Biomarkers In Men Research Articles

Effects of Dried Plum on Bone Biomarkers in Men (P01-028-19)

ObjectivesOsteoporosis in men is an overlooked yet increasingly important clinical problem that, historically, has not received the same degree of awareness as with women. Epidemiologic studies demonstrate that male osteoporosis contributes significantly to the burden of osteoporotic fractures, especially among the aging population. Although several studies of male animals have demonstrated bone protective effects of dried plum, no human study has evaluated the effect of dried plum on bone metabolism in men. For this purpose, we conducted a randomized controlled clinical study to test if daily inclusion of 100 g dried plum will positively influence serum markers of bone metabolism in men. MethodsSixty-six men (50–79 years old) were randomly assigned to one of two treatment groups: 1) control (0 g dried plum) or; 2) 100 g dried plum with fifty-eight subjects completing the study. All groups received 500 mg calcium and 300 IU vitamin D (Shaklee Chewable Cal Mag Plus) as a daily supplement. Blood samples were collected at baseline, and after three and six months to assess biomarkers of bone turnover. ResultsSerum bone specific alkaline phosphatase (BAP) levels decreased significantly at 6 months in both control and dried plum groups. 100 g/day dried plum consumption resulted in a time-dependent reduction in serum tartrate resistant acid phosphatase-5b (TRAP5b) levels, a marker of bone resorption, at three- and six-month time intervals compared to baseline while there were no significant changes in serum TRAP5b levels of the control group. Dried plum consumption significantly decreased C-terminal collagen cross-links (CTX), another marker of bone resorption, three- and six-months compared to baseline. No changes were observed in the control group for CTX levels. ConclusionsThe results of the current study suggest that daily consumption of 100 g dried plum for 6 months has modest bone protective effects in men that are somewhat similar to those observed in postmenopausal osteopenic and older osteopenic women. Funding SourcesThis study was funded by the California Dried Plum Board.

Association of low testosterone with changes in non-cardiovascular biomarkers in adult men

Testosterone has effects on many organs and systems. The purpose of this study was to test the hypothesis that low testosterone is associated with changes in various non-cardiovascular biomarkers in men older than 40 who were tested for possible hypogonadism. We extracted data from 9939 outpatient men who were over 40 years old (median age 56) and who also had concurrent laboratory measurements of total testosterone and one or more biomarkers of interest: estradiol, uric acid, prostate-specific antigen (PSA), sex-hormone binding globulin (SHBG), luteinizing hormone, creatinine, bone alkaline phosphatase (BAP), creatine kinase, hemoglobin A1c, and 25-hydroxy-vitamin D, and body mass index (BMI). In a smaller exploratory study of 19 otherwise healthy men presenting for evaluation of possible hypogonadism, pre-albumin (a.k.a.transthyretin, a marker of anabolism) and testosterone were measured. Men with lower levels of testosterone had significantly (p < 0.001) lower mean levels of PSA, SHBG, luteinizing hormone, and estradiol. Overall, men with low levels of testosterone also had significantly (p < 0.001) higher mean levels of LDH and BAP, but these associations varied between men who were younger or older than 56 years. There was a moderate but statistically significant positive correlation (r = 0.63, p < 0.05) between testosterone levels and pre-albumin. These results confirm our hypothesis that testosterone deficiency is associated with a broad range of systemic changes demonstrable in hormonal and non-hormonal serum assays in men over 40 years old being tested for possible hypogonadism.

Consumption of whole grain/bran rye instead of refined wheat decrease concentrations of TNF-R2, e-selectin, and endostatin in an exploratory study in men with prostate cancer

Rye consumption has shown beneficial effects on prostate cancer tumors, as indicated by slower initial tumor growth in animal models and lowering of prostate-specific antigen (PSA) in humans. This study evaluated the effects of whole grain/bran rye consumption on low-grade inflammation and endothelial function biomarkers in men with prostate cancer. Seventeen men with untreated, low-grade prostate cancer consumed 485g rye whole grain and bran products (RP) per day or refined wheat products with added cellulose (WP) in a randomized crossover design. Fasting blood samples were taken before and after 2, 4, and 6 weeks of treatment. Concentrations of tumor nuclear factor-receptor 2 (TNF-R2), e-selectin, and endostatin were significantly lower after consumption of the RP diet compared with WP (p<0.05). Cathepsin S concentration was positively correlated to TNF-R2 and endostatin concentrations across all occasions. Strong correlations were consistently found between intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and between interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1RA). No effect of intervention was found in 92 inflammation-related protein biomarkers measured in a proximity extension assay. RP diet lowered TNF-R2, e-selectin, and endostatin, compared with WP in men with prostate cancer. These effects were accompanied by a reduction in PSA.

