The Effect of the Lateral First Metatarsal Head Shape on Hallux Valgus in Forced Turnout in Pre-Pointe Female Ballet Dancers: A Pilot Study.

BACKGROUND: A rounded lateral first metatarsal head shape is associated with higher rates of hallux abducto valgus recurrence following corrective surgery; however, the effect of the lateral first metatarsal head shape on the hallux abduction angle (HAA) has not yet been explored in a nonpathologic, pre-pointe ballet dancer population. The primary purpose of this study was to investigate the effect of the lateral first metatarsal head shape on the HAA when pre-pointe female dancers force their turnout. METHODS: Seventeen female, pre-pointe ballet students (mean age, 10.8 ± 0.95 years) participated in this study. Fluoroscopic images of each dancer's dominant foot were taken, and the lateral first metatarsal head shape was classified visually. Each dancer performed three consecutive stances of natural double-leg upright posture: both functional and forced turnout. HAAs were obtained by marking medial bony landmarks on paper and were compared to photographic measurements. RESULTS: No significant difference was found between the round and angular lateral first metatarsal head shape for the change in HAA from natural double-leg upright posture to forced turnout. Hallux abduction angle significantly increased by 4.6° (P < .001) in forced turnout compared to the natural double-leg upright posture for the photographic method, whereas the paper method demonstrated an increase of 2.6° (P = .007). No statistical differences were found between the paper and photographic methods in measuring the HAA for all stances. CONCLUSIONS: Our findings suggest no association between the HAA and lateral first metatarsal head shape; however, HAA does increase when a dancer assumes forced turnout. The paper method demonstrated similar reliability to the photographic method and shows the potential for future use as a clinical tool in assessing hallux abducto valgus.

Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system.

Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators of these key cellular programs, we engineer a dual endogenous reporter system by genome-editing the SOX9 and KRT20 loci of human CRC cell lines to express fluorescent reporters, broadcasting aberrant stem cell-like and differentiation activity, respectively. By applying a CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs to this platform, we identify factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominate SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency and required for in vivo growth of human CRC models. These studies highlight the utility of biologically designed endogenous reporter platforms to uncover regulators with therapeutic potential.

Utilizing a dual endogenous reporter system to identify functional regulators of aberrant stem cell and differentiation activity in colorectal cancer.

Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators that regulate these key cellular programs in CRC, we developed an endogenous reporter system by genome-editing human CRC cell lines with knock-in fluorescent reporters at the SOX9 and KRT20 locus to report aberrant stem cell-like activity and differentiation, respectively, and then performed pooled genetic perturbation screens. Constructing a dual reporter system that simultaneously monitored aberrant stem cell-like and differentiation activity in the same CRC cell line improved our signal to noise discrimination. Using a focused-library CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs, we identified factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominated SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency in CRC and required for in vivo growth of human CRC models. These studies highlight the utility of a biologically designed endogenous reporter system to uncover novel therapeutic targets for drug development.

Prostate-specific membrane antigen positron emission tomography in addition to multiparametric magnetic resonance imaging and biopsies to select prostate cancer patients for focal therapy.

