Corrigendum to "RPN (Radius, Position of tumour, iNvasion of renal sinus) Classification and Nephrometry Scoring System: An Internationally Developed Clinical Classification To Describe the Surgical Difficulty for Renal Masses for Which Robotic Partial Nephrectomy Is Planned" [Eur. Urol. Open Sci. 54 (2023) 33-42].

[This corrects the article DOI: 10.1016/j.euros.2023.05.007.].

Aberrations in circulating ceramide levels are associated with poor clinical outcomes across localised and metastatic prostate cancer.

BACKGROUND: Dysregulated lipid metabolism is associated with more aggressive pathology and poorer prognosis in prostate cancer (PC). The primary aim of the study is to assess the relationship between the plasma lipidome and clinical outcomes in localised and metastatic PC. The secondary aim is to validate a prognostic circulating 3-lipid signature specific to metastatic castration-resistant PC (mCRPC). PATIENTS AND METHODS: Comprehensive lipidomic analysis was performed on pre-treatment plasma samples from men with localised PC (N = 389), metastatic hormone-sensitive PC (mHSPC)(N = 44), or mCRPC (validation cohort, N = 137). Clinical outcomes from our previously published mCRPC cohort (N = 159) that was used to derive the prognostic circulating 3-lipid signature, were updated. Associations between circulating lipids and clinical outcomes were examined by Cox regression and latent class analysis. RESULTS: Circulating lipid profiles featuring elevated levels of ceramide species were associated with metastatic relapse in localised PC (HR 5.80, 95% CI 3.04-11.1, P = 1 × 10-6), earlier testosterone suppression failure in mHSPC (HR 3.70, 95% CI 1.37-10.0, P = 0.01), and shorter overall survival in mCRPC (HR 2.54, 95% CI 1.73-3.72, P = 1 × 10-6). The prognostic significance of circulating lipid profiles in localised PC was independent of standard clinicopathological and metabolic factors (P < 0.0002). The 3-lipid signature was verified in the mCRPC validation cohort (HR 2.39, 95% CI 1.63-3.51, P = 1 × 10-5). CONCLUSIONS: Elevated circulating ceramide species are associated with poorer clinical outcomes across the natural history of PC. These clinically actionable lipid profiles could be therapeutically targeted in prospective clinical trials to potentially improve PC outcomes.

Summertime increases in upper-ocean stratification and mixed-layer depth.

The surface mixed layer of the world ocean regulates global climate by controlling heat and carbon exchange between the atmosphere and the oceanic interior1-3. The mixed layer also shapes marine ecosystems by hosting most of the ocean's primary production4 and providing the conduit for oxygenation of deep oceanic layers. Despite these important climatic and life-supporting roles, possible changes in the mixed layer during an era of global climate change remain uncertain. Here we use oceanographic observations to show that from 1970 to 2018 the density contrast across the base of the mixed layer increased and that the mixed layer itself became deeper. Using a physically based definition of upper-ocean stability that follows different dynamical regimes across the global ocean, we find that the summertime density contrast increased by 8.9 ± 2.7 per cent per decade (10-6-10-5 per second squared per decade, depending on region), more than six times greater than previous estimates. Whereas prior work has suggested that a thinner mixed layer should accompany a more stratified upper ocean5-7, we find instead that the summertime mixed layer deepened by 2.9 ± 0.5 per cent per decade, or several metres per decade (typically 5-10 metres per decade, depending on region). A detailed mechanistic interpretation is challenging, but the concurrent stratification and deepening of the mixed layer are related to an increase in stability associated with surface warming and high-latitude surface freshening8,9, accompanied by a wind-driven intensification of upper-ocean turbulence10,11. Our findings are based on a complex dataset with incomplete coverage of a vast area. Although our results are robust within a wide range of sensitivity analyses, important uncertainties remain, such as those related to sparse coverage in the early years of the 1970-2018 period. Nonetheless, our work calls for reconsideration of the drivers of ongoing shifts in marine primary production, and reveals stark changes in the world's upper ocean over the past five decades.

Does urethral length affect continence outcomes following robot assisted laparoscopic radical prostatectomy (RALP)?