Consumption of animal-based and processed food associated with cardiovascular risk factors and subclinical atherosclerosis biomarkers in men.

To evaluate the frequency of food consumption in apparently healthy men and their association with cardiovascular risk factors and biomarkers of subclinical atherosclerosis. In this observational study, 88 men had their food standard obtained through the food frequency questionnaire (FFQ). Associations of dietary patterns with cardiovascular risk factors, such as anthropometric data, laboratory and clinical evaluations, carotid-femoral arterial stiffness (IMT) and pulse wave velocity were evaluated. The highest values were observed, for most of the risk factors evaluated, with the highest frequency of weekly consumption of dairy products, meats, sweets, fats, cold meats, sodas, milk and white chocolate; and lower frequency of weekly consumption of fruits, cereals, vegetables, legumes, oilseeds, and soy. There was no significant difference for coffee and dark chocolate. A diet with high consumption of animal products has a higher correlation with cardiovascular risk factors; the opposite is true for the consumption of plant-based food, associated with the profile of more favorable biomarkers for cardiovascular health and better biochemical and structural parameters.

A Novel Tomato-Soy Juice Induces a Dose-Response Increase in Urinary and Plasma Phytochemical Biomarkers in Men with Prostate Cancer

Tomato and soy intake is associated with reduced prostate cancer risk or severity in epidemiologic and experimental studies. On the basis of the principle that multiple bioactives in tomato and soy may act on diverse anticancer pathways, we developed and characterized a tomato-soy juice for clinical trials. In this phase 2 dose-escalating study, we examined plasma, prostate, and urine biomarkers of carotenoid and isoflavone exposure. Men scheduled for prostatectomy were recruited to consume 0, 1, or 2 cans of tomato-soy juice/d before surgery (mean±SD duration: 24±4.6 d). The juice provided 20.6 mg lycopene and 66 mg isoflavone aglycone equivalents/177-mL can. Plasma carotenoids and urinary isoflavone metabolites were quantified by HPLC-photometric diode array and prostate carotenoids and isoflavones by HPLC-tandem mass spectrometry. We documented significant dose-response increases (P<0.05) in plasma concentrations of tomato carotenoids. Plasma concentrations were 1.86-, 1.69-, 1.73-, and 1.69-fold higher for lycopene, β-carotene, phytoene, and phytofluene, respectively, for the 1-can/d group and 2.34-, 3.43-, 2.54-, and 2.29-fold higher, respectively, for the 2-cans/d group compared with 0 cans/d. Urinary isoflavones daidzein, genistein, and glycitein increased in a dose-dependent manner. Prostate carotenoid and isoflavone concentrations were not dose-dependent in this short intervention; yet, correlations between plasma carotenoid and urinary isoflavones with respective prostate concentrations were documented (R2=0.78 for lycopene, P<0.001; R2=0.59 for dihydrodaidzein, P<0.001). Secondary clustering analyses showed urinary isoflavone metabolite phenotypes. To our knowledge, this is the first demonstration of the phytoene and phytofluene in prostate tissue after a dietary intervention. Secondary analysis showed that the 2-cans/d group experienced a nonsignificant decrease in prostate-specific antigen slope compared with 0 cans/d (P=0.078). These findings provide the foundation for evaluating a well-characterized tomato-soy juice in human clinical trials to define the impact on human prostate carcinogenesis. This trial is registered at clinicaltrials.gov as NCT01009736.

