Oncological and Functional Outcomes of Whole-Gland HIFU as the Primary Treatment for Localized Prostate Cancer: A Systematic Review.

INTRODUCTION: High-intensity focused ultrasound (HIFU) is regarded as a promising alternative treatment option for localized prostate cancer (PCa) as it has been proposed to offer similar oncologic control to the standard of care, but with significantly reduced treatment-related side effects. This systematic literature review assesses the available evidence of whole-gland HIFU as primary treatment for localized PCa. METHODS: MEDLINE (PubMed) was searched for studies investigating oncological and functional outcomes following whole-gland HIFU as primary treatment for localized PCa. Our primary outcomes for the review were biochemical disease-free survival rates (BDFS), overall and PCa-specific survival rates as well as negative biopsy rates. Our secondary outcomes were functional results and complications of the treatment. RESULTS: A total of 375 articles were identified, of which 35 were included in the present review. All 35 articles were prospective or retrospective case series. Mean/median duration of follow-up across studies was 10.9 to 94 months, and 6618 patients were included in the review. The BDFS rate varied greatly across studies from 21.7% to 89.2% during follow-up. The 10-year PCa-specific survival rate following HIFU was 90%, 99%, and 100% in 3 studies. Negative biopsy rates post-HIFU ranged from 20% to 92.7% across studies. Common side effects to HIFU included urinary incontinence (grade 1: 0%-22.7%), erectile dysfunction (11.6%-77.1%), urinary tract infections (1.5%-47.9%), and bladder outlet obstruction mainly as urethral strictures (7%-41.2%). CONCLUSION: Great variation in oncological and functional outcomes was seen across studies. More prospective trials are needed before whole-gland HIFU can be considered as a treatment option for localized PCa.

Analysis of traumatic event emergency department visits among care home residents aged 65 + years in Southern Jutland, Denmark: implications for comprehensive care and subsequent hospital admissions - a register-based cohort study.

BACKGROUND: Care home residents aged 65 + years frequently experience acute health issues, leading to emergency department visits. Falls and associated injuries are a common cause of these visits and falls in a geriatric population can be a symptom of an incipient acute illness such as infection. Conversely, the traumatic event can cause illnesses to arise due to consequences of the fall, e.g. delirium or constipation due to opioid use. We hypothesised that a traumatic event treat-and-release emergency department visit serves as an indicator for an upcoming acute hospital admission due to non-trauma-related conditions. METHODS: We studied emergency department visits for traumatic events among all care home residents aged 65+ (n = 2601) living in Southern Jutland, Denmark, from 2018 to 2019. Data from highly valid national registers were used to evaluate diagnoses, mortality, and admissions. Cox Regression was used to analyse the hazard of acute hospital admission following an emergency department treat-and-release visit. RESULTS: Most visits occurred on weekdays and during day shifts, and 72.0% were treated and released within 6 h. Contusions, open wounds, and femur fractures were the most common discharge diagnoses, accounting for 53.3% of all cases (n = 703). In-hospital mortality was 2.3%, and 30-day mortality was 10.4%. Among treat-and-release visits (n = 506), 25% resulted in a new hospital referral within 30 days, hereof 13% treat-and-release revisits (duration ≤ 6 h), and 12% hospital admissions (duration > 6 h). Over half (56%) of new hospital referrals were initiated within the first seven days of discharge. Almost three-fourths of subsequent admissions were caused by various diseases. The hazard ratio of acute hospital admissions was 2.20 (95% CI: 1.52-3.17) among residents with a recent traumatic event treat-and-release visit compared to residents with no recent traumatic event treat-and-release visit. CONCLUSION: Traumatic event treat-and-release visits among care home residents serve as an indicator for subsequent hospitalisations, highlighting the need for a more comprehensive evaluation, even for minor injuries. These findings have implications for improving care, continuity, and resource utilisation. TRIAL REGISTRATION: Not relevant.

Surgical Complications Following Renal Transplantation in a Large Institutional Cohort.

