Beatrice Caruso

Associations of Pretreatment Serum Total Testosterone Measurements with Pathology-Detected Gleason Score Cancer

Background and Objective: Prostate cancer is an endocrine-dependent tumor which is still under-investigated for physiopathology factors related to its natural history. The association of pretreatment total testosterone (TT) serum levels with prostate cancer is still a controversial topic. The objective of this study was to investigate potential associations and functional relationships of preoperative TT serum level and pathology-detected Gleason score (pGS). Materials and Methods: Pretreatment and pathological variables of 220 patients operated with radical prostatectomy were retrospectively reviewed. Age, prostate-specific antigen (PSA), percentage of positive biopsy cores (P+), biopsy Gleason score (bGS), pGS, TT and free testosterone were the continuous variables, while clinical stage (cT: cT1c, cT2/3), biopsy Gleason pattern (bGP: ≤3+3, 3+4, >3+4), pathology Gleason pattern (pGP: ≤3+3, 3+4, >3+4), pathology stage (pT: pT2, pT3a, pT3b), pathology nodal staging (pN: pN0, pN1, pNx) and surgical margin invasion by cancer (R-, R+) were the categorical variables. Statistical methods were computed for assessing associations of TT and pGS; moreover, simple and multiple linear regression analysis (SLRA and MLRA) were used for assessing functional relationships of TT and pGS. Results: High-grade tumors (pGS ≥8.0) were associated with bGS >6.0 (p < 0.0001), pGP ≥3+4 (p < 0.0001), P+ >0.31% (p = 0.006), cT2/3 (p = 0.01), TT >15.5 nmol/l (p = 0.0004) and, to a lesser extent, PSA >6.27 μg/l (p = 0.06). The odds ratio (OR) ranked as follows: 2.01 (PSA >6.27 μg/l), 2.88 (cT2/3), 3.23 (P+ >0.31%), 5.53 (TT >15.5 nmol/l) and 12.09 (pGP ≥3+4 and pGS ≥8.0). On SLRA, pGS variation was significantly predicted by bGS (p < 0.0001), P+ (p < 0.0001), PSA (p = 0.0005) and TT (p = 0.02); on MLRA, pGS variation was still significantly predicted by bGS (p < 0.0001), P+ (p = 0.04), PSA (p = 0.03) and TT (p = 0.002). When bGS, P+, PSA and TT were dichotomized to their median value, only bGS (p < 0.0001) and TT (p = 0.001) showed independence in predicting pGS variation. The best model for predicting pGS variations was by dichotomizing TT above its median (>15.5 nmol/l) because the predictive coefficient increased to 0.32, which means that patients with TT >15.5 have a significantly higher estimated risk for high-grade pGS than patients with TT ≤15.5 nmol/l (OR = 1.31). Conclusion: In a patient population undergoing radical prostatectomy, increased pretreatment serum measurements of TT are associated with and functionally related to high-grade pGS; moreover, baseline TT together with bGS and PSA are important factors for predicting pGS and assessing high-grade tumors. Baseline TT serum levels might have prognostic potential for assessing treatment response for continuous as well as intermittent androgen deprivation therapy.

Investigative clinical study on prostate cancer part II: on the role of the pretreatment total PSA to free testosterone ratio as a marker assessing prostate cancer prognostic groups after radical retropubic prostatectomy.

