PTEN and ERG expression in MRI-ultrasound guided fusion biopsy correlated with radical prostatectomy findings in men with prostate cancer

Background

Conventional systematic prostate biopsies (SBx) have multiple limitations, and magnetic resonance imaging (MRI)-ultrasound fusion targeting is increasingly applied (fusion biopsies [FBx]). In our previous studies, we have shown that loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) in radical prostatectomy (RP) specimens predicts poor disease-specific survival, and in active surveillance (AS), PTEN loss in SBx predicts an adverse AS outcome, although SBx PTEN status does not correlate well with the corresponding RP status. Here, we have hypothesized that PTEN and erythroblast transformation-specific related gene (ERG) status in FBx correlate better with RP than they would in SBx.

Methods

A total of 106 men, who had undergone FBx and subsequent RP in a single center between June 2015 and May 2017 were included. Fifty-three of the men had concomitant or previous SBx's. All biopsy and RP specimens were collected, and tissue microarrays (TMA) were constructed from RP specimens. Immunohistochemical stainings for PTEN and ERG expression were conducted on biopsies and RP TMAs and results were compared by using Fisher's exact test.

Results

The immunohistochemical predictive power of FBx, determined by the concordance of biopsy PTEN and ERG status with RP, is superior to SBx (77.6% vs 66.7% in PTEN, 92.4% vs 66.6% in ERG). FBx was superior to SBx in correlation with RP Gleason Grade Groups and MRI prostate imaging reporting and data system scores.

Conclusion

FBx grading correlates with RP histology and MRI findings and predicts the biomarker status in the RP specimens more accurately than SBx. A longer follow-up is needed to evaluate if this translates to better prediction of disease outcomes, especially in AS and radiation therapy where prostatectomy specimens are not available for prognostication.

     

Development of a multivariable risk model integrating urinary cell DNA methylation and cell-free RNA data for the detection of significant prostate cancer

Background

Prostate cancer exhibits severe clinical heterogeneity and there is a critical need for clinically implementable tools able to precisely and noninvasively identify patients that can either be safely removed from treatment pathways or those requiring further follow up. Our objectives were to develop a multivariable risk prediction model through the integration of clinical, urine-derived cell-free messenger RNA (cf-RNA) and urine cell DNA methylation data capable of noninvasively detecting significant prostate cancer in biopsy naïve patients.

Methods

Post-digital rectal examination urine samples previously analyzed separately for both cellular methylation and cf-RNA expression within the Movember GAP1 urine biomarker cohort were selected for a fully integrated analysis (n = 207). A robust feature selection framework, based on bootstrap resampling and permutation, was utilized to find the optimal combination of clinical and urinary markers in a random forest model, deemed ExoMeth. Out-of-bag predictions from ExoMeth were used for diagnostic evaluation in men with a clinical suspicion of prostate cancer (PSA ≥ 4 ng/mL, adverse digital rectal examination, age, or lower urinary tract symptoms).

Results

As ExoMeth risk score (range, 0-1) increased, the likelihood of high-grade disease being detected on biopsy was significantly greater (odds ratio = 2.04 per 0.1 ExoMeth increase, 95% confidence interval [CI]: 1.78-2.35). On an initial TRUS biopsy, ExoMeth accurately predicted the presence of Gleason score ≥3 + 4, area under the receiver-operator characteristic curve (AUC) = 0.89 (95% CI: 0.84-0.93) and was additionally capable of detecting any cancer on biopsy, AUC = 0.91 (95% CI: 0.87-0.95). Application of ExoMeth provided a net benefit over current standards of care and has the potential to reduce unnecessary biopsies by 66% when a risk threshold of 0.25 is accepted.

Conclusion

Integration of urinary biomarkers across multiple assay methods has greater diagnostic ability than either method in isolation, providing superior predictive ability of biopsy outcomes. ExoMeth represents a more holistic view of urinary biomarkers and has the potential to result in substantial changes to how patients suspected of harboring prostate cancer are diagnosed.

