Extracellular vesicles for precision medicine in prostate cancer - Is it ready for clinical translation?

Biofluid-based biomarker tests hold great promise for precision medicine in prostate cancer (PCa) clinical practice. Extracellular vesicles (EV) are established as intercellular messengers in cancer development with EV cargos, including protein and nucleic acids, having the potential to serve as biofluid-based biomarkers. Recent clinical studies have begun to evaluate EV-based biomarkers for PCa diagnosis, prognosis, and disease/therapy resistance monitoring. Promising results have led to PCa EV biomarker validation studies which are currently underway with the next challenge being translation to robust clinical assays. However, EV research studies generally use low throughput EV isolation methods and costly molecular profiling technologies that are not suitable for clinical assays. Here, we consider the technical hurdles in translating EV biomarker research findings into precise and cost-effective clinical biomarker assays. Novel microfluidic devices coupling EV extraction with sensitive antibody-based biomarker detection are already being explored for point-of-care applications for rapid provision in personalised medicine approaches.

The Dedicated Imaging Post-Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) trial protocol: a multicentre, randomised trial of salvage radiotherapy versus surveillance for low-risk biochemical recurrence after radical prostatectomy.

BACKGROUND: Salvage radiation therapy (SRT) and surveillance for low-risk prostate-specific antigen (PSA) recurrence have competing risks and benefits. The efficacy of early SRT to the prostate bed with or without pelvic lymph nodes compared to surveillance in patients with PSA recurrence after radical prostatectomy and no identifiable recurrent disease evident on prostate specific membrane antigen-positron emission tomography/computer tomography (PSMA-PET/CT) is unknown. STUDY DESIGN: The Dedicated Imaging Post-Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) is an open-label, multicentre, randomised Phase II trial. ENDPOINTS: The primary endpoint is 3-year event-free survival, with events comprising one of PSA recurrence (PSA ≥0.2 ng/mL higher than baseline), radiological evidence of metastatic disease, or initiation of systemic or other salvage treatments. Secondary endpoints include patient-reported outcomes, treatment patterns, participant perceptions, and cost-effectiveness. ELIGIBILITY CRITERIA: Eligible participants have PSA recurrence of prostate cancer after radical prostatectomy, defined by serum PSA level of 0.2-0.5 ng/mL, deemed low risk according to modified European Association of Urology biochemical recurrence risk criteria (International Society for Urological Pathology Grade Group ≤2, PSA doubling time >12 months), with no definite/probable recurrent prostate cancer on PSMA-PET/CT. PATIENTS AND METHODS: A total of 100 participants will be recruited from five Australian centres and randomised 1:1 to SRT or surveillance. Participants will undergo 6-monthly clinical evaluation for up to 36 months. Androgen-deprivation therapy is not permissible. Enrolment commenced May 2023. TRIAL REGISTRATION: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN: ACTRN12622001478707).

Intra-individual comparison of prostate-specific membrane antigen positron emission tomography/computed tomography versus bone scan in detecting skeletal metastasis at prostate cancer diagnosis.

OBJECTIVES: To compare the diagnostic performance and radiological staging impact of 68 Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) compared to 99 Tc whole-body bone scan (WBBS) for the detection of skeletal metastasis in the primary staging of prostate cancer (PCa). PATIENTS AND METHODS: A prospective institutional database was retrospectively examined for patients who underwent both PSMA PET and WBBS within a 1 week interval for PCa primary staging. Lesions were categorised as 'negative', 'equivocal', or 'definite' based on nuclear medicine physician interpretation. Metastatic burden was characterised for each imaging modality according to three groups: (i) local disease (no skeletal metastases), (ii) oligometastatic disease (three or fewer skeletal metastases), or (iii) polymetastatic disease (more than three skeletal metastases). RESULTS: There were 667 patients included. The median (interquartile range) prostate-specific antigen level was 9.2 (6.2-16) ng/mL and 60% of patients were high risk according to a modified D'Amico risk classification. The overall distribution of skeletal metastasis detection changed across the two scans overall (P = 0.003), being maintained within high-risk (P = 0.030) and low-risk (P = 0.018) groups. PSMA PET/CT identified more definite skeletal metastases compared to WBBS overall (10.3% vs 7.3%), and according to risk grouping (high: 12% vs 9%, intermediate: 4% vs 1%). Upstaging was more common with PSMA PET/CT than WBBS (P = 0.001). The maximum standardised uptake value (SUVmax ) of the primary tumour was associated with upstaging of skeletal metastases on PSMA PET/CT (P = 0.025), while age was associated with upstaging on WBBS (P = 0.021). The SUVmax of the primary tumour and metastases were both higher according to extent of metastatic disease (P = 0.001 and P < 0.001, respectively). CONCLUSIONS: More skeletal metastases were detected with PSMA PET/CT than WBBS, resulting in a higher upstaging rate mostly in high-risk patients. The SUVmax of the primary tumour and metastases was associated with upstaging.