Objectives: To explore the significance of the pretreatment total prostate-specific antigen (PSA) to free testosterone (FT) ratio (PSA/FT) as a marker for assessing the pathologic Gleason sum (pGS) and levels of tumor extension (pT) in prostatectomy specimens. Patients and Methods: 128 of 135 consecutive patients diagnosed with prostate cancer underwent radical prostatectomy. Simultaneous pretreatment serum samples were obtained to measure serum total testosterone, FT and total PSA levels. The statistical design of the study included 2 sections: the first part trying to explore the role of the PSA/FT ratio in clustering patients with different pathologic prognostic factors, and the second to investigate the PSA/FT ratio distribution in different groups of patients according to the pathologic stage and pGS of the specimen after radical prostatectomy. Results: The average age was 65.80 (range 51.21–77.26) years, mean PSA was 8.88 (range 1.22–44.27) µg/l, mean FT was 35.32 (range 13.70–69.30) pmol/l, and the mean PSA/FT ratio was 0.27 (range 0.04–1.48). The PSA/FT ratio significantly clustered both the pT and pGS groups. Analysis of variance for the distribution of the PSA/FT ratio was significant for the pT model groups. The mean PSA/FT ratio increased as the tumor extended and grew through the prostate gland (high-stage disease). Analysis of variance for the different distributions of the PSA/FT ratio was significant for all model pGS groups. In our investigation we also found (data not shown) that a PSA/FT ratio of ≧0.40 was strongly correlated with large extensive (pT3b+pT4) and high-grade cancers (pGS8+pGS9). Conclusions: Prostate cancer patients may be classified into 3 different pathologic prognostic groups according to the PSA/FT ratio: low risk (PSA/FT ≤0.20), intermediate risk (PSA/FT >0.20 and ≤0.40), and high risk (PSA/FT >0.40 and ≤1.5). The PSA/FT ratio may be considered as the marker expressing different biology groups of prostate cancer patients, and it is strongly associated with pT and pGS.

Investigative clinical study on prostate cancer: on the role of the pretreatment total PSA to free testosterone ratio in selecting different biology groups of prostate cancer patients

ObjectivesTo show that prostate cancer biology is related to serum levels of both free testosterone (FT) and prostate-specific antigen (PSA), that PSA level is linearly related to FT and that the PSA to FT ratio may be considered as the growth rate parameter expressing cancer phenotype biology.Materials and methodsThe study includes 135 consecutive patients diagnosed with prostate cancer. Pretreatment simultaneous serum samples for analyzing total testosterone (TT), FT and total PSA levels were obtained. The study was assessed according to a multidimensional approach of the five continuous variables including TT, FT, PSA, AGE and percentage of positive biopsies (=P+). The all sets of data were considered as one—sample with no groupings among the observations. Multivariate analysis included factor analysis (FA) and principal component analysis (PCA). Multivariate inferential statistics for comparing different groups of patients according to the PSA to free testosterone ratio (PSA/FT) included Hotteling’s multivariate two-sample T²-Test for comparing two mean vectors as well as Box’s M-Test with the chi-square approximation for comparing multiple covariance matrices when patients were sampled in more than two groups.ResultsFactor analysis showed the two natural grouping of variables, FT-TT and PSA-P+. PCA assessed FT and PSA as the two variables with large variances having a notable influence on the first two principal components. Multiple linear regression analysis showed that all the income variables, except age, significantly predicted the PSA/FT ratio. Patients were first sampled according to the PSA/FT ratio in group 1 (PSA/FTxa0≤xa00.20) and group 2 (PSA/FTxa0>xa00.20), and Hotteling’s multivariate two sample T²-Test was significant (Pxa0<xa00.01). Patients were then sampled according to the PSA/FT ratio in group 1 (PSA/FTxa0≤xa00.20), group 2 (PSA/FTxa0>xa00.20 andxa0≤xa00.40), and group 3 (PSA/FTxa0>xa00.40), and Box’s M-Test comparing the covariance matrices of the 3 groups differed significantly (Pxa0<xa00.001). Finally, patients were sampled according to the PSA/FT ratio in 6 groups, and Box’s M-Test was again significant (Pxa0<xa00.001).ConclusionsThe PSA to FT ratio is the growing rate parameter expressing different biology patterns and assessing different groups of prostate cancer patients. In our opinion, the results of the present study might have wide applications in understanding, assessing and planning prostate cancer studies including basic science, screening, assessing risk of the disease, predicting disease stage as well natural history after a planned treatment involving biochemical recurrence, progression, hormone refractory prostate cancer and disease-specific survival.

