The Influence of Stress and Binge-Patterned Alcohol Drinking on Mouse Skeletal Muscle Protein Synthesis and Degradation Pathways.

Adverse experiences (e.g., acute stress) and alcohol misuse can both impair skeletal muscle homeostasis, resulting in reduced protein synthesis and greater protein breakdown. Exposure to acute stress is a significant risk factor for engaging in alcohol misuse. However, little is known about how these factors together might further affect skeletal muscle health. To that end, this study investigated the effects of acute stress exposure followed by a period of binge-patterned alcohol drinking on signaling factors along mouse skeletal muscle protein synthesis (MPS) and degradation (MPD) pathways. Young adult male C57BL/6J mice participated in the Drinking in the Dark paradigm, where they received 2-4 h of access to 20% ethanol (alcohol group) or water (control group) for four days to establish baseline drinking levels. Three days later, half of the mice in each group were either exposed to a single episode of uncontrollable tail shocks (acute stress) or remained undisturbed in their home cages (no stress). Three days after stress exposure, mice received 4 h of access to 20% ethanol (alcohol) to model binge-patterned alcohol drinking or water for ten consecutive days. Immediately following the final episode of alcohol access, mouse gastrocnemius muscle was extracted to measure changes in relative protein levels along the Akt-mTOR MPS, as well as the ubiquitin-proteasome pathway (UPP) and autophagy MPD pathways via Western blotting. A single exposure to acute stress impaired Akt singling and reduced rates of MPS, independent of alcohol access. This observation was concurrent with a potent increase in heat shock protein seventy expression in the muscle of stressed mice. Alcohol drinking did not exacerbate stress-induced alterations in the MPS and MPD signaling pathways. Instead, changes in the MPS and MPD signaling factors due to alcohol access were primarily observed in non-stressed mice. Taken together, these data suggest that exposure to a stressor of sufficient intensity may cause prolonged disruptions to signaling factors that impact skeletal muscle health and function beyond what could be further induced by periods of alcohol misuse.

The effects of voluntary binge-patterned ethanol ingestion and daily wheel running on signaling of muscle protein synthesis and degradation in female mice.

Excessive ethanol ingestion can reduce skeletal muscle protein synthesis (MPS) through the disruption of signaling along the Akt-mTOR pathway and increase muscle protein degradation (MPD) through the Ubiquitin Proteasome Pathway (UPP) and autophagy. Identification of interventions that curb the disrupting effects of alcohol misuse on MPS and MPD are of central importance for the prevention of chronic health complications that arise from muscle loss. Physical activity is one potential strategy to combat the deleterious effects of alcohol on skeletal muscle. Therefore, the purpose of this study was to investigate the interaction between daily wheel running and binge-patterned ethanol consumption, through episodes of voluntary binge-patterned ethanol drinking, on signaling factors along the Akt-mTOR, Ubiquitin-Proteasome, and autophagy pathways. Adult female C57BL/6J mice received daily access to cages with or without running wheels for 2.5 h/day for five weeks. During the final five days of the study, mice received 2-4 h of daily access to sipper tubes containing water (n = 14 sedentary; n = 15 running) or 20% ethanol (n = 14 sedentary; n = 16 running) 30 min after running wheel access, using the "Drinking in the Dark" (DID) model of binge-patterned ethanol consumption. Immediately after the final episode of DID, gastrocnemius muscle was extracted. Western blotting was performed to measure proteins along Akt-mTOR, Ubiquitin-Proteasome, and autophagy pathways, and PCR was used to assess mRNA expression of atrogenes. Ethanol access increased expression of MAFbx by 82% (p = 0.048), but did not robustly influence Akt-mTOR or UPP signaling. Daily wheel access did not prevent alcohol-induced MAFbx expression; however, ethanol access decreased the phosphorylation of p70S6K by 45% in running mice (p = 0.020). These results suggest that physical activity may be insufficient to prevent alcohol-induced changes to signaling factors along pathways involved in muscle loss. Instead, binge-patterned ethanol ingestion may impair the benefits of physical activity on factors involved in MPS.

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Angiogenic potential is reduced in skeletal muscle of aged women.

