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BACKGROUND: Adverse events induced by intravesical bacillus Calmette-Guérin (BCG) to treat high-grade non-muscle-invasive bladder cancer (NMIBC) often lead to treatment discontinuation. The EAU-RF NIMBUS trial found a reduced number of standard-dose BCG instillations to be inferior with the standard regimen. Nonetheless, it remains important to evaluate whether patients in the reduced BCG treatment arm had better quality of life (QoL) due to a possible reduction in toxicity or burden. OBJECTIVE: To evaluate whether patients in the EAU-RF NIMBUS trial experienced better QoL after a reduced BCG instillation frequency. DESIGN SETTING AND PARTICIPANTS: A total of 359 patients from 51 European sites were randomized to one of two treatment arms between December 2013 and July 2019. The standard frequency arm (n = 182) was 6 weeks of BCG induction followed by 3 weeks of maintenance at months 3, 6, and 12. The reduced frequency arm (n = 177) was BCG induction at weeks 1, 2, and 6, followed by maintenance instillations at weeks 1 and 3 of months 3, 6, and 12. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Analyses were performed using an intention-to-treat analysis and a per-protocol analysis. QoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 version 3.0 (QLQ-C30 v.03) prior to the first and last instillations of each BCG cycle. Group differences were determined using linear regression corrected for QoL at baseline. Differences in QoL over time were tested for significance using a linear mixed model. Side effects were recorded by the treating physician using a standardized form. Chi-square tests were used to compare the side-effect frequency between the arms. RESULTS AND LIMITATIONS: There were no significant differences in the means of each QoL scale between the two arms. There were also no significant changes over time in all QoL domains for both arms. However, differences in the incidence of general malaise at T1 (before the last induction instillation), frequency, urgency, and dysuria at T7 (before the last maintenance instillation) were detected in favor of the reduced frequency arm. CONCLUSIONS: Reducing the BCG instillation frequency does not improve the QoL in NMIBC patients despite lower storage symptoms. PATIENT SUMMARY: In this study, we evaluated whether a reduction in the number of received bacillus Calmette-Guérin instillations led to better quality of life in patients with high-grade non-muscle-invasive bladder cancer. We found no difference in the quality of life between the standard and the reduced bacillus Calmette-Guérin instillation frequency. We conclude that reducing the number of instillations does not lead to better quality of life in patients with high-grade non-muscle-invasive bladder cancer.

BackgroundCurrently, follow-up protocols are applied equally to men on active surveillance (AS) for prostate cancer (PCa) regardless of findings at their initial follow-up biopsy. To determine whether less intensive follow-up is suitable following negative biopsy findings, we assessed the risk of converting to active treatment, any subsequent upgrading, volume progression (>33% positive cores), and serious upgrading (grade group >2) for negative compared with positive findings on initial follow-up biopsy.Methods13,161 men from 24 centres participating in the Global Action Plan Active Surveillance Prostate Cancer [GAP3] consortium database, with baseline grade group ≤2, PSA ≤ 20 ng/mL, cT-stage 1-2, diagnosed after 1995, and ≥1 follow-up biopsy, were included in this study. Risk of converting to treatment was assessed using multivariable mixed-effects survival regression. Odds of volume progression, any upgrading and serious upgrading were assessed using mix-effects binary logistic regression for men with ≥2 surveillance biopsies.Results27% of the cohort (n = 3590) had no evidence of PCa at their initial biopsy. Over 50% of subsequent biopsies in this group were also negative. A negative initial biopsy was associated with lower risk of conversion (adjusted hazard ratio: 0.45; 95% confidence interval [CI]: 0.42-0.49), subsequent upgrading (adjusted odds ratio [OR]: 0.52; 95%CI: 0.45-0.62) and serious upgrading (OR: 0.74; 95%CI: 0.59-92). Radiological progression was not assessed due to limited imaging data.ConclusionDespite heterogeneity in follow-up schedules, findings from this global study indicated reduced risk of converting to treatment, volume progression, any upgrading and serious upgrading among men whose initial biopsy findings were negative compared with positive. Given the low risk of progression and high likelihood of further negative biopsy findings, consideration should be given to decreasing follow-up intensity for this group to reduce unnecessary invasive biopsies.

