Biomarkers In Men Research Articles

Impact of Serum γ-Glutamyltransferase on Overall Survival in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Docetaxel.

Simple Summaryγ-Glutamyltransferase (GGT) is a biomarker of oxidative stress and its elevation in the serum is linked to poor survival in various malignancies; however, reports on metastatic castration-resistant prostate cancer (mCRPC) are scarce. Moreover, the source of serum GGT in men with mCRPC is largely unknown. The aims of this study were to determine the impact of serum GGT on overall survival in men with mCRPC receiving docetaxel therapy, and to examine the association between systemic and local GGT levels using immunohistochemistry. Of note, high serum GGT was associated with adverse overall survival as were low hemoglobin and high prostate-specific antigen levels. Additionally, tissue GGT expression status in prostate specimens was moderately positively associated with serum GGT. We demonstrated that pre-therapeutic serum GGT was an independent prognosticator in men with mCRPC receiving docetaxel therapy, and that overexpression of GGT in cancer cells might be responsible for the elevation of serum GGT.Background: Reports on the prognostic significance of serum γ-glutamyltransferase (GGT) in men with metastatic castration-resistant prostate cancer (mCRPC) are limited. In addition, GGT expression status in cancer tissues has not been well characterized regardless of cancer types. Methods: This retrospective study included 107 consecutive men with mCRPC receiving docetaxel therapy. The primary endpoints were associations of serum GGT with overall survival (OS) and prostate-specific antigen (PSA) response. The secondary endpoint was an association of serum GGT with progression-free survival (PFS). Additionally, GGT expression status was immunohistochemically semi-quantified using tissue microarrays. Results: A total of 67 (63%) men died during follow-up periods (median 22.5 months for survivors). On multivariable analysis, high Log GGT was independently associated with adverse OS (HR 1.49, p = 0.006) as were low hemoglobin (HR 0.79, p = 0.002) and high PSA (HR 1.40, p < 0.001). In contrast, serum GGT was not significantly associated with PSA response or PFS. Moreover, incorporation of serum GGT into established prognostic models (i.e., Halabi and Smaletz models) increased their C-indices for predicting OS from 0.772 to 0.787 (p = 0.066) and from 0.777 to 0.785 (p = 0.118), respectively. Furthermore, there was a positive correlation between serum and tissue GGT levels (ρ = 0.53, p = 0.003). Conclusions: Serum GGT may be a prognostic biomarker in men with mCRPC receiving docetaxel therapy. GGT overexpression by prostate cancer cells appears to be responsible for the elevation of GGT in the serum.

Effects of 12 Months Consumption of 100 g Dried Plum (Prunes) on Bone Biomarkers, Density, and Strength in Men.

Several male animal studies have demonstrated bone-protective effects of dried plum; however, no human male study has evaluated the effect of dried plum on bone health. We conducted a randomized controlled clinical study to test if daily inclusion of 100 g of dried plum in the diet positively influenced bone mineral density (BMD), bone strength, and bone biomarkers in men. Sixty-six men were randomly assigned to one of two daily treatment groups: (1) control (0 g dried plum) or (2) 100 g dried plum. Blood samples were collected at baseline and after 3, 6, and 12 months to assess bone biomarkers. Bone was measured at baseline and after 6 and 12 months via dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Tartrate-resistant acid phosphatase-5b (TRAP5b) and C-terminal collagen cross-link (CTX) levels decreased significantly in the dried plum group at 3-, 6-, and 12-month intervals compared with baseline. No changes were observed in the control group for TRAP5b and CTX levels. Bone-specific alkaline phosphatase levels decreased significantly after 6 and 12 months in the control and dried plum groups. BMD for total body, spine (L1-L4), hip, and ulna did not change in the control and dried plum groups from baseline to 6 or 12 months. In the proximal tibia, endosteal circumferences increased significantly within the dried plum group during the course of treatment. The results suggest that daily consumption of 100 g dried plum for 12 months has modest bone-protective effects in men. ClinicalTrials.gov identifier: NCT04720833.

Classic and Novel Sex Hormone Binding Globulin Effects on the Cardiovascular System in Men.

