Kristian Novakovic

Primary care physician PSA screening practices before and after the final U.S. Preventive Services Task Force recommendation

OBJECTIVES In May 2012, United States Preventive Services Task Force (USPSTF) finalized its recommendation against prostate-specific antigen (PSA) screening in all men. We aimed to assess trends in PSA screening frequency amongst primary care physicians (PCPs) surrounding the May 2012 USPSTF recommendation. METHODS AND MATERIALS The electronic data warehouse was used to identify men aged between 40 and 79 years with no history of prostate cancer or urology visit who were evaluated by an internal medicine or family practice physician between 2007 and 2012. Analyses were directed toward PSA testing within 6-month time period from June to November, with particular focus on the 2011 (pre-USPSTF recommendation) and 2012 (post-USPSTF recommendation) cohorts. The primary outcome measure was proportion of men with at least 1 PSA test during the 6-month pre- and post-USPSTF recommendation periods. RESULTS A total of 112,221 men met inclusion criteria. There was a significant decrease in screening frequency between the 2011 and 2012 cohorts (8.6% vs. 7.6%, P = 0.0001; adjusted odds ratio 0.89, 95% confidence interval 0.83-0.95). This decrease was most evident amongst patients aged 40 to 49 years (5.6% vs. 4.6%, P = 0.004) and 70 to 79 years (7.9% vs. 6.2%, P = 0.01). A significant decrease was also observed in patients with highest previous PSA value<1.0 (P<0.0001) and 1.0 to 2.49 ng/ml (P = 0.0074). CONCLUSIONS Since the USPSTF recommendation was finalized, there is evidence of continuing decreases in PSA testing by PCPs. PCPs may be shifting toward more selective screening practices, as decreases in screening are most pronounced in the youngest and oldest patients and in those with history of PSA values<2.5 ng/ml.

Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death

BACKGROUND Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. OBJECTIVE To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death. DESIGN, SETTING, AND PARTICIPANTS A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Mutation carrier rates and their effect on lethal PCa were analyzed using the Fishers exact test and Cox regression analysis, respectively. RESULTS AND LIMITATIONS The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed. CONCLUSIONS Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. PATIENT SUMMARY Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.

The Impact of Prostate Biopsy on Urinary Symptoms, Erectile Function, and Anxiety

Transrectal ultrasound-guided prostate needle biopsy (PB) is considered the gold standard for the diagnosis of prostate cancer. Recently, lower urinary tract symptoms and erectile dysfunction have been reported following PB. We reviewed the literature on PB and these symptoms and summarized known findings between these conditions and other variables, such as periprostatic nerve block, saturation biopsy, serial biopsies, and psychological factors associated with PB and cancer. A PubMed search was performed using keywords “prostate biopsy,” “complications,” “erectile dysfunction,” “lower urinary tract symptoms,” “anxiety,” and “quality of life.” Eleven key papers are discussed and personal experience is drawn upon. Based upon available evidence, PB appears to be associated with short-term exacerbation of urinary symptoms in some men, as well as associated with anxiety and temporary erectile dysfunction, without a distinct relationship to periprostatic nerve block or the number of cores biopsied. Additional studies are warranted to determine the definitive etiology of these symptoms and to determine if interventions could reduce patient morbidity. In the interim, patients should be educated and counseled about these risks before undergoing PB.

The prognostic significance of perineural invasion and race in men considering active surveillance

To determine the importance of perineural invasion (PNI) on diagnostic biopsy in men enrolled in active surveillance (AS).

Genetic basis of kidney cancer: a model for developing molecular-targeted therapies

and affects 1 in 35 000 individuals in the USA. To identify the VHL disease gene, families with several members showing the clinical manifestations of VHL were evaluated at the National Cancer Institute (NCI). Studies of families with hereditary renal cancer showing germline translocations involving the short arm of chromosome 3 prompted an analysis of restriction fragment length polymorphisms in tumour tissue from patients with sporadic RCC [5]. That study showed a non-random loss of heterozygosity (LOH) on the short arm of chromosome 3 in tumour tissue from patients with sporadic, nonhereditary RCC. This led to the hypothesis that a null mutation on the corresponding locus of the homologous chromosome 3 might be important in the development of renal cancer [5]. In 1993, Latif et al. [6] reported a linkage analysis on 221 VHL kindred to identify the VHL gene on a small region of the distal portion of chromosome 3p. The identification of VHL somatic mutations in clear cell RCC, with the lack of other chromosomal deletions in localized renal tumours, strongly implicated the VHL gene in th7e origin or early development of renal tumours [7]. This conclusion was further supported by Lubensky et al. [8], who found LOH in the VHL gene in microscopic tumours and in atypical cysts in kidneys from VHL patients. In cases where no mutation was identified, hypermethylation in the 5 ′ region of the VHL gene was found to be an alternative mechanism for inactivation of gene expression [9]. The link between the VHL mutation in the germline and the clinical manifestations of the syndrome was subsequently confirmed by the identification of a spectrum of germline mutations in 99% of VHL families [10,11].