KEY POINTS: The risk of cardiovascular disease and associated skeletal muscle microvascular rarefaction is enhanced in women after menopause, yet knowledge about the angiogenic potential in ageing women is generally sparse. Aged healthy and sedentary women were found to present a markedly impaired capacity for proliferation of skeletal muscle derived microvascular endothelial cells compared to young women. Vascular endothelial growth factor (VEGF) levels in skeletal muscle myocytes and release of VEGF from myocytes tended to be lower in aged compared to young women. The aged women did not show a detectable increase in skeletal muscle capillarization with 8 weeks of intense aerobic cycle training. Combined, the findings indicate that aged women have a reduced potential for capillary growth in skeletal muscle which, with ageing, may lead to age-induced microvascular rarefaction. ABSTRACT: Skeletal muscle angiogenic potential was examined in cell cultures derived from aged and young women, and the effect of 8 weeks of intense cycle training on muscle capillary growth was determined in the group of aged women. Basal muscle samples were obtained from healthy sedentary aged (n = 12; 64 ± 4.2 years) and young women (n = 5; 24 ± 3.2 years) for endothelial cell and skeletal muscle myocyte isolation and experiments. In addition, the aged women completed an 8-week training intervention. Peak oxygen uptake and muscle samples for histology and protein determination were obtained before and after the training period. Before training, muscle microdialysate was collected from the aged women at rest and during exercise. In Part 1 of the experiments, growth-supplement stimulated proliferation of endothelial cells was ∼75% lower in cells from aged compared to young women (P < 0.001). There was a tendency for a lower vascular endothelial growth factor (VEGF) concentration in muscle conditioned media (P = 0.0696) and for a lower VEGF content in the myocytes (P = 0.0705) from aged compared to young women. Endothelial proliferation was found to be highly dependent on mitochondrial function. Acute exercise resulted in a modest (1.3-fold; P = 0.0073) increase in muscle interstitial VEGF protein in the aged women. In Part 2, 8 weeks of intense training did not change muscle capillarization (P ≥ 0.1502) in the aged women, but led to an increased amount of muscle VEGF (P = 0.0339). In conclusion, aged women have impaired angiogenic potential, which is associated with a compromised response both at the skeletal muscle myocyte and microvascular endothelial cell level.

Exercise-Induced Adaptations to the Mouse Striatal Adenosine System.

Adenosine acts as a key regulator of striatum activity, in part, through the antagonistic modulation of dopamine activity. Exercise can increase adenosine activity in the brain, which may impair dopaminergic functions in the striatum. Therefore, long-term repeated bouts of exercise may subsequently generate plasticity in striatal adenosine systems in a manner that promotes dopaminergic activity. This study investigated the effects of long-term voluntary wheel running on adenosine 1 (A1R), adenosine 2A (A2AR), dopamine 1 (D1R), and dopamine 2 (D2R) receptor protein expression in adult mouse dorsal and ventral striatum structures using immunohistochemistry. In addition, equilibrative nucleoside transporter 1 (ENT1) protein expression was examined after wheel running, as ENT1 regulates the bidirectional flux of adenosine between intra- and extracellular space. The results suggest that eight weeks of running wheel access spared age-related increases of A1R and A2AR protein concentrations across the dorsal and ventral striatal structures. Wheel running mildly reduced ENT1 protein levels in ventral striatum subregions. Moreover, wheel running mildly increased D2R protein density within striatal subregions in the dorsal medial striatum, nucleus accumbens core, and the nucleus accumbens shell. However, D1R protein expression in the striatum was unchanged by wheel running. These data suggest that exercise promotes adaptations to striatal adenosine systems. Exercise-reduced A1R and A2AR and exercise-increased D2R protein levels may contribute to improved dopaminergic signaling in the striatum. These findings may have implications for cognitive and behavioral processes, as well as motor and psychiatric diseases that involve the striatum.

Effect of Pharmacologic Prophylaxis on Venous Thromboembolism After Radical Prostatectomy: The PREVENTER Randomized Clinical Trial.