Prediction of biochemical recurrence after radical prostatectomy from primary tumour characteristics.

OBJECTIVES: To construct and externally calibrate a predictive model for early biochemical recurrence (BCR) after radical prostatectomy (RP) incorporating clinical and modern imaging characteristics of the primary tumour. PATIENTS AND METHODS: Patients who underwent RP following multiparametric magnetic resonance imaging, prostate biopsy and prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA-PET/CT), from two centres in Australia and the Netherlands. The primary outcome was biochemical recurrence-free survival (BRFS), where BCR was defined as a rising PSA level of ≥0.2 ng/mL or initiation of postoperative treatment per clinician discretion. Proportional hazards models to predict time to event were developed in the Australian sample using relevant pre- and post-surgical parameters and primary tumour maximum standardised uptake value (SUVmax) on diagnostic PSMA-PET/CT. Calibration was assessed in an external dataset from the Netherlands with the same inclusion criteria. RESULTS: Data from 846 patients were used to develop the models. Tumour SUVmax was associated with worse predicted 3-year BRFS for both pre- and post-surgical models. SUVmax change from 4 to 16 lessened the predicted 3-year BRFS from 66% to 42% for a patient aged 65 years with typical pre-surgical parameters (PSA level 8 ng/mL, Prostate Imaging-Reporting and Data System score 4/5 and biopsy Gleason score ≥4 + 5). Considering post-surgical variables, a patient with the same age and PSA level but pathological stage pT3a, RP Gleason score ≥4 + 5 and negative margins, SUVmax change from 4 to 16 lessened the predicted 3-year BRFS from 76% to 61%. Calibration on an external sample (n = 464) showed reasonable performance; however, a tendency to overestimate survival in patients with good prognostic factors was observed. CONCLUSION: Tumour SUVmax on diagnostic PSMA-PET/CT has utility additional to commonly recognised variables for prediction of BRFS after RP.

The Cost-Effectiveness of Germline BReast CAncer Gene Testing in Metastatic Prostate Cancer Followed by Cascade Testing of First-Degree Relatives of Mutation Carriers.

OBJECTIVES: Patients with metastatic prostate cancer (mPCa) with BReast CAncer gene (BRCA) mutations benefit from targeted treatments (eg, olaparib). In addition, family members of affected patients have increased risk of hereditary cancers and benefit from early detection and prevention. International guidelines recommend genetic testing in mPCa; however, the value for money of testing patients with mPCa and cascade testing of blood-related family members has not been assessed. In this context, we evaluated the cost-effectiveness of germline BRCA testing in patients with mPCa followed by cascade testing of first-degree relatives (FDRs) of mutation carriers. METHODS: We conducted a cost-utility analysis of germline BRCA testing using 2 scenarios: (1) testing patients with mPCa only and (2) testing patients with mPCa and FDRs of those who test positive. A semi-Markov multi-health-state transition model was constructed using a lifetime time horizon. The analyses were performed from an Australian payer perspective. Decision uncertainty was characterized using probabilistic analyses. RESULTS: Compared with no testing, BRCA testing in mPCa was associated with an incremental cost of AU$3731 and a gain of 0.014 quality-adjusted life-years (QALYs), resulting in an incremental cost-effectiveness ratio of AU$265 942/QALY. Extending testing to FDRs of variant-positive patients resulted in an incremental cost-effectiveness ratio of AU$16 392/QALY. Probability of cost-effectiveness at a willingness-to-pay of AU$75 000/QALY was 0% in the standalone mPCa analysis and 100% in the cascade testing analysis. CONCLUSION: BRCA testing when performed as a standalone strategy in patients with mPCa may not be cost-effective but demonstrates significant value for money after the inclusion of cascade testing of FDRs of mutation carriers.

Associations of objectively measured physical activity, sedentary time and cardiorespiratory fitness with adipose tissue insulin resistance and ectopic fat.

