Nicolò De Luyk

High Testosterone Preoperative Plasma Levels Independently Predict Biopsy Gleason Score Upgrading in Men with Prostate Cancer Undergoing Radical Prostatectomy.

Purpose: The study aims to investigate the potential associations between preoperative plasma levels of total testosterone (TT) and biopsy Gleason score (bGS) upgrading in prostate cancer (PCA) patients undergoing radical prostatectomy (RP). Materials and Methods: Exclusion criteria were treatment with 5α-reductase inhibitors, LH-releasing hormone analogues or testosterone replacement. Criteria of bGS upgrading were as follows: (i) bGS 6 to pathological Gleason score (pGS) >6, (ii) bGS 7 with pattern 3 + 4 to pGS 7 with pattern 4 + 3 or to pGS >7, (iii) bGS 7 with pattern 4 + 3 to pGS >7. Patients who showed bGS >7 were excluded from the cohort. Results: The study included 209 patients. Tumor upgrading was assessed in 76 (36.4%) cases of the entire cohort, in 51 out of 130 cases (39.2%) of the bGS 6 group and 25 out of 79 patients (31.6%) in the bGS 7 cluster. Logistic regression models showed that independent clinical covariates predicting the risk of bGS upgrading included TT (OR 1.058; p = 0.027) and prostate-specific antigen (PSA) density (OR 23.3; p = 0.008) as well as TT (OR 1.057; p = 0.029) with PSA (OR 1.061; p = 0.023). The model suggests that 1 unit increase in TT plasma levels increases the odds of bGS upgrading by 5.8 or 5.7%. Conclusions: In summary, we have determined that high TT preoperative plasma levels independently predict bGS upgrading in men with PCA undergoing RP. Preoperative plasma levels of TT might be included as a potential marker for assessing the risk bGS upgrading.

Chronic Inflammation in Prostate Biopsy Cores is an Independent Factor that Lowers the Risk of Prostate Cancer Detection and is Inversely Associated with the Number of Positive Cores in Patients Elected to a First Biopsy

Objectives: To investigate associations of chronic inflammatory infiltrate (CII) with prostate cancer (PCa) risk and the number of positive cores in patients elected to a first set of biopsies. Materials and Methods: Excluding criteria were as follows: active surveillance, prostate specific antigen (PSA) ≥ 30 ng/l, re-biopsies, incidental PCa, less than 14 cores, metastases, or 5-alpha reductase inhibitors. The cohort study was classified as negative (control group) and positive cores between 1 and 2 or > 2. Results: The cohort included 421 cases who did not meet the exclusion criteria. PCa was detected in 192 cases (45.6%) of which the number of positive cores was between 1 and 2 in 77 (40.1%) cases. The median PSA was 6.05 ng/ml (range 0.3-29 ng/ml). Linear regression models showed that CII was an independent predictor inversely associated with the risk of PCa. Multinomial logistic regression models showed that CII was an independent factor that was inversely associated with PCa risk in cases with positive cores between 1 and 2 (OR = 0.338; p = 0.004) or more than 2 (OR = 0.076; p < 0.0001) when compared to the control group. Conclusion: In a cohort of men undergoing the first biopsy set after prostate assessment, the presence of CII in the biopsy core was an independent factor inversely associated with PCa risk as well as with the number of positive biopsy cores (tumor extension). Clinically, the detection of CII in negative biopsy cores might reduce the risk of PCa in repeat biopsies as well as the probability of detecting multiple positive cores.