BACKGROUND: Post-operative urinary incontinence is a significant concern for patients choosing to undergo a radical prostatectomy (RP) for treatment of prostate cancer. The aim of our study was to determine the effect of pre-operative MUL on 12 month continence outcomes in men having robot-assisted laparoscopic prostatectomy (RALP). METHODS: We use the South Australian Prostate Cancer Clinical Outcomes Collaborative (SA-PCCOC) database, to identify 602 patients who had undergone RALP by a high volume surgeon. Only patients who received an assessment and education by a specialist pelvic floor physiotherapist, had completed EPIC questionnaires before treatment and did not have radiotherapy treatment within 12 months of surgery were included. MUL measurements were taken from pre-operative magnetic resonance imaging (MRI) scans. The short-form version of the Expanded Prostate Cancer Index Composite (EPIC-26) was used to measure continence outcomes. Continence was defined as 100/100 in the EPIC-26 Urinary Continence domain score. RESULTS: The observed median MUL in this study was 14.6 mm. There was no association between MUL and baseline continence. MUL was associated with continence at 12 months post RALP (OR 1.13, 95% CI 1.03-1.21, p = 0.0098). In men who were continent before surgery, MUL was associated with return to continence at 12 months after RALP (OR 1.15, 1.05-1.28, p = 0.006). MUL was also associated with change in continence after surgery (ß = 1.22, p = 0.002). CONCLUSIONS: MUL had no effect on baseline continence but had a positive and significant association with continence outcomes over 12 months post RALP.

Prostate MRI evolution in clinical practice: Audit of tumour detection and staging versus prostatectomy with staged introduction of multiparametric MRI and Prostate Imaging Reporting and Data System v2 reporting.

INTRODUCTION: We conducted a retrospective audit to compare dominant nodule detection and local staging before and after the introduction of functional sequences and PI-RADS v2 reporting to MRI prostate scans in routine private practice. METHODS: A retrospective audit was performed of 245 patients in four separate groups undergoing robotic prostatectomy for prostate cancer by a single urologist between 2009 and 2017. The initial 100 consecutive patients had T2 imaging only. The next 43 patients had T2 and DWI. 52 subsequent patients had T2, DWI and DCE sequences (mpMRI). A final 50 consecutive patients had mpMRI using PI-RADS v2 reporting. Preoperative MRI reports were compared with prostatectomy histopathology to determine the sensitivity of MRI in detecting dominant tumour nodule and T3 extension. RESULTS: The addition of DWI and DCE sequences improved sensitivity for detection of dominant tumour nodule, with a significant further increase using PI-RADS v2 reporting (38% for T2 vs. 62% for T2/DWI vs. 67% for mpMRI vs 91% for PI-RADS v2). The accuracy of detecting T3 disease was initially very low. The use of additional imaging techniques did not significantly influence this, but the use of a three category likelihood of extraprostatic extension in the PI-RADS v2 group had a significant increase in detection of T3 disease (sensitivity 27% vs. 23% vs. 38% vs 63%). CONCLUSION: This audit tracks the significant improvements in MRI detection of prostate cancer dominant tumour nodule and T3 extension in patients undergoing prostatectomy with changing techniques and reporting standards in routine clinical practice.

A patient-derived explant (PDE) model of hormone-dependent cancer.

Breast and prostate cancer research to date has largely been predicated on the use of cell lines in vitro or in vivo. These limitations have led to the development of more clinically relevant models, such as organoids or murine xenografts that utilize patient-derived material; however, issues related to low take rate, long duration of establishment, and the associated costs constrain use of these models. This study demonstrates that ex vivo culture of freshly resected breast and prostate tumor specimens obtained from surgery, termed patient-derived explants (PDEs), provides a high-throughput and cost-effective model that retains the native tissue architecture, microenvironment, cell viability, and key oncogenic drivers. The PDE model provides a unique approach for direct evaluation of drug responses on an individual patient's tumor, which is amenable to analysis using contemporary genomic technologies. The ability to rapidly evaluate drug efficacy in patient-derived material has high potential to facilitate implementation of personalized medicine approaches.