Background: Successful renal transplantation (RTx) relies on immunosuppression and an optimal surgical course with few surgical complications. Studies reporting the postoperative complications after RTx are heterogeneous and often lack systematic reporting of complications. This study aims to describe and identify postoperative short-term and long-term complications after RTx in a large institutional cohort and identify risk factors for a complicated surgical course. Methods: The study is a retrospective single-center cohort of 571 recipients who underwent living or deceased donor open RTx between 2014 and 2021. Data were collected on background information and perioperative and postoperative data. Complications were defined as short-term (<30 d) or long-term (>30 d) after transplantation and graded according to the Clavien-Dindo classification. Multivariable logistic regression was performed to evaluate risk factors for serious short-term complications and multivariable time-dependent Cox regression to evaluate risk factors for long-term complications. Results: A total of 351 patients received a graft from a deceased donor, and 144 of these grafts were on perfusion machine before transplantation. One or more short-term complications occurred in 345 (60%) patients. Previous RTx was associated with short-term Clavien-Dindo >2 complications in recipients (odds ratio = 2.08; 95% confidence interval [CI], 1.18-3.69; P = 0.01). Being underweight (body mass index <18.5) in combination with increasing age increased the odds of short-term Clavien-Dindo >2 and vascular complications. Increasing blood loss per 100 mL was associated with increased odds of short-term Clavien-Dindo >2 (odds ratio = 1.11; 95% CI, 1.01-1.21; P = 0.032). No associations were found for long-term complications after RTx. The 5-y cumulative incidence of graft loss was 12.6% (95% CI, 8.9-16.3). Conclusions: Short-term complications are common after RTx, and risk factors for severe short-term complications include previous RTx, increasing age, and low body mass index. No risk factors were identified for severe long-term complications. Further studies should explore whether new surgical techniques can reduce surgical complications in RTx.

Systemic interrogation of immune-oncology-related proteins in patients with locally advanced prostate cancer undergoing androgen deprivation and intensity-modulated radiotherapy.

PURPOSE: The primary objective was to establish whether blood-based leucine-rich alpha-2-glycoprotein (LRG1) can predict outcomes in patients with locally advanced prostate cancer undergoing androgen-deprivation therapy (ADT) and radiotherapy (RT) and to determine how it may relate to 92 immune-oncology (I-O)-related proteins in this setting. METHODS: Baseline blood level of LRG1 from patients treated with ADT and RT enrolled in the CuPCa (n = 128) and IMRT (n = 81) studies was measured using ELISA. A longitudinal cohort with matched blood samples from start of ADT, start of RT, and end of RT protocol from 47 patients from the IMRT cohort was used to establish levels of I-O proteins by high-multiplexing Proximal Extension Assay by Olink Proteomics. Statistical analyses using Kaplan-Meier, Cox regression, and LIMMA analyses were applied to predict the prognostic value of LRG1 and its correlation to I-O proteins. RESULTS: High baseline levels of LRG1 predicted a low frequency of treatment failure in patients undergoing ADT + RT in both the CuPCa and the IMRT cohorts. LRG1 was moderately correlated with CD4, IL6, and CSF1. We identified I-O proteins predicting metastatic failure (MF) at different timepoints. CONCLUSION: LRG1 biomarker is associated with I-O proteins and can be used to improve stratification and monitoring of prostate cancer patients undergoing ADT + RT. This work will require further in-depth analyses in independent cohorts with treatment outcome data.

Using BCG Vaccine to Enhance Nonspecific Protection of Health Care Workers During the COVID-19 Pandemic: A Randomized Controlled Trial.

