tested the relationship between CT scan findings and LNI. Discrimination accuracy was quantified with the area under the curve. RESULTS AND LIMITATIONS Overall, a CT scan that suggested LNI was found in 73 patients (4.7%). Of them, only 24 patients (32.8%) had histologically proven LNI at ePLND. Overall, sensitivity, specificity, and accuracy of CT scan were 13%, 96.0%, and 54.6%, respectively. In patients with low-, intermediate-, or high-risk PCa according to NCCN classification, sensitivity was 8.3%, 96.3%, and 52.3%, respectively; specificity was 3.6%, 97.3%, and 50.5%, respectively; and accuracy was 17.9%, 94.3%, and 56.1%, respectively. Similarly, in patients with a nomogram-derived LNI risk ≥ 50%, sensitivity, specificity, and accuracy were only 23.9%, 94.7%, and 59.3%, respectively. At multivariable analyses, inclusion of CT scan findings did not improve the accuracy of LNI prediction (81.4% compared with 81.3%; p=0.8). Lack of a central scan review represents the main limitation of our study. CONCLUSIONS In contemporary patients with PCa, the accuracy of CT scan as a preoperative nodal-staging procedure is poor, even in patients with high LNI risk. Therefore, the need for and the extent of PLND should not be based on the results obtained by CT scan.

Impact of Adjuvant Radiation Therapy on Urinary Continence Recovery After Radical Prostatectomy

BACKGROUND Little is known about the impact of adjuvant radiation therapy (aRT) after radical prostatectomy (RP) on urinary continence (UC). OBJECTIVE To evaluate the impact of aRT on UC recovery in patients with unfavourable pathologic characteristics. DESIGN, SETTING, AND PARTICIPANTS The study included 361 patients with either pT2 with positive surgical margin(s) or pT3a/pT3b node-negative disease treated with RP at a tertiary care referral centre. INTERVENTION Patients were stratified according to the administration of aRT into two groups: group 1 (no aRT; n=208; 57.8%) and group 2 (aRT; n=153; 42.2%). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Continence was defined as no use of protective pads. Log-rank test was used to compare the rate of UC recovery according to aRT status. The association between aRT and UC was also tested in Cox regression models after accounting for age, Cancer of the Prostate Risk Assessment (CAPRA) score, nerve-sparing (NS) status, Charlson Comorbidity Index, body mass index, and year of surgery. RESULTS AND LIMITATIONS At a mean follow-up of 30 mo, 254 patients (70.4%) recovered complete UC. The 1- and 3-yr UC recovery was 51% and 59% for patients submitted to aRT versus 81% and 87% for patients not receiving aRT, respectively (p<0.001). At univariable analysis, older age (p<0.001), presence of non-organ-confined disease (p<0.001), non-NS procedure (p<0.001), and delivery of aRT (p<0.001) were significantly associated with lower UC. At multivariable analysis, the delivery of aRT remained an independent predictor of worse UC recovery (hazard ratio: 0.57; p=0.001). Patients treated with aRT had a 1.6-fold higher risk of incontinence. Younger age (p=0.02), lower CAPRA score (p=0.03), and NS approach (p<0.001) also represented independent predictors of UC recovery. The main limitations of the study are related to the lack of validated questionnaires in the evaluation of UC and in the lack of information regarding UC status at aRT. CONCLUSIONS The delivery of aRT has a detrimental effect on UC. The oncologic benefits must be balanced with an impaired UC recovery. Patients should be informed of such impairment before adjuvant treatments are planned.

Patterns of Clinical Recurrence of Node-positive Prostate Cancer and Impact on Long-term Survival.

BACKGROUND The patterns of recurrence of patients with node-positive prostate cancer (PCa) at radical prostatectomy (RP) are still unknown. OBJECTIVE To describe recurrence patterns, to identify predictors of progression, and to test the impact of the site of clinical recurrence (CR) on cancer-specific mortality (CSM). DESIGN, SETTING, AND PARTICIPANTS We included 1003 patients with node-positive PCa treated with RP and extended pelvic lymph node dissection. Patients who experienced biochemical recurrence (BCR; n=370) and CR (n=183) were identified. CR was defined as positive imaging after BCR. Patients were stratified according to the first site of CR: local and/or nodal (recurrence in the prostatic bed and/or pelvic nodes), retroperitoneal, bony, or visceral. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable competing-risks regression analyses identified predictors of systemic recurrence (ie, retroperitoneal, bony, and/or visceral) and tested the association between the site of recurrence and CSM after accounting for the risk of other-cause mortality. RESULTS AND LIMITATIONS When considering patients experiencing BCR, pathologic Gleason score, time to BCR, and the administration of a positron emission tomography/computed tomography scan represented predictors of systemic recurrence (all p ≤ 0.002). Among patients who experienced CR, recurrence was local and/or nodal in 56 (30.5%), retroperitoneal in 25 (13.7%), skeletal in 77 (42.1%), and visceral in 25 (13.7%). Among patients experiencing local recurrence, 27 (48.2%) had positive margins, 29 (51.8%) had adjuvant radiotherapy, and 22 (39.5%) had salvage radiotherapy. Patients experiencing local and/or nodal recurrence had higher 5-yr CSM-free survival rates compared with those with retroperitoneal, skeletal, and visceral recurrence (79.3%, 76.3%, 50.8%, and 35.3%, respectively; p<0.001). The site of recurrence represented an independent predictor of CSM (p ≤ 0.04). CONCLUSIONS In approximately one-third of patients who are pN+ and experience CR, the prostatic bed and pelvic lymph nodes represent the first sites of recurrence. These patients have a more favorable prognosis compared with those with skeletal and visceral metastases. These data have important implications for the selection of the optimal postoperative management of pN+ patients who experience CR. Although patients with local and/or pelvic nodal recurrence might benefit from nonsystemic salvage therapies, men with visceral and skeletal recurrence might represent ideal candidates for systemic approaches. PATIENT SUMMARY Not all patients with pN+ prostate cancer who experience clinical recurrence harbor distant metastatic disease. Local and/or nodal recurrence occurs in one-third of these cases. These patients share a more favorable prognosis than their counterparts with systemic recurrence. These results are important for tailoring the optimal postoperative management for each node-positive patient with recurrent disease after surgery.