BACKGROUND/OBJECTIVES: Inadequate movement, excess adiposity, and insulin resistance augment cardiometabolic risk. This study examined the associations of objectively measured moderate-to-vigorous intensity physical activity (MVPA), sedentary time and cardiorespiratory fitness (CRF), with adipose tissue insulin resistance and ectopic fat. METHODS: Data were combined from two previous experimental studies with community volunteers (n = 141, male = 60%, median (interquartile range) age = 37 (19) years, body mass index (BMI) = 26.1 (6.3) kg·m-2). Adipose tissue insulin resistance was assessed using the adipose tissue insulin resistance index (Adipo-IR); whilst magnetic resonance imaging (MRI) was used to measure liver, visceral (VAT) and subcutaneous abdominal adipose tissue (ScAT). Sedentary time and MVPA were measured via an ActiGraph GT3X+ accelerometer. Generalized linear models examined the association of CRF, MVPA, and sedentary time with Adipo-IR and fat depots. Interaction terms explored the moderating influence of age, sex, BMI and CRF. RESULTS: After controlling for BMI and cardiometabolic variables, sedentary time was positively associated with Adipo-IR (ß = 0.68 AU [95%CI = 0.27 to 1.10], P < 0.001). The association between sedentary time and Adipo-IR was moderated by age, CRF and BMI; such that it was stronger in individuals who were older, had lower CRF and had a higher BMI. Sedentary time was also positively associated with VAT (ß = 0.05 L [95%CI = 0.01 to 0.08], P = 0.005) with the relationship being stronger in females than males. CRF was inversely associated with VAT (ß = -0.02 L [95%CI = -0.04 to -0.01], P = 0.003) and ScAT (ß = -0.10 L [95%CI = -0.13 to -0.06], P < 0.001); with sex and BMI moderating the strength of associations with VAT and ScAT, respectively. CONCLUSIONS: Sedentary time is positively associated with adipose tissue insulin resistance which regulates lipogenesis and lipolysis. CRF is independently related to central fat storage which is a key risk factor for cardiometabolic disease.

Clinical impact of Prostate-Specific Membrane Antigen Positron Emission Tomography (PET) on intensification or deintensification of advanced renal cell carcinoma management.

PURPOSE: There is an emerging role of the use of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in renal cell carcinoma. Herein, we report our experience in use of PSMA PET in recurrent or metastatic renal cell carcinoma (RCC). METHODS: A retrospective analysis of all patients who underwent PSMA PET for suspected recurrent or de-novo metastatic RCC between 2015 and 2020 at three institutions was performed. The primary outcome was change in management (intensification or de-intensification) following PSMA PET scan. Secondary outcomes included histopathological correlation of PSMA avid sites, comparison of sites of disease on PSMA PET to diagnostic CT and time to systemic treatment.

Synchronous vs independent reading of prostate-specific membrane antigen positron emission tomography (PSMA-PET) and magnetic resonance imaging (MRI) to improve diagnosis of prostate cancer.

OBJECTIVES: To identify whether synchronous reading of multiparametric magnetic resonance imaging (mpMRI) and 68 Ga-PSMA-11 positron emission tomography (PET)/computed tomography (prostate-specific membrane antigen [PSMA-PET]) images can improve diagnostic performance and certainty compared with mpMRI/PSMA-PET reported independently and synthesized, while also assessing concordance between imaging modalities and agreement with histopathology. METHODS: This was a retrospective analysis of 100 patients randomly selected from the PRIMARY trial, a prospective Phase II multicentre imaging trial. Three dual-trained radiologist/nuclear medicine physicians re-reported the mpMRI and PSMA-PET both independently and synchronously for the same patients in random order, blinded to previous results. Diagnostic performance was assessed for mpMRI/PSMA-PET images read synchronously or independently and then synthesized. Agreement between imaging results and histopathology was examined. 'Concordance' between imaging modalities was defined as overlapping lesions. Reporting certainty was evaluated by the individual reporters for each modality. RESULTS: International Society of Urological Pathology Grade Group ≥2 cancer was present in 60% of patients on biopsy. Synchronous reading of mpMRI/PSMA-PET increased sensitivity compared to mpMRI or PSMA-PET alone (93% vs 80% vs 88%, respectively), although specificity was not improved (63% vs 58% vs 78%, respectively). No significant difference in diagnostic performance was noted between mpMRI/PSMA-PET read synchronously and mpMRI or PSMA-PET reported independently and then synthesized. Most patients had concordant imaging (60%), while others had discordant lesions only (28%) or a mixture (concordant and discordant lesions; 12%). When mpMRI/PSMA-PET findings were concordant and positive, 95% of patients had clinically significant prostate cancer (csPCa). When PSMA-PET alone was compared to synchronous PSMA-PET/MRI reads, there was an improvement in reader certainty in 20% of scans. CONCLUSION: Synchronous mpMRI/PSMA-PET reading improves reader certainty and sensitivity for csPCa compared to mpMRI or PSMA-PET alone. However, synthesizing the results of independently read PSMA-PET and mpMRI reports provided similar diagnostic performance to synchronous PSMA-PET/MRI reads. This may provide greater flexibility for urologists in terms of referral patterns, reducing healthcare system costs and improving efficiencies in prostate cancer diagnosis.

Reducing Bias and Quantifying Uncertainty in Fluorescence Produced by PCR.