BACKGROUND: The BCG (Bacillus Calmette-Guérin) vaccine can induce nonspecific protection against unrelated infections. We aimed to test the effect of BCG on absenteeism and health of Danish health care workers (HCWs) during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A single-blinded randomized controlled trial included 1221 HCWs from 9 Danish hospitals. Participants were randomized 1:1 to standard dose BCG or placebo. Primary outcome was days of unplanned absenteeism. Main secondary outcomes were incidence of COVID-19, all-cause hospitalization, and infectious disease episodes. RESULTS: There was no significant effect of BCG on unplanned absenteeism. Mean number of days absent per 1000 workdays was 20 in the BCG group and 17 in the placebo group (risk ratio, 1.23; 95% credibility interval, 0.98-1.53). BCG had no effect on incidence of COVID-19 or all-cause hospitalization overall. In secondary analyses BCG revaccination was associated with higher COVID-19 incidence (hazard ratio [HR], 2.47; 95% confidence interval [CI], 1.07-5.71), but also reduced risk of hospitalization (HR, 0.28; 95% CI, .09-.86). The incidence of infectious disease episodes was similar between randomization groups (HR, 1.09; 95% CI, .96-1.24). CONCLUSIONS: In this relatively healthy cohort of HCWs, there was no overall effect of BCG on any of the study outcomes. CLINICAL TRIALS REGISTRATION: NCT0437329 and EU Clinical Trials Register (EudraCT number 2020-001888-90).

Associations between care home residents' characteristics and acute hospital admissions - a retrospective, register-based cross-sectional study.

BACKGROUND: Care home residents are frail, multi-morbid, and have an increased risk of experiencing acute hospitalisations and adverse events. This study contributes to the discussion on preventing acute admissions from care homes. We aim to describe the residents' health characteristics, survival after care home admission, contacts with the secondary health care system, patterns of admissions, and factors associated with acute hospital admissions. METHOD: Data on all care home residents aged 65 + years living in Southern Jutland in 2018-2019 (n = 2601) was enriched with data from highly valid Danish national health registries to obtain information on characteristics and hospitalisations. Characteristics of care home residents were assessed by sex and age group. Factors associated with acute admissions were analysed using Cox Regression. RESULTS: Most care home residents were women (65.6%). Male residents were younger at the time of care home admission (mean 80.6 vs. 83.7 years), had a higher prevalence of morbidities, and shorter survival after care home admission. The 1-year survival was 60.8% and 72.3% for males and females, respectively. Median survival was 17.9 months and 25.9 months for males and females, respectively. The mean rate of acute hospitalisations was 0.56 per resident-year. One in four (24.4%) care home residents were discharged from the hospital within 24 h. The same proportion was readmitted within 30 days of discharge (24.6%). Admission-related mortality was 10.9% in-hospital and 13.0% 30 days post-discharge. Male sex was associated with acute hospital admissions, as was a medical history of various cardiovascular diseases, cancer, chronic obstructive pulmonary disease, and osteoporosis. In contrast, a medical history of dementia was associated with fewer acute admissions. CONCLUSION: This study highlights some of the major characteristics of care home residents and their acute hospitalisations and contributes to the ongoing discussion on improving or preventing acute admissions from care homes. TRIAL REGISTRATION: Not relevant.

Intensive care professionals' perspectives on dysphagia management: A focus group study.

BACKGROUND: Intensive care unit (ICU)-acquired dysphagia has severe consequences for patients including increased morbidity and mortality. Standard operating procedures, however, including systematic evaluation of swallowing function and access to specialised assessment and training may be limited. Dysphagia management relies on multiprofessional collaboration, but practice is variable and nonstandardised. OBJECTIVE: The objective of this study was to explore and compare nurses', physicians', and occupational therapists' perceptions of dysphagia management in the ICU. MATERIALS AND METHODS: Six focus group interviews with 33 participants (23 nurses, four physicians, and six occupational therapists) were conducted and analysed using the framework method with a matrix developed from the first interview. Content from the interviews was plotted into the matrix, condensed, and refined. FINDINGS: Clinical dysphagia management depended on recognising signs of dysphagia in patients at risk. Assessment, therapeutic methods, and care differed among professional groups according to knowledge and roles. Interprofessional collaboration and responsibility for dysphagia management across the care continuum was determined by availability of resources, practical skills, knowledge, and formal decision-making competence and judged effective when based on mutual respect and recognition of healthcare professionals' different perspectives. CONCLUSION: Systematic interprofessional collaboration in ICU dysphagia management requires working towards a common goal of preventing aspiration and rehabilitating the patients' ability to swallow safely. This is based on dysphagia assessment, using appropriate therapeutic interventions, sharing knowledge, and improving skills among professional groups.

Exploring the validity of identifying care home residents through a new national register.