Treatment of Lymph Node–Positive Prostate Cancer: Teaching Old Dogmas New Tricks

The optimal treatment of men with positive lymph nodes after radical prostatectomy (RP) is an active debate in the urologic community. In addition, this topic has seemed to gain scientific attention in recent years because of the shift to offering RP to higher risk patients. However, patients with positive lymph nodes represent a paradigmatic group for which indications for and typesof treatmenthavebeenbased mainly on eminence-based rather than on evidence-based medicine. In the past, these patients were generally not considered suitable for radical treatment because of the assumption that cure was neither possible nor helpful. For several years, any definitive therapy attempt was denied because of undisputed dogma: Patients with lymph node metastasis are affected by a systemic disease. This assumption led to threemisguided concepts in clinical practice. First, maximizing local control was considered either useless or of limited therapeutic value. Second, extending the template of pelvic lymph node dissection (PLND) was not justified because, according to opponents of such an extensive approach, these patients would progress anyway, regardless of the extent of PLND. Third, patients with positive lymph nodes needed lifelong adjuvant androgen-deprivation therapy because of the presence of disseminated disease. Such statements can certainly be challenged today. We should still understand whether the presence of pelvic lymph node metastases indicates systemic dissemination. The etymology of the term metastasis shows that it comes from the Greek terms meta-, meaning across, and histanai, meaning to place. Therefore, the terms indicate a tumor spread outside of the organ of origin. For this reason, strictly speaking, patients with lymph node invasion have metastatic disease. However, such statement should be balanced by several key and still unknown aspects of the metastasizing process of prostate cancer (PCa). Cancer cells that spread to the lymph nodes have acquired certain phenotypic changes that confer to them the ability to invade lymphatic vessels and access lymph nodes; however, we still do not know what happens next. Lymph nodes can represent the door to hematogenous dissemination to other organs [1]. Tumor cells could spread from lymph nodes to distant organs via blood vessels associated with the nodes or by entering the venous system via the major lymphatic ducts and then spreading via blood vessels. In mice with metastatic lymph nodes, the expression of lymphangiogenesis signals the increased probability of metastasization to additional organs [2]. However, in some cases, these draining lymph nodes may also represent dead ends rather than temporary stopping points from which more distant metastases are launched [3]. Moreover, as demonstrated in breast cancer, these cells may have specific epigenetic modifications that predispose to selective metastasization to the lymph nodes instead of visceral organs [4]. Therefore, the routes of systemic and nodal metastasization may also be different and separated. Cancer metastasized to the lymph nodes can also enter a quiescent state. This status is well known as tumor dormancy [5]. Tumor dormancy ensues when cancer cell proliferation is counteracted by other mechanisms such as apoptosis because of impaired vascularization or immunosurveillance, and cellular dormancy ensues when growth of the cancer cells is arrested. Several mechanisms can explain tumor dormancy, including disruption of crosstalk between EURO P E AN URO L OG Y 6 5 ( 2 0 1 4 ) 2 6 – 2 9

Assessing the most accurate formula to predict the risk of lymph node metastases from prostate cancer in contemporary patients treated with radical prostatectomy and extended pelvic lymph node dissection

BACKGROUND AND PURPOSE The aim of this study was to perform a head-to-head comparison of the Roach formula vs. two other newly developed prediction tools for lymph node invasion (LNI) in prostate cancer, namely the Nguyen and the Yu formulas. MATERIAL AND METHODS We included 3115 patients treated with radical prostatectomy and extended pelvic lymph node dissection (ePLND), between 2000 and 2010 at a single center. The predictive accuracy of the three formulas was assessed and compared using the area-under-curve (AUC) and calibration methods. Moreover, decision curve analysis compared the net-benefit of the three formulas in a head-to-head fashion. RESULTS Overall, 10.8% of patients had LNI. The LNI-predicted risk was >15% in 25.5%, 3.4%, and 10.2% of patients according to the Roach, Nguyen and Yu formula, respectively. The AUC was 80.5%, 80.5% and 79%, respectively (all p>0.05). However, the Roach formula demonstrated more favorable calibration and generated the highest net-benefit relative to the other examined formulas in decision curve analysis. CONCLUSIONS All formulas demonstrated high and comparable discrimination accuracy in predicting LNI, when externally validated on ePLND treated patients. However, the Roach formula showed the most favorable characteristics. Therefore, its use should be preferred over the two other tools.

