Ghrelin proteolysis increases in plasma of men, but not women, with obesity.

AIMS: Since plasma ghrelin can undergo des-acylation and proteolysis, the aim of this study was to investigate the extent to which an enhancement of these reactions is associated to the decrease of ghrelin in plasma after food intake or in individuals with obesity. MAIN METHODS: we performed an intervention cross-sectional study, in which levels of ghrelin, desacyl-ghrelin (DAG), glucose, insulin, ghrelin des-acylation and ghrelin proteolysis were assessed in plasma before and after a test meal in 40 people (n = 21 males) with normal weight (NW, n = 20) or overweight/obesity (OW/OB, n = 20). KEY FINDINGS: Preprandial ghrelin and DAG levels were lower, whereas preprandial ghrelin proteolysis was ∼4.6-fold higher in plasma of males with OW/OB. In males, ghrelin proteolysis positively correlated with glycemia. Ghrelin and DAG levels were also lower in females with OW/OB, but preprandial ghrelin proteolysis was not different between females with NW or OW/OB. Ghrelin and DAG levels decreased postprandially in males and females, independently of BMI, and ghrelin proteolysis increased postprandially ∼2 folds only in individuals with NW. Ghrelin des-acylation remained unaffected by BMI or feeding status in both sexes. SIGNIFICANCE: Current study shows that ghrelin proteolysis increases in males with obesity as well as after meal in lean individuals. Therefore, ghrelin proteolysis may be an important checkpoint and, consequently, a putative pharmacological target to control circulating ghrelin levels in humans.

Pretest Genetic Education Video Versus Genetic Counseling for Men Considering Prostate Cancer Germline Testing: A Patient-Choice Study to Address Urgent Practice Needs.

PURPOSE: Germline testing (GT) for prostate cancer (PCA) is now central to treatment and hereditary cancer assessment. With rising demand for and shortage of genetic counseling (GC), tools to deliver pretest informed consent across practice settings are needed to improve access to GT and precision care. Here, we report on Evaluation and Management for Prostate Oncology, Wellness, and Risk (EMPOWER), a patient-choice study for pretest video-based genetic education (VBGE) versus GC to inform urgent practice needs. PATIENTS AND METHODS: Men with PCA or at risk for PCA (family history of PCA) were eligible and could choose pretest VBGE or GC. Outcomes included decisional conflict for GT, change in genetics knowledge, satisfaction, and intention to share results with family and/or providers. Descriptive statistics summarized results with counts and percentages for categorical variables and mean ± standard deviation for continuous variables. Data were compared with Fisher's exact, chi-squared, or Wilcoxon two-sample tests. Mean change in genetics knowledge was compared with t tests. The significance level was set a priori at .05. RESULTS: Data on the first 127 participants were analyzed. Characteristics were White (85.8%), bachelor's degree (66.9%), and PCA diagnosis (90.6%). The majority chose VBGE (71%) versus GC (29%; P < .001). No differences were observed in decisional conflict for GT or satisfaction. Cancer genetics knowledge improved in both groups without significant difference (+0.9 VBGE, +1.8 GC, P = .056). Men who chose VBGE had higher intention to share GT results (96.4% VBGE v 86.4% GC, P = .02). Both groups had high rates of GT uptake (VBGE 94.4%, GC 92%). CONCLUSION: A substantial proportion of men opted for pretest VBGE, with comparable patient-reported outcomes and uptake of GT. The results support the use of pretest video to address the critical GC shortage in the precision era.

Preventing Prostate Biopsy Complications: to Augment or to Swab?

OBJECTIVE: To use data from a large, prospectively- acquired regional collaborative database to compare the risk of infectious complications associated with three American Urologic Association- recommended antibiotic prophylaxis pathways, including culture-directed or augmented antibiotics, following prostate biopsy. METHODS: Data on prostate biopsies and outcomes were collected from the Pennsylvania Urologic Regional Collaborative, a regional quality collaborative working to improve the diagnosis and treatment of prostate cancer. Patients were categorized as receiving one of three prophylaxis pathways: culture-directed, augmented, or provider-discretion. Infectious complications included fever, urinary tract infections or sepsis within one month of biopsy. Odds ratios of infectious complication by pathway were determined, and univariate and multivariate analyses of patient and biopsy characteristics were performed. RESULTS: 11,940 biopsies were included, 120 of which resulted in infectious outcomes. Of the total biopsies, 3246 used "culture-directed", 1446 used "augmented" and 7207 used "provider-discretion" prophylaxis. Compared to provider-discretion, the culture-directed pathway had 84% less chance of any infectious outcome (OR= 0.159, 95% CI = [0.074, 0.344], P < 0.001). There was no difference in infectious complications between augmented and provider-discretion pathways. CONCLUSIONS: The culture-directed pathway for transrectal prostate biopsy resulted in significantly fewer infectious complications compared to other prophylaxis strategies. Tailoring antibiotics addresses antibiotic-resistant bacteria and reduces future risk of resistance. These findings make a strong case for incorporating culture-directed antibiotic prophylaxis into clinical practice guidelines to reduce infection following prostate biopsies.