AIMS: Identifying permanent care home residents in Denmark by national registers is subject to error. The current register-based method has a sensitivity of 87% and a positive predictive value of 57%. The Danish National Health Data Authority has generated a new register named Care Home Data (in Danish: Plejehjemsdata) to increase the quality of register-based studies on care home residents. This study aimed to investigate the validity of Care Home Data. METHODS: We generated the gold standard by retrieving information from the four municipalities of Southern Jutland on all individuals living permanently in a care home facility in 2019. Care Home Data generates information on care home residents by pairing addresses of every apartment in Danish care home facilities with the addresses of Danish citizens. The agreement between Care Home Data and the gold standard was analysed by calculating the sensitivity and positive predictive value. RESULTS: According to the municipalities, a total of 2081 individuals resided permanently in care home facilities in Southern Jutland in 2019 (gold standard). Care Home Data identified 2128 permanent care home residents; of which 2019 individuals were identified by both the municipalities and Care Home Data (true positives); 62 individuals were not identified by Care Home Data (false negatives), and 109 individuals identified by Care Home Data did not appear in data from the municipalities (false positives). This gave a sensitivity of Care Home Data of 97.0% and a positive predictive value of 94.9%. CONCLUSIONS: Care Home Data is a much improved tool for identifying citizens permanently residing in care homes with very high sensitivity and positive predictive value.

Low Blood Levels of LRG1 Before Radical Prostatectomy Identify Patients with High Risk of Progression to Castration-resistant Prostate Cancer.

Background: After radical prostatectomy (RP), depending on stage, up to 40% of patients with prostate cancer (PCa) will experience biochemical failure (BF). Despite salvage therapy, approximately one-third of these patients will need permanent hormone therapy (pHT) and are at risk of progression to castration-resistant PCa (CRPC). Prognostic markers herald the need for neoadjuvant, adjuvant, or multimodal treatment. Objective: To evaluate the added value of blood LRG1 in predicting treatment failure in patients who have undergone radical prostatectomy (RP). Design setting and participants: We quantified LRG1 in serum or plasma sampled before radical prostatectomy from patients from the Martini-Klinik (Martini; n = 423), the Danish CuPCa cohort (CuPCa; n = 182), and Oslo University Hospital (OUH; n = 145). Outcome measurements and statistical analysis: The endpoints were BF, pHT, and CRPC. The association between LRG1 and survival outcomes was evaluated using Kaplan-Meier estimation and Cox proportional-hazards modeling. The added predictive value of LRG1 in nested models was estimated using the concordance index, time-dependent area under the receiver operating characteristic curve, and decision curve analysis. Results and limitations: In multivariable Cox models using preoperative characteristics, LRG1 was associated with an estimated lower risk of BF in the Martini cohort (adjusted hazard ratio [aHR] 0.68, 95% confidence interval [CI] 0.52-0.90) and in the CuPCa cohort (aHR 0.47, 95% CI 0.30-0.73). Using preoperative prognostic variables, our data showed that doubling of LRG1 was also associated with a lower risk of pHT receipt in the CuPCa cohort (aHR 0.43, 95% CI 0.20-0.93) and of CRPC development in the OUH cohort (aHR 0.32, 95% CI 0.15-0.69). Similar aHR values were observed using either preoperative or postoperative variables for all endpoints. Conclusions: PCa patients with high blood LRG1 are at lower risk of BF, pHT receipt, and progression to CRPC. Since LRG1 adds value to established prognostic models, new prognostic factor combinations including LRG1 should be considered in future studies. Patient summary: We measured concentrations of the blood-based protein LRG1 before surgery for prostate cancer. Patients with high LRG1 levels had better disease-free survival, suggesting that LRG1 can help in predicting prognosis.

Surgical Approaches and Outcomes in Living Donor Nephrectomy: A Systematic Review and Meta-analysis.

