Armen Aprikian

Use of Statins and the Risk of Death in Patients With Prostate Cancer

PURPOSE To determine whether the use of statins after prostate cancer diagnosis is associated with a decreased risk of cancer-related mortality and all-cause mortality and to assess whether this association is modified by prediagnostic use of statins. PATIENTS AND METHODS A cohort of 11,772 men newly diagnosed with nonmetastatic prostate cancer between April 1, 1998, and December 31, 2009, followed until October 1, 2012, was identified using a large population-based electronic database from the United Kingdom. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% CIs of mortality outcomes associated with postdiagnostic use of statins, lagged by 1 year to account for latency considerations and to minimize reverse causality, and considering effect modification by prediagnostic use of statins. RESULTS During a mean follow-up time of 4.4 years (standard deviation, 2.9 years), 3,499 deaths occurred, including 1,791 from prostate cancer. Postdiagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR, 0.76; 95% CI, 0.66 to 0.88) and all-cause mortality (HR, 0.86; 95% CI, 0.78 to 0.95). These decreased risks of prostate cancer mortality and all-cause mortality were more pronounced in patients who also used statins before diagnosis (HR, 0.55; 95% CI, 0.41 to 0.74; and HR, 0.66; 95% CI, 0.53 to 0.81, respectively), with weaker effects in patients who initiated the treatment only after diagnosis (HR, 0.82; 95% CI, 0.71 to 0.96; and HR, 0.91; 95% CI, 0.82 to 1.01, respectively). CONCLUSION Overall, the use of statins after diagnosis was associated with a decreased risk in prostate cancer mortality. However, this effect was stronger in patients who also used statins before diagnosis.

Postoperative urinary retention: anesthetic and perioperative considerations.

Urinary retention is common after anesthesia and surgery, reported incidence of between 5% and 70%. Comorbidities, type of surgery, and type of anesthesia influence the development of postoperative urinary retention (POUR). The authors review the overall incidence and mechanisms of POUR associated with surgery, anesthesia and analgesia. Ultrasound has been shown to provide an accurate assessment of urinary bladder volume and a guide to the management of POUR. Recommendations for urinary catheterization in the perioperative setting vary widely, influenced by many factors, including surgical factors, type of anesthesia, comorbidities, local policies, and personal preferences. Inappropriate management of POUR may be responsible for bladder overdistension, urinary tract infection, and catheter-related complications. An evidence-based approach to prevention and management of POUR during the perioperative period is proposed.

Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma.

Pp125FAK, a protein tyrosine kinase (PTK) co‐localized with integrins in focal adhesion plaques, is known to transduce signals involved in the regulation of cell adhesion and motility as well as the anchorage‐independent growth of transformed cells. We investigated whether pp125FAK could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up‐regulation of pp125FAK expression, its activation by phosphorylation on tyrosine and its association with paxillin and p50csk were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp125FAK signalling complexes. The increase in expression and activation of pp125FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of pp125FAK and FAK mRNA were observed in highly tumorigenic PC‐3 cells as was the presence of activated pp125FAK, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, pp125FAK formed signalling complexes with both paxillin and p50csk in PC‐3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp125FAK activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.

Outcome of sextant biopsy according to gland volume

OBJECTIVES To reassess positive rate of sextant biopsy according to gland size. METHODS We evaluated 1974 consecutive men with systematic sextant biopsy, among whom we examined biopsy yield according to gland-volume intervals of 10 cc. RESULTS Decreasing yield of sextant biopsy is strongly associated with increasing gland volume (P < 0.001). Highest biopsy rate (39.6%) was recorded among men with prostates smaller than 20 cc. The lowest biopsy rate (10.1%) was recorded among men with prostates between 80 and 89.9 cc. Among men with biopsy-proven cancer, age, serum prostate-specific antigen, and Gleason grade were comparable (P > 0.05) throughout the range of gland-volume intervals. CONCLUSIONS Our findings suggest that gland size represents an important determinant contributing to the yield of sextant biopsy in men at risk of harboring a nonpalpable, isoechoic cancer. Consequently, an individualized sector biopsy approach, based on prostate volume, may warrant consideration because it may ensure superior detection of clinically significant disease among all men at risk, regardless of prostate size.

Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation.

Late‐stage prostate cancer patients are refractory to hormone therapy and exhibit a high propensity to develop skeletal metastasis. In this regard, the role of a novel cytokine system belonging to the tumor necrosis factor (TNF) family that is critical for osteoclastic osteolysis and that consists of receptor activator of NF‐κB ligand (RANKL), its receptor (RANK), and decoy receptor osteoprotegerin (OPG) is of potential interest.

PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer

PTEN haploinsufficiency is common in hormone‐sensitive prostate cancer, though the incidence of genomic deletion and its downstream effects have not been elucidated in clinical samples of hormone refractory prostate cancer (HRPC). Progression to androgen independence is pivotal in prostate cancer and mediated largely by the androgen receptor (AR). Since this process is distinct from metastatic progression, we examined alterations of the PTEN gene in locally advanced recurrent, non‐metastatic human HRPC tissues. Retrospective analyses of PTEN deletion status were correlated with activated downstream phospho‐Akt (p‐Akt) pathway proteins and with the androgen receptor. The prevalence of PTEN genomic deletions in transurethral resection samples of 59 HRPC patients with known clinical outcome was assessed by four‐colour FISH analyses. FISH was performed using six BAC clones spanning both flanking PTEN genomic regions and the PTEN gene locus, and a chromosome 10 centromeric probe. PTEN copy number was also evaluated in a subset of cases using single nucleotide polymorphism (SNP) arrays. In addition, the samples were immunostained with antibodies against p‐Akt, p‐mTOR, p‐70S6, and AR. The PTEN gene was deleted in 77% of cases, with 25% showing homozygous deletions, 18% homozygous and hemizygous deletions, and 34% hemizygous deletions only. In a subset of the study group, SNP array analysis confirmed the FISH findings. PTEN genomic deletion was significantly correlated to the expression of downstream p‐Akt (p < 0.0001), AR (p = 0.025), and to cancer‐specific mortality (p = 0.039). PTEN deletion is common in HRPC, with bi‐allelic loss correlating to disease‐specific mortality and associated with Akt and AR deregulation. Copyright

Prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and meta-analysis

Animal and laboratory studies suggest that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce prostate cancer risk. To assess this association, we conducted a systematic review and meta-analysis of observational studies published before January 2003. We derived summary odds ratios (ORs) using both fixed and random effects models and performed subgroup analyses to explore the possible sources of heterogeneity between combined studies. We identified 12 reports (five retrospective and seven prospective studies). Most studies of aspirin use reported inverse associations, but only two were statistically significant. The summary OR for the association between aspirin use and prostate cancer was 0.9 (95% confidence interval: 0.82–0.99; test of homogeneity P=0.32), and varied from 1.0 for retrospective studies to 0.85 for prospective studies. Studies that measured exposure to a mixture of NSAIDs were less consistent. These results indicate an inverse association between aspirin use and prostate cancer risk. The current epidemiological evidence and, in particular, the strong and consistent laboratory evidence underline the need for additional epidemiological studies to confirm the direction and magnitude of the association.

Value of Systematic Transition Zone Biopsies in the Early Detection of Prostate Cancer

PURPOSE A prospective study was done to determine the value of performing 2 systematic transition zone biopsies in addition to systematic sextant peripheral zone biopsies for early detection of prostate cancer. MATERIALS AND METHODS From January 1 to August 31, 1994 we evaluated 847 consecutive patients referred to us for a suspicious lesion on digital rectal examination or an elevated serum prostate specific antigen level. All patients underwent 2 systematic transition zone biopsies in addition to systematic sextant biopsies of the peripheral zone. RESULTS Of the transition zone biopsies 68 (24.4%) contained malignancy, including only 8 (2.9%) with cancer found exclusively in the transition zone. The remaining 271 cases (97.1%) had 1 or more positive peripheral zone biopsies and would have been detected with or without additional systematic transition zone biopsies. The same analysis of 552 patients with a negative digital rectal examination yielded 6 (4.1%) exclusively transition zone tumors among 145 cancers detected in this group. CONCLUSIONS The low additional yield of transition zone biopsies (2.9 to 4.1%) does not warrant their systematic use for the early detection of prostate cancer.

Active surveillance for selected patients with renal masses: updated results with long-term follow-up.

The objective of the current study was to evaluate the outcome of a surveillance strategy in patients with renal masses.

Clinical and Pathobiological Effects of Neoadjuvant Total Androgen Ablation Therapy on Clinically Localized Prostatic Adenocarcinoma

Neodjuvant total androgen ablation therapy leads to involutional changes in prostatic carcinoma and may have the potential to downstage operable prostate cancers. We studied 27 clinically localized prostatic carcinomas after 3 months of combined treatment with a luteinizing hormone-releasing hormone agonist, goserelin acetate, and the antiandrogen flutamide, followed by radical retropubic prostatectomy, for changes in the serum prostatespecific antigen (PSA) level, changes in prostatic volume, therapy-induced histopathologic changes, DNA ploidy, and proliferative activity. Ten hormonally untreated, grade-matched prostatic adenocarcinomas served as controls. The mean pretherapy serum PSA level was 17.5 ng/ml, and posttherapy PSA levels were all < 4.0 ng/ml, with 18 men having undetectable levels. The mean reduction in prostatic volume following hormonal therapy was 37% (range 16–52%). Pathologic staging confirmed 20 pT2NO, six pT3NO, and one pT3N1. All prostates showed residual adenocarcinoma (extremely focal in seven cases [26%] with loss of glandular architecture, cytoplasmic vacuolization, and nuclear pyknosis. High-grade adenocarcinoma was nondiploid in 25% of hormonally treated prostates and 80% of 10 untreated controls. Immunostaining for proliferating cell nuclear antigen showed > 10% nuclear reactivity in 33% of treated carcinomas and 90% of untreated carcinomas. In conclusion, 3 months of neoadjuvant androgen ablation for localized prostatic carcinoma significantly lowers serum PSA and prostatic volume and produces involutional changes in residual carcinomas that mimic high-grade disease. However, pretreated carcinomas have predominantly a diploid DNA content and low proliferative activity as opposed to untreated carcinomas. Thus, grading of pretreated adenocarcinomas by conventional methods may be misleading. Preoperative total androgen ablation has a profound effect on a subset of prostatic carcinoma cells, possibly by facilitating programmed cell death.