     

A five‐CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer

Background

Prognostic biomarkers for localized prostate cancer (PCa) could improve personalized medicine. Our group previously identified a panel of differentially methylated CpGs in primary tumor tissue that predict disease aggressiveness, and here we further validate these biomarkers.

Methods

Pyrosequencing was used to assess CpG methylation of eight biomarkers previously identified using the HumanMethylation450 array; CpGs with strongly correlated (r >0.70) results were considered technically validated. Logistic regression incorporating the validated CpGs and Gleason sum was used to define and lock a final model to stratify men with metastatic‐lethal versus non‐recurrent PCa in a training dataset. Coefficients from the final model were then used to construct a DNA methylation score, which was evaluated by logistic regression and Receiver Operating Characteristic (ROC) curve analyses in an independent testing dataset.

Results

Five CpGs were technically validated and all were retained (P < 0.05) in the final model. The 5‐CpG and Gleason sum coefficients were used to calculate a methylation score, which was higher in men with metastatic‐lethal progression (P = 6.8 × 10^?6) in the testing dataset. For each unit increase in the score there was a four‐fold increase in risk of metastatic‐lethal events (odds ratio, OR = 4.0, 95%CI = 1.8–14.3). At 95% specificity, sensitivity was 74% for the score compared to 53% for Gleason sum alone. The score demonstrated better prediction performance (AUC = 0.91; pAUC = 0.037) compared to Gleason sum alone (AUC = 0.87; pAUC = 0.025).

Conclusions

The DNA methylation score improved upon Gleason sum for predicting metastatic‐lethal progression and holds promise for risk stratification of men with aggressive tumors. This prognostic score warrants further evaluation as a tool for improving patient outcomes.

     

Lung volume changes in Apnoeic Oxygenation using Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE) compared to mechanical ventilation in adults undergoing laryngeal surgery

Background

Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE) using high-flow 100% oxygen during apnoea has gained increased use during difficult airway management and laryngeal surgery due to a slower carbon dioxide rise compared to traditional apnoeic oxygenation. We have previously demonstrated high arterial oxygen partial pressures and an increasing arterial-alveolar carbon dioxide difference during THRIVE. Primary aim of this study was to characterise lung volume changes measured with electrical impedance tomography during THRIVE compared to mechanical ventilation.

Methods

Thirty adult patients undergoing laryngeal surgery under general anaesthesia were randomised to THRIVE or mechanical ventilation. Subjects were monitored with electrical impedance tomography and repeated blood gas measurement perioperatively. The THRIVE group received 100% oxygen at 70 l min⁻¹ during apnoea. The mechanical ventilation group was intubated and normoventilated with an FiO₂ of 0.4.

Results

Mean age were 48.2 (19.9) and 51.3 (12.3) years, and BMI 26.0 (4.5) and 26.0 (3.9) in the THRIVE and mechanical ventilation group respectively. Mean apnoea time in the THRIVE group was 17.9 (4.8) min. Mean apnoea to end-of-surgery time was 28.1 (12.8) min in the mechanical ventilation group. No difference in delta End Expiratory Lung Impedance was seen between groups over time. In the THRIVE group all but three subjects were well oxygenated during apnoea. THRIVE was discontinued for the three patients who desaturated.

Conclusions

No difference in lung volume change over time, measured by electrical impedance tomography, was detected when using THRIVE compared to mechanical ventilation during laryngeal surgery.

     

FOXP3+ regulatory T cells in normal prostate tissue,postatrophic hyperplasia,prostatic intraepithelial neoplasia,and tumor histological lesions in men with and without prostate cancer

Background

The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (T_regs). In the present study we evaluated the prevalence of T_reg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer.

Methods

Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4⁺ T_regs and CD8⁺ T_regs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of T_regs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area.