We present a new approach for relating nucleic-acid content to fluorescence in a real-time Polymerase Chain Reaction (PCR) assay. By coupling a two-type branching process for PCR with a fluorescence analog of Beer's Law, the approach reduces bias and quantifies uncertainty in fluorescence. As the two-type branching process distinguishes between complementary strands of DNA, it allows for a stoichiometric description of reactions between fluorescent probes and DNA and can capture the initial conditions encountered in assays targeting RNA. Analysis of the expected copy-number identifies additional dynamics that occur at short times (or, equivalently, low cycle numbers), while investigation of the variance reveals the contributions from liquid volume transfer, imperfect amplification, and strand-specific amplification (i.e., if one strand is synthesized more efficiently than its complement). Linking the branching process to fluorescence by the Beer's Law analog allows for an a priori description of background fluorescence. It also enables uncertainty quantification (UQ) in fluorescence which, in turn, leads to analytical relationships between amplification efficiency (probability) and limit of detection. This work sets the stage for UQ-PCR, where both the input copy-number and its uncertainty are quantified from fluorescence kinetics.

Optimizing Combined Magnetic Resonance Imaging (MRI)-Targeted and Systematic Biopsy Strategies: Sparing the Multiparametric MRI-Negative Transitional Zone in Presence of Exclusively Peripheral Multiparametric MRI-Suspect Lesions.

PURPOSE: We assessed whether sampling of the transitional zone can be spared in patients with exclusively peripheral prostate cancer (PCa)-suspicious multiparametric magnetic resonance imaging (mpMRI) lesions who undergo combined mpMRI targeted (TBx) and systematic prostate biopsies (SBx). MATERIALS AND METHODS: Of 1,685 patients who underwent extended SBx including transitional zone sampling and had TBx of ≥1 lesion in the peripheral and/or transitional zone, we selected 863 patients with exclusively peripheral PCa-suspicious lesions and negative transitional zone mpMRI. Clinically significant PCa (csPCa) was defined as Gleason score (GS) ≥3+4. Within the selected cohort we performed a retrospective head-to-head comparison of csPCa detection rates between biopsy protocols: A) combination of peripheral TBx plus extended SBx including transitional zone sampling vs B) peripheral TBx plus SBx without any transitional zone sampling. Analyses were complemented with multivariable logistic regression models (LRMs) in the total cohort for predicting csPCa in SBx transitional zone sampling. RESULTS: Compared to the extended protocol (A), omission of systematic transitional zone sampling (B) yielded similar PCa detection for csPCa (48% vs 47%) and GS 3+3 (21% vs 20%). Only 2.0% csPCa was additionally detected with transitional zone SBx sampling (A). LRM confirmed that intraprostatic zonal distribution of mpMRI lesions independently influences csPCa detection rates of transitional zone SBx sampling. CONCLUSIONS: A peripheral TBx plus SBx without any transitional zone sampling protocol (B) yields similar csPCa detection rates as the standard extended protocol (A) but may reduce biopsy-related morbidity. This zone-dependent biopsy strategy warrants prospective evaluation to optimize the extent of systematic biopsies in presence of suspicious mpMRI lesions.

Prospective intra-individual blinded comparison of [18F]PSMA-1007 and [68 Ga]Ga-PSMA-11 PET/CT imaging in patients with confirmed prostate cancer.

INTRODUCTION: [18F]PSMA-1007 has potential advantages over [68 Ga]Ga-PSMA-11, although limited prospective data evaluating diagnostic performance exist. The aims of this study are to describe the concordance of [18FPSMA-1007 and [68 Ga]Ga-PSMA-11 for TNM with the American Joint Committee on Cancer (AJCC) prognostic stage and assess differences in tracer uptake. METHODS: Fifty men (mean age 71.8) were imaged with [68 Ga]Ga-PSMA-11 and [18F]PSMA-1007 < 4 weeks apart. Images were independently reported according to TNM by two experienced nuclear medicine specialists blinded to the other scan and prior imaging. Discordant results were resolved by a third independent nuclear medicine specialist. Quantitative analysis of lesion uptake and physiologic tissue for each tracer was performed by one experienced reader. RESULTS: Scan indications were initial staging (n = 12), biochemical recurrence (n = 27) and metastatic disease evaluation (n = 11). Most patients had ISUP grade group 3 or higher. Median PSA value was 2.7 ng/ml (IQR 0.7-12.0), and a minority of patients (28%) were currently treated with androgen deprivation therapy. [18F]PSMA-1007 uptake was significantly higher than [68Ga]Ga-PSMA-11 in local recurrence, nodal and distant metastases and most physiologic sites (including bone) except for urinary bladder which was significantly lower. [18F]PSMA-1007 upstaged local prostate staging in 5/17 patients, local recurrence in 3/33 patients, regional nodal disease in 3/50 patients and 1 distant metastasis (bladder). [68Ga]Ga-PSMA-11 upstaged regional nodal disease in 1/50 patients and distant metastasis in one patient (right adrenal). Overall AJCC prognostic stage was concordant in 46/50 (92%) patients, with two patients upstaged for both [18F]PSMA-1007 and [68Ga]Ga-PSMA-11. [18F]PSMA-1007 had more equivocal results (one regional node; six equivocal bone lesions, one of which was subsequently confirmed metastatic) than [68Ga]Ga-PSMA-11 (one equivocal local recurrence). CONCLUSION: Overall AJCC prognostic stage was similar (92%) between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11. [18F]PSMA-1007 demonstrates higher uptake within involved nodes and distant metastases and most physiologic sites except urinary bladder which aided [18F]PSMA-1007 local staging of the prostate primary/local recurrence and regional nodal disease adjacent ureters. However, [18F]PSMA-1007 liver uptake obscured a solitary right adrenal metastasis, and more equivocal bone lesions were identified. Trial registration The study was registered with Australia New Zealand Clinical Trials Registry (ACTRN12618000665235) on 24 April 2018.