In This Issue

HomeCirculation ResearchVol. 123, No. 9In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published11 Oct 2018https://doi.org/10.1161/RES.0000000000000232Circulation Research. 2018;123:1009is related toLactobacillus plantarum 299v Supplementation Improves Vascular Endothelial Function and Reduces Inflammatory Biomarkers in Men With Stable Coronary Artery DiseaseRestoring Endothelial Function by Targeting Desert Hedgehog Downstream of Klf2 Improves Critical Limb Ischemia in Adultsis related toMidbody Positioning and Distance Between Daughter Nuclei Enable Unequivocal Identification of Cardiomyocyte Cell Division in MiceUnequivocal Identification of Cardiomyocyte Division (p 1039)Download figureDownload PowerPointHesse et al devise a new method for assessing cardiomyocyte proliferation.A myocardial infarction can lead to the death and destruction of a significant number of heart cells that, due to the limited regenerative capacity of the heart, do not regrow. Scientists are, therefore, vigorously searching for pharmacological agents that can induce the proliferation of cardiomyocytes and regrowth of the myocardium. The gold-standard marker of cell proliferation in vitro is Aurora B-kinase, but Hesse and colleagues argue that this poses a problem in the case of cardiac myocytes, many of which are binucleated. Indeed, Aurora B-kinase-based assays do not differentiate between binucleation and true cell division, the researchers show. The team, therefore, proposes an alternative marker—the positioning of the midbody and the distance between daughter nuclei. Using time-lapse microscopy to image cells from mice expressing fluorescently labeled anillin (a midbody protein), they observed that while true division resulted in symmetrical positioning of the midbody between daughter nuclei, binucleation was marked by randomly located and fragmented midbodies. Furthermore, in binucleation, but not true division, the daughter nuclei remained close together, almost touching. The authors suggest adopting this new strategy could provide a more accurate indication of real proliferation.Dhh Agonists Ameliorate Endothelial Function (p 1053)Download figureDownload PowerPointA Dhh agonist improves vascular function in mice with critical limb ischemia, report Caradu et al.Dysfunction of the vascular endothelium, which can result in leaky, inflamed blood vessels, is often associated with hypertension, diabetes, obesity, and advanced age. Although the pathways leading to endothelial dysfunction are largely unknown, it has been shown that the transcription factor Klf2, essential for endothelial health, is down-regulated in the context of vascular inflammation, high glucose, and disturbed blood flow. And recently, it was shown that morphogen Dhh is suppressed under similar conditions. Intrigued by this apparent coregulation, Caradu and colleagues tested whether Klf2 and Dhh might work in the same pathway. Indeed, they found that Klf2 directly activates the Dhh promoter. Moreover, knock-down of Dhh produced effects similar to those of Klf2 suppression—namely vessel leakiness and increased expression of proinflammatory factors. The team also found that critical limb ischemia is associated with capillary leakage and inflammation in both human patients and mice, and that treatment of the animals with a Dhh agonist could improve endothelial function. Together, the results imply that boosting the Klf2-Dhh pathway might be an effective approach for treating ischemic vascular disease.L Plantarum 299v and Endothelial Function (p 1091)Download figureDownload PowerPointProbiotic treatment improves vascular health in patients with coronary artery disease, report Malik et al.Atherosclerosis and plaque instability have been found to be associated with differences in the microbial composition of the human gut—both in terms of specific species and their diversity. Furthermore, in mice, fecal transfers, antibiotics, and high-fiber diets—all of which can alter the gut microbiome—have been shown to influence vascular health, systemic inflammation, and atherogenesis. Despite this evidence, it is unclear whether treatments that target the microbiome improve human vascular health. To find out, Malik et al gave Lactobacillus plantarum 299v (Lp299v)—a gut microbe shown to have positive cardiovascular effects in animals and human smokers—to 20 men with coronary artery disease. They found that daily treatments for 6 weeks reduced the levels of proinflammatory cytokines in the blood and improved vasodilation in the brachial arteries. Additionally, plasma taken from the subjects after treatment was shown to improve acetylcholine-induced dilation in CAD patient arterioles in tissue culture. The findings suggest that probiotic supplementation might be an additional tool for reducing cardiovascular disease risk, and open the door for further large-scale probiotic trials. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesLactobacillus plantarum 299v Supplementation Improves Vascular Endothelial Function and Reduces Inflammatory Biomarkers in Men With Stable Coronary Artery DiseaseMobin Malik, et al. Circulation Research. 2018;123:1091-1102Midbody Positioning and Distance Between Daughter Nuclei Enable Unequivocal Identification of Cardiomyocyte Cell Division in MiceMichael Hesse, et al. Circulation Research. 2018;123:1039-1052Restoring Endothelial Function by Targeting Desert Hedgehog Downstream of Klf2 Improves Critical Limb Ischemia in AdultsCaroline Caradu, et al. Circulation Research. 2018;123:1053-1065 October 12, 2018Vol 123, Issue 9 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000232PMID: 30355170 Originally publishedOctober 11, 2018 PDF download Advertisement

Abstract A072: Serum sex steroids as prognostic biomarkers in patients receiving androgen-deprivation therapy for recurrent prostate cancer post-radiotherapy: A post hoc analysis of the PR.7 trial