Results

In men with prostate cancer, similarly high numbers of stromal CD4⁺ T_regs were identified in PAH and tumor, but CD4⁺ T_regs were less common in PIN. Greater numbers of epithelial CD4+ T_regs in normal prostatic tissue were positively associated with both Gleason score and pT‐stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4⁺ T_regs in the normal prostatic tissue counterpart.

Conclusions

Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4⁺ T_regs and indicate that transformation of the anti‐tumor immune response may be initiated even before the primary tumor is established.

     

Acute effect of sacral neuromodulation for treatment of detrusor overactivity on urodynamic parameters

Aim

The aim of this study is to evaluate the acute effects of sacral neuromodulation (SNM) on various urodynamic parameters.

Methods

Patients with overactive bladder and detrusor overactivity (DO) who were planned for percutaneous nerve evaluation (PNE) were included. Directly after the PNE, a urodynamic study (UDS) was performed. The stimulation was turned off during the first UDS (UDS 1), and during the second filling cycle, stimulation was turned on (UDS 2). The UDS was followed by a test phase of 1 week and the bladder diaries were evaluated during an outpatient clinic visit. Primary outcome measures were the differences in UDS parameter values with SNM off and on.

Results

Ten female patients were included in the study and completed the study protocol. Eight patients showed ≥50% improvement of symptoms following a test phase. There were no differences between UDS 1 and UDS 2 in the UDS parameters; bladder volume at first sensation, bladder volume at first DO, highest DO pressure, bladder capacity, maximum flow rate, and pressure at maximum flow rate.

Discussion

None of the aforementioned urodynamic parameters was influenced by acute SNM in patients who responded to SNM. To the best of our knowledge, this is the first study investigating the acute effects of SNM on bladder function.

     

Comparison of outcomes between minimally invasive and median sternotomy for double and triple valve surgery: A meta-analysis

Background

Limited data exists demonstrating the efficacy of minimally invasive surgery (MIS) compared to median sternotomy (MS) for multiple valvular disease (MVD). This systematic review and meta-analysis aims to compare operative and peri-operative outcomes of MIS vs MS in MVD.

Methods

PubMed, Ovid, and Embase were searched from inception until August 2019 for randomized and observational studies comparing MIS and MS in patients with MVD. Clinical outcomes of intra- and postoperative times, reoperation for bleeding and surgical site infection were evaluated.

Results

Five observational studies comparing 340 MIS vs 414 MS patients were eligible for qualitative and quantitative review. The quality of evidence assessed using the Newcastle-Ottawa scale was good for all included studies. Meta-analysis demonstrated increased cardiopulmonary bypass time for MIS patients (weighted mean difference [WMD], 0.487; 95% confidence interval [CI], 0.365-0.608; P < .0001). Similarly, aortic cross-clamp time was longer in patients undergoing MIS (WMD, 0.632; 95% CI, 0.509-0.755; P < .0001). No differences were found in operative mortality, reoperation for bleeding, surgical site infection, or hospital stay.

Conclusions

MIS for MVD have similar short-term outcomes compared to MS. This adds value to the use of minimally invasive methods for multivalvular surgery, despite conferring longer operative times. However, the paucity in literature and learning curve associated with MIS warrants further evidence, ideally randomized control trials, to support these findings.

     

Early sacral neuromodulation ameliorates urinary bladder function and structure in complete spinal cord injury minipigs

Aims

To determine the effects of early sacral neuromodulation (SNM) and pudendal neuromodulation (PNM) on lower urinary tract (LUT) function, minipigs with complete spinal cord injury (cSCI) were analyzed. SNM and PNM have been proposed as therapeutic approaches to improve bladder function, for example after cSCI. However, further evidence on efficacy is required before these methods can become clinical practice.