Primary tumour PSMA intensity is an independent prognostic biomarker for biochemical recurrence-free survival following radical prostatectomy.

PURPOSE: The prognostic value of PSMA intensity on PSMA PET/CT due to underlying biology and subsequent clinical implications is an emerging topic of interest. We sought to investigate whether primary tumour PSMA PET intensity contributes to pre- and post-operative prediction of oncological outcomes following radical prostatectomy. METHODS: We performed a retrospective cohort study of 848 men who underwent all of multiparametric MRI (mpMRI), transperineal prostate biopsy, and 68 Ga-PSMA PET/CT prior to radical prostatectomy. PSMA intensity, quantified as maximum standard uptake value (SUVmax), and other clinical variables were considered relative to post-operative biochemical recurrence-free survival (BRFS) using Cox regression and Kaplan-Meier analysis. RESULTS: After a median follow-up of 41 months, 219 events occurred; the estimated 3-year BRFS was 79% and the 5-year BRFS was 70%. Increasing PSMA intensity was associated with less favourable BRFS overall (Log rank p < 0.001), and within subgroups of Gleason score category (Log rank p < 0.03). PSMA intensity was significantly associated with shorter time to biochemical recurrence, after adjusting for pre-operative (HR per 5-unit SUVmax increase = 1.15) and post-operative (HR per 5-unit SUVmax increase = 1.10) parameters. CONCLUSION: These results in a large series of patients confirm PSMA intensity to be a novel, independent prognostic factor for BRFS.

Guideline of guidelines: management of recurrent urinary tract infections in women.

OBJECTIVE: To compare recurrent urinary tract infection (rUTI) guidelines from major urological and non-urological organisations internationally and identify areas of consensus and discrepancy. METHODS: PubMed, Google Scholar and the official webpages of major urological, gynaecological, infectious diseases and general practice organisations were searched for rUTI guidelines in March 2022. Nine guidelines were included for review: European Association of Urology, National Institute for Health and Care Excellence (NICE), Society of Obstetricians and Gynaecologists of Canada, American Academy of Family Physicians, Mexican College of Gynaecology and Obstetrics Specialists, Swiss Society of Gynaecology and Obstetrics, Spanish Society of Infectious Diseases and Clinical Microbiology, German Association of Scientific Medical Societies, and the combined American Urological Association/Canadian Urological Association/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction. RESULTS: The definition and evaluation of rUTIs, and antibiotic prophylaxis strategies, were mostly consistent across guidelines, and emphasised the importance of obtaining urine cultures and limiting cystoscopy and upper tract imaging in women without risk factors. Variable recommendations were noted for symptomatic treatment, self-initiated antibiotics, and antibiotic-sparing preventative strategies such as cranberry, vaginal oestrogen, immunoactive prophylaxis with OM-89, intravesical glycosaminoglycan instillation, and phytotherapeutics. Recent randomised evidence supports the use of methenamine hippurate. Either continuous or post-coital prophylactic antibiotics were supported by all guidelines. None of the guidelines were tailored to the management recurrent complicated UTI. CONCLUSION: Multiple rUTI guidelines were identified and mostly limited their recommendations to otherwise healthy non-pregnant women with uncomplicated cystitis. Variation was noted, particularly in antibiotic-sparing preventative strategies. Some conflicting recommendations are due to more recent guidelines including updated evidence. Future guidelines should consider recommendations to assist management of complex patient groups, such as recurrent complicated UTI.

Event-free survival after radical prostatectomy according to prostate-specific membrane antigen-positron emission tomography and European Association of Urology biochemical recurrence risk groups.