Investigative Clinical Study on Prostate Cancer Part III: Exploring Total PSA and Free Testosterone Distributions and Linear Correlations in Groups and Subgroups of Operated Prostate Cancer Patients according to the Total PSA/FT Ratio

Objectives: Prostate cancer is an interesting tumor for endocrine investigation. The prostate-specific antigen/free testosterone (PSA/FT) ratio has been shown to be effective in clustering patients in prognostic groups as follows: low risk (PSA/FT ≤0.20), intermediate risk (PSA/FT >0.20 and ≤0.40) and high risk (PSA/FT >0.40 and ≤1.5). In the present study we explored the total PSA and FT distributions, and linear regression of FT predicting PSA in the different groups (PSA/FT, pT and pG) and subgroups (pT and pG) of patients according to the prognostic PSA/FT ratio. Patients and Methods: The study included 128 operated prostate cancer patients. Pretreatment simultaneous serum samples were obtained for measuring free testosterone (FT) and total PSA levels. Patients were grouped according to the total PSA/FT ratio prognostic clusters (≤0.20, >0.20 and ≤0.40, >0.40), pT (2, 3a and 3b+4) and pathological Gleason score (pG) (≤6, = 7 >3 + 4, ≧7 >4 + 3). The pT and pG sets were subgrouped according to the prognostic PSA/FT ratio. Linear regression analysis of FT predicting total PSA was computed according to the different PSA/FT prognostic clusters for the: (1) total sample population, (2) pT and pG groups, (3) intraprostatic (pT2) and extraprostatic disease (pT3a/3b/4), and (4) low-intermediate grade (pG ≤6) and high-grade (pG ≧7) prostate cancer. Results: Analysis of variance always showed highly significant different PSA distributions for (1) the different PSA/FT, pT and pG groups; and (2) the pT and pG prognostic subgroups. Significant FT distributions were detected for the (1) PSA/FT and pT groups; and (2) the pT2, pT3a and pG ≤6 prognostic PSA/FT subgroups. Correlation, variance and linear regression analysis of FT predicting total PSA was significant for (1) the PSA/FT prognostic clusters, (2) all the pT2 and pT3a subgroups, and (3) the pT3b/4 subgroup with PSA/FT >0.20 and ≤0.40, and (4) all the pG subsets. Linear regression analysis showed that the slopes of the predicting variable (FT) were always highly significant for patients with (1) intraprostate and extraprostate disease, and (2) low-grade and high-grade prostate cancer. Conclusions: According to the prognostic PSA/FT ratio, significantly lower levels of FT are detected in prostate cancer patients with extensive and high-grade disease. Also, significant linear correlations of FT predicting PSA are assessed in the different groups and subgroups of patients clustered according to the prognostic PSA/FT ratio. Confirmatory studies are needed.

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.

Serum total testosterone is a significant preoperative variable independently contributing to separating the prostate cancer population into prostatectomy Gleason score groups

Aim: To investigate the potential of preoperative serum total testosterone (TT) in contributing to the definition of separate prostatectomy Gleason score (pGS) groups of the prostate cancer (PCa) population. Materials and Methods: The data of 220 patients operated on for PCa were retrospectively reviewed. No patient had previously received 5α-reductase inhibitor, luteinizing hormone-releasing analogs or testosterone replacement treatment. The patient population was grouped according to the pGS as 6 = 3+3, 7 = 3+4, 7 = 4+3 and 8-10. Eight variables were simultaneously investigated in each group: prostate-specific antigen (PSA), TT, free testosterone, age, percentage of positive prostate biopsy cores (P+), biopsy Gleason score (bGS), overall cancer volume estimated as percentage of prostate volume (V+) and prostate weight (Wi). Univariate analysis of variance (ANOVA), multivariate analysis of variance (MANOVA) and multivariate discriminant analysis (MDA) were the statistical methods used for evaluating the data. Results: There were 89 patients in pGS 6 = 3+3, 84 in pGS 7 = 3+4, 24 in pGS 7 = 4+3 and 23 in pGS 8-10. ANOVA showed that bGS (p < 0.0001), P+ (p < 0.0001), V+ (p < 0.0001), PSA (p = 0.0001), Wi (p = 0.0002) and TT (p = 0.01) were significantly different in the four pGS groups. MANOVA tests showed that only bGS (p < 0.0001), V+ (p = 0.0003), TT (p = 0.001) and, to a lesser extent, PSA (p = 0.06) were the significant variables that individually and independently contributed a significant amount to separation of the four pGS groups of the PCa population. MDA showed that the independent variables ranked as bGS (p < 0.0001), TT (p = 0.001), V+ (p = 0.001) and PSA (p = 0.06). Conclusions: Serum TT is a significant preoperative variable that independently contributes to separating the PCa population into pGS score groups. Pretreatment baseline serum TT levels should be measured and their inclusion in neural networks predicting PCa natural history be considered in the patient population diagnosed with PCa.