Abstract Background and Objective: Nadir testosterone values following initiation of androgen deprivation therapy have been shown in several studies to be prognostic for outcome, including time to castration-resistant prostate cancer (TTCRPC) and cancer specific survival (CSS). The biologic reasons for this remain unclear. Using cryopreserved serum from the PR.7 trial of intermittent vs. continuous androgen deprivation therapy(ADT), we determined to assess the role of related sex steroids as prognostic biomarkers in men on androgen deprivation therapy for recurrent cancer post-radiotherapy. Patients and Methods: Canadian patients in the PR.7 trial randomized to the continuous arm were included. Patients were excluded who did not receive ADT(n=3), had &amp;lt;2 years of follow-up (n=2), received exogenous estrogens or glucocorticoids(n=5), or samples were unavailable(n=36). LC-MS/MS was performed using a validated method to simultaneously analyze ten steroids: dehydroepiandrosterone (DHEA), testosterone (T), dihydrotestosterone (DHT), androst-5-ene-β,17β-diol (5-diol), androstenedione (4-dione), androsterone (AD), estrone (E1), estradiol (E2), progesterone, and androstane-3β,17β-diol (3βdiol). Descriptive statistics and correlation analyses were performed, with longitudinal changes categorized as stable, increasing, decreasing, or mixed. The prognostic value of individual steroid tertiles as well as E1:E2, E2:T, and DHT:T ratios were assessed by Kaplan-Meier analysis and Cox proportional hazards adjusted for baseline clinical variables. Outcomes assessed were TTCRPC, CSS, and overall survival (OS). Results: A total of 219 patients were included in the analysis who had a cryopreserved serum available within 2 years of randomization, with 104 patients having 2 subsequent annual samples available for measurement. Values for DHT, T, 4-dione, AD, DHEA, and 5-diol tended to be correlated among samples. Lower DHEA and AD values were significant associated with older age as was lower DHEA and DHT values with poorer performance status. Higher tertiles of E1 and E2 were associated with sooner TTCRP (log-rank, p=0.03, p=0.02, respectively). Similar trends were seen for 4-dione in predicting TTCRPC (log-rank, p=0.07). Upon adjustment, the highest tertile of E2:T had increased hazard ratios (HR) for CSS (HR=2.36, 95% CI I: 0.90-6.21; p=0.08) and TTCRPC (HR=1.70, 95% CI: 0.90-3.23; p=0.10) relative to the lowest tertile. In an analysis of the subset of patients with longitudinal values, increasing levels of AD over time were associated with poorer CSS and OS (log-rank: p=0.04 and p &amp;lt;0.01, respectively). On adjusted analysis, increasing AD levels had a HR for CSS of 3.43 (95% CI: 0.63-18.67; p=0.15) and a HR for OS of 4.75 (95% CI: 1.49-15.17; p &amp;lt;0.01). Limitations include the number of events for some groups. Conclusions: Increased levels of E1, E2, and AD during ADT correlated with adverse TTCRPC and CSS. Serum sex steroids, including both androgens and estrogens, may act as prognostic biomarkers in men receiving ADT for recurrent prostate cancer. Further investigation is warranted to support clinical use. Citation Format: Paul Toren, Azik Hoffman, Keyue Ding, France-Hélène Joncas, Frédéric Pouliot, Yves Fradet, Éric Lévesque, Chantal Guillemette, Laurence Klotz. Serum sex steroids as prognostic biomarkers in patients receiving androgen-deprivation therapy for recurrent prostate cancer post-radiotherapy: A post hoc analysis of the PR.7 trial [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A072.

Complete Blood Cell Count–Derived Inflammation Biomarkers in Men with Age-Related Macular Degeneration

ABSTRACTPurpose: To investigate the role of some blood count–derived inflammation biomarkers in age-related macular degeneration (AMD).Methods: Seventy-nine men with late-stage AMD and 79 male age-matched cataract controls without AMD were recruited in March–December, 2016. A blood sample was taken. The following blood cell count–derived indexes were evaluated: neutrophil/lymphocyte ratio (NLR), derived NLR [dNLR = neutrophils/(white blood cells ‒ neutrophils)], platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), (neutrophils × monocytes)/lymphocyte ratio (SIRI), and (neutrophils × monocytes × platelets)/lymphocyte ratio (AISI).Results: AMD patients had significantly lower median values of white blood cells, monocytes, neutrophils, platelets, and mean platelet volume (MPV). Regarding the combined indexes, only AISI was significantly lower in AMD patients than in controls. Receiver operating characteristics curve analysis revealed that the ability of AISI and MPV to predict AMD is poor.Conclusion: Results suggests that NLR, dNLR, PLR, MLR, SIRI, and AISI are unreliable disease biomarkers in men with AMD. Larger scale studies are necessary to confirm these findings.