In men, 70% of circulating testosterone binds with high affinity to plasma sex hormone binding globulin (SHBG), which determines its bioavailability in their target cells. In recent years, a growing body of evidence has shown that circulating SHBG not only is a passive carrier for steroid hormones but also actively regulates testosterone signaling through putative plasma membrane receptors and by local expression of androgen-binding proteins apparently to reach local elevated testosterone concentrations in specific androgen target tissues. Circulating SHBG levels are influenced by metabolic and hormonal factors, and they are reduced in obesity and insulin resistance, suggesting that SHBG may have a broader clinical utility in assessing the risk for cardiovascular diseases. Importantly, plasma SHBG levels are strongly correlated with testosterone concentrations, and in men, low testosterone levels are associated with an adverse cardiometabolic profile. Although obesity and insulin resistance are associated with an increased incidence of cardiovascular disease, whether they lead to abnormal expression of circulating SHBG or its interaction with androgen signaling remains to be elucidated. SHBG is produced mainly in the liver, but it can also be expressed in several tissues including the brain, fat tissue, and myocardium. Expression of SHBG is controlled by peroxisome proliferator-activated receptor γ (PPARγ) and AMP-activated protein kinase (AMPK). AMPK/PPAR interaction is critical to regulate hepatocyte nuclear factor-4 (HNF4), a prerequisite for SHBG upregulation. In cardiomyocytes, testosterone activates AMPK and PPARs. Therefore, the description of local expression of cardiac SHBG and its circulating levels may shed new light to explain physiological and adverse cardiometabolic roles of androgens in different tissues. According to emerging clinical evidence, here, we will discuss the potential mechanisms with cardioprotective effects and SHBG levels to be used as an early metabolic and cardiovascular biomarker in men.

Network of biomarkers and their mediation effects on the associations between regular exercise and the incidence of cardiovascular & metabolic diseases

This study aimed to understand the biological process related to the prevention of cardiovascular & metabolic diseases (CMD), including diabetes, hypertension, and dyslipidemia via regular exercise. This study included 17,053 subjects aged 40–69 years in the Health Examinees Study from 2004 to 2012. Participation in regular exercise was investigated by questionnaires. Data on 42 biomarkers were collected from anthropometric measures and laboratory tests. We examined the associations between regular exercise and biomarkers using general linear models, between biomarkers and the risk of CMD using cox proportional hazard models, and the mediation effect of biomarkers using mediation analyses. Biomarker networks were constructed based on the significant differential correlations (p < 0.05) between the exercise and non-exercise groups in men and women, respectively. We observed significant mediators in 14 and 16 of the biomarkers in men and women, respectively. Triglyceride level was a noteworthy mediator in decreasing the risk of CMD with exercise, explaining 23.79% in men and 58.20% in women. The biomarker network showed comprehensive relationships and associations among exercise, biomarkers, and CMD. Body composition-related biomarkers were likely to play major roles in men, while obesity-related biomarkers seemed to be key factors in women.

Parkinson mice show functional and molecular changes in the gut long before motoric disease onset

BackgroundThere is increasing evidence that Parkinson’s disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use a transgenic A30P-α-synuclein-overexpressing PD mouse model to identify appropriate candidate markers in the gut before hallmark symptoms begin to manifest.MethodsBased on a gait analysis and striatal dopamine levels, we defined 2-month-old A30P mice as pre-symptomatic (psA30P), since they are not showing any motoric impairments of the skeletal neuromuscular system and no reduced dopamine levels, but an intestinal α-synuclein pathology. Mice at this particular age were further used to analyze functional and molecular alterations in both, the gastrointestinal tract and the ENS, to identify early pathological changes. We examined the gastrointestinal motility, the molecular composition of the ENS, as well as the expression of regulating miRNAs. Moreover, we applied A30P-α-synuclein challenges in vitro to simulate PD in the ENS.ResultsA retarded gut motility and early molecular dysregulations were found in the myenteric plexus of psA30P mice. We found that i.e. neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are significantly altered in the psA30P, thus representing potential biomarkers for early PD. Many of the dysregulated miRNAs found in the psA30P mice are reported to be changed in PD patients as well, either in blood, cerebrospinal fluid or brain tissue. Interestingly, the in vitro approaches delivered similar changes in the ENS cultures as seen in the transgenic animals, thus confirming the data from the mouse model.ConclusionsThese findings provide an interesting and novel approach for the identification of appropriate biomarkers in men.