BACKGROUND: Direct high-quality evidence is lacking evaluating perioperative pharmacologic prophylaxis (PP) after radical prostatectomy (RP) to prevent venous thromboembolism (VTE) leading to significant practice variation. OBJECTIVE: To study the impact of in-hospital PP on symptomatic VTE incidence and adverse events after RP at 30 d, with the secondary objective of evaluating overall VTE in a screening subcohort. DESIGN, SETTING, AND PARTICIPANTS: A prospective, phase 4, single-center, randomized trial of men with prostate cancer undergoing open or robotic-assisted laparoscopic RP was conducted (July 2017-November 2018). INTERVENTION: PP (subcutaneous heparin) plus routine care versus routine care alone. The screening subcohort was offered lower extremity duplex ultrasound at 30 d. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: The primary efficacy outcome was symptomatic VTE incidence (pulmonary embolism [PE] or deep venous thrombosis [DVT]). Primary safety outcomes included the incidence of symptomatic lymphocele, hematoma, or bleeding after surgery. Secondary outcomes were overall VTE, estimated blood loss, total surgical drain output, complications, and surveillance imaging bias. Fisher's exact test and modified Poisson regression were performed. RESULTS AND LIMITATIONS: A total of 501 patients (75% robotic) were randomized and >99% (500/501) completed follow-up. At second interim analysis (N = 445), the symptomatic VTE rate was 2.3% (four PE + DVT and one DVT) for routine care versus 0.9% (one PE + DVT and one DVT) for PP (relative risk 0.40 [95% confidence interval 0.08-2.03], p = 0.3) meeting a futility threshold for early stopping. In the screening subcohort, the overall VTE rate was 3.3% versus 2.4% (p = 0.7). Results were similar at the final analysis (symptomatic VTE: 2.0% vs 0.8%, p = 0.3; overall VTE: 2.9% vs 2.8%, p = 1). No differences were observed in safety or secondary outcomes. All VTE events (seven symptomatic and three asymptomatic) occurred in patients undergoing pelvic lymph node dissection. CONCLUSIONS: This study was not able to demonstrate a statistically significant reduction in symptomatic VTE associated with PP. There was no increase in the development of symptomatic lymphoceles, bleeding, or other adverse events. Given that the event rate was lower than powered for, further research is needed among high-risk patients (Caprini score ≥8) or patients receiving pelvic lymph node dissection. PATIENT SUMMARY: In this report, we randomized patients undergoing radical prostatectomy to perioperative pharmacologic prophylaxis or routine care alone. We found that pharmacologic prophylaxis did not reduce postoperative symptomatic venous thromboembolism significantly for men at routine risk. Importantly, pharmacologic prophylaxis did not increase adverse events, such as formation of lymphoceles or bleeding, and can safely be implemented when indicated for patients with risk factors undergoing radical prostatectomy.

Imoxin prevents dexamethasone-induced promotion of muscle-specific E3 ubiquitin ligases and stimulates anabolic signaling in C2C12 myotubes.

Muscle atrophy is the loss of skeletal muscle mass during several pathological conditions such as long-term fasting, aging, cancer, diabetes, sepsis and immune disorders. Glucocorticoids are known to trigger skeletal muscle atrophy. Dexamethasone (DEX), a synthetic glucocorticoid, induces skeletal muscle atrophy by suppression of protein synthesis and promotion of protein degradation. The double-stranded RNA (dsRNA)-activated protein kinase R (PKR) plays a significant role in mediating lipopolysaccharide-induced inflammation. However, pathological roles of PKR in muscle atrophy are not fully understood. The current study aimed to investigate the effect of imoxin, a PKR inhibitor, on DEX-induced muscle atrophy in C2C12 myotubes. Myotubes were incubated with imoxin at different concentrations with or without 5 µM DEX for 24 h. In the current study, imoxin treatment significantly reduced protein levels of MuRF1 and MAFbx induced by DEX by 88 ± 2% and MAFbx by 99 ± 0%, respectively. Moreover, 5 µM imoxin treatment reduced protein ubiquitination by 42 ± 4% and protein content of nuclear FoxO3α (77 ± 4%) in presence of DEX. Furthermore, 5 µM imoxin treatment stimulated Akt phosphorylation (195 ± 5%), mTOR phosphorylation (171 ± 21 %) and p70S6K1 phosphorylation (314 ± 31 %) under DEX-treated condition even though DEX treatment did not suppressed Akt/mTOR/p70S6K1 axis. These findings suggest that imoxin may protect against DEX-induced skeletal muscle atrophy by alleviating muscle specific E3 ubiquitin ligases and imoxin alone may promote protein synthesis via Akt/mTOR/S6K1 axis in muscle cells.

