Exercise training to increase tumour natural killer-cell infiltration in men with localised prostate cancer: a randomised controlled trial.

OBJECTIVES: To explore the effects of preoperative high-intensity interval training (HIIT) compared to usual care on tumour natural killer (NK)-cell infiltration in men with localised prostate cancer (PCa), as NK-cell infiltration has been proposed as one of the key mechanisms whereby exercise can modulate human tumours. PATIENTS AND METHODS: A total of 30 patients with localised PCa undergoing radical prostatectomy (RP) were randomised (2:1) to either preoperative aerobic HIIT four-times weekly (EX; n = 20) or usual care (CON; n = 10) from time of inclusion until scheduled surgery. Tumour NK-cell infiltration was assessed by immunohistochemistry (CD56+ ) in diagnostic core needle biopsies and corresponding prostatic tissue from the RP. Changes in cardiorespiratory fitness, body composition, blood biochemistry, and health-related quality of life were also evaluated. RESULTS: The change in tumour NK-cell infiltration did not differ between the EX and CON groups (between-group difference: -0.09 cells/mm2 , 95% confidence interval [CI] -1.85 to 1.66; P = 0.913) in the intention-to-treat analysis. The total number of exercise sessions varied considerably from four to 30 sessions. The per-protocol analysis showed a significant increase in tumour NK-cell infiltration of 1.60 cells/mm2 (95% CI 0.59 to 2.62; P = 0.004) in the EX group. Further, the total number of training sessions was positively correlated with the change in NK-cell infiltration (r = 0.526, P = 0.021), peak oxygen uptake (r = 0.514, P = 0.035) and peak power output (r = 0.506, P = 0.038). CONCLUSION: Preoperative HIIT did not result in between-group differences in tumour NK-cell infiltration. Per-protocol and exploratory analyses demonstrate an enhanced NK-cell infiltration in PCa. Future studies are needed to test the capability of exercise to increase tumour immune cell infiltration.

Prescription rates for commonly used drugs before and after a prostate cancer diagnosis.

PURPOSE: To investigate differences in prescription rates of commonly used drugs among prostate cancer patients and cancer-free comparisons and between patients diagnosed with localized and non-localized disease. METHODS: We conducted a register-based study including all men aged 50-85 years diagnosed with prostate cancer in Denmark from 1998 to 2015 and an age-matched cancer-free comparison cohort. We calculated the number of new and total prescriptions from three years before to three years after the date of diagnosis of the case for selected drug classes divided by the number of person-months and stratified by stage at diagnosis. RESULTS: We included 54,286 prostate cancer patients and 249,645 matched comparisons. 30,712 patients were diagnosed with localized disease and 12,884 with non-localized disease. The rates of new prescriptions increased considerably among patients within the year before the diagnosis. Hereafter the rates varied between drug classes. For most drug classes, total prescription rates for patients and comparisons increased similarly in the study period. Total prescription rates varied between men with localized and non-localized disease for all drug classes apart from statins. CONCLUSION: Our findings indicate that a large proportion of prostate cancer cases are likely diagnosed during medical work-up for other reasons than prostate cancer. Increased rates occur within the last year before diagnosis and future studies on the interaction between drug use and prostate cancer should at least include a one year pre-diagnostic lag-time. Post-diagnostic prescription rates demonstrated an increased use of drugs most likely associated with the consequences of the disease.

A Nationwide Analysis of Risk of Prostate Cancer Diagnosis and Mortality following an Initial Negative Transrectal Ultrasound Biopsy with Long-Term Followup.