Zinc-Biofortified Wheat Intake and Zinc Status Biomarkers in Men: Randomized Controlled Trial

Zinc-Biofortified Wheat Intake and Zinc Status Biomarkers in Men: Randomized Controlled Trial

Zinc-Biofortified Wheat Intake and Zinc Status Biomarkers in Men: Randomized Controlled Trial.

Biofortification is a novel method for improving the nutritional value of grains. Wheat is widely consumed worldwide. Thus, wheat zinc biofortification may improve the zinc status of populations. We determined the effect of consuming zinc-biofortified wheat on plasma zinc concentrations and biomarkers of zinc-dependent functions in a controlled feeding study. Thirty-six healthy adult men, aged 18 to 51 y, participated in a 10-wk zinc-controlled feeding trial. After a 2-wk run-in period [metabolic period (MP) 1] (9.3mg zinc/d and 2.1g total phytate/d) to standardize zinc status, the participants consumed bread made from zinc-biofortified wheat (10.9mg zinc/d) with no additional phytate (0.6g/d total phytate) for 6 wk (MP2). During the final 2 wk (MP3), half of the men took a 25-mg zinc supplement daily to determine if the supplement further altered zinc status biomarkers. Repeated-measures linear regression methods were used to compare plasma zinc concentrations, fatty acid desaturase (FADS) activities, glutathione (GSH) concentrations, and DNA strand breaks assessed at enrollment and the end of each metabolic period. Plasma zinc concentrations did not change throughout the study. From the end of MP1 to the end of MP2, the conversion of linoleic acid to γ-linolenic acid (FADS2 activity) increased from 0.020 to 0.025 (P=0.02), and the conversion of dihomo-γ-linolenic acid to arachidonic acid (FADS1 activity) decreased from 6.37 to 5.53 (P=0.01). GSH concentrations and DNA strand breaks did not change. Zinc supplementation (25mg/d) in MP3 did not alter any of the endpoints. In healthy adult men, a 1.6-mg/d increase in dietary zinc from biofortified wheat modified FADS2 and FADS1 activities without changing DNA damage, plasma zinc, or GSH concentrations, demonstrating that FADS activities are more sensitive to small changes in zinc consumed with a meal. This trial was registered at clinicaltrials.gov as NCT03451214.

Low‐Level Light Therapy Downregulates Scalp Inflammatory Biomarkers in Men With Androgenetic Alopecia and Boosts Minoxidil 2% to Bring a Sustainable Hair Regrowth Activity

Background and ObjectivesLow‐level light therapies using visible to infrared light are known to activate several cellular functions, such as adenosine triphosphate and nitric oxide synthesis. However, few clinical observations report its biological consequences for skin and scalp homeostasis. Since scalp inflammation was recognized as a potential physiological obstacle to the efficacy of the reference hair regrowth drug Minoxidil in vivo and since perifollicular inflammation is the hallmark of about 50%–70% follicular units in androgenetic alopecia, we decided to investigate whether the anti‐inflammatory activity of LLLT/GentleWaves® device were assigned to L'Oréal by Light BioScience L.L.C., Virginia Beach, VA (US) could enhance hair regrowth activity of Minoxidil.Study Design/Materials and MethodsWe conducted a first experimental clinical study on 64 men with androgenetic alopecia using LLLT/GentleWaves®, 590‐nm predominant wavelength 70 seconds, specifically pulsed once per day, for 3 days, and we performed a whole‐genome analysis of treated scalp biopsies. In a second clinical study, including 135 alopecic volunteers, we evaluated the hair regrowth activity in response to the upgraded LLLT/GentleWaves® device and Minoxidil.ResultsIn the first clinical study, whole‐genome analysis of treated scalp biopsies showed downregulation of scalp inflammatory biomarkers, such as AP1/FOSB messenger RNA (mRNA) and mir21, together with the disappearance of CD69 mRNA, specific to scalp‐infiltrating T cells of about 50% of the studied volunteers prior to the LLLT/GentleWaves® treatment. In the second clinical study, we observed that LLLT/GentleWaves® was able to boost the hair regrowth activity of a Minoxidil 2% lotion to the extent of the highest concentration (5%) in terms of efficacy, number of responders, and perceived performance.ConclusionsAltogether, these observations suggest the potential benefit of LLLT/GentleWaves® as a noninvasive adjunctive technology for skin and scalp conditions, where a mild perifollicular inflammation is involved. Lasers Surg. Med. 2021. Copyright © 2021 Wiley Periodicals LLC