Active Surveillance of Grade Group 1 Prostate Cancer: Long-term Outcomes from a Large Prospective Cohort.

BACKGROUND: Active surveillance (AS) is the preferred management option for most men with grade group (GG) 1 prostate cancer (PCa). Questions persist regarding long-term outcomes and the optimal approach to AS. OBJECTIVE: To determine survival and metastatic outcomes in AS patients. Secondary objectives were to measure the cumulative incidence and association of patient-level factors on biopsy grade reclassification. DESIGN, SETTING, AND PARTICIPANTS: A prospective, active, open-enrollment cohort study was conducted from 1995 through July 2018 at a tertiary-care academic institution. Patients with very-low-risk or low-risk PCa were enrolled. INTERVENTION: AS with semiannual prostate-specific antigen (PSA) and digital rectal examination, serial prostate biopsy, and multiparametric magnetic resonance imaging (mpMRI). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The 10- and 15-yr cumulative incidences of primary and secondary outcomes were determined. RESULTS AND LIMITATIONS: Overall, 1818 men were monitored on AS for a median of 5.0yr (interquartile range 2.0-9.0). There were 88 non-PCa deaths, four PCa deaths, and one additional case of metastasis. The cumulative incidence of PCa-specific mortality or metastasis was 0.1% (95% confidence interval, 0.04-0.6%) at both 10 and 15yr. The 5-, 10-, and 15-yr cumulative incidences of biopsy grade reclassification were 21%, 30%, and 32%, respectively. On multivariable analysis, biopsy grade reclassification was associated with older age, African-American race, PSA density, and increased cancer volume on biopsy, and men who underwent mpMRI prior to enrollment were less likely to undergo grade reclassification. Our selection and monitoring are more stringent than many other contemporary AS programs. CONCLUSIONS: In a large, single-institution, prospective AS cohort, the risk of cancer death or metastasis was <1% over long-term follow-up. Consistent with clinical guidelines, these data support the use of AS for the management of most men diagnosed with GG1 PCa. PATIENT SUMMARY: This study investigated long-term outcomes in patients with grade group 1 prostate cancer managed with active surveillance (AS). Ten years after enrolling in AS, the risk of metastasis or death from prostate cancer was <1%, while 48% of men switched to treatment. Patients who underwent multiparametric magnetic resonance imaging (mpMRI)/ultrasound-fusion targeted biopsy prior to enrollment were less likely to experience biopsy grade reclassification during follow-up, suggesting a role for mpMRI as part of a comprehensive risk assessment to confirm AS eligibility. These findings support the safety of AS in most men with grade group 1 prostate cancer, but specific outcomes may differ in programs with less intensive monitoring.

Evaluation of Apparent Diffusion Coefficient as a Predictor of Grade Reclassification in Men on Active Surveillance for Prostate Cancer.

OBJECTIVE: To evaluate the association between apparent diffusion coefficient (ADC) on initial multiparametric MRI (mpMRI) and biopsy grade reclassification (GR) to grade group (GG) ≥2 prostate cancer (CaP) in men on active surveillance (AS) with GG 1 CaP. METHODS: We retrospectively identified 242 AS patients with reported ADC values on their initial mpMRI. ADC value from the index lesion was assessed as an independent predictor of GR using a Cox model. To ease clinical interpretation, we used a log-rank test to establish an ADC cutoff of 1128 × 10-6 mm2/s for Kaplan-Meier analysis. RESULTS: Of the 242 men, 70 underwent GR following initial mpMRI, of which 26 (37%) had GR at the index lesion. There was no significant difference in the median interval between biopsies for men with and without GR (P >.9). Men with GR had significantly lower median ADC than those without GR (P = .01). In multivariable analysis adjusting for age, prostate-specific antigen density, and National Comprehensive Cancer Network risk group, a 100-unit decrease in ADC was associated with a 12% increase in the risk of GR (HR = 1.12, 95% CI: 1.01-1.22, P = .03). Two- and 4-year rates of freedom from GR were significantly lower for men with ADC <1128 × 10-6 mm2/s vs ADC ≥1128 × 10-6 mm2/s (62% and 42% vs 78% and 68%, respectively; P <.001). CONCLUSION: For AS patients, lower ADC on initial mpMRI index lesion is associated with increased risk of GR to GG ≥2 CaP and would be a useful component of multivariable risk prediction tools.