OBJECTIVE: To evaluate the additional value of prostate-specific membrane antigen positron emission tomography (PSMA-PET) to conventional diagnostic tools to select patients for hemi-ablative focal therapy (FT). PATIENTS AND METHODS: We performed a retrospective analysis on a multicentre cohort (private and institutional) of 138 patients who underwent multiparametric magnetic resonance imaging (mpMRI), PSMA-PET, and systematic biopsies prior to radical prostatectomy between January 2011 and July 2021. Patients were eligible when they met the consensus criteria for FT: PSA <15 ng/mL, clinical/radiological T stage ≤T2b, and International Society of Urological Pathology (ISUP) grade 2-3. Clinically significant prostate cancer (csPCa) was defined as ISUP grade ≥2, extracapsular extension >0.5 mm or seminal vesicle involvement at final histopathology. The diagnostic accuracy of mpMRI, systematic biopsies and PSMA-PET for csPCa (separate and combined) was calculated within a four-quadrant prostate model by receiver-operating characteristic and 2 × 2 contingency analysis. Additionally, we assessed whether the diagnostic tools correctly identified patients suitable for hemi-ablative FT. RESULTS: In total 552 prostate quadrants were analysed and 272 (49%) contained csPCa on final histopathology. The area under the curve, sensitivity, specificity, positive predictive value and negative predictive value for csPCa were 0.79, 75%, 83%, 81% and 77%, respectively, for combined mpMRI and systematic biopsies, and improved after addition of PSMA-PET to 0.84, 87%, 80%, 81% and 86%, respectively (P < 0.001). On final histopathology 46/138 patients (33%) were not suitable for hemi-ablative FT. Addition of PSMA-PET correctly identified 26/46 (57%) non-suitable patients and resulted in 4/138 (3%) false-positive exclusions. CONCLUSIONS: Addition of PSMA-PET to the conventional work-up by mpMRI and systematic biopsies could improve selection for hemi-ablative FT and guide exclusion of patients for whom whole-gland treatments might be a more suitable treatment option.

68Ga-PSMA-PET/CT in addition to mpMRI in men undergoing biopsy during active surveillance for low- to intermediate-risk prostate cancer: study protocol for a prospective cross-sectional study.

Background: In active surveillance there is significant interest in whether imaging modalities such as multiparametric magnetic resonance imaging (mpMRI) or 68Gallium prostate-specific membrane antigen positron emission tomography/computerized tomography (68Ga-PSMA-PET/CT) can improve the detection of progression to clinically significant prostate cancer (csPCa) and thus reduce the frequency of prostate biopsies and associated morbidity. Recent studies have demonstrated the value of mpMRI in active surveillance; however, mpMRI does miss a proportion of disease progression and thus alone cannot replace biopsy. To date, prostate-specific membrane antigen positron emission tomography (PSMA-PET) has shown additive value to mpMRI in its ability to detect prostate cancer (PCa) in the primary diagnostic setting. Our objective is to evaluate the diagnostic utility of PSMA-PET to detect progression to csPCa in active surveillance patients. Methods: We will perform a prospective, cross-sectional, partially blinded, multicentre clinical trial evaluating the additive value of PSMA-PET with mpMRI against saturation transperineal template prostate biopsy. Two hundred and twenty-five men will be recruited who have newly diagnosed PCa which is suitable for active surveillance. Following enrolment, patients will undergo a PSMA-PET and mpMRI within 3 months of a repeat 12-month confirmatory biopsy. Patients who remain on active surveillance after confirmatory biopsy will then be planned to have a further mpMRI and PSMA-PET prior to a repeat biopsy in 3-4 years. The primary outcome is to assess the ability of PSMA-PET to detect or exclude significant malignancy on repeat biopsy. Secondary outcomes include (I) assess the comparative diagnostic accuracies of mpMRI and PSMA-PET alone [sensitivity/specificity/negative predictive value (NPV)/positive predictive value (PPV)] to detect progression on biopsy based on predefined histologic criteria for progression; (II) comparison of index lesion identification by template biopsies vs. MRI targeted lesions vs. PSMA targeted lesions; (III) evaluation of concordance of lesions identified on final histopathology and each imaging modality (PSMA-PET and/or mpMRI) in the subset of patients proceeding to RP. Discussion: The results of this trial will define the role of PSMA-PET in active surveillance and potentially reduce the number of biopsies needed to detect progression to csPCa. Trial Registration: The current trial was registered with the ANZCTR on the 3/2/2022 with the trial ID ACTRN12622000188730, it is accessible at https://www.anzctr.org.au/.

A Novel Risk Calculator Incorporating Clinical Parameters, Multiparametric Magnetic Resonance Imaging, and Prostate-Specific Membrane Antigen Positron Emission Tomography for Prostate Cancer Risk Stratification Before Transperineal Prostate Biopsy.