Objectives: To evaluate the feasibility of AI-assisted reading of prostate magnetic resonance imaging (MRI) in Organized Prostate cancer Testing (OPT). Methods: Retrospective cohort study including 57 men with elevated prostate-specific antigen (PSA) levels ≥3 µg/L that performed bi-parametric MRI in OPT. The results of a CE-marked deep learning (DL) algorithm for prostate MRI lesion detection were compared with assessments performed by on-site radiologists and reference radiologists. Per patient PI-RADS (Prostate Imaging-Reporting and Data System)/Likert scores were cross-tabulated and compared with biopsy outcomes, if performed. Positive MRI was defined as PI-RADS/Likert ≥4. Reader variability was assessed with weighted kappa scores. Results: The number of positive MRIs was 13 (23%), 8 (14%), and 29 (51%) for the local radiologists, expert consensus, and DL, respectively. Kappa scores were moderate for local radiologists versus expert consensus 0.55 (95% confidence interval [CI]: 0.37–0.74), slight for local radiologists versus DL 0.12 (95% CI: −0.07 to 0.32), and slight for expert consensus versus DL 0.17 (95% CI: −0.01 to 0.35). Out of 10 cases with biopsy proven prostate cancer with Gleason ≥3+4 the DL scored 7 as Likert ≥4. Interpretation: The Dl-algorithm showed low agreement with both local and expert radiologists. Training and validation of DL-algorithms in specific screening cohorts is essential before introduction in organized testing.

Background and objective: The treatment landscape of metastatic prostate cancer (mPCa) has evolved significantly over the past two decades. Despite this, the optimal therapy for patients with mPCa has not been determined. This systematic review identifies available predictive models that assess mPCa patients’ response to treatment. Methods: We critically reviewed MEDLINE and CENTRAL in December 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Only quantitative studies in English were included with no time restrictions. The quality of the included studies was assessed using the PROBAST tool. Data were extracted following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews criteria. Key findings and limitations: The search identified 616 citations, of which 15 studies were included in our review. Nine of the included studies were validated internally or externally. Only one study had a low risk of bias and a low risk concerning applicability. Many studies failed to detail model performance adequately, resulting in a high risk of bias. Where reported, the models indicated good or excellent performance. Conclusions and clinical implications: Most of the identified predictive models require additional evaluation and validation in properly designed studies before these can be implemented in clinical practice to assist with treatment decision-making for men with mPCa. Patient summary: In this review, we evaluate studies that predict which treatments will work best for which metastatic prostate cancer patients. We found that existing studies need further improvement before these can be used by health care professionals.

Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in “real-life” patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

Background and objective: The ability of health care professionals to communicate with patients compassionately and effectively is crucial for shared decision-making, but little research has investigated patient-clinician communication. As part of PIONEER—an international Big Data Consortium led by the European Association of Urology to answer key questions for men with prostate cancer (PCa), funded through the IMI2 Joint Undertaking under grant agreement 777492— we investigated communication between men diagnosed with PCa and the health care professional(s) treating them across Europe. Methods: We used the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Communication 26, which was shared via the PIONEER and patient organisations on March 11, 2022. We sought men who spoke French, Italian, Spanish, German, Dutch, or English who were diagnosed with PCa and were undergoing or had already received treatment for their PCa. Results and limitations: A total of 372 men reported that they communicated with their clinician during either the diagnostic or the treatment period. Overall, the majority of participants reported positive experiences. However, important opportunities to enhance communication were identified, particularly with regard to correcting misunderstandings, understanding the patient’s preferred approach to information presentation, addressing challenging questions, supporting the patient’s comprehension of information, attending to the patient’s emotional needs, and assessing what information had already been given to patients about their disease and treatment, and how much of it was understood. Conclusions and clinical implications: These results help us to identify gaps and barriers to shared treatment decision making. This knowledge will help devise measures to improve patient-health care professional communication in the PCa setting. Patient summary: As part of the PIONEER initiative, we investigated the communication between men diagnosed with prostate cancer and their health care professionals across Europe. A total of 372 men from six different countries participated in the study. Most participants reported positive experiences, but areas where communication could be improved were identified. These included addressing misunderstandings, tailoring the presentation of information to the patient’s preferences, handling difficult questions, supporting emotional needs, and assessing the patient’s understanding of their diagnosis and treatment.