OBJECTIVE: To assess European Association of Urology (EAU) risk groups for biochemical recurrence (BCR) of prostate cancer relative to prostate-specific membrane antigen-positron emission tomography (PSMA-PET) status and oncological outcomes. PATIENTS AND METHODS: A retrospective analysis of a study that incorporated PSMA-PET for men with BCR after radical prostatectomy (RP) was undertaken. EAU risk groups were considered relative to clinical variables, PSMA-PET findings, and deployment of salvage radiotherapy (SRT). The primary oncological outcome was event-free survival (EFS) and this was analysed relative to clinical and imaging variables. An 'event' occurred if prostate-specific antigen (PSA) level rose >0.2 ng/mL above nadir or additional therapies were introduced. RESULTS: A total of 137 patients were included, most of whom had EAU high-risk disease (76%) and/or low PSA levels (80% <0.5 ng/mL) at the time of PSMA-PET. EAU risk group was not associated with regional nodal/distant metastasis on PSMA-PET. Regional nodal/distant metastasis on PSMA PET (compared to negative/local recurrence: hazard ratio [HR] 2.2; P = 0.002) and SRT use (vs no SRT: HR 0.44; P = 0.004) were associated with EFS. EAU high-risk status was not significantly associated with worse EFS (HR 1.7, P = 0.12) compared to EAU low-risk status. Among patients who received SRT, both regional/distant metastasis on PSMA-PET (HR 3.1; P < 0.001) and EAU high-risk status (HR 2.9; P = 0.04) were independently associated with worse EFS, which was driven by patients in the EAU high-risk group with regional/distant metastases (38%; HR 3.1, P = 0.001). CONCLUSIONS: In patients with post-RP BCR, PSMA-PET findings and receipt of SRT predicted EFS. In patients receiving SRT, PSMA status combined with EAU risk grouping was most predictive of EFS. These findings suggest that the EAU risk groups could be improved with the addition of PSMA-PET.

The joint associations of physical activity and TV viewing time with COVID-19 mortality: An analysis of UK Biobank.

We used logistic regression to investigate the joint associations of physical activity level (high: ≥3000 MET-min/week, moderate: ≥600 MET-min/week, low: not meeting either criteria) and TV viewing time (low: ≤1 h/day, moderate: 2-3 h/day, high: ≥4 h/day) with COVID-19 mortality risk in UK Biobank. Additional models were performed with adjustment for body mass index (BMI) and waist circumference. Within the 373, 523 included participants, there were 940 COVID-19 deaths between 16 March 2020 and 12 November 2021. Compared to highly active individuals with a low TV viewing time, highly active individuals with a high TV viewing time were at significantly higher risk of COVID-19 mortality (odds ratio = 1.54, 95% confidence interval = 1.11-2.15). However, the greatest risk was observed for the combination of a low physical activity level and a high TV viewing time (2.29, 1.63-3.21). After adjusting for either BMI or waist circumference, only this latter combination remained at a significantly higher risk, although the effect estimate was attenuated by 43% and 48%, respectively. In sum, a high TV viewing time may be a risk factor for COVID-19 mortality even amongst highly active individuals. Higher adiposity appears to partly explain the elevated risk associated with a low physical activity level and a high TV viewing time.

68Ga-PSMA PET/CT tumour intensity pre-operatively predicts adverse pathological outcomes and progression-free survival in localised prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA) positron emission tomography (PSMA-PET) improves prostate cancer staging. Intraprostatic PSMA intensity may predict clinically relevant oncological outcomes. The aim of this study was to investigate the relationship between intraprostatic PSMA intensity and adverse pathology outcomes, including biochemical progression-free survival (PFS) after radical prostatectomy. METHODS: This is a cohort study of 71 patients with MRI-guided, biopsy-proven prostate cancer and pre-operative 68Ga-PSMA-11 PET/CT prior to radical prostatectomy (RP). Intraprostatic PSMA intensity was correlated to adverse pathology outcomes (Gleason score and upgrading from biopsy, pathological stage) and PFS using multivariate statistical analysis. RESULTS: 68Ga-PSMA-11 PET/CT intensity in vivo predicted all of Gleason score on RP, upgrading from biopsy to RP histopathology, pathological stage, positive surgical margins and PFS. 74.6% (53/71) of patients were free from progression at a median follow-up of 19.5 months (0.4-48 months). Predictive accuracy was particularly enhanced by PSMA among patients with biopsy Gleason score ≤ 3 + 4 (n = 39) as the most significant predictor of PFS according to Cox-proportional hazards regression. Cox-regression adjusted survival analysis predicted a 5.48-fold increase in hazard for Gleason score ≤ 3 + 4 patients with high (SUVmax > 8) compared with low (SUVmax < 8) PSMA intensity. CONCLUSION: Intraprostatic 68Ga-PSMA-11 intensity is prognostic and may be a valuable new biomarker in localised prostate cancer, especially in men with biopsy-proven Gleason 3 + 4 disease considering an initial approach of active surveillance or focal therapy.