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect multiparametric magnetic resonance imaging (mpMRI)-invisible prostate tumours and improve the sensitivity of detection of prostate cancer (PCa) in comparison to mpMRI alone. Numerous risk calculators have been validated as tools for stratification of men at risk of being diagnosed with clinically significant (cs)PCa. Objective: To develop a novel risk calculator using clinical parameters and imaging parameters from mpMRI and PSMA PET/CT in a cohort of patients undergoing mpMRI and PSMA PET/CT before biopsy. Design setting and participants: A total of 291 men from the PRIMARY prospective trial underwent mpMRI and PSMA PET/CT before transperineal prostate biopsy with sampling of systematic and targeted cores. Outcome measurements and statistical analysis: Novel risk calculators were developed using multivariable logistic regression analysis to predict detection of overall PCa (International Society of Urological Pathology grade group [GG] ≥1) and csPCa (GG ≥2). The risk calculators were then compared with the European Randomised Study of Screening for Prostate Cancer risk calculator incorporating mpMRI (ERSPC-MRI). Resampling methods were used to evaluate the discrimination and calibration of the risk calculators and to perform decision curve analysis. Results and limitations: Age, prostate-specific antigen, prostate volume, and mpMRI Prostate Imaging-Reporting and Data System scores were included in the MRI risk calculator, resulting in area under the receiver operating characteristic curve (AUC) values of 0.791 for overall PCa (GG ≥1) and 0.812 for csPCa (GG ≥2). Addition of the maximum standardised uptake value (SUVmax) on PSMA PET/CT for the prostate lesion, and of SUVmax for the mpMRI lesions for the MRI-PSMA risk calculator resulted in AUCs of 0.831 for overall PCa and 0.876 for csPCa (≥ISUP2).The ERSPC-MRI risk calculator had AUCs of 0.758 (p = 0.02) for overall PCa and 0.805 (p = 0.001) for csPCa. Both the MRI and MRI-PSMA risk calculators were superior to the ERSPC-MRI for both overall PCa and csPCa. Conclusions: These novel risk calculators incorporate clinical and radiological parameters for stratification of men at risk of csPCa. The risk calculator including PSMA PET/CT data is superior to a calculator incorporating mpMRI data alone. Patient summary: We evaluated a new risk calculator that uses clinical information and results from two types of scan to predict the risk of clinically significant prostate cancer on prostate biopsy. This risk model can guide patients and clinicians in shared decision-making and may help in avoiding unnecessary prostate biopsies.

The relationship between biochemical recurrence and number of lymph nodes removed during surgery for localized prostate cancer.

PURPOSE: To assess whether completeness of pelvic lymph node dissection (PLND) as measured by lymph node yield reduces biochemical recurrence (BCR) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa), stratified according to Briganti nomogram-derived risk (≥5% vs. < 5%) of lymph node invasion (LNI). METHODS: Retrospective study of 3724 men who underwent RP between January 1995 and January 2015 from our prospectively collected institutional database. All men included had minimum five years follow-up and were not given androgen deprivation therapy or radiotherapy prior to BCR. Primary endpoint was time to BCR as defined by PSA > 0.2ng/ml. Patients were analysed according to Briganti Nomogram derived risk of 'low-risk' (< 5%) vs. 'high-risk' (≥ 5%). Extent of PLND was analysed using number of nodes yielded at dissection as a continuous variable as well as a categorical variable: Group 1 (limited, 1-4 nodes), Group 2 (intermediate, 5-8 nodes) and Group 3(extensive, ≥9 nodes). RESULTS: Median follow-up in the overall cohort was 79.7 months and 65% of the total cohort underwent PLND. There were 2402 patients with Briganti risk of LNI < 5% and 1322 with a Briganti risk of LNI ≥5%. At multivariate analysis, only PSA (HR1.01, p < 0.001), extracapsular extension at RP (HR 1.86, p < 0.001), positive surgical margin (HR 1.61, p < 0.001) and positive lymph node on pathology (HR 1.52, p = 0.02) were independently associated with BCR. In the high-risk group, increased nodal yield at PLND was associated with reduction in risk of BCR (HR 0.97, 95%CI 0.95-1.00 p = 0.05, Cochran Mantel Haenszel test, p < 0.05: respectively). In the low-risk group increased number of nodes at PLND did not reduce risk of BCR. CONCLUSIONS: In this study of extent of PLND at RP, higher nodal yield did not reduce risk of BCR in low-risk men (Briganti risk < 5%), however there was a weak benefit in terms of reduced long-term risk of BCR in high-risk men (Briganti risk ≥5%).