Incorporating Biomarkers into the Primary Prostate Biopsy Setting: A Cost-Effectiveness Analysis

We performed a cost-effectiveness analysis using the PHI (Prostate Health Index), 4Kscore®, SelectMDx™ and the EPI (ExoDx™ Prostate [IntelliScore]) in men with elevated prostate specific antigen to determine the need for biopsy. We developed a decision analytical model in men with elevated prostate specific antigen (3 ng/ml or greater) in which 1 biomarker test was used to determine which hypothetical individuals required biopsy. In the current standard of care strategy all individuals underwent biopsy. Model parameters were derived from a comprehensive review of the literature. Costs were calculated from a health sector perspective and converted into 2017 United States dollars. The cost and QALYs (quality adjusted life-years) of the current standard of care, which was transrectal ultrasound guided biopsy, was $3,863 and 18.085, respectively. Applying any of the 3 biomarkers improved quality adjusted survival compared to the current standard of care. The cost of SelectMDx, the PHI and the EPI was lower than performing prostate biopsy in all patients. However, the PHI was more costly and less effective than the SelectMDx strategy. The EPI provided the highest QALY with an incremental cost-effectiveness ratio of $58,404 per QALY. The use of biomarkers could reduce the number of unnecessary biopsies by 24% to 34% compared to the current standard of care. Applying biomarkers in men with elevated prostate specific antigen to determine the need for biopsy improved quality adjusted survival by decreasing the number of biopsies performed and the treatment of indolent disease. Using SelectMDx or the EPI following elevated prostate specific antigen but before proceeding to biopsy is a cost-effective strategy in this setting.

Impact of Di-2-Ethylhexyl Phthalate Metabolites on Male Reproductive Function: a Systematic Review of Human Evidence

The purpose of this review is to systematically review the literature linking di-2-ethylhexyl phthalate (DEHP) exposure with effects on reproductive health in adult males. Thirty-three papers were included of which 28 were cross-sectional. Twenty-one papers investigated semen samples, 18 investigated reproductive hormones, and three studies investigated time to pregnancy. Studies revealed some but inconsistent indications that higher urinary DEHP metabolite levels are associated with an increase in the proportion of spermatozoa with damaged DNA and to a decrease in sperm concentration and motility. A negative association between DEHP metabolites and testosterone levels was more consistent. DEHP metabolites do not seem to be associated with a delay in time to pregnancy, but data are sparse. The studies on DEHP exposure and reproductive biomarkers in men converge to support the hypothesis that DEHP exposure is related to impaired male reproductive function. Longitudinal studies are needed to establish if the observed associations are causal.

Identification and characterization of circulating tumor cells in post prostatectomy patients with localized high risk prostate cancer.

69 Background: Over 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features that raise the recurrence risk. Better biomarkers could allow for even earlier detection of biochemical recurrence (BCR) and inform adjuvant treatment decisions. Circulating tumor cells (CTCs) may represent the earliest form of metastases, however their role as biomarkers in men with localized PCa is not well defined. Here, we aim to enumerate and molecularly and genomically analyze CTCs using an enrichment-free, unbiased CTC identification technology from men with high-risk, localized PCa after radical prostatectomy (RP) and correlate the analysis with clinical outcomes. Methods: Blood samples from 37 patients with high-risk, localized PCa were obtained 2-5 mos post RP and shipped to Epic. All nucleated cells were subjected to immunofluorescent staining for cytokeratin (CK), CD45, and AR. CTCs were identified using algorithmic analysis. CK+ CTCs were enumerated and subsequently analyzed for AR expression and individually sequenced for copy number alterations (CNA). Patients were followed for BCR, defined as detectable PSA &gt; 0.2ng/dL. Progression free survival (PFS) was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 81.1%(30/37) of patients with an average of 5.2 CTCs/ml (range: 0 – 22.9) detected per patient. AR expression was detected in 18.9% (7/37) of patients. Ninety nine CTCs from 14 patients were picked and sequenced. CNAs were identified in CTCs in commonly mutated genes in PCa, including MYC amplification and CHD1 deletions. Patients with higher traditional CTC (CK+) burdens exhibited a trend towards shorter PFS (hazard ratio: 1.65; 95% confidence interval: 0.7-3.86; p = 0.13). Conclusions: There was a high incidence of CTC detection after RP in patients with high-risk, localized PCa. A trend toward shorter PFS was seen in those with higher CTC burden. Genomic alterations were detectable in CTCs and consistent with established CNAs in PCa. With further testing in appropriately powered cohorts early CTC detection after primary therapy could represent an informative biomarker to stratify patients with high risk PCa.

Prospective randomized trial of genomic classifier impact on treatment decisions in patients at high risk of recurrence following radical prostatectomy (G-MINOR).