Association between Basal Total Testosterone Levels and Tumor Upgrading in Low and Intermediate Risk Prostate Cancer

Purpose: The study aimed to evaluate associations of basal levels of total testosterone (TT) with tumor upgrading to high risk disease in low-intermediate risk prostate cancer (PCA). Materials and Methods: We retrospectively evaluated the records of 135 patients undergoing radical prostatectomy. Evaluated factors included age, body mass index, prostate specific antigen (PSA), TT, prostate volume, PSA density (PSAD), proportion of biopsy positive cores (P+), clinical tumor stage, and biopsy grading system (1 or 2). Factors associating with tumor upgrading were investigated by the multivariate logistic regression analysis. Results: Tumor upgrading rate to high risk disease was 8.9%. TT, PSA, and PSAD were associated with tumor upgrading. On multivariate analysis, independent factors predicting tumor upgrading were PSA (OR 1.324; p = 0.001) and TT (OR 1.005; p = 0.015). Basal TT was dichotomized up to the third quartile (TT > q3) vs. TT ≤ q3 (426.0 ng/dL). The assessed tumor upgrading risk model showed that TT dichotomized to third quartile (TT > q3 vs. TT ≤ q3) stratified the risk of tumor upgrading (OR 6.577; p = 0.010) along increasing levels of PSA (OR 1.3; p < 0.0001). Conclusions: Low and intermediate risk PCA patients show a not negligible risk of tumor upgrading to high risk disease. In this particular subset of patients, basal levels of TT stratify the risk of tumor upgrading.

Clinical Factors Predicting Bilateral Lymph Node Invasion in High-Risk Prostate Cancer

Background: In high-risk prostate cancer (HR-PCA), it is important to consider the factors associated with extensive lymph node invasion (LNI) before planning treatment methods. Objective: To investigate clinical predictors of bilateral LNI in HR-PCA. Materials and Methods: The study evaluated 261 consecutive patients who underwent radical prostatectomy with extended pelvic lymph node dissection. The multivariate multinomial logistic regression model was computed. Results: The high-risk category included 102 cases. Overall, LNI was detected in 28 patients (27.5%) and was bilateral in 11 cases (10.8%). Independent factors associated with LNI were prostate-specific antigen (PSA) and proportion of positive cores. The main model showed that only higher values of PSA increased the odds of bilateral LNI when compared to patients having unilateral LNI (OR 1.058; p = 0.018). The area under the curve of PSA predicting bilateral LNI was 0.819. Conclusions: In HR-PCA, the independent predictor of LNI was PSA, which varied among patients with bilateral and unilateral LNI.

Prostate Volume Index Associates with a Decreased Risk of Prostate Cancer: Results of a Large Cohort of Patients Elected to a First Biopsy Set.

Background/Aims/Objectives: In patients elected to the first prostate biopsy set, the risk of prostate cancer (PCA) may be predicted by clinical factors. The aim of this study was to investigate on prostate volume index (PVI), defined as the ratio of volume of the transitional zone to the volume of the peripheral zone, and PCA risk. Methods: The study retrospectively evaluated 1,327 patients and included only the first biopsy set with 14 cores. PCA risk was assessed by using the multivariate logistic regression model. Results: The analysis evaluated 596 patients. The detection rate of PCA was 49%. Age, prostate specific antigen, PVI and digital rectal exam were independent factors of PCA risk, which was decreased by PVI (OR 0.224; 95% CI 0.157-0.380). The goodness of fit statistics assessed model efficacy. Conclusions: In a large cohort undergoing the first biopsy set, PVI associated with a decreased risk of PCA. Confirmatory studies are required.

Clinical Factors of Disease Reclassification or Progression in a Contemporary Cohort of Prostate Cancer Patients Elected to Active Surveillance

Objectives: To evaluate clinical predictors of disease reclassification or progression (DR/P) in prostate cancer patients elected to active surveillance (AS). Material and Methods: Patients were assessed on the basis of DR/P criteria. Predictors of DR/P were evaluated by multivariate logistic regression and Cox proportional hazards. Results: The median DR/P free time was 16.5 months. DR/P was detected in 30 out of 84 cases (35.7%). In DR/P cases, the median prostate volume (PV) was significantly lower (34.7 vs. 42.7 ml) and the percentage of cases with 2 or 3 vs. 1 initial biopsy positive cores (BPC) was significantly higher (36.7 vs. 7.4%). The multivariate logistic regression model showed that PV (OR 0.9; p = 0.021) and initial n >1 BPC (OR 9.8; p = 0.001) were independent predictors of DR/P. By Cox multivariate proportional hazards, only n >1 BPC predicted early DR/P (hazard ratio 3.1; p = 0.003). Conclusions: In a contemporary cohort of patients elected to AS, independent factors stratifying the risk of DR/P were PV and initial BPC, which also predicted early DR/P. In patients elected to AS, the identification of risk factors of DR/P require early re-biopsy. Confirmatory studies are required.