Development and validation of circulating tumour cell enumeration (Epic Sciences) as a prognostic biomarker in men with metastatic castration-resistant prostate cancer

PurposeTo evaluate the prognostic significance of circulating tumour cell (CTC) number determined on the Epic Sciences platform in men with metastatic castration-resistant prostate cancer (mCRPC) treated with an androgen receptor signalling inhibitor (ARSI). Patients and methodsA pre-treatment blood sample was collected from men with progressing mCRPC starting either abiraterone or enzalutamide as a first-, second- or third-line systemic therapy at Memorial Sloan Kettering Cancer Center (Discovery cohort, N = 171) or as a first- or second-line therapy as part of the multicenter PROPHECY trial (NCT02269982) (Validation cohort, N = 107). The measured CTC number was then associated with overall survival (OS) in the Discovery cohort, and progression-free survival (PFS) and OS in the Validation cohort. CTC enumeration was also performed on a concurrently obtained blood sample using the CellSearch® Circulating Tumor Cell Kit. ResultsIn the MSKCC Discovery cohort, CTC count was a statistically significant prognostic factor of OS as a dichotomous (<3 CTCs/mL versus ≥ 3 CTCs/mL; hazard ratio [HR] = 1.8 [95% confidence interval {CI} 1.3–3.0]) and a continuous variable when adjusting for line of therapy, presence of visceral metastases, prostate-specific antigen, lactate dehydrogenase and alkaline phosphatase. The findings were validated in an independent datas et from PROPHECY (HR [95% CI] = 1.8 [1.1–3.0] for OS and 1.7 [1.1–2.9] for PFS). A strong correlation was also observed between CTC counts determined in matched samples on the CellSearch® and Epic platforms (r = 0.84). ConclusionThe findings validate the prognostic significance of pretreatment CTC number determined on the Epic Sciences platform for predicting OS in men with progressing mCRPC starting an ARSI.

Evaluation of PSA and PSA Density in a Multiparametric Magnetic Resonance Imaging-Directed Diagnostic Pathway for Suspected Prostate Cancer: The INNOVATE Trial.

Simple SummaryAs we start to see the increased, routine, use of multiparametric magnetic resonance imaging (mpMRI) to inform prostate cancer diagnosis and image-guided biopsy, data collected from University College London Hospital describes the expected diagnostic outcomes of PSA and PSA Density in this pathway as well as the potential space remaining for novel biomarkers to further improve the pathway.Objectives: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. Methods: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging–Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. Results: 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. Conclusions: The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing.

Analysis of Blood Pressure, Lipid Profile and Hematological Biomarkers in men Addicted to Tobacco Chewing

Analysis of Blood Pressure, Lipid Profile and Hematological Biomarkers in men Addicted to Tobacco Chewing

Development and validation of circulating tumor cell (Epic Sciences) enumeration as a prognostic biomarker in men with metastatic castration-resistant prostate cancer.