TPS154 Background: Approximately 30% of patients will have ≥pT3 disease and/or positive surgical margins at radical prostatectomy (RP), indicating a high risk of local recurrence. While current guidelines recommend consideration of adjuvant radiotherapy (aRT) in this setting, &lt; 10% undergo aRT. The Decipher assay is a novel, tissue-based genomic classifier (GC) developed and validated in the post-RP setting as a predictor of metastasis. Current retrospective evidence suggests that patients with a high GC score may benefit from aRT, while observation may be safe for those with a lower GC score. However, there are no randomized prospective data evaluating the clinical utility of biomarkers in men with adverse features after RP. Here we see to determine the impact of GC test results on adjuvant treatment decisions for high-risk post-RP patients vs. clinical factors alone. Methods: Genomics in Michigan ImpactiNg Observation or Radiation (G-MINOR) is a 4-year (12-month enrollment, 3-year follow-up) prospective, cluster-crossover, unblinded, study of 350 subjects from twelve Urology practices in the Michigan Urological Surgery Improvement Collaborative (MUSIC). MUSIC is a physician-led quality improvement consortium nearly all academic and community urology practices within the state of Michigan. Each clinical center participating in this trial will be randomly assigned to either a Genomic Classifier (GC)-based strategy or control arm for a period of 3 months. Patients in both arms will receive a predicted risk of recurrence based on a validated clinical nomogram, the CAPRA-S score, enabling a head-to-head comparison of the Decipher assay with a freely-available validated prognostic tool. Random assignments will be generated centrally by a study statistician and provided to centers immediately before commencing enrollment in each 3-month period. Each center will have two GC and two UC enrollment periods, maintaining study-wide balance and blinding of assignments in subsequent periods. Patients will be followed for receipt of adjuvant therapy as well as oncologic (recurrence, metastasis, and death) and patient-reported quality of life. Clinical trial information: NCT02783950.

Presurgical weight loss affects tumour traits and circulating biomarkers in men with prostate cancer

Background:Obesity is associated with aggressive prostate cancer. To explore whether weight loss favourably affects tumour biology and other outcomes, we undertook a presurgical trial among overweight and obese men with prostate cancer.Methods:This single-blinded, two-arm randomised controlled trial explored outcomes of a presurgical weight loss intervention (WLI) that promoted ∼1 kg per week loss via caloric restriction and increased physical activity (PA). Forty overweight/obese men with clinically confirmed prostate cancer were randomised to the WLI presurgery or to a control arm; changes in weight, body composition, quality-of-life, circulating biomarkers, gene expression, and immunohistochemical markers in tumour and benign prostatic tissue were evaluated.Results:The study period averaged 50 days. Mean (s.d.) change scores for the WLI vs control arms were as follows: weight: −4.7 (3.1) kg vs −2.2 (4.4) kg (P=0.0508); caloric intake: −500 (636) vs −159 (600) kcal per day (P=0.0034); PA: +0.9 (3.1) vs +1.7 (4.6) MET-hours per day (NS); vitality: +5.3 (7.l4) vs −1.8 (8.1) (P=0.0491); testosterone: +55.1 (86.0) vs −48.3 (203.7) ng dl−1 (P=0.0418); sex hormone-binding globulin: +14.0 (14.6) vs +1.8 (7.6) nmol l−1 (P=0.0023); and leptin: −2.16 (2.6) vs −0.03 (3.75) (P=0.0355). Follow-up Ki67 was significantly higher in WLI vs control arms; median (interquartile range): 5.0 (2.5,10.0) vs 0.0 (0.0,2.5) (P=0.0061) and several genes were upregulated, for example, CTSL, GSK3B, MED12, and LAMC2.Conclusions:Intentional weight loss shows mixed effects on circulating biomarkers, tumour gene expression, and proliferative markers. More study is needed before recommending weight loss, in particular rapid weight loss, among men with prostate cancer.

24-hour profile of serum sclerostin and its association with bone biomarkers in men.

The osteocyte exerts important effects on bone remodeling, but its rhythmicity and effect on the rhythms of other bone cells are not fully characterized. The purpose of this study was to determine if serum sclerostin displays rhythmicity over a 24-h interval, similar to that of other bone biomarkers. Serum sclerostin, FGF-23, CTX, and P1NP were measured every 2h over a 24-h interval in ten healthy men aged 20-65years. Maximum likelihood estimates of the parameters in a repeated measures model were used to determine if these biomarkers displayed a diurnal, sinusoidal rhythm. No discernible 24-h rhythm was identified for sclerostin (p=0.99) or P1NP (p=0.65). CTX rhythmicity was confirmed (p<0.001), peaking at 05:30 (range 01:30-07:30). FGF-23 levels were also rhythmic (p<0.001), but time of peak was variable (range 02:30-11:30). The only significant association identified between these four bone biomarkers was for CTX and P1NP mean 24-h metabolite levels (r=0.65, p=0.04). Sclerostin levels do not appear to be rhythmic in men. This suggests that in contrast to CTX, serum sclerostin could be measured at any time of day. The 24-h profiles of FGF-23 suggest that a component of osteocyte function is rhythmic, but its timing is variable. Our results do not support the hypothesis that osteocytes direct the rhythmicity of other bone turnover markers (CTX), at least not via a sclerostin-mediated mechanism.