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.SignificanceIn prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

BackgroundActive surveillance (AS) is a management option for men diagnosed with low-risk prostate cancer. Opinions differ on whether it is safe to include young men (≤60 yr) or men with intermediate-risk disease.ObjectiveTo assess whether reasons for discontinuation, treatment choice after AS, and adverse pathology at radical prostatectomy (RP; N1, or ≥GG3, or ≥pT3) differ for men ≤60 yr or those with European Association of Urology (EAU) intermediate-risk disease from those for men >60 yr or those with EAU low-risk disease.Design setting and participantsWe analyzed data from 5411 men ≤60 yr and 14 959 men >60 yr, 14 064 men with low-risk cancer, and 2441 men with intermediate-risk cancer, originating from the GAP3 database (21 169 patients/27 cohorts worldwide).Outcome measurements and statistical analysisCumulative incidence curves were used to estimate the rates of AS discontinuation and treatment choice.Results and limitationsThe probability of discontinuation of AS due to disease progression at 5 yr was similar for men aged ≤60 yr (22%) and those >60 yr (25%), as well as those of any age with low-risk disease (24%) versus those with intermediate-risk disease (24%). Men with intermediate-risk disease are more prone to discontinue AS without evidence of progression than men with low-risk disease (at 1/5 yr: 5.9%/14.2% vs 2.0%/8.8%). Adverse pathology at RP was observed in 32% of men ≤60 yr compared with 36% of men >60 yr (p = 0.029), and in 34% with low-risk disease compared with 40% with intermediate-risk disease (p = 0.048).ConclusionsOur descriptive analysis of AS practices worldwide showed that the risk of progression during AS is similar across the age and risk groups studied. The proportion of adverse pathology was higher among men >60 yr than among men ≤60 yr. These results suggest that men ≤60 yr and those with EAU intermediate-risk disease should not be excluded from opting for AS as initial management.Patient summaryData from 27 international centers reflecting daily clinical practice suggest that younger men or men with intermediate-risk prostate cancer do not hold greater risk for disease progression during active surveillance.

BackgroundThe optimal interval for repeat biopsy during active surveillance (AS) for prostate cancer is yet to be defined. This study examined whether risk of upgrading (to grade group ≥ 2) or risk of converting to treatment varied according to intensity of repeat biopsy using data from the GAP3 consortium's global AS database.Materials and methodsIntensity of surveillance biopsy schedules was categorized according to centers' protocols: (a) Prostate Cancer Research International Active Surveillance project (PRIAS) protocols with biopsies at years 1, 4, and 7 (10 centers; 7532 men); (b) biennial biopsies, that is, every other year (8 centers; 4365 men); and (c) annual biopsy schedules (4 centers; 1602 men). Multivariable Cox regression was used to compare outcomes according to biopsy intensity.ResultsOut of the 13,508 eligible participants, 56% were managed according to PRIAS protocols (biopsies at years 1, 4, and 7), 32% via biennial biopsy, and 12% via annual biopsy. After adjusting for baseline characteristics, risk of converting to treatment was greater for those on annual compared with PRIAS biopsy schedules (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.51-1.83; p