CONTEXT: The use of living kidney donors is increasing and there are several surgical approaches for donor nephrectomy but it remains unknown which procedure is optimal for the patient and the graft. OBJECTIVE: To review different surgical techniques for living donor nephrectomy and compare complication rates, warm ischemia time, and delayed graft function. EVIDENCE ACQUISITION: A systematic review of prospective studies involving surgical complications following living donor nephrectomy was conducted in the MEDLINE/PubMed and EMBASE databases according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Baseline data, perioperative and postoperative parameters, and postoperative complications are reported. Overall complication rates between surgical techniques were compared via analysis of variance with post hoc analysis. We included 35 studies involving 6398 patients and representing six different surgical procedures for living donor nephrectomy. EVIDENCE SYNTHESIS: Hand-assisted laparoscopic donor nephrectomy had a significantly higher overall complication rate compared to open, laparoscopic, retroperitoneoscopic, and laparoendoscopic single-site techniques (p < 0.005). The complication rates were low and no mortality was observed. The main limitation was varying reporting of complications, with only one-third of the studies using the Clavien-Dindo classification. CONCLUSIONS: No specific surgical approach seems superior in terms of complications, which were generally low. Different factors such as warm ischemia time, blood loss, and surgeon expertise define which surgical approach should be chosen. PATIENT SUMMARY: We looked at the different surgical methods for removing the kidney from a living kidney donor. Overall, the different surgical techniques were similar in terms of complications and no donors died in the studies we reviewed. The choice of procedure depends on multiple factors such as the expertise of the surgeon and the surgical center.

Limitation of life-sustaining treatment and patient involvement in decision-making: a retrospective study of a Danish COVID-19 patient cohort.

BACKGROUND: The coronavirus (COVID-19) pandemic and the risk of an extensive overload of the healthcare systems have elucidated the need to make decisions on the level of life-sustaining treatment for patients requiring hospitalisation. The purpose of the study was to investigate the proportion and characteristics of COVID-19 patients with limitation of life-sustaining treatment decisions and the degree of patient involvement in the decisions. METHODS: A retrospective observational descriptive study was conducted in three Danish regional hospitals, looking at all patients ≥ 18 years of age admitted in 2020 with COVID-19 as the primary diagnosis. Lists of hospitalised patients admitted due to COVID-19 were extracted. The data registration included age, gender, comorbidities, including mental state, body mass index, frailty, recent hospital admissions, COVID-19 life-sustaining treatment, ICU admission, decisions on limitations of life-sustaining treatment before and during current hospitalisation, hospital length of stay, and hospital mortality. RESULTS: A total of 476 patients were included. For 7% (33/476), a decision about limitation of life-sustaining treatment had been made prior to hospital admission. At the time of admission, one or more limitations of life-sustaining treatment were registered for 16% (75/476) of patients. During the admission, limitation decisions were made for an additional 11 patients, totaling 18% (86/476). For 40% (34/86), the decisions were either made by or discussed with the patient. The decisions not made by patients were made by physicians. For 36% (31/86), no information was disclosed about patient involvement. CONCLUSIONS: Life-sustaining treatment limitation decisions were made for 18% of a COVID-19 patient cohort. Hereof, more than a third of the decisions had been made before hospital admission. Many records lacked information on patient involvement in the decisions.

The Association between Plasma Levels of Intact and Cleaved uPAR Levels and the Risk of Biochemical Recurrence after Radical Prostatectomy for Prostate Cancer.

Radical prostatectomy (RP) is a curatively intended treatment option for clinically localized non-metastatic prostate cancer (PCa). Novel biomarkers could refine treatment choice based on a better identification of men at risk of biochemical recurrence (BCR) following therapy. The urokinase plasminogen activator receptor (uPAR) system is a promising biomarker of aggressiveness in many cancers. The predictive value of uPAR after curatively intended treatment for PCa remains to be elucidated. This was a prospective evaluation of uPAR analysis in men with prostate cancer (Copenhagen uPAR prostate cancer (CuPCA) database). Risk of BCR following RP was analyzed using cumulative incidences with competing risk and tested with Gray's test. Associations between quartile groups of uPAR levels and BCR were assessed with uni- and multivariate Cox proportional hazards. In total, 532 men were included. With more advanced tumor stage, Gleason score (GS), and prostate-specific antigen (PSA) the uPAR I-III + II-III plasma levels increased. Quartile levels of plasma uPAR I-III, I-III + II-III showed no significant association between the risk of BCR and the plasma uPAR levels in uni- and multivariate analysis. Despite increased levels of uPAR I-III + II-III in advanced tumor stage, intact and cleaved uPAR levels were not associated with BCR and are not predictive biomarkers for BCR following curatively intended treatment of PCa. It is unlikely that further studies of uPAR in RP treated patients is needed.

Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic: A structured summary of a study protocol for a randomised controlled trial in Denmark.

OBJECTIVES: The Bacille Calmette-Guérin (BCG) vaccine against tuberculosis is associated with non- specific protective effects against other infections, and significant reductions in all-cause morbidity and mortality have been reported. We aim to test whether BCG vaccination may reduce susceptibility to and/or the severity of COVID-19 and other infectious diseases in health care workers (HCW) and thus prevent work absenteeism.The primary objective is to reduce absenteeism due to illness among HCW during the COVID-19 pandemic. The secondary objectives are to reduce the number of HCW that are infected with SARS-CoV-2, and to reduce the number of hospital admissions among HCW during the COVID-19 pandemic. HYPOTHESIS: BCG vaccination of HCW will reduce absenteeism by 20% over a period of 6 months. TRIAL DESIGN: Placebo-controlled, single-blinded, randomised controlled trial, recruiting study participants at several geographic locations. The BCG vaccine is used in this study on a different indication than the one it has been approved for by the Danish Medicines Agency, therefore this is classified as a phase III study. PARTICIPANTS: The trial will recruit 1,500 HCW at Danish hospitals.To be eligible for participation, a subject must meet the following criteria: Adult (≥18 years); Hospital personnel working at a participating hospital for more than 22 hours per week.A potential subject who meets any of the following criteria will be excluded from participation in this study: Known allergy to components of the BCG vaccine or serious adverse events to prior BCG administration Known prior active or latent infection with Mycobacterium tuberculosis (M. tuberculosis) or other mycobacterial species Previous confirmed COVID-19 Fever (>38 C) within the past 24 hours Suspicion of active viral or bacterial infection Pregnancy Breastfeeding Vaccination with other live attenuated vaccine within the last 4 weeks Severely immunocompromised subjects. This exclusion category comprises: a) subjects with known infection by the human immunodeficiency virus (HIV-1) b) subjects with solid organ transplantation c) subjects with bone marrow transplantation d) subjects under chemotherapy e) subjects with primary immunodeficiency f) subjects under treatment with any anti-cytokine therapy within the last year g) subjects under treatment with oral or intravenous steroids defined as daily doses of 10 mg prednisone or equivalent for longer than 3 months h) Active solid or non-solid malignancy or lymphoma within the prior two years Direct involvement in the design or the execution of the BCG-DENMARK-COVID trial Intervention and comparator: Participants will be randomised to BCG vaccine (BCG-Denmark, AJ Vaccines, Copenhagen, Denmark) or placebo (saline). An adult dose of 0.1 ml of resuspended BCG vaccine (intervention) or 0.1 ml of sterile 0.9% NaCl solution (control) is administered intradermally in the upper deltoid area of the right arm. All participants will receive one injection at inclusion, and no further treatment of study participants will take place. MAIN OUTCOMES: Main study endpoint: Days of unplanned absenteeism due to illness within 180 days of randomisation.Secondary study endpoints: The cumulative incidence of documented COVID-19 and the cumulative incidence of hospital admission for any reason within 180 days of randomisation.Randomisation: Randomisation will be done centrally using the REDCap tool with stratification by hospital, sex and age groups (+/- 45 years of age) in random blocks of 4 and 6. The allocation ratio is 1:1.Blinding (masking): Participants will be blinded to treatment. The participant will be asked to leave the room while the allocated treatment is prepared. Once ready for injection, vaccine and placebo will look similar, and the participant will not be able to tell the difference.The physicians administering the treatment are not blinded.Numbers to be randomised (sample size): Sample size: N=1,500. The 1,500 participants will be randomised 1:1 to BCG or placebo with 750 participants in each group.Trial Status: Current protocol version 5.1, from July 6, 2020.Recruitment of study participants started on May 18, 2020 and we anticipate having finished recruiting by the end of December 2020. TRIAL REGISTRATION: The trial was registered with EudraCT on April 16, 2020, EudraCT number: 2020-001888-90, and with ClinicalTrials.gov on May 1, 2020, registration number NCT04373291.Full protocol: The full protocol is attached as an additional file, accessible from the Trialswebsite (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

AZGP1 Protein Expression in Hormone-Naïve Advanced Prostate Cancer Treated with Primary Androgen Deprivation Therapy.