A Longitudinal Study of Predictors of Sexual Dysfunction in Men on Active Surveillance for Prostate Cancer

Aim The aim of this study was to examine the relationship between sexual dysfunction, repeat biopsies and other demographic and clinical factors in men on active surveillance (AS). Methods Patient-reported outcomes (PROs) measures were administered at enrollment and every 6 months to assess quality of life (QOL), psychosocial and urological health outcomes. Using mixed-effects models, we examined the impact of repeat biopsies, total number of cores taken, anxiety, age, and comorbidity on sexual function over the first 24 months of enrolling in AS. Main Outcome Measures PROs included the Expanded Prostate Cancer Index Composite-26 (EPIC-26) Sexual Function (SF) subscale, the American Urological Association-Symptom Index (AUA-SI), and the Memorial Anxiety Scale for Prostate Cancer (MAX-PC). Results At enrollment (n = 195), mean age was 66.5 ± 6.8 with a mean EPIC-26 SF score of 61.4 ± 30.4. EPIC-26 SF scores steadily decreased to 53.9 ± 30.7 at 24 months (P < 0.01). MAX-PC scores also progressively decreased over time (P = 0.03). Factors associated with lower EPIC-26 scores over time included age, unemployed status, diabetes, coronary artery disease, and hypertension (all P < 0.05). Higher prostate-specific antigen (PSA) was associated with a more rapid decline in EPIC-26 SF over time (P = 0.03). In multivariable analysis, age, diabetes, and PSA × time interaction remained significant predictors of diminished sexual function. Anxiety, number of biopsies, and total cores taken did not predict sexual dysfunction or change over time in our cohort. Conclusions Men on AS experienced a gradual decline in sexual function during the first 24 months of enrollment. Older age, PSA × time, and diabetes were all independent predictors of diminished sexual function over time. Anxiety, AUA-SI, the number of cores and the number of biopsies were not predictors of reduced sexual function in men in AS.

Variation in Testosterone Levels and Health-related Quality of Life in Men Diagnosed With Prostate Cancer on Active Surveillance

OBJECTIVE To determine the extent to which low testosterone levels impact health-related quality of life in patients undergoing active surveillance (AS) for prostate cancer. MATERIALS AND METHODS Eligible AS patients were grouped as having low, low-normal, or normal testosterone levels (<300 vs 300-400 vs ≥400 ng/dL). Patients were surveyed with the Expanded Prostate Cancer Index Composite-26 (EPIC-26), Patient Reported Outcomes Measurement Information System (PROMIS), Memorial Anxiety Scale for Prostate Cancer, and treatment outlook satisfaction questions at enrollment and successively during follow-up. RESULTS The cohort consisted of 223 patients, 74 (33%) of which had low testosterone levels. The mean age was 66.8 ± 7.2 years, with 85% being Caucasian. Mean prostate-specific antigen did not differ between groups. Obesity was significantly higher for men with low testosterone levels (P < .01). All PROMIS-Global items were comparatively lower in men with lower testosterone. EPIC-26 scores for the sexual domain were worse in men with lower testosterone. After age and obesity adjustment, men with normal testosterone levels had significantly better PROMIS Physical, Overall, and Mental Health, EPIC-26 Hormonal, and treatment satisfaction responses when compared to those patients with low testosterone levels. Those with normal testosterone levels reported hormonal EPIC-26 domain responses 65% higher than for those with low testosterone, and 12% higher treatment satisfaction during 2-year follow-up when corrected for age and obesity (P < .05). CONCLUSION Men with testosterone levels ≥400 ng/dL reported some improved measures of health-related quality of life including greater satisfaction with treatment outcome. These findings are hypothesis generating in the controversial area of exogenous testosterone administration in men on AS.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer

Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa.

Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death

Rong Na a,b,y, S. Lilly Zheng b,c,y, Misop Han d,y, Hongjie Yu , Deke Jiang , Sameep Shah , Charles M. Ewing , Liti Zhang , Kristian Novakovic b [5_TD

Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer.

DIFF], Jacqueline Petkewicz [5_TD