PurposeThe application of automated image analyses could improve and facilitate standardization and consistency of quantification in [18F]DCFPyL (PSMA) PET/CT scans. In the current study, we analytically validated aPROMISE, a software as a medical device that segments organs in low-dose CT images with deep learning, and subsequently detects and quantifies potential pathological lesions in PSMA PET/CT.MethodsTo evaluate the deep learning algorithm, the automated segmentations of the low-dose CT component of PSMA PET/CT scans from 20 patients were compared to manual segmentations. Dice scores were used to quantify the similarities between the automated and manual segmentations. Next, the automated quantification of tracer uptake in the reference organs and detection and pre-segmentation of potential lesions were evaluated in 339 patients with prostate cancer, who were all enrolled in the phase II/III OSPREY study. Three nuclear medicine physicians performed the retrospective independent reads of OSPREY images with aPROMISE. Quantitative consistency was assessed by the pairwise Pearson correlations and standard deviation between the readers and aPROMISE. The sensitivity of detection and pre-segmentation of potential lesions was evaluated by determining the percent of manually selected abnormal lesions that were automatically detected by aPROMISE.ResultsThe Dice scores for bone segmentations ranged from 0.88 to 0.95. The Dice scores of the PSMA PET/CT reference organs, thoracic aorta and liver, were 0.89 and 0.97, respectively. Dice scores of other visceral organs, including prostate, were observed to be above 0.79. The Pearson correlation for blood pool reference was higher between any manual reader and aPROMISE, than between any pair of manual readers. The standard deviations of reference organ uptake across all patients as determined by aPROMISE (SD = 0.21 blood pool and SD = 1.16 liver) were lower compared to those of the manual readers. Finally, the sensitivity of aPROMISE detection and pre-segmentation was 91.5% for regional lymph nodes, 90.6% for all lymph nodes, and 86.7% for bone in metastatic patients.ConclusionIn this analytical study, we demonstrated the segmentation accuracy of the deep learning algorithm, the consistency in quantitative assessment across multiple readers, and the high sensitivity in detecting potential lesions. The study provides a foundational framework for clinical evaluation of aPROMISE in standardized reporting of PSMA PET/CT.

BackgroundThe inclusion criterion for active surveillance (AS) is low- or intermediate-risk prostate cancer. The predictive value of the presence of a suspicious lesion at magnetic resonance imaging (MRI) at the time of inclusion is insufficiently known.ObjectiveTo evaluate the percentage of patients needing active treatment stratified by the presence or absence of a suspicious lesion at baseline MRI.Design setting and participantsA retrospective analysis of the data from the multicentric AS GAP3 Consortium database was conducted. The inclusion criteria were men with grade group (GG) 1 or GG 2 prostate cancer combined with prostate-specific antigen

Cancer survivorship was recently identified as a prostate cancer (PCa) research priority by PIONEER, a European network of excellence for big data in PCa. Despite being a research priority, cancer survivorship lacks a clear and agreed definition, and there is a distinct paucity of patient-reported outcome (PRO) data available on the subject. Data collection on cancer survivorship depends on the availability and implementation of (validated) routinely collected patient-reported outcome measures (PROMs). There have been recent advances in the availability of such PROMs. For instance, the European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) is developing survivorship questionnaires. This provides an excellent first step in improving the data available on cancer survivorship. However, we propose that an agreed, standardised definition of (prostate) cancer survivorship must first be established. Only then can real-world data on survivorship be collected to strengthen our knowledge base. With more men than ever surviving PCa, this type of research is imperative to ensure that the quality of life of these men is considered as much as their quantity of life. Patient summary: As there are more prostate cancer survivors than ever before, research into cancer survivorship is crucial. We highlight the importance of such research and provide recommendations on how to carry it out. The first step should be establishing agreement on a standardised definition of survivorship. From this, patient-reported outcome measures can then be used to collect important survivorship data.

ObjectiveTo assess whether adding prostate volume to the kallikrein panel improves discrimination for ISUP Grade Group 2 or higher (GG2+) disease, as some men may have volume measurements available at the time of blood draw. While prostate volume predicts biopsy outcome, it requires an imaging procedure for measurement. The four kallikrein panel - commercially available as the 4Kscore - predicts risk of GG2+ disease and requires only a blood draw.Materials and methodsA total of 9131 patients with available prostate volume and total PSA ≤25 ng/ml from 5 historical (sextant biopsy, pre-ISUP 2005 grading) and 4 contemporary cohorts (10+ cores, ISUP 2005 grading). Previously published kallikrein panel models were used to predict risk of GG2+. Volume was added to the model in each cohort and change in discrimination was meta-analyzed.ResultsIncreased prostate volume was associated with decreased risk of GG2+ disease after controlling for the kallikrein panel in 7/9 cohorts. However, kallikrein panel discrimination (0.817, 95% CI 0.802, 0.831) was not improved after including volume (AUC difference 0.002, 95% CI -0.003, 0.006). Heterogeneity (P