Comparative study between 68 Ga-prostate-specific membrane antigen positron emission tomography and conventional imaging in the initial staging of prostate cancer.

INTRODUCTION: The management of prostate cancer has undergone significant advances since the introduction of 68 Ga-prostate-specific membrane antigen (68 Ga-PSMA) positron emission tomography (PET) scans. Data on the use of 68 Ga-PSMA PET scans in the setting of biochemical recurrence is widely available. Data on the use of 68 Ga-PSMA PET as an initial staging modality, however, is limited. The aim of this retrospective study was to compare the staging of patients with newly diagnosed prostate cancer between 68 Ga-PSMA PET and current conventional imaging modalities. The potential impact of any change in stage will be analysed. METHODS: Details of all patients who underwent 68 Ga-PSMA PET in South Australia between March 2016 and March 2017 were obtained. One hundred and thirty-one patients with newly diagnosed prostate cancer who had 68 Ga-PSMA PET prior to consideration of definitive treatment were included in this study. The stage pre-68 Ga-PSMA PET (based on conventional imaging) and post-68 Ga-PSMA PET was recorded. The stage was classified as A - localised disease, B - presence of regional lymphadenopathy, C - oligometastatic disease (up to three metastases) and D - widespread metastases. Management plans were recorded. RESULTS: This study showed that the use of 68 Ga-PSMA PET resulted in a change of stage in 37 (28%) patients with an upstage in 17 (13%) patients and a downstage in 20 (15%) patients (P < 0.001). 68 Ga-PSMA PET excluded oligometastatic disease in 11 (8%) patients who had suspicious oligometastatic disease based on a single conventional imaging modality. These 68 Ga-PSMA PET findings impacted on management in at least 24 (18%) patients. CONCLUSION: The use of 68 Ga-PSMA PET scans in initial staging can have a significant impact on staging and management when compared to current conventional imaging modalities.

The inverse relationship between prostate specific antigen (PSA) and obesity.

Obese men have lower serum prostate-specific antigen (PSA) than comparably aged lean men, but the underlying mechanism remains unclear. The aim of this study was to determine the effect of obesity on PSA and the potential contributing mechanisms. A cohort of 1195 men aged 35 years and over at recruitment, with demographic, anthropometric (BMI, waist circumference (WC)) and serum hormone (serum testosterone, estradiol (E2)) PSA and hematology assessments obtained over two waves was assessed. Men with a history of prostate cancer or missing PSA were excluded, leaving 970 men for the final analysis. Mixed-effects regressions and mediation analyses adjusting for hormonal and volumetric factors explore the potential mechanisms relating obesity to PSA. After adjusting for age, PSA levels were lower in men with greater WC (P = 0.001). In a multivariable model including WC, age, E2/testosterone and PlasV as predictors, no statistically significant associations were observed between with PSA and either WC (P = 0.36) or PlasV (P = 0.49), while strong associations were observed with both E2/testosterone (P < 0.001) and age (P < 0.001). In the mediation analyses with PlasV as the mediator, the average causal mediation effect (ACME) explained roughly 20% of the total effect of WC on PSA (P = 0.31), while when E2/testosterone is a mediator, the ACME explained roughly 50% of the effect (P < 0.001). Our findings indicate that lower PSA levels in obese men, as compared to normal weight men, can be explained both by hormonal changes (elevated E2/testosterone ratio) and hemodilution. Hormonal factors therefore represent a substantial but underappreciated mediating pathway.

18-Fluoride labeled sodium fluoride positron emission tomography with computer tomography: the impact of pretreatment staging in intermediate- and high-risk prostate cancer.

