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Shea P. Connell BSc Eve O'Reilly BSc Alexandra Tuzova MSc Martyn Webb MBioSci Rachel Hurst PhD Robert Mills FRCS Urol Fang Zhao MSc Bharati Bapat PhD Colin S. Cooper PhD Antoinette S. Perry PhD Jeremy Clark PhD Daniel S. Brewer PhD 《The Prostate》2020,80(7):547-558
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.3.
Swathi Ramakrishnan Susan E. Steck Lenore Arab Hongmei Zhang Jeannette T. Bensen Elizabeth T. H. Fontham Candace S. Johnson James L. Mohler Gary J. Smith L. Joseph Su Anna Woloszynska 《The Prostate》2019,79(10):1117-1124
Background
African-American (AA) men tend to present with more aggressive prostate cancer (Gleason score >7) than European-American (EA) men. Vitamin D and its metabolites are implicated in prostate cancer biology with vitamin D deficiency, indicated by its metabolite levels in serum or plasma, usually observed in AA men.Objective
To determine if 1, 25-dihydroxy vitamin D3 [1,25(OH)2D] plasma levels in AA and EA prostate cancer patients alter the risk of having aggressive prostate cancer.Design
Research subjects from the North Carolina-Louisiana Prostate Cancer Project (AA n = 435 and EA n = 532) were included. Plasma metabolites 1,25(OH)2D and 25-hydroxyvitamin D3 [25(OH)D] were measured using liquid chromatography with tandem mass spectrophotometry. Research subjects were classified into low (Gleason sum < 7, stage T1-T2, and Prostate-specific antigen (PSA) < 9 ng/mL) or high (Gleason sum > 8 or Gleason sum = 7 with 4 + 3, or PSA > 20 ng/mL, or Gleason sum = 7 and stage T3-T4) aggressive disease.Results
Research subjects in the second and third tertiles of plasma levels of 1, 25(OH)2D had lower odds of high aggressive prostate cancer (AA [ORT2vsT1: 0.66, 95%CI: 0.39-1.12; ORT3vsT1: 0.83, 95%CI: 0.49-1.41] and EA [ORT2vsT1: 0.68, 95%CI: 0.41-1.11; ORT3vsT1: 0.67, 95%CI: 0.40-1.11]) compared with the first tertile, though confidence intervals included the null. Greater 1,25(OH)2D/25(OH)D molar ratios were associated with lower odds of high aggressive prostate cancer more evidently in AA (ORQ4vsQ1: 0.45, CI: 0.24-0.82) than in EA (ORQ4vsQ1: 0.64, CI: 0.35-1.17) research subjects.Conclusions
The 1,25(OH)2D/25(OH)D molar ratio was associated with decreased risk of high aggressive prostate cancer in AA men, and possibly in EA men. Further studies analyzing vitamin D polymorphisms, vitamin D binding protein levels, and prostatic levels of these metabolites may be useful. These studies may provide a better understanding of the vitamin D pathway and its biological role underlying health disparities in prostate cancer.4.
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Ilse M. Groenendijk Jan Groen Jeroen R. Scheepe Bertil F. M. Blok 《Neurourology and urodynamics》2020,39(2):695-701
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.6.
Haya Mohammed BSc MChB M. Yousuf Salmasi MRCS Massimo Caputo PhD Gianni D. Angelini PhD Hunaid A. Vohra PhD 《Journal of cardiac surgery》2020,35(6):1209-1219
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.7.
Elena E. Keller PhD Irina Patras PhD Ioan Hutu PhD Karin Roider MSc Karl-Dietrich Sievert MD Ludwig Aigner PhD Günter Janetschek MD Lukas Lusuardi MD Reinhold Zimmermann MD Sophina Bauer MD 《Neurourology and urodynamics》2020,39(2):586-593
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.8.
Ida-Maria Forsberg Johan Ullman Anton Hoffman Lars I. Eriksson Åse Lodenius Malin J. Fagerlund 《Acta anaesthesiologica Scandinavica》2020,64(10):1491-1498
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.9.
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.10.