Aberrant cell state plasticity mediated by developmental reprogramming precedes colorectal cancer initiation.

Cell state plasticity is carefully regulated in adult epithelia to prevent cancer. The aberrant expansion of the normally restricted capability for cell state plasticity in neoplasia is poorly defined. Using genetically engineered and carcinogen-induced mouse models of intestinal neoplasia, we observed that impaired differentiation is a conserved event preceding cancer development. Single-cell RNA sequencing (scRNA-seq) of premalignant lesions from mouse models and a patient with hereditary polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by regenerative activity, marked by Ly6a (Sca-1), and reactivation of fetal intestinal genes, including Tacstd2 (Trop2). Genetic inactivation of Sox9 prevented adenoma formation, obstructed the emergence of regenerative and fetal programs, and restored multilineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.

Index grade group is superior to composite grade group for prediction of biochemical recurrence following radical prostatectomy.

The pathological grade of prostate cancer is the strongest predictor of recurrence. It is unclear whether the better predictor is the composite of all carcinomas within the prostate, or the highest grade lesion (index). The purpose of this study was to determine whether composite or index grade group better predicts biochemical recurrence (BCR). We undertook a retrospective analysis from a prospective institutional cohort study of men who underwent radical prostatectomy for localised prostate cancer between 2009 and 2020, in which an index and composite grade group was reported. The index grade in this study was defined as the highest grade of any tumour, usually with the highest stage, regardless of volume. Multivariate analysis and Kaplan-Meier plots were utilised. A total of 2024 men underwent radical prostatectomy during the study period; we analysed 1605 with composite grade group 2 or 3 prostate cancer. Median preoperative prostate specific antigen (PSA) was 5.9 ng/L, mean follow up was 56.8 months, 54% were pT2, 76% had multifocal disease and 16% had discordant index and composite grades. Patients with discordant index grade group had a higher risk of BCR [hazard ratio (HR) 2.22, p<0.0001]. The prevalence of BCR in the discordant group was higher at 1, 3, 5 and 7 years (4.7% vs 8.9%, 8.3% vs 18.1%, 14.5% vs 28.8% and 22.5% vs 49.5%, respectively). In cases of discordance, a higher index grade group is associated with increased rates of BCR after radical prostatectomy. Index rather than composite grade group should be used to counsel men post-operatively regarding prognosis and follow-up.

Median 4-year outcomes of salvage irreversible electroporation for localized radio-recurrent prostate cancer.