157 Background: We evaluated the prognostic significance of circulating tumor cell (CTC) number as determined on the Epic Sciences platform in men with metastatic castration resistant prostate cancer (mCRPC) treated with an androgen receptor signaling inhibitor (ARSI). Methods: A pre-treatment blood sample was collected from men with progressing mCRPC starting either abiraterone or enzalutamide as a 1st, 2nd or 3rd line systemic therapy at Memorial Sloan Kettering Cancer Center (Discovery cohort, N=175) or as a 1st and 2nd line therapy as part of the multi-center PROPHECY trial (NCT02269982) (Validation cohort, N=107). Enumeration was performed on the Epic Sciences platform and associated with overall survival (OS) in the Discovery cohort, and progression-free survival (PFS) and OS in the Validation cohort. Matched blood samples from the Validation cohort were to CTC counts measured on the CellSearch Circulating Tumor Cell kit. Results: In the MSKCC Discovery cohort, CTC count was a statistically significant prognostic factor of OS as a dichotomous (&lt; 3 CTCs/mL versus ≥ 3 CTCs/mL; HR = 1.8, (1.3-3.0, 95% CI)) and as a continuous variable when adjusting for line of therapy, presence of visceral metastases, PSA, lactate-dehydrogenase, and alkaline-phosphatase. The findings were validated in an independent dataset (PROPHECY trial) - (HR (95% CI) = 1.8, (1.1-3.0) for OS and 1.7 (1.1-2.9), for PFS). A strong correlation was observed between CTC counts determined in matched samples on the CellSearch and Epic platforms (r = 0.84). Conclusions: The findings validate the prognostic significance of pretreatment CTC number determined on the Epic Sciences platform for predicting OS in men with progressing mCRPC starting an ARSI.

Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy

ObjectiveProgressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes. MethodsWe performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences. ResultsMacrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size. ConclusionThis cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.

The Effect of Aerobic Training on Parathyroid Hormone and Alkaline Phosphatase as Bone Markers in Men with Mild to Moderate Asthma

Background and Aim: Inhalation of corticosteroids in patients with asthma is associated with an increased risk of osteoporosis. This study aimed to assess the effect of aerobic training on alkaline phosphatase (ALP), parathyroid hormone (PTH) as bone biomarkers in men with mild to moderate asthma. Methods: Twenty four sedentary middle-aged men with asthma aged 40±5 years were randomly assigned to two groups as exercise (aerobic training, n=12) and control (no training, n =12). Aerobic training was performed 3 days a week for 12 weeks in the form of running on a flat surface at 60-75% of HRmax. Fasting blood samples were taken before and after the training program for measuring serum ALP and PTH. Results: There were no statistically significant differences between groups with regard to anthropometrical and bone markers at baseline (p>0.05). Aerobic training resulted in significant increase in ALP (p = 0.023) and PTH (p = 0.016) in exercise individuals. All variables remained unchanged in the control group (p>0.05). Conclusion: With an emphasis on the increase in ALP and PTH, it is concluded that relatively long-term aerobic exercise is associated with improved bone formation markers in patients with asthma treated with inhaled corticosteroids. *Corresponding Author: Mojtaba Eizadi; Email: izadim@iau-saveh.ac.ir Please cite this article as: Eizadi M, Behboudi L, Afsharmand Z. The Effect of Aerobic Training on Parathyroid Hormone and Alkaline Phosphatase as Bone Markers in Men with Mild to Moderate Asthma. Arch Med Lab Sci. 2020;6:1-9 (e20). https://doi.org/10.22037/amls.v6. 33535

A randomized controlled trial of a home-based exercise program on prognostic biomarkers in men with prostate cancer: A study protocol

BackgroundHerein, we propose a novel RCT study to collect preliminary data on the impact of a 24-week home-based exercise program that can improve prognosis, physical function, and quality of life (QoL) in men with prostate cancer (PCa). This study will provide data on the feasibility of conducting a home-based exercise study and pilot data on the impact of exercise on circulating concentrations of biomarkers reported in the literature to be beneficial for the prognostication of PCa. Methods/designThirty male patients, clinically-diagnosed with prostate cancer under active surveillance, will be recruited to participate in a 2-arm, 24-week home-based program. Random allocation to each arm - intervention, and control – will be performed in a 1:1 ratio. Participants assigned to the intervention group will perform 30 min of light-to-moderate intensity walking five days a week (40–60% heart rate reserve) and three sets of 15 repetitions of light callisthenic exercises (bodyweight squats, incline push-ups, and hip thrusts) 3 days a week. Participants randomized to the control group will maintain normal activity throughout the 24 weeks. Four visits occurring at baseline, 12-, 18-, and 24-weeks will be used to assess QoL, body composition, prognostic biomarker concentrations, and overall physical function. Primary endpoints include significant changes in prognostic biomarkers. Secondary endpoints include changes in quality of life, physical function and body composition. DiscussionThis study should demonstrate preliminary evidence that a home-based exercise intervention can impact biomarkers of progression while improving quality of life, physical function and body composition. Results from this study have the potential to promote health and wellness while minimizing cancer progression in men with PCa.