Serum Biomarkers of Erectile Dysfunction in Diabetes Mellitus: A Systematic Review of Current Literature

Erectile dysfunction (ED) is a common complication in patients with diabetes mellitus (DM). However, the utility of serum biomarkers as clinical surrogates for the development and/or progression of ED is unknown. To summarize the current literature for serum biomarkers for ED in DM and emphasize areas for future research. Human subject data demonstrating the utility of serum markers for the development and progression of ED in patients with DM. We performed a systematic PubMed-Medline search in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement using Medical Subject Headings (MeSH) for articles published from January 1, 2000 through December 31, 2016 of serum biomarkers for development or progression of ED in patients with DM using erectile dysfunction [MeSH] AND (biomarkers [MeSH] or inflammation mediators [MeSH] or intercellular signaling peptides and proteins [MeSH] or cell adhesion molecules [MeSH]). A thorough review of these studies was completed. Of the 327 abstracts screened, 12 full-text studies were assessed and 1 study was excluded. Eleven studies assessing serum biomarkers for ED in patients with DM were included in this review. The most studied serum biomarkers for ED in men with DM included endothelial dysfunction markers such as serum E-selectin, endothelial progenitor cells, and endothelial microparticles and specific markers of inflammation such as interleukin-10, ratio of tumor necrosis factor-α to interleukin-10, and reactive oxygen species such as nitric oxide and malondialdehyde. Reliable serum biomarkers will enable earlier diagnosis and objective monitoring of disease progression and responses to treatment in patients with ED. Serum biomarkers for ED in men with DM are very limited. Future longitudinal studies with uniform patient characteristics are needed to evaluate the potential clinical use of serum biomarkers in men with DM for the development and progression of ED. Patel DP, Craig JR, Myers JB, etal. Serum Biomarkers of Erectile Dysfunction in Diabetes Mellitus: A Systematic Review of Current Literature. Sex Med Rev 2017:5:339-348.

Comparing diets for weight loss and improvement in biomarkers in men with prostate cancer on surveillance: A pilot study.

159 Background: Weight loss is recommended for treatment of prostate cancer, yet the most efficacious diet is not clear. The diet should improve biomarkers for prostate cancer, not increase risk of other chronic diseases, and be acceptable for long term use. Ascertaining appropriate dietary treatment for men on surveillance is crucial in preventing future cardiovascular disease, which is the leading cause of death in these men. Methods: Men with prostate cancer on surveillance and/or with untreated biochemical relapse followed 2 diets for 8 weeks of weight loss with random assignment to the order: (1) the diet recommended by the Prostate Cancer Foundation (PCF); (2) a plant-based, olive oil diet (PBOO), which included 3 tablespoons of extra virgin olive oil/ daily. After completing both diets, participants selected one of the diets for 6 months of follow-up (FU). Results: 30 started the protocol; 12 dropped out, 11 due to diet compliance (n = 3 PBOO; n = 8 PCF); 18 completed the 8 weeks of both diets and are reported here. Mean age: 66.6 + 5.9; baseline BMI: 30.9 + 2.7 kg/m2. Thirteen of the 18 have chosen the PBOO for FU. Conclusions: These results suggest a benefit with the PBOO diet in lowering insulin and glucose, and improving insulin function compared to the PCF diet. Despite similar weight loss, energy intake was higher on the PBOO diet. In addition, the PBOO diet was preferred over the PCF diet for long-term use. [Table: see text]

Prospective Validation of Diagnostic Tumor Biomarkers in Men Treated With Radiotherapy for Prostate Cancer.