Questioning the Status Quo: Should Gleason Grade Group 1 Prostate Cancer be Considered a "Negative Core" in Pre-Radical Prostatectomy Risk Nomograms? An International Multicenter Analysis.

OBJECTIVE: To assess the impact of excluding Gleason Grade Group 1 (GG1) prostate cancer (CaP) cores from current pre-radical prostatectomy (RP) nomograms. METHODS: Multi-institutional retrospective chart review was performed on all RP patients with prostate biopsy between 2008 and 2018. Patients were individually assessed using the Memorial Sloan Kettering Cancer Center (MSKCC) and Briganti nomograms using the following iterations: (1) Original [ORIG] - all available core data and (2) Selective [SEL] - GG1 cores considered negative. Nomogram outcomes - lymph node invasion (LNI), extracapsular extension (ECE), organ-confined disease (OCD), seminal vesicle invasion (SVI), were compared across iterations and stratified based on biopsy GG. Clinically significant impact on management (CSIM) was defined as change in LNI risk above or below 2% or 5% (Δ2/Δ5). Nomogram outcomes were validated with RP pathology. RESULTS: 7718 men met inclusion criteria. In men with GG2 who also had GG1 cores, SEL better predicted LNI (MSKCC - ORIG 4.97% vs SEL 3.50%; Briganti - ORIG 4.81% vs SEL 2.49%, RP outcome 2.46%), OCD (MSKCC - ORIG 40.91% vs SEL 48.44%, RP outcome: 68.46%) and ECE (MSKCC - ORIG 57.87% vs SEL 50.38%, RP outcome: 30.41%), but not SVI (MSKCC - ORIG 5.42% vs SEL 3.34%, RP outcome: 5.62%). This was also consistent in patients with GG3-5 disease. The greatest CSIM was on GG1-2 CaP; Δ2 and Δ5 in GG1 patients was 26.3%-31.0% and 1.5%-5.2%, respectively, and Δ2 and Δ5 in GG2 patients was 3.4%-22.2% and 12.3%-13.6%, respectively. CONCLUSION: Excluding GG1 CaP cores from pre-RP nomograms better predicts final RP pathologic outcomes. More importantly, this may better reflect extent of true cancer burden.

Prostate Contrast Enhanced Transrectal Ultrasound Evaluation of the Prostate With Whole-Mount Prostatectomy Correlation.

OBJECTIVE: To investigate the diagnostic accuracy of contrast enhanced transrectal ultrasound (CE-TRUS) in comparison with whole-mount radical prostatectomy specimens. METHOD AND MATERIALS: Fifty-eight subjects who underwent CE-TRUS and subsequent radical prostatectomy with whole-mount pathology were included in the study. Each patient underwent evaluation with baseline TRUS and again during CE-TRUS with intravenous infusion of perflutren lipid microsphere (Definity, Lantheus Medical Imaging, N Billerica, MA). A subjective 5 point scale was used to rate each sextant of the prostate in 3 baseline imaging modes and in 5 contrast-enhanced imaging modes. Baseline TRUS and CE-TRUS findings were compared with digitized whole-mount findings. A clustered logistic regression model was computed to compare the area under the receiver operating characteristic curve (Az) for detection of prostate cancer by various modes of ultrasound imaging. RESULTS: Among the 58 whole-mount specimens, a maximum Gleason score of 6 was identified in 29 subjects, a score of 7 was identified in 24 and a score of 8 was identified in 5. The Az for baseline TRUS parameters was 0.55 for grayscale, 0.61 for color Doppler and 0.59 for power Doppler. CE-TRUS parameters demonstrated significant increases in Az with the highest Az for CE-power Doppler (0.66) and flash replenishment imaging (0.64) (P = .04 for comparison to baseline). The combination of CE-power Doppler and flash replenishment imaging resulted in improved Az compared with baseline imaging (0.70 vs 0.59, P= .006). CONCLUSION: Contrast-enhanced ultrasonography demonstrates greater diagnostic accuracy than baseline imaging. Diagnostic accuracy is further improved for "clinically significant" tumor volumes >1 cc.

Evolution of the Liquid Biopsy in Metastatic Prostate Cancer.