Prognostic biomarkers in men with metastatic castration-resistant prostate cancer receiving [177Lu]-PSMA-617.

We analysed quantitative biomarkers derived from both baseline whole-body imaging and blood serum to identify prognostic markers in patients treated within the lutetium-177 prostate-specific membrane antigen (LuPSMA) phase 2 trial. PET image analysis was carried out using whole-body segmentation quantifying molecular tumour volume (SUV > 3 threshold for PSMA, SUV > liver+2sd for fluorodeoxyglucose (FDG) including SUVmax and SUVmean. For baseline bone scans, EXINI bone scan index (BSI) was used to calculate the percentage of involved bone. Baseline alkaline phosphatase (ALP), lactate dehydrogenase (LDH), prostate specific antigen (PSA) and PSA doubling time were also used in this analysis. We used univariate cox regression analysis and log-rank comparison with optimised cut-offs to find suitable biomarkers prognostic of overall survival from time of enrolment. This analysis identified FDG-positive tumour volume (FDGvol; HR 2.6; 95% CI, 1.4-4.8), mean intensity of PSMA-avid tumour uptake (PSMAmean; HR 0.89; 95% CI, 0.8-0.98), bone scan index (BSI; HR 2.3; 95% CI, 1.2-4.4), ALP (HR 1.1; 95% CI, 1-1.2) and LDH (HR 1.2; 95% CI, 1-1.5) as biomarkers prognostic of overall survival. In addition to established biomarkers, both FDG and PSMA PET/CT parameters have prognostic significance for survival in men undergoing LuPSMA therapy.

The Effects of 24-Week, High-Concentration Hydrogen-Rich Water on Body Composition, Blood Lipid Profiles and Inflammation Biomarkers in Men and Women with Metabolic Syndrome: A Randomized Controlled Trial.

PurposeMetabolic syndrome is associated with several medical risk factors including dyslipidemia, hyperglycemia, and obesity, which has become a worldwide pandemic. The sequelae of this condition increase the risk of cardiovascular and neurological disease and increased mortality. Its pathophysiology is associated with redox dysregulation, excessive inflammation, and perturbation of cellular homeostasis. Molecular hydrogen (H2) may attenuate oxidative stress, improve cellular function, and reduce chronic inflammation. Pre-clinical and clinical studies have shown promising effects of H2-rich water (HRW) on specific features of metabolic syndrome, yet the effects of long-term, high-concentration HRW in this prevalent condition remain poorly addressed.MethodsWe conducted a randomized, double-blinded, placebo-controlled trial in 60 subjects (30 men and 30 women) with metabolic syndrome. An initial observation period of one week was used to acquire baseline clinical data followed by randomization to either placebo or high-concentration HRW (> 5.5 millimoles of H2 per day) for 24 weeks.ResultsSupplementation with high-concentration HRW significantly reduced blood cholesterol and glucose levels, attenuated serum hemoglobin A1c, and improved biomarkers of inflammation and redox homeostasis as compared to placebo (P < 0.05). Furthermore, H2 tended to promote a mild reduction in body mass index and waist-to-hip ratio.ConclusionOur results give further credence that high-concentration HRW might have promising effects as a therapeutic modality for attenuating risk factors of metabolic syndrome.

Urinary oxidative stress biomarker levels and reproductive outcomes among couples undergoing fertility treatments.

