Melissa Assel

Comparison Between the Four-kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer

BACKGROUND The four-kallikrein panel and the Prostate Health Index (PHI) have been shown to improve prediction of prostate cancer (PCa) compared with prostate-specific antigen (PSA). No comparison of the four-kallikrein panel and PHI has been presented. OBJECTIVE To compare the four-kallikrein panel and PHI for predicting PCa in an independent cohort. DESIGN, SETTING, AND PARTICIPANTS Participants were from a population-based cohort of PSA-tested men in Stockholm County. We included 531 men with PSA levels between 3 and 15 ng/ml undergoing first-time prostate biopsy during 2010-2012. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Models were fitted to case status. We computed calibration curves, the area under the receiver-operating characteristics curve (AUC), decision curves, and percentage of saved biopsies. RESULTS AND LIMITATIONS The four-kallikrein panel showed AUCs of 69.0 when predicting any-grade PCa and 71.8 when predicting high-grade cancer (Gleason score ≥7). Similar values were found for PHI: 70.4 and 71.1, respectively. Both models had higher AUCs than a base model with PSA value and age (p<0.0001 for both); differences between models were not significant. Sensitivity analyses including men with any PSA level or a previous biopsy did not materially affect our findings. Using 10% predicted risk of high-grade PCa by the four-kallikrein panel or PHI of 39 as cut-off for biopsy saved 29% of performed biopsies at a cost of delayed diagnosis for 10% of the men with high-grade cancers. Both models showed limited net benefit in decision analysis. The main study limitation was lack of digital rectal examination data and biopsy decision being based on PSA information. CONCLUSIONS The four-kallikrein panel and PHI similarly improved discrimination when predicting PCa and high-grade PCa. Both are simple blood tests that can reduce the number of unnecessary biopsies compared with screening with total PSA, representing an important new option to reduce harm. PATIENT SUMMARY Prostate-specific antigen screening is controversial due to limitations of the test. We found that two blood tests, the Prostate Health Index and the four-kallikrein panel, performed similarly and could both aid in decision making among Swedish men undergoing a prostate biopsy.

Influence of blood prostate specific antigen levels at age 60 on benefits and harms of prostate cancer screening: population based cohort study

Objective To determine the relative risks of prostate cancer incidence, metastasis, and mortality associated with screening by serum prostate specific antigen (PSA) levels at age 60. Design Population based cohort study. Setting General male population of Sweden taking part in a screening trial in Gothenburg or participating in a cardiovascular study, the Malmö Preventive Project. Participants The screened group consisted of 1756 men aged 57.5-62.5 participating in the screening arm of the Gothenburg randomized prostate cancer screening trial since 1995. The unscreened group consisted of 1162 men, born in 1921, participating in the Malmö Preventive Project, with PSA levels measured retrospectively in stored blood samples from 1981. Intervention PSA screening versus no screening. Main outcome measures Incidence rate ratios for the effect of screening on prostate cancer diagnosis, metastasis, and death by PSA levels at age 60. Results The distribution of PSA levels was similar between the two cohorts. Differences in benefits by baseline PSA levels were large. Among men with baseline levels measured, 71.7% (1646/2295) had a PSA level <2 ng/mL. For men aged 60 with PSA level <2 ng/mL, there was an increase in incidence of 767 cases per 10 000 without a decrease in prostate cancer mortality. For men with PSA levels ≥2 ng/mL, the reduction in cancer mortality was large, with only 23 men needing to be screened and six diagnosed to avoid one prostate cancer death by 15 years. Conclusions The ratio of benefits to harms of PSA screening varies noticeably with blood PSA levels at age 60. For men with a PSA level <1 ng/mL at age 60, no further screening is recommended. Continuing to screen men with PSA levels >2 ng/mL at age 60 is beneficial, with the number needed to screen and treat being extremely favourable. Screening men with a PSA level of 1-2 ng/mL is an individual decision to be based on a discussion between patient and doctor.

Unexpected Long-term Improvements in Urinary and Erectile Function in a Large Cohort of Men with Self-reported Outcomes Following Radical Prostatectomy

