Faculty Bibliography

PURPOSE: Five genetic variants along chromosomes 8q24 and 17q have a cumulative association with prostate cancer risk. Our research group previously reported an association between these variants and clinicopathological characteristics. More recently 4 additional prostate cancer susceptibility variants were identified on chromosomes 2p15, 10q11, 11q13 and Xp11. We performed cumulative risk assessment incorporating all 9 genetic variants and determined the relationship of the new variants to clinicopathological tumor features. MATERIALS AND METHODS: The genotype of 9 variants was determined in 687 men of European ancestry who underwent radical prostatectomy from 2002 to 2008 and in 777 healthy volunteer controls. We compared the incidence of these variants in prostate cancer cases and controls, and assessed their cumulative risk. We also determined the relationship of carrier status for the 4 new variants and clinicopathological tumor features. RESULTS: Prostate cancer cases had an increased incidence of all 9 risk variants compared to controls. A cumulative model including the 9 single nucleotide polymorphisms provided greater prostate cancer risk stratification than a model restricted to the original 5 single nucleotide polymorphisms described. Specifically men with 6 or more variants were at greater than 6-fold increased risk for prostate cancer. Although 2p15 and 11q13 carriers were more likely to have aggressive features, other clinicopathological features were similar in carriers and noncarriers. CONCLUSIONS: Genetic variants located in 9 regions have a cumulative association with prostate cancer risk. Identification of an increasing number of single nucleotide polymorphisms may provide greater understanding of their combined relationship with CaP risk and disease aggressiveness.

PURPOSE: Among men with biochemical progression after radical prostatectomy little is known about prostate specific antigen at the time of metastasis to bone in hormone naive patients. This information would be useful in determining when to initiate androgen deprivation therapy. MATERIALS AND METHODS: From a large radical prostatectomy series we identified 193 hormone naive men in whom bone metastases developed at a mean of 6 years postoperatively. We examined the prostate specific antigen distribution at bone scan conversion by time from radical prostatectomy to metastasis. ANOVA and linear regression were also used to examine the association of clinicopathological tumor features with prostate specific antigen at bone metastasis. RESULTS: Median prostate specific antigen was 31.9 ng/ml at the initial diagnosis of metastatic disease. Bone scan conversion occurred at a prostate specific antigen of less than 10, 10 to 100 and greater than 100 ng/ml in 50 (25.9%), 98 (50.8%) and 45 (23.3%) men, respectively. Lower prostate specific antigen at diagnosis, higher prostatectomy Gleason scores and shorter time to metastasis were associated with lower prostate specific antigen at bone metastasis, whereas prostate specific antigen at metastasis was not significantly associated with other clinicopathological features. CONCLUSIONS: Prostate specific antigen at the time of bone scan detected metastasis is highly variable. Unlike the pretreatment setting when metastases are rare at a prostate specific antigen of less than 10 ng/ml, 25.9% of bone metastases after radical prostatectomy occurred at a prostate specific antigen of less than 10 ng/ml. Because metastasis may occur at a low prostate specific antigen, patients with biochemical progression managed expectantly need regular bone scans even if prostate specific antigen is low to detect metastasis before symptoms

STUDY TYPE: Aetiology (inception cohort) Level of Evidence 2b. OBJECTIVE: To determine whether there might be differences in bone mineral content (BMC) between men who develop life-threatening prostate cancer and those who do not, as bone is a common site of prostate cancer metastases. SUBJECTS AND METHODS: From 1973 to 1984, BMC was serially measured in 519 participants (778 observations) as part of a longitudinal study of ageing. We examined the association between serial BMC measurements with the development of overall and high-risk prostate cancer over the next one to three decades. For all prostate cancer cases, BMC was censored at the time of diagnosis. RESULTS: During a median (range) overall follow-up of 21.1 (0.2-35.0) years after the last BMC measurement, 76 (14.6%) men were later diagnosed with prostate cancer (18 high-risk and 58 not high-risk). BMC declined with age to a greater extent in healthy controls than among men diagnosed with prostate cancer (P = 0.018, likelihood ratio test), and tended to decline less in high-risk than non-high-risk cases. CONCLUSION: The distribution of BMC was significantly different between men who did and did not develop prostate cancer, over an extended follow-up. Specifically, BMC appeared to decline to a greater extent with age among healthy controls than in men with prostate cancer, especially high-risk disease. The biology underlying the lesser decline in BMC among men with prostate cancer remains unclear, but suggests that host factors in the bony milieu might be associated with prostate cancer development and progression.