In prior retrospective studies, we assessed a number of prostate tumor tissue biomarkers that were associated independently with the clinical outcome of men treated with radiotherapy (RT) ± androgen deprivation therapy (ADT). In this report, the associations of selected biomarkers with biochemical or clinical disease failure (BCDF) were prospectively evaluated in men with T1-T3 prostate cancer on a randomized hypofractionation trial. Biomarkers were analyzed in 263 of 303 men randomly assigned to standard vs moderate hypofractionation. Median follow-up was 65.9 months. Archival tissue was analyzed for Ki-67 (n = 231), MDM2 (n = 209), p16 (n = 195), Cox-2 (n = 126), p53 (n = 206), bcl2 (n = 223), bax (n = 210), and PKA (n = 160). The base model for multivariable Fine-Gray regression analysis included treatment assignment and risk groups. All statistical tests were two-sided. Each biomarker was tested one at a time relative to the base model and selected for inclusion in multivariable analysis. Ki-67 (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.19 to 4.48, P = .01) and bcl2&bax (HR = 2.19, 95% CI = 1.08 to 4.46, P = .03) were statistically significantly related to higher BCDF and were independently statistically significant when considered jointly (Ki-67: HR = 2.26, 95% CI = 1.12 to 4.58, P = .02; bcl2&bax: HR = 2.14, 95% CI = 1.03 to 4.41, P = .04). At 2.5 years postradiotherapy, the C-index of Ki-67 was 73.2%, while for the base model was only 46.2%; Ki-67 was the most statistically significant when tested without bcl2&bax. In this prospective multiple biomarker analysis in men with prostate cancer treated with RT±ADT, both Ki-67 and bcl2&bax were independently related to early BCDF; however, Ki-67 alone is indicated to be the most clinically meaningful by C-index analysis and is universally available.

Branched Chain RNA In Situ Hybridization for Androgen Receptor Splice Variant AR-V7 as a Prognostic Biomarker for Metastatic Castration-Sensitive Prostate Cancer.

The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR-targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues. We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status. We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n = 12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n = 30; Gleason 4 + 5 = 9 in the AR-V7-positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pretreatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naïve metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (log-rank P = 0.044) and a trend toward superior progression-free survival (log-rank P = 0.055). Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts. Clin Cancer Res; 23(2); 363-9. ©2016 AACR.

Abstract 4947: Branched chain RNA in situ hybridization for the detection of androgen receptor splice variants within archival prostate cancer tissue

Abstract Introduction: Androgen receptor (AR) mRNA splice variants have emerged as predictive biomarkers for response to AR targeted therapies. There are no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues. In this pilot study, we developed an RNA ISH assay to detect the constitutively active AR-V7 splice variant, and we correlated AR-V7 expression with clinical outcomes after first-line androgen deprivation therapy (ADT) for metastatic prostate cancer. Methods: We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes (Affymetrix). Automated ISH assays were performed using ViewRNA eZl Detection Kit on the BOND RX IHC and ISH Staining System. A semiquantitative scoring method was used to score the RNA ISH signal in FFPE tissue. We analyzed AR-V7 and full length AR within two prostate cancer cohorts that we hypothesized to represent “low likelihood” and “high likelihood” to have detectable AR-V7. “Low likelihood” men had undergone prostatectomy for Gleason 6 adenocarcinoma, and “high likelihood” men had metastatic castration resistant prostate cancer with tumor tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide). We then analyzed two additional cohorts who experienced a “sustained response” (&amp;gt;2.5 years; n = 13) or “brief response” (&amp;lt;9 months; n = 9) to first-line ADT for metastatic prostate cancer and for whom baseline tumor tissue was available. Results: “High likelihood” cohort samples had detectable AR-V7 with a score of 1+ to 3+ in all samples (n = 12). “Low likelihood” cohort samples had no detectable AR-V7 (n = 10). Given the apparent binary distinction of AR-V7 signal among the above groups, we analyzed pre-treatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naive metastatic disease. Detectable AR-V7 was more common among “brief response” samples (6 of 9) than among “sustained response” samples (4 of 13) (not significant; P = 0.19). Patients without detectable AR-V7 RNA had significantly longer overall survival (OS, logrank P = 0.044), with a non-significant trend toward superior progression-free survival (PFS, logrank P = 0.055). Conclusions: Within an institutional cohort, the RNA ISH assay identified AR-V7 in all tested samples of high clinical likelihood for the splice variant RNA and no tested samples of low clinical likelihood. AR-V7 RNA was detectable in some pretreatment samples, and its presence was associated with significantly shorter overall survival. The potential prognostic and predictive utility of AR-V7 status as determined by RNA ISH from conventionally prepared FFPE tissue warrants further study in larger cohorts. Citation Format: Philip J. Saylor, Richard J. Lee, Kshitij S. Arora, David T. Ting, Vikram Deshpande, Miguel N. Rivera, Rong Hu, Chin-Lee Wu, David T. Miyamoto. Branched chain RNA in situ hybridization for the detection of androgen receptor splice variants within archival prostate cancer tissue. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4947.

What can we learn from critical periods of weight gain in military personnel?

What can we learn from critical periods of weight gain in military personnel?