Marco Sebben

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.

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.

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.

Inverse Association of Prostatic Chronic Inflammation among Prostate Cancer Tumor Grade Groups: Retrospective Study of 738 Consecutive Cases Elected to a First Random Biopsy Set

Objectives: The study aimed to evaluate associations of prostatic chronic inflammation (PCI) with prostate cancer (PCA) grade groups by the International Society of Urological Pathology (ISUP). Methods: The study evaluated retrospectively 738 cases. The patient population was sampled into 3 groups collecting cases without and with PCA including subjects with lSUP grade group 1 and grade groups 2–5. Results: PCI was assessed in 185 patients (25.1%) and PCA in 361 patients (48.9%) of whom 188 (25.5%) had ISUP grade and 173 (23.4%) had ISUP groups 2–5 tumors. PCI inversely related to ISUP groups (p < 0.0001). In multivariate analysis, the risk of ISUP grade group 1 PCA compared to negative cases associated positively with age (OR 1.042; p = 0.001) but inversely with total prostate volume (TPV; OR 0.965; p < 0.0001) and PCI (OR 0.314; p < 0.0001). Intermediate-high grade tumors associated positively with age (OR 1.065; p < 0.0001), prostate specific antigen (OR 1.167; p < 0.0001), and abnormal digital rectal examination (OR 2.251; p < 0.0001) but inversely with TPV (OR 0.921; p < 0.0001) and PCI (OR 0.106; p < 0.0001). Conclusions: PCI decreased the risk of PCA among ISUP tumor grade groups.

Positive Association between Preoperative Total Testosterone Levels and Risk of Positive Surgical Margins by Prostate Cancer: Results in 476 Consecutive Patients Treated Only by Radical Prostatectomy

Objective: To evaluate preoperative total testosterone (TT) as a predictor of positive surgical margins (PSM) in prostate cancer (PCA). Patients and methods: During the period from November 2014 to July 2017, preoperative TT was measured in 476 PCA patients undergoing only radical prostatectomy (RP) and including all risk classes. Surgical margins were stated negative, focal positive (single and less than 1 mL), and multifocal positive (more than 1). The risk of TT and clinical factors associated with the risk of PSM (focal or multifocal versus negative) was evaluated by the multinomial logistic regression model. Results: Overall, PSM were detected in 149 cases (31.3%), which included 99 patients with focal cancer invasion (20.8%) and 50 subjects with multifocal cancer invasion (10.5%). In univariate analysis, PSM associated with higher median levels of TT and prostate-specific antigen than controls. Multifocal PSM associated with higher rates of high-risk PCA (42%) than focal (22.2%) or control cases (18.3%). In multivariate analysis, TT was the only independent factor positively associated with the risk of focal PSM when compared to controls (OR 1.002; p = 0.035). TT (OR 1.003; p = 0.002) and high-risk PCA (OR 1.002; p = 0.047) were independent factors, which positively associated with the risk of multifocal PSM when compared to controls. Risk models were computed. Conclusions: In a large and contemporary cohort of patients elected to primary RP, TT was an independent positive factor associated with the risk of focal and multifocal PSM. TT associated with aggressive PCA biology.

Clinical factors stratifying the risk of tumor upgrading to high-grade disease in low-risk prostate cancer

Purpose: To identify clinical factors stratifying the risk of tumor upgrading to increasing patterns of the tumor grading system in low-risk prostate cancer (PCa). Methods: We evaluated the records of 438 patients who underwent radical prostatectomy. Associations between clinical factors and tumor upgrading were assessed by the univariate and multivariate multinomial logistic regression model. Results: Low-risk PCa included 170 cases (38.8%) and tumor upgrading was detected in 111 patients (65.3%): 72 (42.4%) had pathology Gleason pattern (pGP) 3 + 4, 27 (15.9%) pGP 4 + 3, and 12 (7.1%) pGP 4 + 4. Prostate- specific antigen (PSA) and proportion of positive cores (P+) were independent predictors of upgrading to high-risk disease. These factors also stratified the risk of tumor upgrading to the increasing patterns of the tumor grading system. The model allowed the identification of pGP 4 + 4. The main difference between high-risk PCa and other upgraded tumors related to PSA load (odds ratio 2.4) that associated with high volume disease in the specimen. Conclusions: Low-risk PCa is a heterogeneous population with significant rates of tumor upgrading. Significant clinical predictors stratifying the risk of tumor upgrading to increasing patterns of the grading system included PSA and P+. These factors allowed the identification of the subset hiding high-grade disease requiring further investigations before delivering active treatments.