Prostate cancer mortality and metastasis under different biopsy frequencies in North American active surveillance cohorts.

BACKGROUND: Active surveillance (AS) is an accepted means of managing low-risk prostate cancer. Because of the rarity of downstream events, data from existing AS cohorts cannot yet address how differences in surveillance intensity affect metastasis and mortality. This study projected the comparative benefits of different AS schedules in men diagnosed with prostate cancer who had Gleason score (GS) ≤6 disease and risk profiles similar to those in North American AS cohorts. METHODS: Times of GS upgrading were simulated based on AS data from the University of Toronto, Johns Hopkins University, the University of California at San Francisco, and the Canary Pass Active Surveillance Cohort. Times to metastasis and prostate cancer death, informed by models from the Scandinavian Prostate Cancer Group 4 trial, were projected under biopsy surveillance schedules ranging from watchful waiting to annual biopsies. Outcomes included the risk of metastasis, the risk of death, remaining life-years (LYs), and quality-adjusted LYs. RESULTS: Compared with watchful waiting, AS biopsies reduced the risk of prostate cancer metastasis and prostate cancer death at 20 years by 1.4% to 3.3% and 1.0% to 2.4%, respectively; and 5-year biopsies reduced the risk of metastasis and prostate cancer death by 1.0% to 2.4% and 0.6% to 1.6%, respectively. There was little difference between annual and 5-year biopsy schedules in terms of LYs (range of differences, 0.04-0.16 LYs) and quality-adjusted LYs (range of differences, -0.02 to 0.09 quality-adjusted LYs). CONCLUSIONS: Among men diagnosed with GS ≤6 prostate cancer, obtaining a biopsy every 3 or 4 years appears to be an acceptable alternative to more frequent biopsies. Reducing surveillance intensity for those who have a low risk of progression reduces the number of biopsies while preserving the benefit of more frequent schedules.

The association between clinically determined periodontal disease and prostate-specific antigen concentration in men without prostate cancer: the 2009-2010 National Health and Nutrition Examination Survey.

PURPOSE: We evaluated the association between clinically assessed periodontal disease and serum prostate-specific antigen (PSA) concentration in men without a prostate cancer diagnosis in a US nationally representative sample of non-institutionalized men. METHODS: Included were 1263 men aged ≥ 40 years who participated in the National Health and Nutrition Examination Survey in 2009-2010. Measurements of periodontal health and tooth count were used to define periodontal disease severity (no, mild, moderate, severe) and edentulism. Linear and logistic regressions were used to estimate the association of periodontal disease severity and edentulism with PSA concentration and elevated PSA, respectively. RESULTS: Adjusting for age and other factors including race, body mass index, and education, the natural logarithm of PSA concentration did not change with increasing severity (mild - 0.20, 95% confidence interval [CI] - 0.34 to - 0.05; moderate - 0.12, 95% CI - 0.26 to 0.01; severe - 0.16, 95% CI - 0.43 to 0.12; edentulism - 0.16, 95% CI - 0.35 to 0.04; P-trend 0.13) compared with dentate men without periodontal disease. Although the multivariable-adjusted ORs of elevated PSA were not statistically significant, participants with more severe periodontal disease were less likely to have PSA > 2.0 and > 2.5 ng/mL, but more likely to have PSA > 4.0 ng/mL, compared to dentate men without periodontal disease. Similar non-significant associations with PSA were observed when comparing edentulous men to dentate men without periodontal disease. CONCLUSIONS: In this US nationally representative sample, men with periodontal disease did not have higher serum PSA and were not more likely to have clinically elevated PSA after taking into account age and other factors, contrary to the hypothesis. This study suggests that periodontal disease does not notably affect the specificity of PSA for prostate cancer screening.

In-office Transperineal Prostate Biopsy Using Biplanar Ultrasound Guidance: A Step-by-Step Guide.