BACKGROUND It is generally assumed that if a man does not regain urinary continence or erectile function within 12 mo of radical prostatectomy (RP), then the chance of subsequent recovery is low. OBJECTIVE To determine the probability of achieving good urinary function (UF) or erectile function (EF) up to 48 mo postoperatively in men who reported poor UF or EF at 12 mo after RP. DESIGN, SETTING, AND PARTICIPANTS We identified 3187 patients who underwent RP from 2007 through 2013 at a tertiary institution and had extended multidisciplinary follow-up with patient-reported UF and EF scores at ≥12 mo. INTERVENTION Open or minimally invasive RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcome was good UF as defined by a urinary score ≥17 (range: 0-21) or good EF as defined by a modified International Index of Erectile Function-6 score ≥22 (range: 1-30). The probability of functional recovery beyond 12 mo was determined by Kaplan-Meier analyses. RESULTS AND LIMITATIONS Among patients incontinent at 12 mo, the probability of achieving good UF at 24, 36, and 48 mo was 30%, 49%, and 59%. In patients experiencing erectile dysfunction at 12 mo, the probability of recovering EF at 24, 36, and 48 mo was 22%, 32%, and 40%. On multivariable analyses, 12-mo functional score and age were associated with recovery, but only score was consistently significant. CONCLUSIONS Men with incontinence or erectile dysfunction at 12 mo have higher than anticipated rates of subsequent functional improvement. Probability of recovery is strongly influenced by score at 12 mo. Further research should address the impact of ongoing multidisciplinary follow-up care on our observed rates of recovery. PATIENT SUMMARY Many prostate cancer patients continue to recover urinary and erectile function after 12 mo. The level of functional recovery by 12 mo is associated with long-term recovery and should be discussed by the physician and patient when deciding on rehabilitative interventions.

New Chronic Kidney Disease and Overall Survival After Nephrectomy for Small Renal Cortical Tumors.

OBJECTIVE To evaluate kidney functional and overall survival (OS) outcomes in a cohort of patients who underwent partial nephrectomy (PN) or radical nephrectomy (RN) for tumors ≤4 cm. MATERIALS AND METHODS We performed a retrospective study on 2110 patients who underwent PN or RN with normal contralateral kidneys and normal serum creatinine from 1989 through 2012. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Primary end points were baseline incidence of CKD, OS, and new onset of eGFR ≤60 and ≤45 mL/min/1.73 m(2). RESULTS Preoperatively, 30% and 8% of the cohort had eGFR ≤60 and ≤45 mL/min/1.73 m(2), respectively. Five-year freedom from eGFR ≤60 mL/min/1.73 m(2) was 24% (95% confidence interval [CI], 19%-30%) and 76% (95% CI, 72%-78%) for RN and PN, respectively, and 5-year freedom from eGFR ≤45 mL/min/1.73 m(2) was 51% (95% CI, 45%-56%) and 91% (95% CI, 89%-93%) for RN and PN, respectively. On multivariable analysis, hazard ratio for RN vs PN was 4.98 (95% CI, 4.11-6.04, P <.0001) for new onset of eGFR ≤60 mL/min/1.73 m(2) and 9.28 (95% CI, 7.26-11.86, P <.0001) for new onset of eGFR ≤45 mL/min/1.73 m(2). The RN group had a higher rate of death per year than the partial group (hazard ratio = 1.61, 95% CI, 1.24-2.08, P = .0003). CONCLUSION The present study confirms published works demonstrating that a significant proportion of patients have pre-existing CKD. In patients with normal kidney function, RN is associated with a significantly higher risk for developing CKD and worse OS than PN.

Screening for Prostate Cancer Starting at Age 50–54 Years. A Population-based Cohort Study

BACKGROUND Current prostate cancer screening guidelines conflict with respect to the age at which to initiate screening. OBJECTIVE To evaluate the effect of prostate-specific antigen (PSA) screening versus zero screening, starting at age 50-54 yr, on prostate cancer mortality. DESIGN, SETTING, AND PARTICIPANTS This is a population-based cohort study comparing 3479 men aged 50 yr through 54 yr randomized to PSA-screening in the Göteborg population-based prostate cancer screening trial, initiated in 1995, versus 4060 unscreened men aged 51-55 yr providing cryopreserved blood in the population-based Malmö Preventive Project in the pre-PSA era, during 1982-1985. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cumulative incidence and incidence rate ratios of prostate cancer diagnosis, metastasis, and prostate cancer death. RESULTS AND LIMITATIONS At 17 yr, regular PSA-screening in Göteborg of men in their early 50s carried a more than two-fold higher risk of prostate cancer diagnosis compared with the unscreened men in Malmö (incidence rate ratio [IRR] 2.56, 95% confidence interval [CI] 2.18, 3.02), but resulted in a substantial decrease in the risk of metastases (IRR 0.43, 95% CI 0.22, 0.79) and prostate cancer death (IRR 0.29, 95% CI 0.11, 0.67). There were 57 fewer prostate cancer deaths per 10000 men (95% CI 22, 92) in the screened group. At 17 yr, the number needed to invite to PSA-screening and the number needed to diagnose to prevent one prostate cancer death was 176 and 16, respectively. The study is limited by lack of treatment information and the comparison of the two different birth cohorts. CONCLUSIONS PSA screening for prostate cancer can decrease prostate cancer mortality among men aged 50-54 yr, with the number needed to invite and number needed to detect to prevent one prostate cancer death comparable to those previously reported from the European Randomized Study of Screening for Prostate Cancer for men aged 55-69 yr, at a similar follow-up. Guideline groups could consider whether guidelines for PSA screening should recommend starting no later than at ages 50-54 yr. PATIENT SUMMARY Guideline recommendations about the age to start prostate-specific antigen screening could be discussed.