PURPOSE: To assess the predictive ability of prostate-specific antigen (PSA) velocity (PSAV) and doubling time (PSADT) for biopsy progression and adverse pathology at prostatectomy among men with low-risk prostate cancer enrolled on an active-surveillance program. METHODS: We evaluated 290 men who met criteria for active surveillance (ie, PSA density < 0.15 ng/mL/cm(3) and Gleason score < or = 6 with no pattern > or = 4, involving < or = 2 cores with cancer, and < or = 50% involvement of any core by cancer) with two or more serial PSA measurements after diagnosis from 1994 to 2008. Follow-up included twice-yearly digital rectal exam and PSA measurements and yearly surveillance biopsy. Treatment was recommended for biopsy progression (ie, Gleason score > or = 7, or > 2 positive cores, or > 50% core involvement). Sensitivity and specificity of postdiagnostic PSAV and PSADT were explored by using receiver operating characteristic (ROC) analysis. RESULTS: Overall, 188 (65%) men remained on active surveillance, and 102 (35%) developed biopsy progression at a median follow-up of 2.9 years. PSADT was not significantly associated with subsequent adverse biopsy findings (P = .83), and PSAV was marginally significant (P = .06). No PSAV or PSADT cut point had both high sensitivity and specificity (area under the curve, 0.61 and 0.59, respectively) for biopsy progression. In those who eventually underwent radical prostatectomy, PSAV (P = .79) and PSADT (P = .87) were not associated with the presence of unfavorable surgical pathology. CONCLUSION: Postdiagnostic PSA kinetics do not reliably predict adverse pathology and should not be used to replace annual surveillance biopsy for monitoring men on active surveillance.

OBJECTIVE: To determine whether the placement of small-calibre, rapidly absorbed prophylactic periprostatic sutures before the mobilization of the prostate could reduce blood loss during open retropubic radical prostatectomy (RRP). PATIENTS AND METHODS: In 2007, during open RRP, we began placing prophylactic haemostatic sutures of 4-0 and 3-0 plain catgut in the anterior portions of the distal neurovascular bundles (NVBs) and lateral to the proximal NVBs and prostate pedicles before initiating the nerve-sparing dissection and mobilizing the prostate gland. To evaluate whether this reduced intraoperative blood loss, we compared estimated blood loss (EBL), non-autologous transfusion rates, and postoperative haemoglobin (Hb) levels between 100 consecutive patients treated immediately before and 100 consecutive patients treated immediately after the adoption of the prophylactic periprostatic suture technique. RESULTS: Before the use of prophylactic haemostatic sutures, the mean intraoperative blood loss was 1285 mL, and one patient (1%) received an intraoperative non-autologous transfusion. After the adoption of prophylactic sutures, the mean EBL was 700 mL (P < 0.001), and there were no transfusions. The mean Hb concentration the morning after RRP was 10.9 g/dL before and 11.8 g/dL after the initiation of prophylactic haemostatic sutures (P < 0.001). CONCLUSION: Prophylactic periprostatic haemostatic sutures significantly reduce intraoperative blood loss during open RRP.

OBJECTIVE: To determine the relationship between perineural invasion (PNI) on prostate biopsy and radical prostatectomy (RP) outcomes in a contemporary RP series, as there is conflicting evidence on the prognostic significance of PNI in prostate needle biopsy specimens. PATIENTS AND METHODS: From 2002 to 2007, 1256 men had RP by one surgeon. Multivariable logistic regression and Cox proportional hazards models were used to examine the relationship of PNI with pathological tumour features and biochemical progression, respectively, after adjusting for prostate-specific antigen level, clinical stage and biopsy Gleason score. Additional Cox models were used to examine the relationship between nerve-sparing and biochemical progression among men with PNI. RESULTS: PNI was found in 188 (15%) patients, and was significantly associated with aggressive pathology and biochemical progression. On multivariate analysis, PNI was significantly associated with extraprostatic extension and seminal vesicle invasion (P < 0.001). Biochemical progression occurred in 10.5% of patients with PNI, vs 3.5% of those without PNI (unadjusted hazard ratio 3.12, 95% confidence interval 1.77-5.52, P < 0.001). However, PNI was not a significant independent predictor of biochemical progression on multivariate analysis. Finally, nerve-sparing did not adversely affect biochemical progression even among men with PNI. CONCLUSION: PNI is an independent risk factor for aggressive pathology features and a non-independent risk factor for biochemical progression after RP. However, bilateral nerve-sparing surgery did not compromise the oncological outcomes for patients with PNI on biopsy.

OBJECTIVE: To compare the prevalence and extent of benign glands at the bladder neck (BN) margin in a large population undergoing open retropubic radical prostatectomy (RRP) and robotic-assisted laparoscopic RP (RALP), as RALP was previously suggested to be associated with a higher rate of benign glands at the surgical margin than RRP. PATIENTS AND METHODS: From 2005 to 2008, 137 RRP and 152 RALP were performed by one surgeon. Pathology slides were re-reviewed while unaware of origin to examine the extent of benign glands at the BN margin (minimal, moderate, or extensive). Statistical analysis was used to assess the prevalence and extent of benign glands in the two procedures. RESULTS: Benign prostatic glands were present at the margins in 89 (58.2%) RALP and 57 (41.6%) RRP specimens (P= 0.005). There were also a significantly greater extent of benign glands in RALP vs RRP (P= 0.031). After multivariate adjustment for prostate-specific antigen (PSA) level, clinical stage, and biopsy Gleason score, RALP maintained a significant association with both the presence (P= 0.019) and extent (P= 0.018) of benign glands at the BN. Two patients with organ-confined disease (no cancerous margins) with benign glands at the BN margin had an initially high postoperative PSA level. CONCLUSIONS: Benign prostate glands were present at the BN margin in a greater proportion of RALP than RRP specimens, possibly due to differences in the surgical approach to BN dissection. Additional study is necessary to determine the long-term biological significance, if any, of these histological differences.