PURPOSE: Magnetic resonance imaging (MRI) targeted prostate biopsy has been shown to find many high-grade prostate cancers in men with concurrent negative transrectal ultrasound (TRUS) systematic biopsy. The oncologic risk of such tumors can be explored by looking at long-term outcomes of men with negative TRUS biopsy followed without MRI. The aim was to analyze the mortality after initial and second negative TRUS biopsy. MATERIALS AND METHODS: All men who underwent initial TRUS biopsies between January 1, 1995 and December 31, 2016 in Denmark were included. A total of 37,214 men had a negative initial TRUS biopsy and 6,389 underwent a re-biopsy. Risk of cause-specific mortality was analyzed with competing risks. Diagnosis of Gleason score ≥7 prostate cancer following negative biopsies was analyzed with multivariable logistic regression including time to re-biopsy, prostate specific antigen (PSA), age and digital rectal examination. RESULTS: The 15-year prostate cancer-specific mortality was 1.9% (95% CI: 1.7-2.1). Prostate cancer-specific mortality was 1.3% (95% CI: 0.9-1.6) and 4.6% (95% CI: 3.4-5.8) for men with PSA <10 and >20 ng/ml, respectively. Of the TRUS re-biopsies 12% were Gleason score ≥7 and risk of Gleason score ≥7 increased with longer time to re-biopsy (p <0.001). Mortality after re-biopsy was similar to after initial biopsy. CONCLUSIONS: Men with negative TRUS biopsies have a very low prostate cancer-specific mortality, especially with PSA <10 ng/ml. This raises serious questions about the routine use of MRI targeting for initial prostate biopsy and suggests that MRI targeting should only be recommended for men with PSA >10 ng/ml after negative biopsy.

Open vs robot-assisted radical cystectomy (BORARC): a double-blinded, randomised feasibility study.

OBJECTIVE: To examine surgical outcomes and feasibility of blinding patients and care providers to the surgical technique of radical cystectomy (RC). PATIENTS AND METHODS: Single-centre, parallel-group, double-blinded, randomised feasibility study of open RC (ORC) vs robot-assisted RC with intracorporeal urinary diversion (iRARC) in an 'Enhanced Recovery After Surgery' setup. A total of 50 patients aged ≥18 years with bladder cancer planned for RC with an ileal conduit were included. Patients with previous major abdominal/pelvic surgery, pelvic radiation or anaesthesiological contraindications were excluded. Primary outcomes were proportion of unblinded patients and success of blinding using Bang's Blinding Index. Secondary outcomes included length of stay (LOS), complication rates, blood loss, pain, and opioid consumption. RESULTS: A total of 26% of the patients were unblinded before discharge. We demonstrated that patients and doctors remained blinded for the allocated treatment, but nurses did not. Blood loss was greater in the ORC group as was operative time in the iRARC group. We found no difference in complication rate, LOS, or use of analgesics. CONCLUSIONS: The present study demonstrates that blinding of surgical technique in RC is possible. The results of secondary outcomes are consistent with the findings of previous unblinded randomised controlled trials. Our study highlights that it is possible to perform a blinded phase III study to explore the optimal surgical technique in RC.

Quality of life and secondary outcomes for open versus robot-assisted radical cystectomy: a double-blinded, randomised feasibility trial.

PURPOSE: This study aims to examine quality of life (QoL) before and after radical cystectomy (RC) and compare robot-assisted laparoscopy with intracorporeal urinary diversion (iRARC) to open radical cystectomy (ORC). METHODS: This study is a predefined secondary analysis of a single-centre, double-blinded, randomised feasibility trial. Fifty patients were randomly assigned to iRARC with ileal conduit (n = 25) or ORC with ileal conduit (n = 25). Patients were followed 90 days postoperatively. The primary outcome was patient-reported QoL using the EORTC Cancer-30 and muscle-invasive bladder cancer BLM-30 QoL questionnaires before and after RC. Differences between randomisation arms as well as changes over time were evaluated. Secondary outcomes included 30- and 90 day complication rates, 90 day readmission rates, and 90 day days-alive-and-out-of-hospital and their relationship to QoL. RESULTS: All patients underwent the allocated treatment. We found no difference in QoL, complication rates, readmission rates, and days-alive-and-out-of-hospital between randomisation arms. An overall improvement in QoL was found in the following domains: future perspectives, emotional functioning, and social functioning. Sexual functioning worsened postoperatively. There was no association between having experienced a major complication or lengthy hospitalisation and worse postoperative QoL. CONCLUSION: The QoL does not appear to depend on surgical technique. Apart from sexual functioning, patients report stable or improved QoL within the first 90 postoperative days.

Center experience and other determinants of patient radiation exposure during prostatic artery embolization: a retrospective study in three Scandinavian centers.