BACKGROUND: 18-Fluoride labeled sodium fluoride (Na-18-F) positron emission tomography with computer tomography (PET/CT) has a better sensitivity and specificity than whole body bone scan (WBBS) in detecting osseous metastatic prostate cancer. We performed a pilot study of 20 men to examine what level of impact Na-18-F PET/CT has on management plans when used for staging newly diagnosed prostate cancer. MATERIALS AND METHODS: Twenty men were prospectively enrolled into the study in South Australia. Men were eligible if they had newly diagnosed, untreated, and biopsy-confirmed intermediate- or high-risk prostate cancer (D'Amico classification). WBBS and Na-18-F PET/CT scans were performed within 1 week of each other. Following review of the WBBS, treatment type and intent was documented by the treating urologist. The Na-18-F PET/CT scan was then reviewed. The impact of the Na-18-F PET/CT was measured on whether treatment modality or intent was subsequently altered: high impact = treatment intent or modality was changed; medium impact = treatment modality was modified; low impact = no change in treatment. RESULTS: In 18 men (90%), the WBBS and Na-18-F PET/CT were negative for osseous metastases. In one man (5%), the WBBS demonstrated widespread osseous metastases which were similarly demonstrated on the Na-18-F PET/CT. One man (5%) had a normal WBBS; however, the Na-18-F PET/CT demonstrated widespread osseous metastases. Subsequently, in 19 men (95%), the results of the two scans were congruent and the addition of the Na-18-F PET/CT scan demonstrated a low impact on management. In one man (5%), the addition of the Na-18-F PET/CT had a high impact as treatment type and intent was altered. CONCLUSIONS: Our pilot study is the first of its kind in Australia, and our findings suggest that Na-18-F PET/CT is a safe and feasible modality for staging prostate cancer. However, its true impact on prostate cancer management warrants further investigation.

Strong and highly variable push of ocean waves on Southern Ocean sea ice.

Sea ice in the Southern Ocean has expanded over most of the past 20 y, but the decline in sea ice since 2016 has taken experts by surprise. This recent evolution highlights the poor performance of numerical models for predicting extent and thickness, which is due to our poor understanding of ice dynamics. Ocean waves are known to play an important role in ice break-up and formation. In addition, as ocean waves decay, they cause a stress that pushes the ice in the direction of wave propagation. This wave stress could not previously be quantified due to insufficient observations at large scales. Sentinel-1 synthetic aperture radars (SARs) provide high-resolution imagery from which wave height is measured year round encompassing Antarctica since 2014. Our estimates give an average wave stress that is comparable to the average wind stress acting over 50 km of sea ice. We further reveal highly variable half-decay distances ranging from 400 m to 700 km, and wave stresses from 0.01 to 1 Pa. We expect that this variability is related to ice properties and possibly different floe sizes and ice thicknesses. A strong feedback of waves on sea ice, via break-up and rafting, may be the cause of highly variable sea-ice properties.

Transperitoneal Robot-Assisted Radical Prostatectomy Should Be Considered in Prostate Cancer Patients with Pelvic Kidneys.

We highlight two cases of transperitoneal robot-assisted radical prostatectomy (RARP) in patients with pelvic kidneys because of congenital development and renal transplant. These uncommon cases present a challenge to the surgeon contemplating surgery because of access and anomalous vascular and ureteral anatomy. We describe the technical considerations that are paramount in effectively completing transperitoneal RARP, and believe it should be considered as a treatment option in men with pelvic kidneys.

Evidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumors.

PURPOSE: Targeting Hsp90 has significant potential as a treatment for prostate cancer, but prototypical agents such as 17-allylamino-17 demethoxygeldanamycin (17-AAG) have been ineffective in clinical trials. Recently, a phase I study aimed at defining a biologically active dose reported the first response to an Hsp90 inhibitor in a patient with prostate cancer, which supports the development of new generation compounds for this disease. EXPERIMENTAL DESIGN: The biological actions of two new synthetic Hsp90 inhibitors, NVP-AUY922 and NVP-HSP990, were evaluated in the prostate cancer cell lines PC-3, LNCaP, and VCaP and in an ex vivo culture model of human prostate cancer. RESULTS: In cell lines, both NVP-AUY922 and NVP-HSP990 showed greater potency than 17-AAG with regard to modulation of Hsp90 client proteins, inhibition of proliferation, and induction of apoptotic cell death. In prostate tumors obtained from radical prostatectomy that were cultured ex vivo, treatment with 500 nmol/L of NVP-AUY922, NVP-HSP990, or 17-AAG caused equivalent target modulation, determined by the pharmacodynamic marker Hsp70, but only NVP-AUY922 and NVP-HSP990 showed antiproliferative and proapoptotic activity. CONCLUSIONS: This study provides some of the first evidence that new generation Hsp90 inhibitors are capable of achieving biologic responses in human prostate tumors, with both NVP-AUY922 and NVP-HSP990 showing potent on-target efficacy. Importantly, the ex vivo culture technique has provided information on Hsp90 inhibitor action not previously observed in cell lines or animal models. This approach, therefore, has the potential to enable more rational selection of therapeutic agents and biomarkers of response for clinical trials.