Methods

Eleven adults, female Göttingen minipigs with cSCI at vertebral level T11-T12 were included: SNM (n = 4), PNM (n = 4), and SCI control (SCIC: n = 3). Tissue from six healthy minipigs was used for structural comparisons. Stimulation was started 1 week after cSCI. Awake urodynamics was performed on a weekly basis. After 16 weeks follow-up, samples from the urinary bladder were taken for analyses.

Results

SNM improved bladder function with better capacities and lower detrusor pressures at voiding and avoided the emergence of detrusor sphincter dyssynergia (DSD). PNM and untreated SCI minipigs had less favorable outcomes with either DSD or constant urinary retention. Structural results revealed SCI-typical fibrotic alterations in all cSCI minipigs. However, SNM showed a better-balanced distribution of smooth muscle to connective tissue with a trend towards the reduced progression of bladder wall scarring.

Conclusion

Early SNM led to an avoidance of the emergence of DSD showing a more physiological bladder function during a 4 month follow-up period after cSCI. This study might pave the way for the clinical continuation of early SNM for the treatment of neurogenic LUT dysfunction after SCI.

     

Influence of the neural microenvironment on prostate cancer

Background

Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease.

Method

We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy.

Result

Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non‐neoplastic epithelial cells.

Conclusion

Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer.

     

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial—Protocol and statistical analysis plan

Introduction

Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods

The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion

The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

     

Safety and Efficacy of a Non-Invasive High-Intensity Focused Electromagnetic Field (HIFEM) Device for Treatment of Urinary Incontinence and Enhancement of Quality of Life

Background and Objectives

Urinary incontinence is a common and distressing condition which interferes with everyday life. Patients frequently experience discomfort related to urine leakage and the subsequent need to use absorbent pads. Since the continence mechanism is primarily maintained by a proper function of pelvic floor muscles (PFM), many treatment methods focused on strengthening of the PFM have been introduced in the past. The aim of this study was to evaluate the safety and efficacy of a high-intensity focused electromagnetic technology (HIFEM) for treatment of urinary incontinence with emphasis on effects on prospective patients’ quality of life.

Study Design/Materials and Methods

The study followed an institutional review board approved protocol. A total of 75 women (55.45 ± 12.80 years, 1.85 ± 1.28 deliveries) who showed symptoms of stress, urge, or mixed urinary incontinence were enrolled. They received six HIFEM treatments (2 per week) in duration of 28 minutes. Outcomes were evaluated after the sixth treatment and at the 3-month follow-up. The primary outcome was to assess changes in urinary incontinence by the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and changes in the number of absorbent pads used per day. The secondary outcome was subjective evaluation of the therapy and self-reported changes in quality of life. The statistical analysis was conducted by paired T-test and Pearson correlation coefficient ( α = 0.05).

Results

After the sixth session, 61 out of 75 patients (81.33%) reported significant reduction of their symptoms. The average improvement of 49.93% in ICIQ-SF score was observed after the sixth treatment, which further increased to 64.42% at the follow-up (both P < 0.001). Individually, the highest level of improvement was reached in patients suffering from mixed urinary incontinence (69.90%). The reduction of absorbent pads averaged 43.80% after the sixth treatment and 53.68% at 3 months (both P < 0.001), while almost 70% of patients (30 out of 43) reported decreased number of used pads. At the follow-up, a highly significant medium correlation (r = 0.53, P < 0.001) was found between the ICIQ-SF score improvement and the reduction in pad usage. A substantial decrease in the frequency of urine leakage triggers was documented. Patients reported no pain, downtime or adverse events, and also reported additional beneficial effects of the therapy such as increased sexual desire and better urination control.