OBJECTIVES: To evaluate the safety, and short to mid-term oncological and quality-of-life (QoL) outcomes of focal irreversible electroporation (IRE) for radio-recurrent prostate cancer (PCa) at a median follow-up of 4 years. PATIENTS AND METHODS: This was a single-centre series of men with biopsy-proven radio-recurrent PCa treated with IRE between December 2013 and February 2022, with a minimum follow-up of 6 months. Follow-up included magnetic resonance imaging at 6 months, and standard transperineal saturation template biopsies at 12 months. Further biopsies were guided by suspicion on serial imaging or prostate-specific antigen (PSA) levels. Validated questionnaires were used to measure functional outcomes. Significant local recurrence was defined as any International Society of Urological Pathology (ISUP) score ≥ 2 on biopsies. Progression-free survival was defined as no signs of local or systemic disease on either imaging or template biopsies, or according to the Phoenix criteria for biochemical recurrence. RESULTS: Final analysis was performed on 74 men with radio-recurrent PCa (median age 69 years, median PSA level 5.4 ng/mL, 76% ISUP score 2/3). The median (range) follow-up was 48 (27-68) months. One rectal fistula occurred, and eight patients developed urethral sloughing that resolved with transurethral resection. Among patients who returned questionnaires (30/74, 41%), 93% (28/30) had preserved urinary continence and 23% (7/30) had sustained erectile function at 12-month follow-up. Local control was achieved in 57 patients (77%), who needed no further treatment. Biopsy diagnosed 41(55%) patients received follow up template biopsies, in-field recurrences occurred in 7% (3/41), and out-field recurrences occurred in 15% of patients (6/41). The metastasis-free survival rate was 91% (67/74), with a median (interquartile range) time to metastases of 8 (5-27) months. The Kaplan-Meier estimated 5-year progression-free survival rate was 60%. CONCLUSIONS: These short- to mid-term safety, oncological and QoL outcome data endorse results from smaller series and show the ability of salvage focal IRE to safely achieve oncological control in patients with radio-recurrent PCa.

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.

Median 5-year outcomes of primary focal irreversible electroporation for localised prostate cancer.

OBJECTIVES: To evaluate longer-term oncological and functional outcomes of focal irreversible electroporation (IRE) as primary treatment for localised clinically significant prostate cancer (csPCa) at a median follow-up of 5 years (up to 10 years). PATIENTS AND METHODS: All patients that underwent focal IRE as primary treatment for localised PCa between February 2013 and August 2021 with a minimum 12 months of follow-up were analysed. Follow-up included 6-month magnetic resonance imaging (MRI) and standardised transperineal saturation template ± targeted biopsies at 12 months, and further biopsies in the case of clinical suspicion on serial imaging and/or prostate-specific antigen (PSA) levels. Failure-free survival (FFS) was defined as no progression to radical treatment or nodal/distant disease. Local recurrence was defined as any International Society of Urological Pathology Grade of ≥2 on biopsy. RESULTS: A total of 229 patients were analysed with a median (interquartile range [IQR]) follow-up of 60 (40-80) months. The median (IQR) age was 68 (64-74) years, the median (IQR) PSA level was 5.9 (4.1-8.2) ng/mL, and 86% harboured intermediate-risk disease and 7% high-risk disease. In all, 38 patients progressed to radical treatment (17%), at a median (IQR) of 35 (17-53) months after IRE. Kaplan-Meier FFS rates were 91% at 3 years, 84% at 5 years and 69% at 8 years. Metastasis-free survival was 99.6% (228/229), PCa-specific and overall survival were 100% (229/229). Residual csPCa was found in 24% (45/190) during follow-up biopsy and MRI showed a complete ablation in 82% (186/226). Short-term urinary continence was preserved (98%, three of 144 at baseline, 99%, one of 131 at 12 months) and erections sufficient for intercourse decreased by 13% compared to baseline (71% to 58%). CONCLUSION: Longer-term follow-up confirms our earlier findings that focal IRE provides acceptable local and distant oncological control in selected men with less urinary and sexual toxicity than radical treatment. Long-term follow-up and external validation of these findings, is required to establish this new treatment paradigm as a valid treatment option.

Salvage irreversible electroporation for radio-recurrent prostate cancer - the prospective FIRE trial.