Abhinav Sidana Matthew J. Watson Arvin K. George Ardeshir R. Rastinehad Srinivas Vourganti Soroush Rais-Bahrami Akhil Muthigi Mahir Maruf Jennifer B. Gordetsky Jeffrey W. Nix Maria J. Merino Baris Turkbey Peter L. Choyke Bradford J. Wood Peter A. Pinto 《Urologic oncology》2018,36(7):341.e1-341.e7
Introduction and objectives
Patients with persistently elevated prostate specific antigen (PSA) and prior negative 12-core TRUS prostate biopsy (or biopsies) (systematic biopsy—SBx) are a diagnostic challenge. Repeat SBx or saturation biopsy in this cohort has been shown to have an even lower yield. The aim of our study is to compare the prostate cancer yield of magnetic resonance imaging (MRI) fusion biopsy (FBx) to SBx in a multi-institutional cohort comprised of patients with prior negative biopsies.Methods
A multi-institutional review was performed on patients with a history of one or more prior negative SBx who underwent multiparametric MRI (mpMRI), followed by FBx and SBx in the same session. Imaging protocol was standardized across institutions and institutional genitourinary radiologists and pathologists reviewed mpMRI and pathology, respectively. Gleason score (GS) distribution and risk classifications were recorded. Prostate cancer with GS ≥3 + 4 was defined as clinically significant (CS). Univariate and multivariable logistic regression was done to identify predictors of cancer detection on SBx and FBx.Results
Seven-hundred seventy-nine patients from four institutions were included in the study. Median age and prostate specific antigen (IQR) were 63.1 (58.5–68.0) years and 8.5 (5.9–13.1) ng/dl, respectively. Median number of prior negative biopsies (range) was 2.0 (1–16). The cancer detection rate (CDR) in the cohort was 346/779 patients (44.4%). Total CS CDR was 30.7% (239/779 patients), with FBx detecting 26.3% (205/779) of patients with CS disease and SBx diagnosing an additional 4.4% (34/779) of patients (P<0.001). Furthermore, of all cancers detected by each modality, FBx detected a higher proportion of CS cancer compared to SBx (one negative biopsy: 75 vs. 50%, P<0.001, 2–3 negative biopsy: 76 vs. 61%, P = 0.006, 4 or more negative biopsies: 84 vs. 52%, P = 0.006). As such, SBx added a relatively small diagnostic value to FBx for detecting CS disease (one negative biopsy 3.5%, 2–3 negative biopsies 5%, 4 or more negative biopsies: 1%). FBx also outperformed SBx for upgrading patients to an intermediate or high-risk cancer category (GS>6) (one negative biopsy 11.5% vs. 3.6%, 2–3 negative biopsy 10.3% vs. 5.3%, 4 or more negative biopsies 19.1% vs. 1.1%). On multivariable analysis, the number of prior negative biopsies was a significant negative predictor of CS CDR on SBx (P = 0.006), but not on FBx (P = 0.151).Conclusions
Using a large multi-institutional cohort, we were able to demonstrate that FBx outperformed SBx in patients with prior negative systematic biopsy. This was due, in part, to the decreasing CS CDR by SBx with increased number of prior biopsies. The yield of FBx stayed constant and did not decrease with increased number of prior negative biopsies. Therefore, repeat SBx alone in patients with multiple prior negative biopsies will be hindered by lower yield and FBx should be utilized concurrently in these patients. 相似文献11.
Marie Warrer Petersen Tine Sylvest Meyhoff Marie Helleberg Maj-Brit Nørregaard Kjær Anders Granholm Carl Johan Steensen Hjortsø Thomas Steen Jensen Morten Hylander Møller Peter Buhl Hjortrup Mik Wetterslev Gitte Kingo Vesterlund Lene Russell Vibeke Lind Jørgensen Klaus Tjelle Thomas Benfield Charlotte Suppli Ulrik Anne Sofie Andreasen Thomas Mohr Morten H. Bestle Lone Musaeus Poulsen Mette Friberg Hitz Thomas Hildebrandt Lene Surland Knudsen Anders Møller Christoffer Grant Sølling Anne Craveiro Brøchner Bodil Steen Rasmussen Henrik Nielsen Steffen Christensen Thomas Strøm Maria Cronhjort Rebecka Rubenson Wahlin Stephan Jakob Luca Cioccari Balasubramanian Venkatesh Naomi Hammond Vivekanand Jha Sheila Nainan Myatra Christian Gluud Theis Lange Anders Perner 《Acta anaesthesiologica Scandinavica》2020,64(9):1365-1375
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.12.
Correlations of SELENOF and SELENOP genotypes with serum selenium levels and prostate cancer
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《The Prostate》2018,78(4):279-288
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.13.
Julene B. Samuels MD Andrea Pezzella MD Joseph Berenholz MD Red Alinsod MD 《Lasers in surgery and medicine》2019,51(9):760-766
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.14.
Background
Prostate cancer often evolves resistance to androgen deprivation therapy leading to a lethal metastatic castrate‐resistant form. Besides androgen independence, subpopulations of the tumor are genetically heterogeneous. With the advent of tumor genome sequencing we asked which has the greater influence on reducing tumor size: genetic background, heterogeneity, or drug potency?Methods
A previously developed theoretical evolutionary dynamics model of stochastic branching processes is applied to compute the probability of tumor eradication with two targeted drugs. Publicly available data sets were surveyed to parameterize the model.Results
Our calculations reveal that the greatest influence on successful treatment is the genetic background including the number of mutations overcoming resistance. Another important criteria is the tumor size at which it is still possible to achieve tumor eradication, for example, 2‐4 cm large tumors have at best a 10% probability to be eradicated when 50 mutations can confer resistance to each drug.Conclusion
Overall, this study finds that genetic background and tumor heterogeneity are more important than drug potency in treating mCRPC. It also points toward identifying metastatic sites early using biochemical assays and/or dPET.15.