Clinical insignificance of [18F]PSMA-1007 avid non-specific bone lesions: a retrospective evaluation.

PURPOSE: [18F]PSMA-1007 offers advantages of low urinary tracer excretion and theoretical improved spatial resolution for imaging prostate cancer. However, non-specific bone lesions (NSBLs), defined as mild to moderate focal bone uptake without a typical morphological correlate on CT, are a common finding on [18F]PSMA-1007 PET/CT. The purpose of this study was to investigate the clinical outcomes of patients with [18F]PSMA-1007 avid NSBLs, to determine whether patients with NSBLs represent a higher risk clinical cohort, and to determine whether SUVmax can be used as a classifier of bone metastasis. METHODS: A retrospective audit of 214 men with prostate cancer was performed to investigate the clinical outcomes of [18F]PSMA-1007 avid NSBLs according to defined criteria. We also compared the serum PSA, Gleason score, and uptake time of patients with [18F]PSMA-1007 avid NSBLs to patients without [18F]PSMA-1007 avid bone lesions. Finally, we analysed an SUVmax threshold to identify bone metastases using ROC curve analysis. RESULTS: Ninety-four of 214 patients (43.9%) demonstrated at least one NSBL. No [18F]PSMA-1007 avid NSBLs met criteria for a likely malignant or definitely malignant lesion after a median 15.8-month follow-up interval (11.9% definitely benign, 50.3% likely benign, and 37.7% equivocal). There were no statistically significant differences in serum PSA, Gleason score, and uptake time between patients with [18F]PSMA-1007 avid NSBLs and those without [18F]PSMA-1007 avid bone lesions. All NSBLs with adequate follow-up had SUVmax ≤ 11.1. The value of the highest SUVmax distinguished between NSBLs and definite prostate cancer bone metastases, whereby an SUVmax threshold of ≥ 7.2 maximized the Youden's index. CONCLUSION: [18F]PSMA-1007 avid NSBLs rarely represent prostate cancer bone metastases. When identified in the absence of definite metastatic disease elsewhere, it is appropriate to classify those with SUVmax < 7.2 as likely benign. NSBLs with SUVmax 7.2-11.1 may be classified as equivocal or metastatic, with patient clinical risk factors, scan appearance, and potential management implications used to guide interpretation.

Histological comparison between predictive value of preoperative 3-T multiparametric MRI and 68 Ga-PSMA PET/CT scan for pathological outcomes at radical prostatectomy and pelvic lymph node dissection for prostate cancer.

OBJECTIVE: To evaluate the ability of preoperative multiparametric magnetic resonance imaging (mpMRI) and a gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68 Ga-PSMA PET/CT) scan to predict pathological outcomes and also identify a group of men with a <5% risk of histological pelvic lymph node metastasis (LNM) at pelvic lymph node dissection (PLND) performed during a robot-assisted laparoscopic radical prostatectomy (RALP) for prostate cancer. We then aimed to compare these results to known risk calculators for LNM, including the Cancer of the Prostate Risk Assessment (CAPRA) score, Memorial Sloan Kettering Cancer Centre (MSKCC) and Briganti nomograms. PATIENTS AND METHODS: Between July 2014 and September 2019 only men who had both a preoperative mpMRI and staging 68 Ga-PSMA PET/CT at our institution followed by a RALP with PLND referred to a single specialist uropathology laboratory were considered for inclusion. The data were collected retrospectively prior to February 2019 and in a prospective manner thereafter. A model was built to allocate probabilities of the men with a negative 68 Ga-PSMA PET/CT scan having a <5% risk of histologically LNM at RALP based on the preoperative radiological staging. RESULTS: A total of 233 consecutive men met the inclusion criteria of which 58 men (24.9%) had a LNM identified on PLND histology. The median (range) International Society of Urological Pathology (ISUP) Grade was 5 (1-5) and the median (range) prostate-specific antigen level was 7.4 (1.5-72) ng/mL. The median (range) number of resected lymph nodes was 16 (1-53) and the median (range) number of positive nodes identified on histology was 2 (1-22). Seminal vesicle invasion on mpMRI was more common in node-positive men than in the absence of LNM (31% vs 12%). The maximum standardised uptake value of the primary tumour on 68 Ga-PSMA PET/CT was higher in men with LNM (median 9.2 vs 7.2, P = 0.02). Suspected LNM were identified in 42/233 (18.0%) men with 68 Ga-PSMA PET/CT compared with 22/233 (9.4%) men with mpMRI (P = 0.023). The positive and negative predictive value for 68 Ga-PSMA PET/CT was 66.7% and 84.3% respectively, compared to 59.1% and 78.7% for mpMRI. A predictive model showed only two men (4.2%) with a negative preoperative 68 Ga-PSMA PET/CT would be positive for a histological LNM if they are ISUP Grade < 5 and Prostate Imaging-Reporting and Data System (PI-RADS) <5; or ISUP Grade 5 with PI-RADS < 4. An inspection of three additional variables: CAPRA score, MSKCC and Briganti nomograms did not improve the predictive probability for this group. However, of the 61 men with ISUP Grade 4-5 malignancy and also a PI-RADS 5 mpMRI, 20 (32.8%) men had a microscopic LNM despite a negative preoperative 68 Ga-PSMA PET/CT. CONCLUSION: Preoperative 68 Ga-PSMA/PET CT was more sensitive in identifying histological pelvic LNM than 3-T mpMRI. Men with a negative 68 Ga-PSMA PET/CT have a lower risk of LNM than predicted with CAPRA scores or MSKCC and Briganti nomograms. We identified that the combination of a negative preoperative 68 Ga-PSMA PET/CT, ISUP biopsy Grade <5 and PI-RADS <5 prostate mpMRI, or an ISUP Grade 5 with PI-RADS <4 on mpMRI was associated with a <5% risk of a LNM. The addition of CAPRA scores, MSKCC and Briganti nomograms did not improve the predictive probability within this model. Conversely, men with ISUP Grade 4-5 malignancy associated with a PI-RADS 5 prostate mpMRI had a >30% risk of microscopic LNM despite a negative preoperative 68 Ga-PSMA PET/CT and this high-risk group would appear suitable for an extended PLND at the time of a radical prostatectomy.