OBJECTIVES: To evaluate the effects of center experience and a variety of patient- and procedure-related factors on patient radiation exposure during prostatic artery embolization (PAE) in three Scandinavian centers with different PAE protocols and levels of experience. Understanding factors that influence radiation exposure is crucial in effective patient selection and procedural planning. METHODS: Data were collected retrospectively for 352 consecutive PAE procedures from January 2015 to June 2020 at the three centers. Dose area product (DAP (Gy·cm2)) was selected as the primary outcome measure of radiation exposure. Multiple patient- and procedure-related explanatory variables were collected and correlated with the outcome variable. A multiple linear regression model was built to determine significant predictors of increased or decreased radiation exposure as reflected by DAP. RESULTS: There was considerable variation in DAP between the centers. Intended unilateral PAE (p = 0.03) and each 10 additional patients treated (p = 0.02) were significant predictors of decreased DAP. Conversely, increased patient body mass index (BMI, p < 0.001), fluoroscopy time (p < 0.001), and number of digital subtraction angiography (DSA) acquisitions (p < 0.001) were significant predictors of increased DAP. CONCLUSIONS: To minimize patient radiation exposure during PAE radiologists may, in collaboration with clinicians, consider unilateral embolization, pre-interventional CTA for procedure planning, using predominantly anteroposterior (AP) projections, and limiting the use of cone-beam CT (CBCT) and fluoroscopy. KEY POINTS: • Growing center experience and intended unilateral embolization decrease patient radiation exposure during prostatic artery embolization. • Patient BMI, fluoroscopy time, and number of DSA acquisitions are associated with increased DAP during procedures. • Large variation in radiation exposure between the centers may reflect the use of CTA before and CBCT during the procedure.

Prescription rates for drugs used in treatment of benign prostatic hyperplasia and erectile dysfunction before and after prostate cancer diagnosis.

BACKGROUND: Symptoms and treatment of benign prostatic hyperplasia (BPH) or erectile dysfunction (ED) may lead to prostate cancer workup, and patterns of prescriptions before diagnosis may affect findings of pharmacoepidemiological studies. Usage of BPH and ED drugs after diagnosis may be related to prostate cancer treatment. We investigated differences in prescription rates of BPH and ED drugs among prostate cancer patients and cancer-free comparisons and between patients with localized and non-localized disease. MATERIAL AND METHODS: A nationwide register-based study, including all Danish men aged 50-85 years diagnosed with prostate cancer during 1998-2015 and an age-matched comparison cohort without cancer. We calculated rates of new and total prescriptions in 1-month intervals from 3 years before to 3 years after cancer diagnosis for drugs used to treat BPH and ED, overall and stratified by clinical stage. RESULTS: We identified 54,286 men with prostate cancer and a comparison cohort of 249,645 age-matched men. The new prescription rate for BPH drugs increased for men with prostate cancer in the year before diagnosis and peaked 1 month before diagnosis with an 18-fold higher rate. Men with prostate cancer had a higher total prescription rate of BPH drugs 3 years before diagnosis, notably among men with localized disease. Before diagnosis, the new prescription rates for ED drugs were similar among men with prostate cancer and comparisons. After diagnosis, men with prostate cancer had a 7-fold higher rate of new prescriptions for ED drugs. Among men with localized disease, the total prescription rate of ED drugs increased in the months following diagnosis. CONCLUSION: Differences in prescription rates suggest increased prostate cancer surveillance among men receiving BPH drugs, whereas the post-diagnostic increase in ED drugs among men with localized disease is compatible with the increased risk of ED following prostate cancer treatment.

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

BACKGROUND: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. METHODS: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). INTERPRETATION: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. FUNDING: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

Risk of depression after diagnostic prostate cancer workup - A nationwide, registry-based study.