Abstract Background High expression of the RNA-binding protein RBM3 has previously been found to be associated with good prognosis in breast cancer, ovarian cancer, malignant melanoma and colorectal cancer. The aim of this study was to examine the prognostic impact of immunohistochemical RBM3 expression in prostate cancer. Findings Immunohistochemical RBM3 expression was examined in a tissue microarray with malignant and benign prostatic specimens from 88 patients treated with radical prostatectomy for localized disease. While rarely expressed in benign prostate gland epithelium, RBM3 was found to be up-regulated in prostate intraepithelial neoplasia and present in various fractions and intensities in invasive prostate cancer. High nuclear RBM3 expression was significantly associated with a prolonged time to biochemical recurrence (BCR) (HR 0.56, 95% CI: 0.34-0.93, p = 0.024) and clinical progression (HR 0.09, 95% CI: 0.01-0.71, p = 0.021). These associations remained significant in multivariate analysis, adjusted for preoperative PSA level in blood, pathological Gleason score and presence or absence of extracapsular extension, seminal vesicle invasion and positive surgical margin (HR 0.41, 95% CI: 0.19-0.89, p = 0.024 for BCR and HR 0.06, 95% CI: 0.01-0.50, p = 0.009 for clinical progression). Conclusion Our results demonstrate that high nuclear expression of RBM3 in prostate cancer is associated with a prolonged time to disease progression and, thus, a potential biomarker of favourable prognosis. The value of RBM3 for prognostication, treatment stratification and follow-up of prostate cancer patients should be further validated in larger studies.

Abstract Background We have previously demonstrated that elevated concentrations of tumour-associated trypsin inhibitor (TATI) in both tumour tissue (t-TATI) and in serum (s-TATI) are associated with a poor prognosis in colorectal cancer patients. It was also found that s-TATI concentrations were lower in patients with rectal cancer compared to patients with colon cancer. In this study, we investigated the effects of neoadjuvant radiotherapy (RT) on concentrations of t-TATI and s-TATI in patients with rectal cancer. Methods TATI was analysed in serum, normal mucosa and tumour tissue collected at various time points in 53 rectal cancer patients enrolled in a case-control study where 12 patients received surgery alone, 20 patients 5 × 5 Gy (short-term) preoperative RT and 21 patients 25 × 2 Gy (long-term) preoperative RT. T-TATI was analysed by immunohistochemistry and s-TATI was determined by an immunofluorometric assay. Mann-Whitney U test and Wilcoxon Z (Z) test were used to assess t-TATI and s-TATI concentrations in relation to RT. Spearman's correlation (R) test was used to explore the associations between t-TATI, s-TATI and clinicopathological parameters. Overall survival (OS) according to high and low t-TATI and s-TATI concentrations was estimated by classification and regression tree analysis, Kaplan-Meier analysis and the log rank test. Results RT did not affect concentrations of t-TATI or s-TATI. In patients receiving short-term but not long-term RT, s-TATI concentrations were significantly higher 4 weeks post surgery than in serum drawn prior to surgery (Z = -3.366, P < 0.001). T-TATI expression correlated with male gender (R = 0.406, P = 0.008). High t-TATI expression in surgical specimens was associated with a significantly shorter OS (P = 0.045). S-TATI concentrations in serum drawn at all time points were associated with an impaired OS (P = 0.035 before RT, P = 0.001 prior to surgery, P = 0.043 post surgery). At all time points, s-TATI correlated with higher age (P < 0.001-0.021) and with increased s-creatinine concentrations assessed prior to surgery (P = 0.041). Conclusions The results presented here further validate the utility of t-TATI and s-TATI as prognostic biomarkers in patients with rectal cancer, independent of neoadjuvant RT.