Naftopidil for the treatment of benign prostate hyperplasia: a systematic review

Abstract Objectives: The aim of the study was to systematically review the effects of the adrenoreceptor A1D antagonist naftopidil in the management of lower urinary tract symptoms (LUTS). Methods: A structured and comprehensive MEDLINE search was conducted for original articles, reviews, and metanalyses assessing the clinical pharmacology as well as the safety of naftopidil in the treatment of LUTS secondary to BPH. English-language publications dating from 1950 to 2013 were considered. Results: In the considered timeframe, 14 randomized clinical trials (RCT) were reported. Overall, the outcome measures assessed in the various reports included in the present review were changes from baseline in: International Prostate Symptom Score (IPSS), quality of life (QoL) score, maximum urinary flow rate (Qmax), residual volume (PVR), and adverse effects. Although additional well designed, worldwide, placebo-controlled and randomized studies are necessary to confirm the long-term outcomes of naftopidil pharmacotherapy, current data suggest that naftopidil administration in BPH patients provides comparable improvements in total IPSS, QoL, and urinary symptoms from baseline relative to 0.2 mg/d tamsulosin and 8 mg/d silodosin. However, improvements in Qmax are generally less with naftopidil than with tamsulosin. Reported adverse effects related to naftopidil administration are negligible and usually mild. Conclusion: It remains unknown whether the data reported on naftopidil in the Japanese population are applicable in symptomatic BPH patients from western countries given that: (1) no English-language clinical trials have compared naftopidil to placebo in Western countries; (2) all clinical trials available were carried out in Japan; (3) in the comparative studies with tamsulosin, the dose of this drug was lower than the recommended dose in Western countries; (4) no data from long-term clinical trials evaluating drug safety beyond 18 weeks.

Follow-up After Treatment for Renal Cell Carcinoma: The Evidence Beyond the Guidelines

CONTEXT Postoperative follow-up is considered the standard of care for nonmetastatic renal cell carcinoma (RCC). However, level 1 evidence regarding a proper follow-up protocol for RCC is still lacking, making clinical practice extremely heterogeneous. OBJECTIVE To evaluate systematically and summarise the evidence supporting the current clinical guidelines on follow-up after RCC treatment. EVIDENCE ACQUISITION A search of Medline, PubMed and Scopus was performed to identify articles published in the last 5 yr addressing the role of follow-up in the RCC setting. Relevant studies were then screened, and the data were extracted, analysed, and summarised. The Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria were applied. EVIDENCE SYNTHESIS Although several series regarding oncologic outcomes and protocols of surveillance after nephrectomy for localised RCC have been published in the literature, the individual preferences of the treating urologist make the daily clinical scenario extremely heterogeneous regarding follow-up indications and modality. Clinical guidelines support a stage-specific stratification of patient prognosis based on pathologic staging or prognostic models. In the context of a prospectively durable follow-up protocol exposing patients to several imaging tests, concerns about radiation exposure must be taken into account. A better understanding of tumour biology, which would lead to a correct individualisation of patient prognosis through the use of validated prognostic tools, would allow for a more tailored follow-up treatment. CONCLUSIONS A consensus regarding the pattern and modalities of surveillance after treatment for RCC is still lacking. A standardised evidence-based surveillance protocol that would allow for the early detection of recurrences and limit unnecessary radiation exposure and unwarranted costs is mandatory. PATIENT SUMMARY A surveillance protocol after treatment for a renal tumour is essential for the early detection and treatment of eventual metastases. A general consensus regarding timing and modalities for follow-up protocol still does not exist, but published evidence commonly sustains some general principles.

Optimizing postoperative sexual function after radical prostatectomy

Erectile dysfunction (ED) is one of the complications associated with pelvic surgery. The significance of ED as a complication following pelvic surgery, especially radical prostatectomy (RP), lies in the negative impact that it has on patients’ sexual and overall life. In the literature, rates of ED following RP range from 25% to 100%. Such variety is associated with pelvic dissection and conservation of neurovascular structures. Another important factor impacting on postoperative ED is the preoperative erectile function of the patient. Advances in the knowledge of pelvic anatomy and pathological mechanisms led to a refinement of pelvic surgical techniques, with attention to the main structures that if damaged compromise erectile function. These improvements resulted in lower postoperative ED rates and better erectile recovery, especially in patients undergoing RP. Furthermore, surgery alone is not sufficient to prevent this complication, and thus, several medical strategies have been tested with the aim of maximizing erectile function recovery. Indeed it seems that prevention of postoperative ED must be addressed by a multimodal approach. The aim of this review is to give a picture of recent knowledge, novel techniques and therapeutic approaches in order to reach the best combination of treatments to reduce the rate of ED after pelvic surgery.