Biomarkers for predicting the risk of castration-resistant prostate cancer (CRPC) in men treated with primary androgen deprivation therapy (ADT) are lacking. We investigated whether Zinc-alpha 2 glycoprotein (AZGP1) expression in the diagnostic biopsies of men with hormone-naïve prostate cancer (PCa) undergoing primary ADT was predictive of the development of CRPC and PCa-specific mortality. The study included 191 patients who commenced ADT from 2000 to 2011. The AZGP1 expression was evaluated using immunohistochemistry and scored as high or low expression. The risks of CRPC and PCa-specific mortality were analyzed using stratified cumulative incidences and a cause-specific COX regression analysis for competing risk assessment. The median follow-up time was 9.8 (IQR: 6.1-12.7) years. In total, 94 and 97 patients presented with low and high AZGP1 expression, respectively. A low AZGP1 expression was found to be associated with a shorter time to CRPC when compared to patients with a high AZGP1 expression (HR: 1.5; 95% CI: 1.0-2.1; p = 0.03). However, the multivariable analysis demonstrated no added benefit by adding the AZGP1 expression to prediction models for CRPC. No differences for PCa-specific mortality between the AZGP1 groups were observed. In conclusion, a low AZGP1 expression was associated with a shorter time to CRPC for PCa patients treated with first-line ADT but did not add any predictive information besides well-established clinicopathological variables.

Validation of the four-miRNA biomarker panel MiCaP for prediction of long-term prostate cancer outcome.

Improved prostate cancer prognostic biomarkers are urgently needed. We previously identified the four-miRNA prognostic biomarker panel MiCaP ((miR-23a-3p × miR-10b-5p)/(miR-133a-3p × miR-374b-5p)) for prediction of biochemical recurrence (BCR) after radical prostatectomy (RP). Here, we identified an optimal numerical cut-off for MiCaP dichotomisation using a training cohort of 475 RP patients and tested this in an independent cohort of 281 RP patients (PCA281). Kaplan-Meier, uni- and multivariate Cox regression analyses were conducted for multiple endpoints: BCR, metastatic-(mPC) and castration-resistant prostate cancer (CRPC), prostate cancer-specific (PCSS) and overall survival (OS). Functional effects of the four MiCaP miRNAs were assessed by overexpression and inhibition experiments in prostate cancer cell lines. We found the numerical value 5.709 optimal for MiCaP dichotomisation. This was independently validated in PCA281, where a high MiCaP score significantly [and independent of the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score] predicted BCR, progression to mPC and CRPC, and PCSS, but not OS. Harrell's C-index increased upon addition of MiCaP to CAPRA-S for all endpoints. Inhibition of miR-23a-3p and miR-10b-5p, and overexpression of miR-133a-3p and miR-374b-5p significantly reduced cell survival. Our results may promote future implementation of a MiCaP-based test for improved prostate cancer risk stratification.

Elevated miR-615-3p Expression Predicts Adverse Clinical Outcome and Promotes Proliferation and Migration of Prostate Cancer Cells.