Survival Outcomes of Men with Lymph Node-positive Prostate Cancer After Radical Prostatectomy: A Comparative Analysis of Different Postoperative Management Strategies

BACKGROUND Optimal management of patients with lymph node metastasis (LNM) after radical prostatectomy (RP) remains undefined. OBJECTIVE We evaluated the association between three different management strategies and survival in prostate cancer with LNM after RP. DESIGN, SETTING, AND PARTICIPANTS We analyzed data of 1338 patients with LNM after RP from three tertiary care centers. Three hundred and eighty-seven patients (28%) were observed, 676 (49%) received lifelong adjuvant androgen deprivation therapy (ADT), and 325 (23%) received adjuvant external beam radiation therapy (EBRT) and ADT. Three hundred and sixty-eight men were followed for more than 10 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcome measure was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS) and other-cause mortality. Kaplan-Meier methods were used to visualize OS for the three treatment groups. Cox proportional hazards regression was utilized to compare OS and CSS among the three groups. RESULTS AND LIMITATIONS ADT+EBRT was associated with better OS than ADT alone (hazard ratio [HR]: 0.46, 95% confidence interval [CI]: 0.32-0.66, p<0.0001) or observation (HR: 0.41, 95% CI: 0.27-0.64, p<0.0001). Higher-risk patients benefited more from ADT+EBRT than lower-risk patients. Ten-year mortality risk difference between ADT+EBRT, observation, or ADT alone ranged from 5% in low-risk patients to 40% in high-risk patients. Adjuvant ADT+EBRT was also associated with better CSS than observation or ADT alone (p<0.0001), ADT had better CSS compared to observation (HR: 0.64, 95% CI: 0.43-0.95, p=0.027). However, ADT was associated with an increased risk of other-cause mortality (HR: 3.05, 95% CI: 1.45-6.40, p=0.003) compared with observation, resulting in similar OS between ADT and observation (HR: 0.90, 95% CI: 0.65-1.25, p=0.5). While selection bias might remain, its effect would operate in the opposite direction to our findings. CONCLUSIONS In men with LNM after RP, ADT+EBRT improved survival over either observation or adjuvant ADT alone. This survival benefit increases with higher-risk disease. PATIENT SUMMARY Lymph node metastasis following radical prostatectomy is associated with poor survival outcomes. However, we found that adjuvant androgen deprivation therapy with external beam radiation therapy improved survival in these patients.

Inhibition of Circulating Dipeptidyl Peptidase 4 Activity in Patients with Metastatic Prostate Cancer

Cancer is responsible for many deaths and is a major source of healthcare expenditures. The identification of new, non-invasive biomarkers might allow improvement of the direct diagnostic or prognostic ability of already available tools. Here, we took the innovative approach of interrogating the activity of exopeptidases in the serum of cancer patients with the aim of establishing a distinction based on enzymatic function, instead of simple protein levels, as a means to biomarker discovery. We first analyzed two well-characterized mouse models of prostate cancer, each with a distinct genetic lesion, and established that broad exopeptidase and targeted aminopeptidase activity tests reveal proteolytic changes associated with tumor development. We also describe new peptide-based freeze-frame reagents uniquely suited to probe the altered balance of selected aminopeptidases, as opposed to the full array of exopeptidases, and/or their modulators in patient serum or plasma. One particular proteolytic activity was impaired in animals with aggressive disease relative to cancer-free littermates. We identified the protease in question as dipeptidyl peptidase 4 (DPP4) by analyzing selected knockout mice and evaluating the effect of specific inhibitors. DPP4 activity was also reduced in the sera of patients with metastatic prostate cancer relative to patients with localized disease or healthy controls. However, no significant differences in DPP4 serum levels were observed, which established the loss of activity as the result of impaired enzymatic function. Biochemical analysis indicated that reduced activity was the result not of post-translational modifications or allosteric changes, but instead of a low-molecular-weight inhibitor. After we adjusted for age and total prostate-specific antigen, reduced DPP4 activity remained a significant predictor of cancer status. The results of this proof-of-principle study suggest that DPP4 activity might be a potential blood-based indicator of the presence of metastatic cancer of prostatic origin, either by itself or, more likely, as a means to improve the sensitivity and specificity of existing markers.