Comparative biomarker expression and RNA integrity in biospecimens derived from radical retropubic and robot-assisted laparoscopic prostatectomies.

BACKGROUND: Knowledge of preanalytic conditions that biospecimens are subjected to is critically important because novel surgical procedures, tissue sampling, handling, and storage might affect biomarker expression or invalidate tissue samples as analytes for some technologies. METHODS: We investigated differences in RNA quality, gene expression by quantitative real-time PCR, and immunoreactive protein expression of selected prostate cancer biomarkers between tissues from retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP). Sections of tissue microarray of 23 RALP and 22 RRP samples were stained with antibodies to androgen receptor (AR) and prostate-specific antigen (PSA) as intersite controls, and 14 other candidate biomarkers of research interest to three laboratories within the Australian Prostate Cancer BioResource tissue banking network. Quantitative real-time PCR was done for AR, PSA (KLK3), KLK2, KLK4, and HIF1A on RNA extracted from five RALP and five RRP frozen tissue cores. RESULTS: No histologic differences were observed between RALP and RRP tissue. Biomarker staining grouped these samples into those with increased (PSA, CK8/18, CKHMW, KLK4), decreased (KLK2, KLK14), or no change in expression (AR, ghrelin, Ki67, PCNA, VEGF-C, PAR2, YB1, p63, versican, and chondroitin 0-sulfate) in RALP compared with RRP tissue. No difference in RNA quality or gene expression was detected between RALP and RRP tissue. CONCLUSIONS: Changes in biomarker expression between RALP and RRP tissue exist at the immunoreactive protein level, but the etiology is unclear. IMPACT: Future studies should account for changes in biomarker expression when using RALP tissues, and mixed cohorts of RALP and RRP tissue should be avoided.

Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia.

BACKGROUND: Lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH; BPH-LUTS) may be associated with erectile dysfunction (ED). OBJECTIVE: To evaluate the effects of once-daily tadalafil on erectile function in men with ED and BPH-LUTS. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis of a phase 2-3, multinational, randomized, double-blind, placebo-controlled, parallel-group study of men with ED and moderate-to-severe LUTS secondary to BPH who reported being sexually active. In contrast to typical ED trials, no sexual activity threshold was required to participate. INTERVENTIONS: Screening and 4-wk washout period for patients taking BPH and/or ED treatments; 4-wk placebo run-in period; then once-daily placebo or tadalafil 2.5, 5, 10, or 20 mg for 12 wk. MEASUREMENTS: International Index of Erectile Function-Erectile Function (IIEF-EF) domain score, International Prostate Symptom Score (IPSS), peak urinary flow rate (Q(max)), and postvoid residual volume (PVR). Analyses were performed in men who reported being sexually active with a female partner and who expected to remain so throughout the study. IIEF-EF data are presented for the BPH/ED population overall and for subgroups stratified by baseline age group, body mass index, BPH-LUTS severity, prostate-specific antigen, prior alpha-blocker use, and prior ED therapy. RESULTS AND LIMITATIONS: Overall, 581 men were included (placebo, n=115; tadalafil 2.5 mg, n=113; tadalafil 5 mg, n=117; tadalafil 10 mg, n=120; tadalafil 20 mg, n=116). IIEF-EF domain score improvements from baseline to end point with tadalafil were 5.4 (2.5 mg), 6.8 (5 mg), 7.9 (10 mg), and 8.2 (20 mg) versus 2.0 with placebo (least-squares means; all p values <0.001). IIEF-EF domain score improvements were observed with tadalafil for all subgroup analyses, with no significant differences between subgroup or subgroup-by-treatment interaction terms. IPSS improvements from baseline to end point were significantly greater for all tadalafil doses versus placebo (all p values <0.05). Changes in Q(max) and PVR were small and not clinically meaningful. CONCLUSIONS: These data support the use of once-daily tadalafil in men with ED and BPH-LUTS. TRIAL REGISTRATION: http://www.clinicaltrials.gov: NCT00384930.