Investigative Clinical Study on Prostate Cancer Part VI: Follicle-Stimulating Hormone and the Pituitary-Testicular-Prostate Axis at the Time of Initial Diagnosis and Subsequent Cluster Selection of the Patient Population

Aim: To evaluate the physiopathology of follicle-stimulating hormone (FSH) along the pituitary-testicular-prostate axis at the time of initial diagnosis of prostate cancer in relation to the available clinical variables and to the subsequent cluster selection of the patient population. Patients and Methods: The study included 98 patients who were diagnosed with prostate cancer. Age, percentages of positive cores (P+) at transrectal ultrasound scan biopsy, biopsy Gleason score (bGS), luteinizing hormone (LH), FSH, total testosterone, free testosterone (FT) and prostate-specific antigen (PSA) were the continuous clinical variables. All patients had not previously received hormonal manipulations. FSH correlation and multiple linear analyses were computed in the population. The FSH/PSA ratio was computed and then ranked for clustering the population as groups A (0.13≤FSH/PSA≤0.57), B (0.57<FSH/PSA≤1.61) and C (1.61<FSH/PSA≤19.4). The model was assessed by simple linear and multiple linear regression analysis and differences between the groups were assessed by analysis of variance. Results: In the patient population, FSH correlated to LH (p < 0.0001), FT (p = 0.007) and age (p = 0.004). FSH was independently predicted by both LH (p < 0.0001) and PSA (p = 0.04). PSA predicted FSH/PSA A (p < 0.0001), B (p < 0.0001) and C (p = 0.04). On multiple regression analysis, FSH/PSA A was predicted by PSA (p < 0.0001), P+ (p = 0.03) and bGS (p = 0.04); FSH/PSA B by LH (p = 0.002) and PSA (p < 0.0001); FSH/PSA C by LH (p < 0.0001) and PSA (p < 0.0001). Moreover, FSH/PSA A, B and C differed for mean values of FSH (p < 0.0001), LH (p < 0.0001), PSA (p < 0.0001) and PSA/FT ratio (p < 0.0001). FSH/PSA clusters showed features of decreasing aggressive disease as the FSH/PSA ratio progressed from A to C. Conclusion:At the diagnosis of prostate cancer and along the pituitary-testis-prostate axis in a patient population FSH significantly correlated to LH, FT and age, and FSH was independently and significantly predicted by both LH and PSA. Because of the independent prediction of PSA by FSH, the prostate cancer population at diagnosis was clustered and ranked according to the FSH/PSA ratio in groups A, B and C. Also, the predictive model of PSA on FSH for the different groups proved to be effective at selecting potential prognostic clusters in which the risk of progression might be assessed as low (group C), intermediate (group B) and high (group A). The FSH/PSA model might be considered as a tool for prostate cancer study and for use in individualized, risk-adapted approaches. However, confirmatory studies are needed.

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

OBJECTIVESnTo 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.nnnPATIENTS AND METHODSnAfter 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.nnnRESULTSnTT 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).nnnCONCLUSIONSnPreoperative 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.

Prostate cancer volume associates with preoperative plasma levels of testosterone that independently predicts high grade tumours which show low densities (quotient testosterone/tumour volume)