Bladder infusion versus standard catheter removal for trial of void: a systematic review and meta-analysis.

PURPOSE: To compare the efficacy and time-to-discharge of two methods of trial of void (TOV): bladder infusion versus standard catheter removal. METHODS: Electronic searches for randomized controlled trials (RCTs) comparing bladder infusion versus standard catheter removal were performed using multiple electronic databases from dates of inception to June 2020. Participants underwent TOV after acute urinary retention or postoperatively after intraoperative indwelling catheter (IDC) placement. Quality assessment and meta-analyses were performed, with odds ratio and mean time difference used as the outcome measures. RESULTS: Eight studies, comprising 977 patients, were included in the final analysis. Pooled meta-analysis demonstrated that successful TOV was significantly higher in the bladder infusion group compared to standard TOV (OR 2.41, 95% CI 1.53-3.8, p = 0.0005), without significant heterogeneity (I2=19%). The bladder infusion group had a significantly shorter time-to-decision in comparison to standard TOV (weighted mean difference (WMD)-148.96 min, 95% CI - 242.29, - 55.63, p = 0.002) and shorter time-to-discharge (WMD - 89.68 min, 95% CI - 160.55, - 18.88, p = 0.01). There was no significant difference in complication rates between the two groups. CONCLUSION: The bladder infusion technique of TOV may be associated with a significantly increased likelihood of successful TOV and reduced time to discharge compared to standard TOV practices.

Higher levels of physical activity are associated with reduced tethering and migration of pro-inflammatory monocytes in males with central obesity.

Despite evidence that monocyte migration is accentuated by central adiposity, the impact of physical activity (PA) and exercise, particularly in the post-prandial state, on limiting migration are not established. We hypothesised that PA and a single bout of walking exercise would be associated with reduced ex vivo monocyte tethering and migration in middleaged males with central obesity (CO). Objective levels of PA were measured for 7 days in lean males (LE, N=12, mean (SD) age 39 (10) years, waist circumference 81.0 (6.3) cm) and males with CO (N=12, mean (SD) age 40 (9) years, waist circumference 115.3 (13.9) cm), followed by donation of a fasted blood sample. On the same day, CO undertook a bout of walking exercise, before donation of a second fasted blood sample. An ex vivo assay, coupled to flow cytometry, determined tethering and migration of classical, intermediate, and non-classical monocytes. C-C and CXC chemokine receptor (CCR2, CCR5 and CX3CR1) expression were also determined on total and classical monocytes. Monocyte subsets (total, classical, intermediate and CCR2+ monocytes), metabolic (glucose and lipids) and inflammatory (C-reactive protein) markers were greater in CO vs. LE (lower highdensity lipoprotein); however, adjustments for PA mitigated group differences for glucose, lipids, and monocyte subsets. Ex vivo tethering and migration (absolute and relative) of most monocyte subsets was greater in CO vs LE. Relative monocyte tethering and migration was largely not influenced by PA; however, higher PA was associated with reduced absolute migration and tethering of CD16 expressing monocytes in CO. Prior walking had no impact on these variables. These results highlight that regular PA, not single exercise bouts may limit the migration of pro-inflammatory monocytes in CO. These changes may relate to physiological parameters in blood (i.e. number of cells and their adhesion), rather than differences in chemokine receptor expression.