Are urinary levels of oxidative stress biomarkers associated with reproductive outcome success following fertility treatments? Levels of oxidative stress in the middle tertile for women are associated with the highest levels of reproductive success while no associations were noted for men. Oxidative stress may contribute to adverse fertility outcomes in the general population, but findings from couples undergoing fertility treatments are sparse. This prospective cohort study included 481 women and 249 of their male partners undergoing fertility treatments from 2007 to 2015, from the Environment and Reproductive Health (EARTH) study in Boston, MA. One urine sample per participant was collected at each cycle and analysed for two oxidative stress markers: 8-isoprostane-PGF2α (8-iso-PGF2α) and 8-isoprostane-PGF2α metabolite (F2-isoP-M). Reproductive outcomes were abstracted from medical records and included the fertilization rate, for IVF (oocytes fertilized/mature oocytes retrieved), and rates of implantation, clinical pregnancy and live birth, for both IVF and IUI. Cluster-weighted generalized estimating equations were used to analyse adjusted associations between exposure tertiles and outcomes. Levels of F2-isoP-M in the middle tertile were associated with the most success among women. Women in the upper tertile of F2-isoP-M had an adjusted mean live birth rate after IVF and IUI of 23% (95% CI: 17, 29) compared to 38% (95% CI: 31, 45) for women in the middle tertile and 27% (95% CI: 21, 34) in the lower tertile. The fertilization rate during IVF was higher for women with 8-iso-PGF2α in the middle tertile (0.77 [95% CI: 0.73, 0.80]) compared to women in the lower (0.69 [95% CI: 0.64, 0.73]) or upper tertiles (0.66 [95% CI: 0.61, 0.71]). No significant associations were found for other measured outcomes with 8-iso-PGF2α, or between any oxidative stress biomarker in men and reproductive outcomes in their partners. Isoprostanes are short-lived biomarkers and this study may not have captured the most relevant window of susceptibility for oxidative stress on the outcomes of interest. Findings from this study may not be generalizable to couples attempting conception without fertility assistance. This study suggests that a non-linear association may exist between oxidative stress and reproductive outcomes in a population undergoing fertility treatment, a finding not previously identified in the literature. Oxidative stress may represent the mechanism through which environmental chemicals are associated with adverse reproductive outcomes. This research was supported by the Intramural Research Program of the National Institutes of Environmental Health Sciences (NIEHS) (ZIA ES103314) and by NIEHS grants R01ES022955, R01ES009718 and R01ES00002. There are no competing interests to report. N/A.

887P - Urine extracellular vesicle GATA2 mRNA alone and in a multigene test predicts initial prostate biopsy result