Objective To investigate potential associations of preoperative total testosterone (TT) with tumor volume (TV) and grade of prostate cancer (PCa). Methods Patients who were under medications impacting on the hypothalamic-pituitary-adrenal-testis-prostate axis were excluded. TT was measured preoperatively at least 1 month after biopsies and TV was calculated on the removed prostate specimen. Other continuous variables included total prostate specific antigen (PSA), percentage of positive cores (P+) and weight (W) of the removed prostate. Patients were categorized according to the pathologic Gleason score (pGS) in 3 groups (pGS 6, 7 and > 7). Invasion of the seminal vesicles was coded as seminal vesicle invasion (SVI). Results The median levels of TT were significantly and increasingly higher from pGS 6 (14.7 nmol/L) to pGS 7 (15.0 nmol/L) and pGS > 7 (18.8 nmol/L). The median values of TV were also detected significantly and increasingly higher from pGS 6 (5.6 mL) to pGS 7 (8.1 mL) and pGS > 7 (14.8 mL). The median preoperative levels of PSA were also increasing from pGS 6 (5.9 μg/L) to pGS 7 (6.2 μg/L) and pGS > 7 (7.7 μg/L). There was a significant and positive correlation of TV to PSA, TT and P+. Multiple linear regression analysis showed that TV was significantly and independently predicted by TT, PSA and P+. High grade PCa (pGS > 7) independently associated with TV, TT, P+ and SVI. The median density values of TT relative to TV (quotient TT/TV) significantly decreased from pGS 6 (2.6 nmol/L/mL) to pGS 7 (1.9 nmol/L/mL) and pGS > 7 (1.4 nmol/L/mL). The median density values of PSA relative to TV (quotient PSA/TV) also significantly decreased from pGS (1.1 μg/L/mL) to pGS 7 (0.7 μg/L/mL) and pGS > 7 (0.6 μg/L/mL). Conclusion The investigation shows that TT relates to volume and grade of PCa; moreover, the density of TT relative to TV inversely associates with rate of increase of cancer that depends on the grade of the tumour.

Follicle-Stimulating Hormone and the Pituitary-Testicular-Prostate Axis at the Time of Initial Diagnosis of Prostate Cancer and Subsequent Cluster Selection of the Patient Population Undergoing Standard Radical Prostatectomy

Aim: A preceding exploratory analysis has shown that follicle-stimulating hormone (FSH) was significantly correlated to and predicted by prostate-specific antigen (PSA) in a prostate cancer population. The aim of the study was to evaluate FSH physiopathology along the pituitary-testicular-prostate (PTP) axis at the time of initial diagnosis of prostate cancer in an operated population clustered according to the FSH/PSA ratio. Patients and Methods: The study included 93 patients who underwent standard radical prostatectomy. Age, percentages of positive cores at transrectal ultrasound scan biopsy (TRUSB) (P+), biopsy Gleason score (bGS), pathology Gleason score (pGS), luteinizing hormone (LH), FSH, prolactin hormone (PRL), total testosterone (TT), free testosterone (FT), estradiol (ESR) and PSA were the continuous variables. Category variables were pT and biopsy/pathology Gleason pattern I/II (b/pGPI/II). The population was clustered according to the FSH/PSA ratio which was computed from empirical data and then ranked for clustering the population as groups A (range 0.13 ≤ FSH/PSA ≤ 0.20), B (range 0.20 < FSH/PSA ≤ 0.50), C (range 0.50 < FSH/PSA ≤ 0.75), D (range 0.75 < FSH/PSA ≤ 1.00), E (range 1.00 < FSH/PSA ≤ 1.25), F (range 1.25 < FSH/PSA ≤ 2.00), G (range 2.00 < FSH/PSA ≤ 2.25), H (range 2.25 < FSH/PSA ≤ 6.40) and I (range 6.40 < FSH/ PSA ≤ 19.40). The model was assessed by simple linear regression analysis and differences between the groups were investigated by analysis of variance (ANOVA) for continuous variables and by contingency tables for category variables. Results: FSH was significantly correlated to and predicted by PSA in groups A (p = 0.04), B (p < 0.0001), C (p < 0.0001), D (p < 0.0001), E (p < 0.0001), F (p < 0.0001), G (p < 0.0001), H (p = 0.0001) and I (p = 0.001). Also, clusters (A–I) differed significantly for mean values of FSH (p < 0.0001), LH (p < 0.0001), TT (p = 0.04), PSA (p < 0.0001), bGS (p = 0.005), pGS (p = 0.01) and PSA/FT ratio (p < 0.0001); moreover, the nine groups showed significant different frequency distributions of pGPI (p = 0.02), pGPII (p = 0.0002) and bGPI (p = 0.04). Conclusion: The ranking FSH/PSA ratio significantly clustered, along the PTP axis, an operated population diagnosed with prostate cancer. Also, the ranking FSH/PSA ratio selected prostate cancer clusters expressing different levels of hormonal disorder along the PTP axis and prognostic potential with different risks of progression. As a theory, in the current advancing world, the ranking FSH/PSA model might be considered as an interesting and effective tool for prostate cancer study as well as individualized, risk-adapted approaches of the disease. However, confirmatory studies are needed.