Bilateral lymph node micrometastases and seminal vesicle invasion associated with same clinical predictors in localized prostate cancer.

Aim To determine clinical factors associated with multiple bilateral lymph node micrometastases and seminal vesicle invasion (pT3b) in organ-confined prostate cancer (PCa). Methods The study excluded patients under androgen deprivation, with lymph node involvement (cN1 status), and having undergone unilateral pelvic lymph node dissection (PLND) during radical prostatectomy (RP). Lymph node micrometastases were classified as unilateral (pN1m) and bilateral (pN1b). Analysis considered multivariate multinomial logistic regression models. Results Between January 2013 and March 2015, 140 patients underwent PLND during RP. Lymph node micrometastases were detected in 28 cases (20%) including pN1m in 19 (13.6%) and pN1b in 9 (6.4%). Independent clinical predictors of pN1b included prostate-specific antigen (PSA, µg/L) >12.5 (odds ratio [OR] = 43.0), proportion of positive biopsy cores (PBC) >0.57 (OR = 6.7), and biopsy Gleason grade (bGG) >3 (OR = 7.5). Independent pT3b predictors included PSA>12.5 (OR = 3.8), PBC>0.57 (OR = 4.1), and bGG>3 (OR = 3.8). Conclusions In cN0 patients with localized PCa undergoing PLND, a nonnegligible rate of multiple lymph node micrometastases was detected (32.2%). In the natural history of PCa, there is a close association between pT3b and pN1b disease. Prostate cancer patients who are at high risk of extraglandular extension need selective pelvic staging by multiparametric magnetic resonance imaging to assess seminal vesicle invasion. Operated patients with pT3b and pNx status need close PSA monitoring because of the high probability of occult multiple bilateral lymph node micrometastases.

Low-Risk Prostate Cancer and Tumor Upgrading in the Surgical Specimen: Analysis of Clinical Factors Predicting Tumor Upgrading in a Contemporary Series of Patients Who were Evaluated According to the Modified Gleason Score Grading System

Objective: To identify significant clinical factors associated with prostate cancer (PCa) upgrading the low-risk PCa patients graded according to the modified Gleason score system. Materials and Methods: The logistic regression model was used to evaluate the records of 438 patients. Results: There were 170 cases (38.8%) of low-risk PCa and tumors were upgraded in 111 patients (65.3%). Only prostate specific antigen (PSA) and the proportion of positive cores (P+) were independent predictors of tumor upgrading. Further exploration was investigated by categorizing and regressing PSA (≤ 5.0 vs. > 5.0 ng/ml) and P+ (≤ 0.20 vs. > 0.20). The odds ratio of PSA > 5 ng/ml was 1.32 and of P+ > 0.20 was 2.71. The population was stratified into very low-risk with PSA ≤ 5 ng/ml and P+ ≤ 0.20 (class A), low-risk with PSA > 5 ng/ml and P+ ≤ 0.20 (class B), intermediate risk with PSA ≤ 5 ng/ml and P+ > 0.20 (class C), and high risk with PSA > 5 ng/ml and P+ 0.20 (class D). Upgrading rates were extremely low in class A (9%), extremely high in D (50.5%), and moderate (20%) in B and C. Conclusion: Patients diagnosed with low-risk PCa at biopsy are a heterogeneous population because they include subsets with undetected high-grade disease. Significant clinical predictors of upgrading include the PSA value and P+. In low-risk PCa, we identified a high-risk upgrading subgroup that needed repeat biopsies in order to reclassify the tumor grade and to reassess the clinical risk category.