OBJECTIVE: To compare the risk of depression after diagnostic workup for prostate cancer (PCa), regardless of the histopathologic outcome, with that of a cancer-free population. METHODS: A nationwide cohort of Danish men who had a prostatic biopsy sample in 1998-2011 was identified from the Danish Prostate Cancer Registry and compared to an age-matched cohort from the background population. Men with other cancers, major psychiatric disorder, or prior use of antidepressants were excluded. The risk of depression defined as hospital contact for depression or prescription for antidepressants was determined from cumulative incidence functions and multivariate Cox regression models. RESULTS: Of 54,766 men who underwent diagnostic workup for PCa, benign results were found for 21,418 and PCa was diagnosed in 33,347. During up to 18 years of follow-up, the adjusted hazard of depression was higher in men with PCa than in the background population, with the highest risk in the two years after diagnosis (hazard ratio (HR) 2.77, 95% CI 2.66-2.87). Comorbidity and lowest or highest income were significant risk factors for depression and the cumulative incidence was substantially higher in men with metastatic or high-risk disease. In men with benign histopathology the HR for depression was 1.22 (95% CI 1.14-1.31) in the first two years but no different from the background population after that. CONCLUSIONS: Diagnostic workup for PCa is associated with an increased risk of depression, mainly among men with a diagnosis of PCa. Clinicians should be aware of depressive symptoms in prostate cancer patients.

The impact of positive surgical margins on salvage radiation or androgen deprivation therapy following radical prostatectomy - a nationwide study.

BACKGROUND: The extent to which positive surgical margins (PSM) affect the risk of subsequent salvage radiation therapy (sRT) or androgen depletion therapy (ADT) following radical prostatectomy (RP) is not well described. Initiation of additional therapies after RP depend on patient preference, individual factors, local guidelines, and life expectancy. The aim of this study was to analyze differences between margin status in risk of subsequent treatment for PCa following RP in a retrospective population-based cohort from Denmark. METHODS: Patients who underwent RP were identified in The Danish Prostate Cancer Registry (DaPCaR). Subsequent sRT and ADT were assessed in uni- and multivariate settings and validated with receiver operating characteristic (ROC). RESULTS: PSM was associated with an increased risk of sRT (HR = 1.85, p < .001) and receiving ADT (HR:1.39, p = .007). Margin status only had a minor impact on the predictive ability for sRT (area under the curve (AUC): p < .001) and no significant impact for subsequent ADT (AUC: p = 1). Significant inter-institutional difference in the association between PSM with sRT or ADT was observed. CONCLUSION: PSM is associated with the risk of sRT and initiation of ADT, however this association is weak. Our results underline that factors beyond tumor characteristics play a major role for initiation of sRT and ADT.

Vitamin D levels and the risk of prostate cancer and prostate cancer mortality.

BACKGROUND: Vitamin D has a role in bone turnover and potentially bone-metastatic spread of prostate cancer (PCa). The aim of this observational study was to address the association between levels of serum vitamin D, diagnosis of PCa and subsequent mortality in men who underwent a biopsy of the prostate. METHODS: All men who underwent prostatic biopsy in the Danish PCa Registry (DaPCaR) and who had a serum vitamin D measurement during the period 2004 to 2010 (n = 4,065) were identified. Men were categorized by clinical cut-offs based on seasonally adjusted serum vitamin D levels in <25 (deficient), 25-50 (insufficient), 50-75 (sufficient) and >75 nmol/L (high) serum vitamin D. Logistic regression model for association between vitamin D and risk of PCa diagnosis and multivariate survival analyses were applied. RESULTS: No association between serum vitamin D and risk of PCa was found. Overall survival was lowest for serum vitamin D deficiency and a significantly higher PCa specific mortality (HR: 2.37, 95%CI: 1.45-3.90, p < .001) and other cause mortality (HR: 2.08, 95%CI: 1.33-3.24, p = .001) was found for PCa patients with serum vitamin D deficiency compared to serum vitamin D sufficiency. CONCLUSION: No association was found between serum vitamin D categories and risk of PCa in men who underwent biopsy of the prostate. Men with PCa and serum vitamin D deficiency had a higher overall and PCa specific mortality compared to men with a sufficient level of serum vitamin D.

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.

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.

Trends in incidence and 5-year mortality in men with newly diagnosed, metastatic prostate cancer-A population-based analysis of 2 national cohorts.

