Renato B. Corradi

Other biomarkers for detecting prostate cancer.

Prostate‐specific antigen (PSA) has been used for detecting prostate cancer since 1994. Although it is the best cancer biomarker available, PSA is not perfect. It lacks both the sensitivity and specificity to accurately detect the presence of prostate cancer. None of the PSA thresholds currently in use consistently identify patients with prostate cancer and exclude patients without cancer. Novel approaches to improve our ability to detect prostate cancer and predict the course of the disease are needed. Additional methods for detecting prostate cancer have been evaluated. Despite the discovery of many new biomarkers, only a few have shown some clinical value. These markers include human kallikrein 2, urokinase‐type plasminogen activator receptor, prostate‐specific membrane antigen, early prostate cancer antigen, PCA3, α‐methylacyl‐CoA racemase and glutathione S‐transferase π hypermethylation. We review the reports on biomarkers for prostate cancer detection, and their possible role in the clinical practice.

Prostatic specific antigen for prostate cancer detection

Prostate-specific antigen (PSA) has been used for prostate cancer detection since 1994. PSA testing has revolutionized our ability to diagnose, treat, and follow-up patients. In the last two decades, PSA screening has led to a substantial increase in the incidence of prostate cancer (PC). This increased detection caused the incidence of advanced-stage disease to decrease at a dramatic rate, and most newly diagnosed PC today are localized tumors with a high probability of cure. PSA screening is associated with a 75% reduction in the proportion of men who now present with metastatic disease and a 32.5% reduction in the age-adjusted prostate cancer mortality rate through 2003. Although PSA is not a perfect marker, PSA testing has limited specificity for prostate cancer detection, and its appropriate clinical application remains a topic of debate. Due to its widespread use and increased over-detection, the result has been the occurrence of over-treatment of indolent cancers. Accordingly, several variations as regards PSA measurement have emerged as useful adjuncts for prostate cancer screening. These procedures take into consideration additional factors, such as the proportion of different PSA isoforms (free PSA, complexed PSA, pro-PSA and B PSA), the prostate volume (PSA density), and the rate of change in PSA levels over time (PSA velocity or PSA doubling time). The history and evidence underlying each of these parameters are reviewed in the following article.

Histological subtype of renal cell carcinoma significantly affects survival in the era of partial nephrectomy

OBJECTIVES To analyze whether the histological subtype of renal cell carcinoma (RCC) affects survival after surgical resection in contemporary patients, and if so, whether prognostic significance differs according to the type of surgical resection or tumor stage. MATERIALS AND METHODS From 2006 to 2014, 2,237 patients underwent surgical resection (25% radical nephrectomy and 75% partial nephrectomy [PN]) for nonmetastatic RCC at a tertiary referral center. Estimated survival function curves and Cox regression models evaluated the effect of histological subtype on recurrence-free survival (RFS) and overall survival (OS). Interaction analyses tested whether the effect of histological subtype depends on the type of surgical resection or tumor stage. RESULTS Patients with RCC stage T2 or lower and those with low-grade conventional clear cell, papillary or chromophobe RCC of any stage had 5-year RFS probabilities>90%. Patients with clear cell papillary RCC stage T3 or greater had predicted 5-year RFS of 81%. However, 5-year OS probabilities were>94% for clear cell papillary RCC of any stage. High-grade conventional clear cell and papillary RCC stage T2 or lower, low-grade conventional clear cell and chromophobe RCC of any stage conferred 5-year OS probabilities of >93%. Unclassified RCC demonstrated the lowest OS probabilities at any stage. In multivariable analyses, histological subtype affected RFS (P<0.0001) and OS (P = 0.026) following surgical resection, with no differences in this association for radical nephrectomy vs. PN (RFS, P = 0.2; OS, P = 0.4), and across pathologic stages (RFS, P = 0.1; OS, P = 0.3). Compared with low-grade conventional clear cell RCC, chromophobe (hazard ratio [HR] = 0.72, 95% CI: 0.30-1.75) and papillary RCC (HR = 0.30, 95% CI: 0.09-0.97) conferred lower risk of recurrence. Chromophobe (HR = 0.67, 95% CI: 0.30-1.52) and clear cell papillary RCC (HR = 0.91, 95% CI: 0.12-6.78) conferred the lowest risk of all-cause mortality. CONCLUSIONS In the era of PN for RCC, histological subtype remained a significant predictor of survival, regardless of type of surgical resection or tumor stage.