Adult Prostate Sarcoma: The Memorial Sloan Kettering Experience

OBJECTIVE To present our institutional experience with adult prostate sarcoma over 30 years. MATERIALS AND METHODS We reviewed 38 cases of adult prostate sarcoma diagnosed and treated at our institution between 1982 and 2012. Univariate Cox proportional hazards regression was used to determine if there was an association between specific disease characteristics (tumor size, histology, American Joint Committee on Cancer stage, and metastasis at diagnosis) and cancer-specific survival (CSS). RESULTS A total of 38 patients were included, with a median age of 50 years (range, 17-73 years). Most men presented with lower urinary tract symptoms (45%), hematuria (24%), or acute urinary retention (21%). Diagnosis was established with prostate needle biopsy (68%) or transurethral resection of the prostate (18%). The predominant histologic subtypes were leiomyosarcoma (13 cases, 34%) and rhabdomyosarcoma (12 cases, 32%). Rhabdomyosarcoma was associated with poorer CSS (hazard ratio, 3.00; 95% confidence interval [CI], 1.13-7.92; P = .027) compared with leiomyosarcoma. We did not observe a significant relationship between tumor size and CSS. Overall, median CSS was 2.9 years (95% CI, 1.5-5.4), with 7.7 years for clinically localized disease (95% CI 2.5; upper bound not reached) and 1.5 years for metastatic disease (95% CI 1.1, 2.7). CONCLUSION Adult prostate sarcoma has a poor prognosis, especially in cases of metastatic disease at the time of diagnosis. Surgery remains the standard of care, but it provides limited benefit to those with metastatic disease or as a consolidation therapy after partial response to systemic therapy.

Erectile Function Recovery after Radical Prostatectomy in Men with High Risk Features.

PURPOSE We describe the efficacy of radical prostatectomy to achieve complete primary tumor excision while preserving erectile function in a cohort of patients with high risk features in whom surgical resection was tailored according to clinical staging, biopsy data, preoperative imaging and intraoperative findings. MATERIALS AND METHODS In a retrospective review we identified 584 patients with high risk features (prostate specific antigen 20 ng/ml or greater, clinical stage T3 or greater, preoperative Gleason grade 8-10) who underwent radical prostatectomy between 2006 and 2012. The probability of neurovascular bundle preservation was estimated based on preoperative characteristics. Positive surgical margin rates and erectile function recovery were determined in patients who had some degree of neurovascular bundle preservation. RESULTS The neurovascular bundles were resected bilaterally in 69 (12%) and unilaterally in 91 (16%) patients. The remaining patients had some degree of bilateral neurovascular bundle preservation. Preoperative features associated with a lower probability of neurovascular bundle preservation were primary biopsy Gleason grade 5 and clinical stage T3 disease. Among the patients with some degree of neurovascular bundle preservation 125 of 515 (24%) had a positive surgical margin, and 75 of 160 (47%) men with preoperatively functional erections and available erectile function followup had recovered erectile function within 2 years. CONCLUSIONS High risk features should not be considered an indication for complete bilateral neurovascular bundle resection. Some degree of neurovascular bundle preservation can be done safely by high volume surgeons in the majority of these patients with an acceptable rate of positive surgical margins. Nearly half of high risk patients with functional erections preoperatively recover erectile function after radical prostatectomy.

Genetic Polymorphisms of CFH and ARMS2 Do Not Predict Response to Antioxidants and Zinc in Patients with Age-Related Macular Degeneration: Independent Statistical Evaluations of Data from the Age-Related Eye Disease Study

PURPOSE Considerable controversy has erupted in recent years regarding whether genotyping should be part of standard care for patients with age-related macular degeneration (AMD) who are being considered for treatment with antioxidants and zinc. We aimed to determine whether genotype predicts response to supplements in AMD. DESIGN Three separate statistical teams reanalyzed data derived from the Age-Related Eye Disease Study (AREDS), receiving data prepared by the AREDS investigators and, separately, data from investigators reporting findings that support the use of genotyping. PARTICIPANTS The population of interest was AREDS participants with AMD worse than category 1 and genotyping data available. Data from the 2 groups overlap imperfectly with respect to measurements made: the largest common set involved 879 participants for whom the same CFH and ARMS2 single nucleotide polymorphisms were measured by both groups. METHODS Each team took a separate but complementary approach. One team focused on data concordance between conflicting studies. A second team focused on replicating the key claim of an interaction between genotype and treatment. The third team took a blank slate approach in attempting to find baseline predictors of treatment response. MAIN OUTCOME MEASURES Progression to advanced AMD. RESULTS We found errors in the data used to support the initial claim of genotype-treatment interaction. Although we found evidence that high-risk patients had more to gain from treatment, we were unable to replicate any genotype-treatment interactions after adjusting for multiple testing. We tested 1 genotype claim on an independent set of data, with negative results. Even if we assumed that interactions in fact did exist, we did not find evidence to support the claim that supplementation leads to a large increase in the risk of advanced AMD in some genotype subgroups. CONCLUSIONS Patients who meet criteria for supplements to prevent AMD progression should be offered zinc and antioxidants without consideration of genotype.