We reviewed the literature for the biologic, prognostic, and predictive significance of circulating prostate cancer tumor cells (CTCs), and circulating tumor DNA in the blood of metastatic castration resistant prostate cancer patients. CTCs demonstrate robust prognostic value independent of PSA in predicting overall survival. The CTC androgen receptor variant receptor 7 phenotype predicts resistance to androgen receptor synthesis inhibitors and sensitivity to taxane based chemotherapy in metastatic castration resistant prostate cancer patients who are candidates for second line therapy. Research is rapidly pivoting toward circulating tumor DNA analysis because the approach is sensitive, prognostic, cost effective, and it can elucidate mechanisms of systemic therapy.

Hematologic Toxicity of Concurrent Administration of Radium-223 and Next-generation Antiandrogen Therapies.

PURPOSE/OBJECTIVES: Radium-223 is a first-in-class radiopharmaceutical recently approved for the treatment of castration-resistant prostate cancer in patients with symptomatic bone metastases. Initial studies investigating Radium-223 primarily used nonsteroidal first-generation antiandrogens. Since that time, newer antiandrogen therapies have demonstrated improved survival in patients with castration-resistant prostate cancer. It has been suggested that the rational combination of these newly approved agents with Radium-223 may lead to improved response rates and clinical outcomes. Currently, there is lack of information regarding the safety of concurrent administration of these agents with radiopharmaceuticals. Here, we report on hematologic toxicity findings from our institution in patients receiving concurrent Radium-223 and next-generation antiandrogen therapies with either enzalutamide or abiraterone. MATERIALS/METHODS: In a retrospective study, we analyzed patients who received Radium-223 as part of an early-access trial, and following FDA approval in May 2013, patients receiving Radium-223 as part of standard care. Radium-223 was given at standard dosing of 50 kBq/kg each month for 6 total cycles. Complete blood counts were performed before treatment monthly and following each injection. Blood counts from patients receiving Radium alone and concurrently with next-generation antiandrogens were compared. To date, 25 total patients were analyzed, with a median of 5 monthly doses received per patient. Fourteen patients received concurrent therapy during monthly Radium-223 with either enzalutamide (n=8) or abiraterone (n=6). RESULTS: Six patients expired due to disease progression. Two patients discontinued treatment due to grade 3 myelosuppression. For patients receiving either Radium alone and with concurrent next-generation antiandrogen therapy, there did not appear to be any statistically significant differences between initial and nadir blood counts. Mean change from initial neutrophil count to nadir was 1.9×10/L in patients receiving Radium alone, versus 2.3×10/L in patients receiving concurrent therapy (P=0.77). Mean change from initial hemoglobin value to nadir was 1.5 g/L in patients receiving Radium alone, versus 1.8 g/L in patients receiving concurrent therapy (P=0.31). Mean change from initial platelet count to nadir was 52.3×10 cells/L in patients receiving Radium alone versus 70.6×10 cells/L in patients receiving concurrent therapy (P=0.39). Individual blood counts for each measured laboratory are included in the supplemental data. PSA was stable or decreased in 22% of patients receiving Radium alone versus 35% of patients receiving combination treatment (P=0.24). CONCLUSIONS: Concurrent administration of Radium-223 and next-generation antiandrogen therapies appears to be well tolerated with similar toxicities to standard administration of Radium-223 alone. This particular cohort of patients represents a high-risk, heavily pretreated group of patients with advanced metastatic disease and significant marrow burden. Despite these risk factors, hematologic toxicity was modest and was in the range expected for this risk group based on previous trials. To date, this is the first study investigating the toxicity of combination treatment. Further studies investigating the safety and efficacy of combination treatments are warranted.

Adjuvant versus salvage radiation therapy for prostate cancer patients with adverse pathologic features: comparative analysis of long-term outcomes.

OBJECTIVES: To compare long-term outcomes of men with adverse pathologic features after adjuvant radiation therapy (ART) versus salvage radiation therapy (SRT) after radical prostatectomy at our institution. METHODS: Patients treated with postprostatectomy radiation therapy with pT3 tumors, or pT2 with positive surgical margins, were identified. Cumulative freedom from biochemical failure (FFBF), freedom from metastatic failure (FFMF), and overall survival rates were estimated utilizing the Kaplan-Meier method. Multivariate analyses were performed to determine independent prognostic factors correlated with study endpoints. Propensity score analyses were performed to adjust for confounding because of nonrandom treatment allocation. RESULTS: A total of 186 patients with adverse pathologic features treated with ART or SRT were identified. The median follow-up time after radical prostatectomy was 103 and 88 months after completion of radiation therapy. The Kaplan-Meier estimates for 10-year FFBF was 73% and 41% after ART and SRT, respectively (log-rank, P=0.0001). Ten-year FFMF was higher for patients who received ART versus SRT (98.6% vs. 80.9%, P=0.0028). On multivariate analyses there was no significant difference with respect to treatment group in terms of FFBF, FFMF, and overall survival after adjusting for propensity score. CONCLUSIONS: Although unadjusted analyses showed improved FFBF with ART, the propensity score-adjusted analyses demonstrated that long-term outcomes of patients treated with ART and SRT do not differ significantly. These results, with decreased effect size of ART after adjusting for propensity score, demonstrate the potential impact of confounding on observational research.