miR-615-3p has previously been described as up-regulated in prostate cancer (PC) tissue samples compared with nonmalignant controls; however, its prognostic potential and functional role in PC remain largely unknown. In this study, we investigated the clinical and biological relevance of miR-615-3p in PC. The expression of miR-615-3p was measured in PC tissue specimens from 239 men who underwent radical prostatectomy (RP), and it was investigated if miR-615-3p could predict postoperative biochemical recurrence (BCR). These findings were subsequently validated in three independent RP cohorts (n = 222, n = 273, and n = 387) and functional overexpression studies conducted in PC cells (PC3M). High miR-615-3p expression was significantly associated with BCR in four independent PC patient cohorts (P < 0.05, log-rank test). In addition, high miR-615-3p expression was a significant predictor of PC-specific survival in univariate (hazard ratio, 3.75; P < 0.001) and multivariate (hazard ratio, 2.66; P = 0.008) analysis after adjustment for the Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) nomogram in a merged RP cohort (n = 734). Moreover, overexpression of miR-615-3p in PC cells (PC3M) significantly increased cell viability, proliferation, apoptosis, and migration. Together, our results suggest that miR-615-3p is a significant predictor of postoperative BCR and PC-specific survival and has oncogenic functions in PC cells.

Predictive value of AZGP1 following radical prostatectomy for prostate cancer: a cohort study and meta-analysis.

AIMS: Zinc-alpha 2-glycoprotein (AZGP1) is a promising tissue biomarker to predict outcomes in men undergoing treatment for localised prostate cancer (PCa). We aimed to examine the association between AZGP1 expression and the endpoints: risk of biochemical failure (BF), initiating castration-based treatment, developing castration-resistant PCa (CRPC) and PCa-specific mortality following radical prostatectomy (RP). METHODS: The study included a prospective cohort of 302 patients who underwent RP for PCa from 2002 to 2005. AZGP1 expression was analysed using immunohistochemistry on tissue microarray RP specimens and was scored semiquantitively as low or high expression. Risk of all endpoints was analysed using stratified cumulative incidences and cause-specific Cox regression, and validated with receiver operating curves, calibration and discrimination in competing-risk analyses. A meta-analysis was performed including previous studies investigating AZGP1 expression and risk of BF following RP. RESULTS: Median time of follow-up was 14.0 years. The cumulative incidence of all endpoints was significantly higher in patients with low AZGP1 expression compared with patients with high AZGP1 expression (p<0.001). In a multivariate analysis, low AZGP1 expression increases the risk of BF (HR 2.7; 95% CI 1.9 to 3.8; p<0.0001), castration-based treatment (HR 2.2; 95% CI 1.2 to 4.2; p=0.01) and CRPC (HR 2.3; 95% CI 1.1 to 5.0; p=0.03). Validation showed a low risk of prediction error and a high model performance for all endpoints. In a meta-analysis, low AZGP1 was associated with BF (HR 1.7; 95% CI 1.2 to 2.5). CONCLUSIONS: Low AZGP1 expression is associated with the risk of aggressive time-dependent outcomes in men undergoing RP for localised PCa.

5hmC Level Predicts Biochemical Failure Following Radical Prostatectomy in Prostate Cancer Patients with ERG Negative Tumors.

This study aimed to validate whether 5-hydroxymethylcytosine (5hmC) level in combination with ERG expression is a predictive biomarker for biochemical failure (BF) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa). The study included 592 PCa patients from two consecutive Danish RP cohorts. 5hmC level and ERG expression were analyzed using immunohistochemistry in RP specimens. 5hmC was scored as low or high and ERG was scored as negative or positive. Risk of BF was analyzed using stratified cumulative incidences and multiple cause-specific Cox regression using competing risk assessment. Median follow-up was 10 years (95% CI: 9.5⁻10.2). In total, 246 patients (41.6%) had low and 346 patients (58.4%) had high 5hmC level. No significant association was found between 5hmC level or ERG expression and time to BF (p = 0.2 and p = 1.0, respectively). However, for men with ERG negative tumors, high 5hmC level was associated with increased risk of BF following RP (p = 0.01). In multiple cause-specific Cox regression analyses of ERG negative patients, high 5hmC expression was associated with time to BF (HR: 1.8; 95% CI: 1.2⁻2.7; p = 0.003). In conclusion, high 5hmC level was correlated with time to BF in men with ERG negative PCa, which is in accordance with previous results.

Proteogenomic Characterization of Patient-Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration-Resistant Prostate Cancer.

PURPOSE: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood.Experimental Design: We applied mass spectrometry-based proteomics to a unique set of 17 prostate cancer patient-derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. RESULTS: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. CONCLUSIONS: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.