Conclusions

This study demonstrated that HIFEM technology is able to safely and effectively treat a wide range of patients suffering from urinary incontinence. After six treatments, an improvement in ICIQ-SF score and reduction in absorbent pads usage was observed. Based on subjective evaluation, these changes positively influenced quality of life. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

     

Mortality and renal prognosis in isolated metformin-associated lactic acidosis treated with continuous renal replacement therapy and citrate-calcium-anticoagulation

Introduction

Use of metformin increases plasma lactate concentration and may lead to metformin-associated lactic acidosis (MALA). Previous studies have suggested severe MALA to have a mortality of 17%-21%, but have included patients with other coincident conditions such as sepsis. The treatment of choice is continuous renal replacement therapy (CRRT), which has been performed using heparin analogues or no anticoagulation in former studies.

Materials and Methods

Patients admitted to the Intensive Care Unit of Turku University Hospital Finland with lactic acidosis without any other recognizable etiology than concomitant metformin treatment who required CRRT between years 2010 and 2019 were included. CRRT was performed using regional citrate-calcium-anticoagulation. Data extracted included patient demographics, comorbidities, and clinical parameters at 6-hour intervals about 72 hours from admission. Creatinine and estimated glomerular filtration rate (eGFR) were measured at 1 year after MALA.

Results

A total of 23 patients with isolated MALA were included in the study. Median (IQR) pH was 6.88 (6.81-7.07) and lactate 16.1 (11.9-23.0) mmol/L on admission. Median (IQR) duration of CRRT was 62 (41-70) hours. Seven patients (30%) required mechanical ventilation with a mean duration of 6.0 ± 3.0 days. 90-day mortality was 4.3% and 1-year mortality 13.0%. Creatinine (P = .02) and eGFR (P = .03) remained significantly altered at 1 year of follow-up compared to baseline.

Conclusions

MALA can be treated effectively and safely with CRRT and citrate-calcium-anticoagulation, usually required for 2-3 days. Mortality of patients with MALA treated with CRRT is low when other conditions inducing lactic acidosis are excluded. MALA episode may be associated with long-lasting kidney injury.

     

1,25(OH)2D and 24,25(OH)2D production in the developing kidney

To clarify the state of vitamin D production by the developing kidney, firstly, we measured serum levels of 1,25(OH)₂D and 24,25(OH)₂D in humans of different ages (pregnant and nonpregnant women, adult males, children and newborn infants) and secondly, we measured 1- and 24-hydroxylase activity in the kidney mitochrondria of rats at different ages. The mean serum levels of 1,25(OH)₂D in pregnant women, cord blood and newborns were significantly higher than those in children and non-pregnant women and adult males. In newborns, the level increased with gestational age. Synthesis of 1,25(OH)₂D was, at least in part, under the control of the fetus and newborn, rather then being solely a reflection of the conditions prevailing in the mother. The 1-hydroxylase activity in mitochondria was highest in the 1- to 2-month-old rats, and it decreased gradually thereafter. The change in 1-hydroxylase activity with age was due to a change in the V_max of the system.     

Primary whole‐gland ablation for localized prostate cancer with high‐intensity focused ultrasound: The important predictors of biochemical recurrence

Objectives

To identify predictive factors of biochemical recurrence for patients undergoing high‐intensity focused ultrasound treatment for localized prostate cancer.

Methods

We retrospectively identified patients receiving whole‐gland prostate ablation with high‐intensity focused ultrasound for localized prostate cancer from 2009 to 2015. All the patients received pre‐high‐intensity focused ultrasound radical transurethral resection of the prostate. We included perioperative parameters as follows: age, preoperative prostate volume, stage of operation, initial prostate‐specific antigen, T stage, postoperative prostate‐specific antigen nadir, Gleason score, time to prostate‐specific antigen nadir and the presence of prostate‐specific antigen biochemical recurrence. Multivariable Cox regression and Kaplan–Meier analysis were used for investigating predictors of recurrence, and receiver operating characteristic analysis was used for the cut‐off values of prostate‐specific antigen nadir.