Quality of erection questionnaire correlates: change in erection quality with erectile function, hardness, and psychosocial measures in men treated with sildenafil for erectile dysfunction.

INTRODUCTION: The validated Quality of Erection Questionnaire (QEQ) is a six-question, patient-reported outcome measure for comprehensively evaluating satisfaction with the quality of erections in terms of hardness, onset, and duration, which can be used to develop and monitor individualized treatment goals. AIMS: To further validate the QEQ by determining responsiveness/sensitivity to change in erectile function, erection hardness grade, and psychosocial outcomes in men treated with sildenafil for erectile dysfunction (ED). METHODS: This open-label, noncomparative, multicenter trial of sildenafil (50 or 100 mg as needed for 10 weeks) enrolled men with ED who were in a stable, sexual relationship for at least 6 months. Previous phosphodiesterase type 5 inhibitor use must have been no more than 6 doses ever and no doses more recently than the previous 4 weeks. MAIN OUTCOME MEASURES: The baseline to week 10 change in the QEQ total score and its correlations with the end-of-treatment Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) score and with changes in: (i) International Index of Erectile Function (IIEF) domain scores; (ii) Self-Esteem And Relationship (SEAR) questionnaire component scores; and (iii) the frequency of erections graded hard enough for penetration (grade 3) or completely hard (grade 4) on the event log Erectile Hardness Grading Scale. RESULTS: The mean +/- standard deviation transformed QEQ total score tripled from 22.0 +/- 21.1 to 69.9 +/- 35.9 (P < 0.0001), and correlated positively with the end-of-treatment EDITS index score (r = 0.71) and with changes in IIEF domain scores (r = 0.29-0.86), SEAR component scores (r = 0.37-0.78), and the percentage of occasions that grade 3 or 4 erections were achieved (r = 0.66). CONCLUSIONS: The brief, easy-to-administer QEQ is responsive to the benefits of sildenafil treatment of men for ED and has convergent validity with measures of clinical and psychosocial outcomes.

A systematic review of holmium laser prostatectomy for benign prostatic hyperplasia.

PURPOSE: We undertook a systematic review to assess the safety and efficacy of holmium laser prostatectomy compared to transurethral resection of the prostate. MATERIALS AND METHODS: We searched literature databases through August 2002. Holmium laser studies, including holmium laser resection of the prostate (HoLRP) and holmium laser enucleation of the prostate (HoLEP), of any design, and the transurethral prostatectomy (TURP) arms of randomized controlled trials (RCTs) with sample sizes greater than 50 patients, date restricted to 1995 onward, were included for comparison. RESULTS: Three RCTs comparing HoLRP and TURP, and 2 RCTs comparing HoLEP and TURP were identified. For each of the holmium procedures there was also 1 nonrandomized comparative study and a number of case series (HoLRP 13, HoLEP 10). With the exception of 1 randomized trial the quality of the available evidence was poor, with the other RCTs lacking information regarding methods of randomization, allocation concealment and blinding. The majority of studies were characterized by relatively short followup periods and significant losses to followup. In terms of safety the data suggest that the holmium laser procedures are superior to TURP with regard to a number of key indicators of blood loss (transfusion rates, postoperative bladder irrigation, duration of catheterization and length of hospital stay), although amount of blood loss was rarely reported. In terms of efficacy the holmium laser procedures appear to be similarly effective to TURP in relieving the symptoms of benign prostatic hyperplasia. CONCLUSIONS: Holmium laser prostatectomy is at least as effective as TURP for managing the symptoms of benign prostatic hyperplasia. However, at the present time the long-term durability of the holmium procedures with respect to TURP cannot be determined due to a lack of published studies with sufficient followup.