BackgroundProstate specific antigen (PSA) detection in blood is widely used to screen for prostate cancer (PCa). However, PSA has limited utility in discriminating high risk tumors (Gleason score≥7) from indolent-low risk tumors, which leads to unnecessary biopsies and highlights the need to identify better biomarkers for the detection of clinically significant PCa. GATA2 is a pioneer transcription factors which expression is increased in high-risk prostate cancer (PCa), but its utility in discriminating for PCa remains untested. MethodsTo determine whether extracellular vesicle (EV) GATA2 mRNA provides clinically relevant information to distinguish PCa, we prospectively analyzed non-digital rectal exam (DRE) urine EV GATA2 mRNA levels from 165 males with suspicion of PCa prior to biopsy and correlated GATA2 levels alone and combined in a multigene (PCA3 and TMPRSS2) EV mRNA assay to biopsy result. ResultsProstate origin of GATA2 mRNA detected in urine EVs was confirmed by observing that GATA2 mRNA levels significantly dropped after prostatectomy (p<0.05) and positively correlated to PCa tissue GATA2 mRNA levels. GATA2 increased in biopsy-positive PCa patients (p<0.0001) and high-grade disease (p<0.01). Multivariable analysis showed that GATA2 is an independent predictive factor of any cancer and high-grade PCa. GATA2 alone and combined in a multigene test with PCA3 and TMPRSS2-ERG (GAPT-E) improved discrimination of any cancer (GAPT-E1) and high-grade cancer (GAPT-E2): standard of care (SOC) area under the curve (AUC) of 0.62 and 0.65, SOC plus GATA2 AUC of 0.68 and 0.69, and SOC plus GAPT-E (1-2) AUC of 0.75 and 0.75, respectively. A GAPT-E1 cut-point of 57 would avoid 25.6% of unnecessary prostate biopsies and 13.7% of total biopsies with NPV 50% and missing 9% of PCa. Limitations include lack of PCa volume and imaging assessment of the cohort. ConclusionsNon-DRE urine EV GATA2 mRNA alone and in combination with other urine EV biomarkers in men with suspicion of PCa provides useful information to distinguish any cancer and high-risk PCa and may reduce the number of biopsies. Legal entity responsible for the studyThe authors. FundingNCI/NIH. DisclosureK. Yadav: Full / Part-time employment: SEMA4. A. Tewari: Research grant / Funding (self): Boston Scientific Corporation, Medtronic, Inc. (10/15/2013); Licensing / Royalties: DNA Based Bicistronic Vectors with Inducible and Constitutive Promoters - ID#: 160608, High Intensity Focus Ultrasound and CPG-Brachyury-siRNA for Treatment of Prostate Cancer - ID# 160403, Patent for a Catheterless Device and Approach, Uretheral Catheter; Leadership role: Global Prostate Cancer Research Foundation, Kalyani Prostate Cancer Institute, Peter Georgescu Foundation Award, Promaxo; Advisory / Consultancy: Roivant, Siemens. W.K. Kelly: Advisory / Consultancy: Sanofi, Foundation Medicine; Travel / Accommodation / Expenses: Janssen Oncology; Honoraria (self): Janssen Oncology, Constellation Pharmaceuticals; Research grant / Funding (institution): Sanofi, Novartis, Janssen Oncology, Bayer, Exelixis, Seattle Genetics, Endocyte. B.E. Leiby: Advisory / Consultancy: Bayer. L. Gomella: Honoraria (self), Advisory / Consultancy: Astellas/Janssen/Mdx Health/Strand; Research grant / Funding (self): FKD; Licensing / Royalties: Jefferson IP. All other authors have declared no conflicts of interest.

Identification and Characterization of Circulating Tumor Cells in Men Who have Undergone Prostatectomy for Clinically Localized, High Risk Prostate Cancer.

Approximately 15% of men with newly diagnosed prostate cancer have high risk features which increase the risk of recurrence and metastasis. Better predictive biomarkers could allow for earlier detection of biochemical recurrence and change surveillance and adjuvant treatment paradigms. Circulating tumor cells are thought to represent the earliest form of metastases. However, their role as biomarkers in men with high risk, localized prostate cancer is not well defined. Two to 5 months after prostatectomy we obtained blood samples from 37 patients with high risk, localized prostate cancer, defined as stage T3a or higher, Gleason score 8 or greater, or prostate specific antigen 20 ng/ml or greater. Circulating tumor cells were enumerated using a commercial platform. Matched tumor and single circulating tumor cell sequencing was performed. Circulating tumor cells were detected in 30 of 37 samples (81.1%) with a median of 2.4 circulating tumor cells per ml (range 0 to 22.9). Patients with detectable circulating tumor cells showed a trend toward shorter recurrence time (p=0.12). All patients with biochemical recurrence had detectable circulating tumor cells. Androgen receptor over expression was detected in 7 of 37 patients (18.9%). Patients with biochemical recurrence had more circulating tumor cell copy number aberrations (p=0.027). Matched tumor tissue and single circulating tumor cell sequencing revealed heterogeneity. We noted a high incidence of circulating tumor cell detection after radical prostatectomy and shorter time to biochemical recurrence in men with a higher circulating tumor cell burden and more circulating tumor cell copy number aberrations. Genomic alterations consistent with established copy number aberrations in prostate cancer were detectable in circulating tumor cells but often discordant with cells analyzed in bulk from primary lesions. With further testing in appropriately powered cohorts early circulating tumor cell detection could be an informative biomarker to assist with adjuvant treatment decisions.