Results

Among 182 patients, 26.9% had prostate‐specific antigen biochemical recurrence after high‐intensity focused ultrasound during the median follow‐up period of 32.21 months. Gleason score ≥7 (Gleason score 7, hazard ratio 2.877, P = 0.027), stage ≥T2b (T2b, hazard ratio 3.16, P = 0.027) and prostate‐specific antigen nadir (hazard ratio 1.11, P < 0.001) were statistically significant, whereas there was no significance in prostate volume and initial prostate‐specific antigen. We posit that a cut‐off level of prostate‐specific antigen nadir 0.43 ng/mL might be considered as an independent predictive factor for prostate‐specific antigen biochemical recurrence in high‐intensity focused ultrasound patients in multivariate analysis (P < 0.001, hazard ratio 7.39, 95% confidence interval 3.56–15.37), and created a new nadir‐related prediction model for biochemical recurrence prediction.

Conclusions

Postoperative prostate‐specific antigen nadir of 0.43 ng/mL can be considered an important predictive factor for biochemical recurrence in primary whole‐prostate gland high‐intensity focused ultrasound treatment, and the nadir‐related prediction model might provide a reference for early salvage treatment. Furthermore, Gleason score ≥7, stage ≥T2b might be associated with unfavorable outcomes, although prostate volume and higher initial prostate‐specific antigen appear not to be associated with biochemical recurrence for the high‐intensity focused ultrasound treatment.

     

Lack of In vitro evidence for storage of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) and 1,25(OH)2D3 binding protein in skeletal matrix

A few studies have reported on the measurement of 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃) in bone, using chloroform/methanol extraction and radioreceptor assay. As the significance of bone 1,25(OH)₂D₃ content was not defined in any of these reports, the objective of the current investigation was to determine whether 1,25(OH)₂D₃ may be stored in skeletal matrix. Bone powder samples from the iliac crest were extracted in ethylacetate/cyclohexane and 1,25(OH)₂D₃ isolated from the extract by means of Sephadex LH-20 and high pressure liquid chromatographic separation and subsequently measured by radioimmunoassay (RIA). Within the detection range of the RIA, no 1,25(OH)₂D₃ could be measured, suggesting that 1,25(OH)₂D₃ is not stored in skeletal matrix. Vitamin D bone concentrations previously measured may therefore have reflected plasma contamination. Consistent with this hypothesis, only traces of skeletal 1,25(OH)₂D₃ binding protein were measured when compared with serum values. Although 1,25(OH)₂D₃ may act as a potential local determinant of bone remodeling, there is no evidence supporting a delayed paracrine function by matrix-derived 1,25(OH)₂D₃.     

The Relationship Between Metformin and Serum Prostate‐Specific Antigen Levels

BACKGROUND

Metformin is the first‐line oral antihyperglycemic of choice for individuals with type 2 diabetes. Recent evidence supports a role for metformin in prostate cancer chemoprotection. However, whether metformin indeed influences prostate biology is unknown. We aimed to study the association between metformin and serum prostate‐specific antigen (PSA) levels—the primary prostate cancer biomarker.

METHODS

We conducted a cross‐sectional study of 326 prostate cancer‐free men with type 2 diabetes were recruited between 2004 and 2013 at St. Michael's Hospital. Men were excluded if they had a PSA ≥10‐ng/ml, or used >2,550‐mg/d metformin or supplemental androgens. Multivariate linear regressions quantified the association between metformin dose and log‐PSA. Secondary analyses quantified the association between other antihyperglycemics (sulfonylureas, thiazolidinediones) and PSA; sensitivity analyses tested covariate interactions.

RESULTS

Median PSA was 0.9‐ng/ml (IQR: 0.5–1.6‐ng/ml). Metformin dose associated positively with BMI, HbA1c, diabetes duration, and number of statin, acetylsalicylic acid, diuretic users, and number of antihyperglycemics used, and negatively with LDL‐C. In multivariate models, PSA changed by ?8% (95%CI: ?13 to ?2%, P = 0.011) per 500‐mg/d increase in metformin. Men with diabetes for ≥6 years (n = 163) saw a greater difference in PSA per 500‐mg/d metformin (?12% [95% CI: ?19 to ?4%, P = 0.002], P‐interaction = 0.018). Serum PSA did not relate with sulfonylureas, thiazolidinediones, or total number of antihyperglycemic agents used. Our findings are limited by the cross‐sectional design of this study.