Abstract Background There is an insufficient number of reliable prognostic and response predictive biomarkers in colorectal cancer (CRC) management. In a previous study, we found that high tumour tissue expression of tumour-associated trypsin inhibitor (TATI) correlated with liver metastasis and an impaired prognosis in CRC. The aim of this study was to investigate the prognostic validity of serum TATI (s-TATI) in CRC. We further assessed the prognostic value of carcino-embryonic antigen in serum (s-CEA) and the interrelationship between s-TATI and TATI in tissue (t-TATI). Methods Using an immunofluorometric assay, s-TATI levels were analysed in 334 preoperatively collected serum samples from patients with CRC. Spearman's Rho and Chi-square test were used for analysis of correlations between s-TATI and clinicopathological parameters, s-CEA and t-TATI. Kaplan-Meier analysis and Cox uni- and multivariate regression analysis were used to estimate disease free survival (DFS) and overall survival (OS) according to quartiles of s-TATI and cut-offs derived from ROC-analysis of s-TATI and s-CEA. Results Increased levels of s-TATI were associated with a reduced DFS (HR = 2.00; 95% CI 1.40-2.84, P < 0.001) and OS (HR = 2.40; 95% CI 1.74-3.33, P < 0.001). (HR = 2.89; 95% CI 1.96-4.25). This association remained significant in multivariate analysis. The association for OS remained significant in multivariate analysis (HR = 1.51; 95% CI 1.03-2.22, P = 0.034 for DFS and HR = 1.78; 95% CI 1.25-2.53, P = 0.001 for OS). There was no significant association between s-TATI and t-TATI. The prognostic value of s-CEA was also evident, but somewhat weaker than for s-TATI. Conclusions High preoperative s-TATI levels predict a poor prognosis in patients with CRC, and the prognostic value is independent of established prognostic parameters and t-TATI expression. These data suggest that s-TATI might be a useful marker for prognostic stratification in CRC.

Abstract Background Death of smooth muscle cells in the atherosclerotic plaques makes the plaques more prone to rupture, which can initiate an acute ischemic event. The development of atherosclerosis includes the migration of immune cells e.g. monocytes/macrophages and T lymphocytes into the lesions. Immune cells can release antimicrobial peptides. One of these, human cathelicidin antimicrobial peptide hCAP-18, is cleaved by proteinase 3 generating a 4.5 kDa C-terminal fragment named LL-37, which has been shown to be cytotoxic. The aim of the study was to explore a potential role of LL-37 in the pathophysiology of atherosclerosis. Methods We investigated the presence of LL-37 in human atherosclerotic lesions obtained at autopsy using immunohistochemistry. The direct effects of LL-37 on cultured vascular smooth muscle cells and isolated neutrophil granulocytes were investigated with morphological, biochemical and flow cytometry analysis. Results The neointima of atherosclerotic plaques was found to contain LL-37-like immunoreactivity, mainly in macrophages. In cultured smooth muscle cells, LL-37 at 30 μg/ml caused cell shrinkage, membrane blebbing, nuclear condensation, DNA fragmentation and an increase in caspase-3 activity as studied by microscopy, ELISA and enzyme activity assay, respectively. Flow cytometry demonstrated that LL-37 in a subset of the cells caused a small but rapidly developing increase in membrane permeability to propidium iodide, followed by a gradual development of FITC-annexin V binding. Another cell population stained heavily with both propidium iodide and FITC-annexin V. Neutrophil granulocytes were resistant to these effects of LL-37. Conclusion This study shows that LL-37 is present in atherosclerotic lesions and that it induces death of vascular smooth muscle cells. In a subset of cells, the changes indicate the development of apoptosis triggered by an initial mild perturbation of plasma membrane integrity. The findings suggest a role for LL-37 as a mediator of immune cell-induced death of vascular smooth muscle cells in atherosclerosis.