Patterns of care for elderly men diagnosed with favorable-risk prostate cancer from 2004 to 2008: a population-based analysis.

OBJECTIVES: With the widespread use of prostate-specific antigen testing, an increasing number of men are diagnosed with favorable-risk prostate cancer (PC). Recently, emphasis has been placed on active surveillance for selected men with favorable-risk PC to avoid unnecessary treatment for tumors that may be clinically insignificant. We performed a population-based analysis to assess patterns of initial treatment (IT) for a contemporary cohort of elderly men diagnosed with a favorable-risk PC in the United States. METHODS: We used the Surveillance, Epidemiology, and End Results database to identify men aged more than or equal to 70 years diagnosed with a favorable-risk PC from 2004 to 2008. Multivariable logistic regression analyses were performed to determine patient, tumor, and socioeconomic factors associated with IT. RESULTS: A total of 15,108 men more than or equal to 70 years with a favorable-risk PC were identified. Prostatectomy was performed in 2.6% of patients. Fifty-nine percent of patients were recommended to undergo radiation therapy (RT). Among patients 70 to 74 years, 66.45% were recommended to undergo RT. Fifty-nine percent, 36.6%, and 15.8% of patients between 75 and 79, 80 and 84, and more than or equal to 85 years were recommended to receive RT, respectively. Factors significantly associated with IT on multivariable logistic regression analysis included: younger age, white race, Gleason Score 6 (vs.≤5), married marital status, and no history of prior malignancy. We also identified significant geographic variations in patterns of IT. CONCLUSIONS: A large percentage of elderly men diagnosed with favorable-risk PC undergo IT, most commonly with RT. Future research should be performed to identify barriers to patient and physician acceptance of active surveillance.

Enhancing prostate cancer care through the multidisciplinary clinic approach: a 15-year experience.

PURPOSE: To report on the 15-year prostate cancer experience of our multidisciplinary genitourinary cancer clinic established in 1996 at the National Cancer Institute (NCI) -designated Jefferson Kimmel Cancer Center. Patients with genitourinary cancers were evaluated weekly by multiple specialists at a single site, and we focus on the 83% of patients with prostate cancer. To our knowledge, our multidisciplinary genitourinary cancer clinic is the longest continuously operating center of its kind at an NCI Cancer Center in the United States. METHODS: Data from Jefferson's Oncology Data Services were compared to SEER prostate cancer outcomes. Data on treatment changes in localized disease, patient satisfaction, and related parameters were also assessed. RESULTS: Ten-year survival data approach 100% in stage I and II prostate cancer. Ten-year data for stage III (T3 N0M0) and stage IV (T4 N0M0) disease show that our institutional survival rate exceeds SEER. There is a shift toward robotically assisted laparoscopic radical prostatectomy and a slight decrease in brachytherapy relative to external beam radiation therapy in localized disease. Patient satisfaction is high as measured by survey instruments. CONCLUSION: Our long-term experience suggests a benefit of the multidisciplinary clinic approach to prostate cancer, most pronounced for high-risk, locally advanced disease. A high level of satisfaction with this patient-centered model is seen. The multidisciplinary clinic approach to prostate cancer may enhance outcomes and possibly reduce treatment regret through a coordinated presentation of all therapeutic options. This clinic model serves as an interdisciplinary educational tool for patients, their families, and our trainees and supports clinical trial participation.

Effective testosterone suppression for prostate cancer: is there a best castration therapy?

Achieving and maintaining effective suppression of serum testosterone levels in men treated with androgen ablation is one of the essential strategies in the management of prostate cancer. Historically, a serum testosterone below 50 ng/dL was considered to be the castrate level. Current data suggest that the new target for either surgical or chemical castration is a serum testosterone level of lower than 20 ng/dL in an attempt to maximize therapeutic outcomes. Testosterone breakthrough and the acute-on-chronic effects of administration of a luteinizing hormone-releasing hormone analogue may cause testosterone levels to periodically rise, sometimes to noncastrate levels. The goal of androgen ablation is to identify those agents that will most consistently achieve and maintain the lowest testosterone levels possible.