A five‐CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer
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Milan S. Geybels PhD Andrew S. McDaniel MD PhD Ming Yu PhD Suzanne Kolb MPH Hong Zong MD Kelly Carter BS Javed Siddiqui MS Anqi Cheng MS Jonathan L. Wright MD MPH Colin C. Pritchard MD PhD Raymond Lance MD Dean Troyer MD Jian‐Bing Fan PhD Elaine A. Ostrander PhD James Y. Dai PhD Scott A. Tomlins MD PhD Janet L. Stanford PhD MPH 《The Prostate》2018,78(14):1084-1091
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.16.
《The Prostate》2018,78(2):128-139
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.17.
Epigenetic markers in circulating cell‐free DNA as prognostic markers for survival of castration‐resistant prostate cancer patients
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《The Prostate》2018,78(5):336-342
Background
: Noninvasive biomarkers to guide personalized treatment for castration‐resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell‐free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis.Methods
: In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5 mL of plasma and before performing a methylation‐specific PCR, bisulfate modification was carried out.Results
: The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n = 47) were higher than in controls (n = 30). In the survival analysis, the group with baseline marker levels below median had significant less PCa‐related deaths (P‐values <0.02) and did not reach the median survival point. The survival distributions for the groups were statistically significant for the cfDNA concentration, GSTP1 and APC copies, as well as PSA combined with GSTP1 + APC (P‐values <0.03). Furthermore, there were strong positive correlations between PSA and marker response after starting treatment (P‐values <0.04).Conclusions
: In conclusion, this study showed the kinetics of methylated cfDNA (GSTP1 and APC) in plasma of CRPC patients after starting treatment. Furthermore, the value of the markers before treatment is prognostic for overall survival. These results are promising for developing a test to guide treatment‐decision‐making for CRPC patients.18.
Viranda H. Jayalath Christopher Ireland Neil E. Fleshner Robert J. Hamilton David J.A. Jenkins 《The Prostate》2016,76(15):1445-1453
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.19.
Christophe K. Mannaerts Amir Kajtazovic Olivia A.P. Lodeizen Maudy Gayet Marc R.W. Engelbrecht Gerrit J. Jager Hessel Wijkstra Theo M. de Reijke Harrie P. Beerlage 《Urologic oncology》2019,37(5):298.e1-298.e9
Purpose
Incorporation of multiparametric magnetic resonance imaging (mpMRI) and targeted biopsy (TBx) in the diagnostic pathway for prostate cancer (CaP) is rapidly becoming common practice. In men with a prebiopsy positive mpMRI a TBx only approach, thereby omitting transrectal ultrasound-guided systematic biopsy (SBx), has been postulated. In this study we evaluated the additional clinical relevance of SBx in men with a positive prebiopsy mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] ≥ 3) undergoing TBx for CaP detection, Gleason grading and CaP localization.Material and methods
Prospective data of 255 consecutive men with a prebiopsy positive mpMRI (PI-RADS ≥?3) undergoing 12-core SBx and subsequent MRI-transrectal ultrasound fusion TBx in 2 institutions between 2015 and 2018 was obtained. The detection rate for significant CaP (Gleason score [GS] ≥ 3?+?4) for TBx and SBx were compared. The rate of potentially missed significant CaP by a TBx only approach was determined and GS concordance and CaP localization by TBx and SBx was evaluated.Results
TBx yielded significant CaP in 113 men (44%) while SBx yielded significant CaP in 110 men (43%) (P = 0.856). Insignificant CaP was found in 21 men (8%) by TBx, while SBx detected 34 men (13%) with insignificant CaP (P = 0.035). A TBx only approach, omitting SBx, would have missed significant CaP in 13 of the 126 men (10%) with significant CaP on biopsy. Ten of the 118 men (8%), both positive on TBx and SBx, were upgraded in GS by SBx while 11 men (9%) had higher maximum tumor core involvement on SBx. Nineteen of the 97 men (20%) with significant CaP in both TBx and SBx were diagnosed with unilateral significant CaP on mpMRI and TBx while SBx demonstrated bilateral significant CaP.Conclusions
In men with a prebiopsy positive mpMRI, TBx detects high-GS CaP while reducing insignificant CaP detection as compared to SBx. SBx and TBx as stand-alone missed significant CaP in 13% and 10% of the men with significant CaP on biopsy, respectively. A combination of SBx and TBx remains necessary for the most accurate assessment of detection, grading, tumor core involvement, and localization of CaP. 相似文献20.
Yuval Freifeld Yin Xi Niccolo Passoni Solomon Woldu Brad Hornberger Kenneth Goldberg Aditya Bagrodia Ganesh Raj Vitaly Margulis Jeffrey A. Cadeddu Yair Lotan Franto Francis Ivan Pedrosa Claus G. Roehrborn Daniel N. Costa 《Urologic oncology》2019,37(1):57-62