BACKGROUND: Early detection has increased prostate cancer (PCa) incidence. Randomized trials have demonstrated that early detection reduces the incidence of de novo metastatic PCa. Concurrently, life-prolonging treatments have been introduced for patients with advanced PCa. On a populations-based level, the authors analyzed whether early detection and improved treatments changed the incidence and 5-year mortality of men with de novo metastatic PCa. METHODS: Men diagnosed with PCa during the periods 1980 to 2011 and 1995 to 2011 were identified in the US Surveillance, Epidemiology, and End Results (SEER) program and the Danish Prostate Cancer Registry (DaPCaR), respectively, and stratified according to period of diagnosis. Age-standardized incidence rates were calculated. Five-year mortality rates for de novo metastatic PCa were analyzed using competing risk analysis. RESULTS: Totals of 426,266 and 47,024 men were identified in SEER and DaPCaR, respectively. Of these, 29,555 and 6874 had de novo metastatic PCa. The incidence of de novo metastatic PCa decreased (from 12.0 to 4.4 per 100,000 men) in the SEER cohort (1980-2011), whereas it increased (from 6.7 to 9.9 per 100,000 men) in the DaPCaR cohort (1995-2011). Five-year PCa mortality in the SEER cohort was stable for men diagnosed with de novo metastatic PCa from 1980 to 1994 and increased slightly in the latest periods studied (P < .0001), whereas it decreased by 16.6% (P < .0001) in the DaPCaR cohort. CONCLUSIONS: Despite earlier detection, de novo metastatic PCa remains associated with a high risk of 5-year disease-specific mortality. The reduced 5-year PCa mortality in the Danish cohort is largely explained by lead-time. Early detection strategies do indeed decrease the incidence of de novo metastatic PCa, as observed in the SEER cohort. This achievement, however, must be weighed against the unsolved issue of overdetection and overtreatment of indolent PCa. Cancer 2018;124:2931-8. © 2018 American Cancer Society.

The impact of the 2005 International Society of Urological Pathology consensus guidelines on Gleason grading - a matched-pair analysis.

OBJECTIVES: To investigate whether the International Society of Urological Pathology (ISUP) 2005 revision of the Gleason grading system has influenced the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), as the new guideline implies that some prostate cancers previously graded as Gleason score 6 (3 + 3) are now considered as 7 (3 + 4). PATIENTS AND METHODS: A matched-pair analysis was conducted. In all, 215 patients with Gleason score 6 or 7 (3 + 4) prostate cancer on biopsy who underwent RP before 31 December 2005 (pre-ISUP group), were matched 1:1 by biopsy Gleason score, clinical tumour category, PSA level, and margin status to patients undergoing RP between 1 January 2008 and 31 December 2011 (post-ISUP group). Patients were followed until BCR defined as a PSA level of ≥0.2 ng/mL. Risk of BCR was analysed in a competing-risk model. RESULTS: The median follow-up was 9.5 years in the pre-ISUP group and 4.8 years in the post-ISUP group. The 5-year cumulative incidences of BCR were 34.0% and 13.9% in the pre-ISUP and post-ISUP groups, respectively (P < 0.001). The difference in cumulative incidence applied to both patients with Gleason score 6 (P < 0.001) and 7 (3 + 4) (P = 0.004). There was no difference in the 5-year cumulative incidence of BCR between patients with pre-ISUP Gleason score 6 and post-ISUP Gleason score 7 (3 + 4) (P = 0.34). In a multiple Cox-proportional hazard regression model, ISUP 2005 grading was a strong prognostic factor for BCR within 5 years of RP (hazard ratio 0.34; 95% confidence interval 0.22-0.54; P < 0.001). CONCLUSION: The revision of the Gleason grading system has reduced the risk of BCR after RP in patients with biopsy Gleason score 6 and 7 (3 + 4). This may have consequences when comparing outcomes across studies and historical periods and may affect future treatment recommendations.

[Allergen management in the food industry]. / Allergenmanagement in der Lebensmittelindustrie.