CONCLUSIONS

Metformin dose‐dependently inversely associated with serum PSA, independent of other antihyperglycemic medications. Whether metformin confers a dose‐dependent benefit on prostate tumorigenesis and progression warrants investigation. Prostate 76:1445–1453, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.

     

1,25(OH)2D3 receptor regulation and 1,25(OH)2D3 effects in primary cultures of growth cartilage cells of the rat

Summary Vitamin D deficiency leads to disturbed calcification of growth cartilage and enlargement of growth plate, illustrating that chondrocytes are a target for vitamin D. This observation prompted an investigation of 1,25(OH)₂D₃ receptor expression and action of vitamin D metabolites on chondrocyte proliferation. In primary cultures of tibial growth cartilage of male SD rats (80 g), specific binding of [³H]-1,25(OH)₂D₃ is noted in both the logarithmic growth phase and at confluence (N_max 12780 molecules/cell versus 4368 molecules/cell). Scatchard analysis revealed the presence of a single class of noninteracting binding sites. K_D was 10⁻¹¹ M irrespective of growth phase. The binding macromolecule had a sedimentation coefficient of 3.5 S. Interaction with DNA was demonstrated by DNA cellulose affinity chromatography. In immunohistology, growth cartilage cells (rabbit tibia) expressed nuclear 1,25(OH)₂D₃ receptors most prominently in the proliferative and hypertrophic zone. This corresponds to binding data which showed highest N_max in the proliferating cartilage. 1,25(OH)₂D₃ in the presence of delipidated fetal calf serum (FCS) had a biphasic effect on cell proliferation and density, i.e., stimulation at 10⁻¹² M and dose-dependent inhibition at 10⁻¹⁰ M and below. Inhibition was specific and not seen with 24,25(OH)₂D₃ or dexamethasone. Growth phase-dependent 1,25(OH)₂D₃ receptor expression and effects of 1,25(OH)₂D₃ on chondrocyte proliferation point to a role of vitamin D in the homeostasis of growth cartilage.     

Correlations of SELENOF and SELENOP genotypes with serum selenium levels and prostate cancer

Background

Selenium status is inversely associated with the incidence of prostate cancer. However, supplementation trials have not indicated a benefit of selenium supplementation in reducing cancer risk. Polymorphisms in the gene encoding selenoprotein 15 (SELENOF) are associated with cancer incidence/mortality and present disproportionately in African Americans. Relationships among the genotype of selenoproteins implicated in increased cancer risk, selenium status, and race with prostate cancer were investigated.

Methods

Tissue microarrays were used to assess SELENOF levels and cellular location in prostatic tissue. Sera and DNA from participants of the Chicago‐based Adiposity Study Cohort were used to quantify selenium levels and genotype frequencies of the genes for SELENOF and the selenium‐carrier protein selenoprotein P (SELENOP). Logistic regression models for dichotomous patient outcomes and regression models for continuous outcome were employed to identify both clinical, genetic, and biochemical characteristics that are associated with these outcomes.

Results

SELENOF is dramatically reduced in prostate cancer and lower in tumors derived from African American men as compared to tumors obtained from Caucasians. Differing frequency of SELENOF polymorphisms and lower selenium levels were observed in African Americans as compared to Caucasians. SELENOF genotypes were associated with higher histological tumor grade. A polymorphism in SELENOP was associated with recurrence and higher serum PSA.

Conclusions

These results indicate an interaction between selenium status and selenoprotein genotypes that may contribute to the disparity in prostate cancer incidence and outcome experienced by African Americans.