Physiology of the Hypothalamic Pituitary Gonadal Axis in the Male

Testosterone synthesis and male fertility are the results of the perfect coordination of the hypothalamic-pituitary-gonadal axis. A negative feedback finely controls the secretion of hormones at the 3 levels. Congenital or acquired disturbance at any level leads to an impairment of reproductive function and the clinical syndrome of hypogonadism. In some cases, this condition is reversible. Once the diagnosis is made, testosterone replacement therapy is the standard therapy; however, novel therapies may improve spermatogenesis while elevating testosterone levels.

Localizing sites of disease in patients with rising serum prostate-specific antigen up to 1 ng/ml following prostatectomy: How much information can conventional imaging provide?

PURPOSE Accurate identification of the source of a detectable serum prostate-specific antigen (PSA) in the postprostatectomy setting is a major challenge among the urologic community. The aim of this study was to assess positivity rates of imaging examinations performed in patients with early PSA rise after prostatectomy and to summarize the management strategies adopted in this clinical scenario. METHODS Institutional Review Board-approved retrospective study of 142 postprostatectomy patients with PSA rise up to 1ng/ml who underwent evaluation with combination of multiparametric pelvic magnetic resonance imaging (MRI)±whole-body or bone MRI, bone scintigraphy, computed tomography (CT) chest-abdomen-pelvis, 18F-fludeoxyglucose-positron emission tomography (PET)/CT or 18F-sodium fluoride-PET/CT at a single tertiary cancer center. Imaging results were summarized per modality and compared with pathology findings. RESULTS Pelvic MRI was positive in 15/142 (11%) patients (14 patients with local recurrence in the surgical bed and 1 patient with pelvic osseous metastases). Of these 15, 10 patients underwent additional imaging examinations; none revealed positive findings. Of the 127 patients with negative pelvic MRI, 54 (43%) underwent additional imaging examinations; only 1/54 had positive findings (false-positive T8 lesion on bone scintigraphy and FDG-PET/CT; biopsy was negative for cancer). Overall, 12/16 patients with positive imaging findings and 75/126 (60%) patients with negative imaging received treatment (radiation, hormones or chemotherapy). CONCLUSION The conventional imaging identified sites of disease, almost always in the form of local recurrence, in a minority of patients with early PSA rise postprostatectomy.

Prognostic value of lymph node yield during nephroureterectomy for upper tract urothelial carcinoma

INTRODUCTION Lymph node dissection (LND) performed during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) remains controversial and difficult to evaluate. The aim of this study was to investigate whether removal of more lymph nodes during RNU is safe and improves oncologic outcomes. METHODS We evaluated 422 patients who underwent RNU with concomitant LND for upper tract urothelial carcinoma between 1976 and 2015, assessing for an association between total nodes removed, recurrence-free survival, and cancer-specific survival using Cox proportional hazards models. We also investigated the relationship between nodal yield and perioperative metrics and intersurgeon variability using linear regression. RESULTS In our cohort of 442 patients, 239 developed recurrences and 94 patients died of disease. Median follow-up among survivors was 3.7 years (interquartile range: 1.2, 7.4). The median nodal yield was 9 (interquartile range: 4, 16). Among patients with node-positive disease (pN1), we observed a significant improvement in recurrence-free survival (hazard ratio = 0.84 per 5 nodes removed, P = 0.039) and a nonsignificant improvement in cancer-specific survival with an increase in the nodal yield (hazard ratio = 0.90 per 5 nodes removed, P = 0.2). There was no evidence of an association between node yield and operative time, estimated blood loss, or 30-day complications on multivariable analysis. There was significant heterogeneity among surgeons regarding the extent of LND (P<0.0001). CONCLUSIONS We found that a more extensive node dissection may improve oncologic outcomes in a subset of high-risk patients without significantly increasing operative time or serious complications. Additionally, we identified considerable intersurgeon heterogeneity regarding the extent of LND furthering the notion of surgeon variability as a nonstandardized factor.

Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors.

Purpose: PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors, including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition. Experimental Design: Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies and then examined treatment responses, including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed. Results: Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases, and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8+:regulatory T cell (Treg) and CD4+FoxP3-:Treg ratios in primary renal tumors and increased T-cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts. Conclusions: Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone. Clin Cancer Res; 24(3); 592–9. ©2017 AACR.

Repeat prostate biopsies prior to radical prostatectomy do not impact erectile function recovery and mid- to long-term continence

A growing number of men undergo repeat biopsies prior to radical prostatectomy for prostate cancer. However, the long‐term impact of repeat biopsies on functional outcomes in this patient population remains unelucidated. Thus, we compared functional outcomes between patients who underwent single biopsy versus repeat biopsies before radical prostatectomy.

Does Subclassification of Pathologically Organ Confined (pT2) Prostate Cancer Provide Prognostic Discrimination of Outcomes after Radical Prostatectomy

Purpose: We tested the latest update in the prostate cancer staging system by assessing the prognostic association of pT2 subclassification with the probability of survival related outcomes in patients who underwent radical prostatectomy. Materials and Methods: We retrospectively analyzed the records of a total of 15,305 patients who underwent radical prostatectomy at 2 referral centers between 1985 and 2016, and had pT2 disease at the final pathological evaluation. Descriptive statistics were used to compare baseline data stratified by pT2 substages (pT2a/b vs pT2c). Cox regression models were adjusted for institution analyzed differences in the rate of biochemical recurrence, metastasis, cancer specific death and overall mortality. Multivariable Cox regression models were used to evaluate the predictive value of pT2 subclassification for survival, including the linear predictor from the Stephenson nomogram. Results: Prostate specific antigen levels and Gleason score differed significantly between the pT2 substages (each p <0.0001). At a median followup of 6.0 years (IQR 3.3–10.1) 2,083 patients had biochemical recurrence, 161 had metastases, 43 had died of prostate cancer and 1,032 had died of another cause. On univariate analysis the pT2 subclassification was significantly associated with biochemical recurrence (p = 0.001) and distant metastasis (p = 0.033) but not with cancer specific death (p = 0.6) or overall mortality (p = 0.3). Multivariable analysis showed no evidence of a significant association between the pT2 subclassification and biochemical recurrence (p = 0.4) or distant metastasis (p = 0.6). Multivariable analysis of cancer specific death and overall mortality was omitted due to lack of significance on univariate analysis. Conclusions: Subclassification of pT2 prostate cancer is not a prognostic indicator of survival related outcomes after radical prostatectomy. Our results validate the elimination of pT2 substages in the updated staging system.

MP70-12 PREDICTING EXTENSIVE DISEASE AMONG POTENTIAL CANDIDATES FOR HEMI-ABLATIVE FOCAL THERAPY FOR PROSTATE CANCER

HIFU; in eight patients (19,5%) the catheter was maintained until day 15. Nine men (21,9%) had self-resolving, mild to moderate, dysuria (median duration 7 days). Urinary tract infection was noted in 5 men (12,2%). Mean 6-months PSA was 2,4 ng/ml (0,2-9). Forthy patients (97,6%) had normal mpMRI findings 6-months after HIFU. One patient showed focal abnormal signal at mpMRI around the treated area: fusion biopsies confirmed the persistence of microfocal PCa with Gleason score 3+3 (treatment failure); in this patients a retreatment was performed. No major complication was observed. IPSS score showed no significant difference before and 6-months after HIFU. At 6 months, all patients were completely continent, and potency was maintained in 30 of 31 preoperatively potent patients. CONCLUSIONS: The integration between fusion biopsy and Focal One device allows to date the most accurate detection and treatment of index focus of PCa. This preliminary experience with 6-months follow-up time indicates that HIFU focal ablation of prostate cancer leads to 00Trifecta00 outcomes (cancer control, continence, sexual potency) in 91,5% of 41 men. The integration of new technologies enables the accurate and early diagnosis of recurrence after focal ablative treatment, leaving the possibility of a precise HIFU retreatment.