OBJECTIVE: To provide a step-by-step guide for performing in-office transperineal prostate biopsy using biplanar ultrasound guidance. PATIENTS AND METHODS: Biopsies are performed using a freehand technique with the PrecisionPoint Transperineal Access System (Perineologic, Cumberland, MD). This disposable needle guide includes 3 components: a rail/clamp subassembly, a needle carriage with 5 aperture holes, and a 15 gauge access needle. The device is clamped to a side-fire biplanar ultrasound probe, ensuring alignment of the biopsy needle with the probe's ultrasound arrays. Once the patient is sufficiently anesthetized using 1% lidocaine, the access needle is engaged into the perineal skin. This allows for multiple passes of the biopsy needle through a common puncture site. A separate puncture is made for each side of the prostate and the aperture hole is chosen based on the overall height of the prostate. Biopsies are taken using a disposable 18 gauge biopsy gun. RESULTS: The presented video details our approach for performing transperineal prostate biopsy under local anesthesia. Biopsies are performed in the office setting without the need for periprocedural antibiotics. The PrecisionPoint Transperineal Access System ensures proper alignment of the biopsy needle with the ultrasound probe, while minimizing the number of individual needle sticks to the perineal skin. The use of biplanar ultrasound makes it possible to guide the biopsy needle with excellent precision to virtually any area of the prostate. The descried technique can be used for systematic biopsies as well as for targeted biopsies using cognitive fusion with magnetic resonance imaging. CONCLUSION: We provide a step-by-step guide for performing in-office transperineal prostate biopsy. The presented technique minimizes the risk of infectious complications by eliminating the need for biopsy needles to pass through the rectal mucosa. Biopsies are performed without the need for periprocedural antibiotics, thus furthering the goals of antibiotic stewardship.

Association between Liver Fibrosis and Serum PSA among U.S. Men: National Health and Nutrition Examination Survey (NHANES), 2001-2010.

BACKGROUND: To evaluate the association of liver fibrosis scores with PSA level among U.S. adult men overall and by race/ethnicity. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES), 2001-2010, were used. Males ages ≥40 years without a prostate cancer diagnosis and who had serum PSA, liver enzymes, albumin, and platelet counts measured as part of NHANES protocol were included. Liver fibrosis was measured using three scores: aspartate aminotransferase to platelet ratio index (APRI), fibrosis 4 index (FIB-4), and NAFLD fibrosis score (NFS). We assessed overall and race/ethnicity-stratified geometric mean PSA by fibrosis score using predictive margins by linear regression, and the association of abnormal fibrosis scores (APRI > 1, FIB-4 > 2.67, NFS > 0.676) and elevated PSA (>4 ng/mL) by logistic regression. RESULTS: A total of 6,705 men were included. Abnormal liver fibrosis scores were present in 2.1% (APRI), 3.6% (FIB-4), and 5.6% (NFS). Men with higher fibrosis scores had lower geometric mean PSA (all P trend < 0.02). Men with abnormal APRI had a lower odds of PSA > 4 ng/mL [adjusted OR (aOR) = 0.33; 95% confidence interval (CI), 0.11-0.96]. Compared with men with 0 abnormal scores, those with 2 or 3 abnormal fibrosis scores had a lower odds of PSA > 4 ng/mL (aOR = 0.55; 95% CI, 0.33-0.91). The patterns were similar by race/ethnicity. CONCLUSIONS: Men of all race/ethnicities with higher liver fibrosis scores had lower serum PSA, and men with advanced fibrosis scores had a lower odds of an elevated PSA. IMPACT: These findings support further research to inform the likelihood of delay in prostate cancer detection in men with abnormal liver function.

PTEN status assessment in the Johns Hopkins active surveillance cohort.

BACKGROUND: Up to half of men with Gleason score 6 (GS6) prostate cancers initially managed with active surveillance (AS) will eventually require definitive therapy, usually due to tumor grade reclassification during follow-up. We examined the association between PTEN status on biopsy and subsequent clinicopathologic outcomes in men with GS6 cancers who enrolled in AS. METHODS: We performed a case-control study of men enrolled in the Johns Hopkins AS cohort with diagnostic biopsy tissue available for immunohistochemical (IHC) staining. IHC was performed for PTEN using genetically validated protocols for all patients. Cases included men who underwent grade reclassification to GS ≥ 3 + 4 = 7 on biopsy within 2 years of follow-up (i.e., early reclassification) or reclassification to GS ≥ 4 + 3 = 7 on biopsy or radical prostatectomy during follow-up (i.e., extreme reclassification). Control patients were diagnosed with GS6 cancer and monitored on AS for at least 8 years without undergoing biopsy reclassification. RESULTS: Among 67 cases with adequate tissue, 31 men underwent early reclassification and 36 men underwent extreme reclassification. Cases were compared to 65 control patients with adequate tissue for assessment. On initial prostate biopsy, cases were older (median age 67 vs. 65, p = 0.024) and were less likely to meet very-low-risk criteria (64 vs 79%, p = 0.042) as compared to controls. Although not statistically significant, PTEN loss was observed in only 1 (1.5%) of 65 controls as compared to 6 (9%) of 67 cases (p = 0.062). CONCLUSIONS: PTEN loss was rare among men with GS6 prostate cancer enrolled in AS at Johns Hopkins. Despite this, PTEN loss was more frequent among men who underwent early or extreme reclassification to higher-grade cancer as compared to controls. Additional studies in larger low-risk cohorts may better elucidate a potential role for PTEN in selecting patients for AS.