BackgroundAccurate tumor volume estimation is important for evaluating the response to radionuclide therapy and external beam radiotherapy as well as to other pharmaceuticals. A common method for monitoring the growth of subcutaneous tumors in pre-clinical models and assessing the treatment response is to measure the tumor length and width by external calipers to estimate its volume. This procedure relies on an assumption of a spheroidal tumor shape wherein the tumor depth equals the width and can yield considerably inaccuracies. Ultrasound imaging is a non-invasive technique that can measure all three axes of the tumor and might be an alternative to caliper measurement with potentially greater accuracy and comparable ease-of-use and throughput. Both 2D and 3D ultrasound imaging are possible, the former offering short scan times without the need for anesthesia and heating-valuable factors for longitudinal studies in large animal cohorts. Nevertheless, tumor volume estimation accuracy by 2D ultrasound imaging has seen limited investigation. In this study we have evaluated the accuracy of tumor volume estimation by caliper and 2D ultrasound with comparisons to reference measurements by magnetic resonance imaging (MRI) in a pre-clinical model of prostate cancer treated with either external beam radiotherapy, radionuclide therapy, or no treatment.ResultsTumor volumes were measured longitudinally in 29 mice by caliper, ultrasound, and MRI before and after external beam radiotherapy, [177Lu]Lu-PSMA-617 radionuclide therapy, or no treatment. Caliper measurements had a marked bias, overestimating the tumor volumes by a median of 150% compared to MRI. Ultrasound measurements were markedly more accurate, with a median bias of -21% compared to MRI.ConclusionUltrasound imaging is a reliable and accurate method for tumor volume estimation in pre-clinical models of radiotherapy, whereas caliper measurements are prone to overestimation.

ObjectiveTo develop a model and methodology for predicting the risk of Gleason upgrading in patients with prostate cancer on active surveillance (AS) and using the predicted risks to create risk-based personalised biopsy schedules as an alternative to one-size-fits-all schedules (e.g. annually). Furthermore, to assist patients and doctors in making shared decisions on biopsy schedules, by providing them quantitative estimates of the burden and benefit of opting for personalised vs any other schedule in AS. Lastly, to externally validate our model and implement it along with personalised schedules in a ready to use web-application.Patients and methodsRepeat prostate-specific antigen (PSA) measurements, timing and results of previous biopsies, and age at baseline from the world's largest AS study, Prostate Cancer Research International Active Surveillance (PRIAS; 7813 patients, 1134 experienced upgrading). We fitted a Bayesian joint model for time-to-event and longitudinal data to this dataset. We then validated our model externally in the largest six AS cohorts of the Movember Foundation's third Global Action Plan (GAP3) database (>20 000 patients, 27 centres worldwide). Using the model predicted upgrading risks; we scheduled biopsies whenever a patient's upgrading risk was above a certain threshold. To assist patients/doctors in the choice of this threshold, and to compare the resulting personalised schedule with currently practiced schedules, along with the timing and the total number of biopsies (burden) planned, for each schedule we provided them with the time delay expected in detecting upgrading (shorter is better).ResultsThe cause-specific cumulative upgrading risk at the 5-year follow-up was 35% in PRIAS, and at most 50% in the GAP3 cohorts. In the PRIAS-based model, PSA velocity was a stronger predictor of upgrading (hazard ratio [HR] 2.47, 95% confidence interval [CI] 1.93-2.99) than the PSA level (HR 0.99, 95% CI 0.89-1.11). Our model had a moderate area under the receiver operating characteristic curve (0.6-0.7) in the validation cohorts. The prediction error was moderate (0.1-0.2) in theGAP3 cohorts where the impact of the PSA level and velocity on upgrading risk was similar to PRIAS, but large (0.2-0.3) otherwise. Our model required re-calibration of baseline upgrading risk in the validation cohorts. We implemented the validated models and the methodology for personalised schedules in a web-application (http://tiny.cc/biopsy).ConclusionsWe successfully developed and validated a model for predicting upgrading risk, and providing risk-based personalised biopsy decisions in AS of prostate cancer. Personalised prostate biopsies are a novel alternative to fixed one-size-fits-all schedules, which may help to reduce unnecessary prostate biopsies, while maintaining cancer control. The model and schedules made available via a web-application enable shared decision-making on biopsy schedules by comparing fixed and personalised schedules on total biopsies and expected time delay in detecting upgrading.

BackgroundInnovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.ObjectiveTo present the results from the APCCC 2019.Design, setting, and participantsSimilar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.Outcome measurements and statistical analysisThe panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.Results and limitationsPanellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.ConclusionsThese voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.Patient summaryThe Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.

BackgroundCareful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa).ObjectiveUsing Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation.Design, setting, and participantsWe compared data from 10296 men on AS from 21 centres across 12 countries.Outcome measurements and statistical analysisCumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation.Results and limitationsDuring 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4-28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0-13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5-2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4-2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5yr, 4561 had follow-up for