Due to the lack of causative immunotherapies, individuals with food allergies have to rely on correct labelling for even minute amounts of allergenic constituents. It is not relevant to the allergic whether the source of the culprit food is an ingredient or an allergen that entered the food unintentionally, as is the case with so-called cross-contacts or hidden allergens.Efficient allergen management is the manufacturer's prerequisite for coping with allergenic foods in the food production environment and handling them in a way that avoids cross-contact. If it is technically not feasible to eliminate cross-contacts entirely, it must be ensured that these cross-contacts do not enter the final product without being detected.This article discusses measures that should be considered in allergen management. Examples include recording all relevant allergens in the production facility, staff sensitization and training, and taking into account all areas of production from incoming raw materials to outgoing goods.For the evaluation of unavoidable cross-contacts, it is possible today to draw on data from clinical trials for many of the substances that are subject to labelling. This data can be used to assess the risk of the final product.However, the data from threshold studies is not legally binding, so it is left to the manufacturer to assess the level up to which the food is safe for the allergic. In particular the non-harmonized approach of the EU member countries' food safety authorities currently represents a major obstacle, as this can lead to food recalls even though existing levels were evaluated as being safe according to the risk assessments performed.

[Allergen analysis]. / Allergenanalytik.

The fundamental requirement when testing for and ensuring compliance with legally required labelling regulations is the reliable analysis of food allergens. This can be carried out by means of either DNA (deoxyribonucleic acid) or protein detection. Protein detection has the advantage of directly detecting the allergenic component and can currently be carried out using immunological (enzyme-linked immunosorbent assay [ELISA])/lateral flow devices [LFD]) or mass spectrometry-based techniques. DNA detection is indirect, but allows the presence of food allergens to be validated through the use of another marker. Each method has its pros and cons, which have to be considered on a case-by-case basis. ELISA is quantitative, quick and easy to carry out and has high sensitivity. LFD testing is ideal for industrial applications, as the tests can be carried out on-site. Both antibody-based tests may have problems with processed foods and false positive results. Mass-spectrometric techniques show a lot of promise, but are currently still time-consuming and complex to carry out. They also run into problems with processed foods and their degree of sensitivity is matrix and parameter dependent. For these reasons, this technique is only occasionally used. Polymerase chain reaction (PCR) provides the highest specificity and, depending on the target sequence, a very good to good level of sensitivity. Despite the high stability of DNA, PCR is still subject to the influence of processing and matrix related factors. Due to natural variation and production-related changes in the structures relevant in the process of detection, all methods exhibit a relatively high level of uncertainty of measurement. At present, there is no method which provides the absolute correct quantification. However, by means of laboratory-based analyses it is possible to calibrate for the allergen in question and thus be able to make reliable measurements using methods that are already available.

The predictive value of ERG protein expression for development of castration-resistant prostate cancer in hormone-naïve advanced prostate cancer treated with primary androgen deprivation therapy.

BACKGROUND: Biomarkers predicting response to primary androgen deprivation therapy (ADT) and risk of castration-resistant prostate cancer (CRPC) is lacking. We aimed to analyse the predictive value of ERG expression for development of CRPC. METHODS: In total, 194 patients with advanced and/or metastatic prostate cancer (PCa) treated with first-line castration-based ADT were included. ERG protein expression was analysed in diagnostic specimens using immunohistochemistry (anti-ERG, EPR3864). Time to CRPC was compared between ERG subgroups using multiple cause-specific Cox regression stratified on ERG-status. Risk reclassification and time-dependent area under the ROC curves were used to assess the discriminative ability of ERG-status. Time to PSA-nadir, proportion achieving PSA-nadir ≤0.2 ng/ml, and risk of PCa-specific death were secondary endpoints. RESULTS: Median follow-up was 6.8 years (IQR: 4.9-7.3). In total, 105 patients (54.1%) were ERG-positive and 89 (45.9%) were ERG-negative. No difference in risk of CRPC was observed between ERG subgroups (P = 0.51). Median time to CRPC was 3.9 years (95%CI: 3.2-5.1) and 4.5 years (95%CI: 2.3-not reached) in the ERG-positive and ERG-negative group, respectively. Compared to a model omitting ERG-status, the ERG-stratified model showed comparable AUC values 1 year (77.6% vs. 78.0%, P = 0.82), 2 years (71.7% vs. 71.8%, P = 0.85), 5 years (68.5% vs. 69.9%, P = 0.32), and 8 years (67.9% vs. 71.4%, P = 0.21) from ADT initiation. No differences in secondary endpoints were observed. CONCLUSIONS: ERG expression was not associated with risk of CRPC suggesting that ERG is not a candidate biomarker for predicting response to primary ADT in patients diagnosed with advanced and/or metastatic PCa.