Older Age Predicts Biopsy and Radical Prostatectomy Grade Reclassification to Aggressive Prostate Cancer in Men on Active Surveillance.

PURPOSE: Age at prostate cancer diagnosis has been positively associated with prostate cancer specific mortality and in men on active surveillance with a higher risk of biopsy grade reclassification to Gleason score 3 + 4 or greater (Grade Group 2 or greater). However, to our knowledge the association between age and biopsy grade reclassification to an aggressive phenotype (Gleason score 4 + 3 or greater [Grade Group 3 or greater]) has not been explored. MATERIALS AND METHODS: From 1995 to 2016 we followed 1,625 men 41 to 81 years old with NCCN® (National Comprehensive Cancer Network®) very low (68%) or low (32%) risk prostate cancer on active surveillance. We determined the rate of biopsy grade reclassification to Grade Group 3 or greater. Competing risk analysis was applied to evaluate the association between age at enrollment and the risk of biopsy grade reclassification. Additionally, in men who underwent radical prostatectomy after biopsy grade reclassification we assessed the rate of radical prostatectomy grade reclassification (ie radical prostatectomy Grade Group greater than biopsy Grade Group). RESULTS: The 5-year incidence of biopsy grade reclassification to Grade Group 3 or greater was 4%, 7% and 14% in men younger than 60, 60 to 69 and 70 years old or older, respectively (p <0.001). On univariate analysis older age was associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.43, p <0.001). On multivariable analysis adjusting for year of diagnosis, race, prostate specific antigen density and cancer volume at diagnosis older age remained associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.19, p <0.001). In men who underwent radical prostatectomy after biopsy grade reclassification those who were older had a higher rate of radical prostatectomy grade reclassification (p <0.05). CONCLUSIONS: In men on active surveillance older age at diagnosis was positively associated with biopsy grade reclassification to Grade Group 3 or greater and radical prostatectomy grade reclassification. These observations imply that for many older men, active surveillance as opposed to watchful waiting remains a more appropriate management strategy.

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

BACKGROUND: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). OBJECTIVE: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. RESULTS AND LIMITATIONS: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ≥4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point. CONCLUSIONS: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. PATIENT SUMMARY: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.

Clinical Evaluation of an Individualized Risk Prediction Tool for Men on Active Surveillance for Prostate Cancer.

OBJECTIVE: To determine whether providing individualized predictions of health outcomes to men on active surveillance (AS) alleviates cancer-related anxiety and improves risk understanding. MATERIALS AND METHODS: We consecutively recruited men from our large, institutional AS program before (n = 36) and after (n = 31) implementation of a risk prediction tool. Men in both groups were surveyed before and after their regular visits to assess their perceived cancer control, biopsy-specific anxiety, and burden from cancer-related information. We compared pre-/post-visit differences between men who were and were not shown the tool using two-sample t-tests. Satisfaction with and understanding of the predictions were elicited from men in the intervention period. RESULTS: Men reported a relatively high level of cancer control at baseline. Men who were not shown the tool saw a 6.3 point increase (scaled from 0 to 100) in their perceived cancer control from before to after their visit whereas men who were shown the tool saw a 12.8 point increase, indicating a statistically significant difference between groups (p = .04). Biopsy-specific anxiety and burden from cancer information were not significantly different between groups. Men were satisfied with the tool and demonstrated moderate understanding. CONCLUSION: Providing individualized predictions to men on AS helps them better understand their cancer risk and should be considered at other clinical sites.