Intraprostatic chronic inflammation is associated with a reduced risk of prostate cancer in patients elected to a first random biopsy set

Objectives To investigate the associations of clinical factors and intraprostatic chronic inflammatory infiltrate (CII) with the risk of prostate cancer (PCa) in a large contemporary cohort of patients elected to a first random biopsy set. Materials and Methods The study evaluated 596 patients who were elected to a first random biopsy set because of suspected PCa in the period between September 2010 and September 2015. The multivariate logistic regression model investigated the possible associations of clinical factors and intraprostatic CII with PCa. Results Prostate cancer was detected in 292 of 596 patients (49%). Intraprostatic CII was detected in 26.3% of cases. Age (odds ratio, OR = 1.060; p<.0001), prostate-specific antigen (PSA; OR = 1.174; p<.0001), prostate volume (PV; OR = 0.951; p<.0001) and abnormal digital rectal examination (DRE; OR = 2.170; p = 0.001) were independent predictors of PCa risk; moreover, intraprostatic CII was an important independent factor lowering the risk of PCa (OR = 0.258; p<.0001) in the multivariate clinical model. Conclusions In a large contemporary cohort of patients elected to a first random biopsy set, the detection of intraprostatic CII was not negligible (26.3%) and associated with a reduced risk of PCa. In the prostate microenvironment, intraprostatic CII might lower the risk of PCa by activating the response of the immune system at the early stages of cancer induction and progression. Specific serum biomarkers and imaging modalities associated with intraprostatic CII are required. Advanced basic science research is warranted to investigate and develop the controversial topic of intraprostatic chronic inflammation in relation to PCa.

The preoperative serum ratio of total prostate specific antigen (PSA) to free testosterone (FT), PSA/FT index ratio, and prostate cancer. Results in 220 patients undergoing radical prostatectomy

OBJECTIVES To evaluate associations of preoperative total prostate specific antigen (PSA) to free testosterone (FT), the PSA/FT index ratio, with features of pathology prostate cancer (PCA) and to investigate its prognostic potential in clustering the PCA population. PATIENTS AND METHODS After excluding criteria, the records of 220 patients who underwent radical prostatectomy (RP) were retrospectively reviewed. Serum samples of PSA, total testosterone (TT) and FT were collected at 8.00 A.M., one month after biopsies and before RP. The PSA/FT ratio was computed in the population of patients who were clustered in groups according to ranking intervals of the PSA/FT ratio which identified at least 4 clusters which were coded as A, B, C, and D. The independent associations of the PSA/FT index ratio were assessed by statistical methods and a two-sided P < 0.05 was considered to indicate statistical significance. RESULTS TT correlated to FT which was a significant predictor of PSA in the population of patients who were subsequently clustered, according to increasing interval values of the PSA/FT index ratio, in groups that showed a stronger linear association of FT with PSA. The PSA/FT index ratio significantly associated with pathology features of prostate cancer such as pathology Gleason score (pGS), invasion of the seminal vesicles (pT3b), proportion of positive cores (P+) and proportion of cancer involving the volume of the prostate. In the population of patients, TT, PSA/FT index ratio and P+ independently associated with pGS ≥ 7 and pT3b; moreover, the odds ratio (OR) of the PSA/FT index ratio resulted 9.11 which was stronger than TT (OR = 1.11) and P+ (OR = 8.84). In the PCA population, TT, PSA/FT index ratio and P+ also independently associated with pT3b PCA; interestingly, the OR of PSA/FT index resulted 54.91 which was stronger than TT (OR = 1.31) and P+ (26.43). CONCLUSIONS Preoperative PSA/FT index ratio is an independent strong factor which directly associates with aggressive features of pathology PCA; moreover, it might express prognostic potential for clustering the patient population in risk classes. Confirmatory studies are required.