OBJECTIVES: To prospectively assess the safety, functional- and oncological-outcomes of irreversible electroporation (IRE) as salvage therapy for radio-recurrent focal prostate cancer in a multicenter setting. PATIENTS AND METHODS: Men with focal recurrent PCa after external beam radiation or brachytherapy without metastatic disease on staging imaging and co-registration between mpMRI and biopsies were prospectively included in this multicenter trial. Adverse events were reported following the Clavien-Dindo classification. Validated questionnaires were used for patient-reported functional outcomes. Follow-up consisted of 3 monthly prostate specific antigen (PSA) levels, a 6-month mpMRI and standardised transperineal template mapping biopsies at 12-months. Thereafter follow-up was guided by MRI and/or PSMA-PET/CT and PSA. Local recurrence was defined as any ISUP score ≥2 on biopsies. RESULTS: 37 patients were analysed with a median (interquartile range (IQR)) follow up of 29 (22-43) months. Median age was 71 (53-83), median PSA was 3.5 ng/mL (2.7-6.1). 28 (75.5%) patients harboured intermediate risk and 9 patients (24.5%) high risk PCa. Seven patients (19%) reported self-limiting urgency, frequency, or hematuria (grade 1-2). Seven patients (19%) developed a grade 3 AE; urethral sludge requiring transurethral resection. At 12 months post treatment 93% of patients remained continent and erectile function sufficient for intercourse deteriorated from 35% to 15% (4/27). Local control was achieved in 29 patients (78%) and 27 patients (73%) were clear of local and systemic disease. Four (11%) patients had local recurrence only. Six (16%) patients developed metastatic disease with a median time to metastasis of 8 months. CONCLUSION: The FIRE trial shows that salvage IRE after failed radiation therapy for localised PCa is safe with minimal toxicity, and promising functional and oncological outcomes. Salvage IRE can offer a possible solution for notoriously difficult to manage radio recurrent prostate tumours.

Final Analysis of the Magnetic Resonance Imaging in Active Surveillance Trial.

PURPOSE: This study aimed to assess the medium-term oncologic outcomes of an active surveillance protocol, replacing confirmatory biopsy with serial multiparametric magnetic resonance imaging. MATERIALS AND METHODS: A total of 172 men were enrolled in this single-arm prospective trial. Men with prostate cancer (Gleason 3+3=6 or Gleason 3+4=7 with ≤10% Gleason pattern 4 overall and <2 cores Gleason pattern 4) eligible for surveillance were included in the study. Men underwent baseline multiparametric magnetic resonance imaging and template ± targeted biopsy, then multiparametric magnetic resonance imaging at years 1 and 2 with a 3-year end-of-protocol biopsy. Biopsies during the 3-year protocol period were triggered by abnormalities on multiparametric magnetic resonance imaging and/or increases in prostate specific antigen density (>0.2 ng/ml/cc). RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of multiparametric magnetic resonance imaging to detect progression to clinically significant prostate cancer were 57% (95% CI 39%-74%), 82% (95% CI 74%-89%), 50% (95% CI 38%-62%), and 86% (95% CI 81%-90%), respectively. Both multiparametric magnetic resonance imaging and prostate specific antigen density were significant predictors for progression (multiparametric magnetic resonance imaging OR 6.20, 95% CI 2.72-14.16, P < .001; prostate specific antigen density OR 6.19, 95% CI 2.14-17.92, P = .001). Only 2.3% (4/172) of patients had false-negative multiparametric magnetic resonance imaging and high-risk pathological features (pT3 or high-volume International Society of Urological Pathology >2). After a median 69 months (Q1-Q3 56-79) follow-up of all patients in the cohort, freedom from biochemical recurrence, metastasis, and prostate cancer-related death were 99.3%, 100%, and 100%, respectively. CONCLUSIONS: Final analysis of the Magnetic Resonance Imaging in Active Surveillance trial indicates that there is minimal risk to omitting 1-year confirmatory biopsy during active surveillance if baseline magnetic resonance-targeted + saturation template biopsy was performed; however, standardized 3-year systematic biopsy should be performed due to occasional magnetic resonance imaging-invisible tumors.

Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging to Detect Residual Prostate Cancer Following Irreversible Electroporation-A Multicenter Validation Study.

BACKGROUND: Accurate monitoring following focal treatment of prostate cancer (PCa) is paramount for timely salvage treatment or retreatment. OBJECTIVE: To evaluate the diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI) to detect residual PCa in the short-term follow-up of focal treatment with irreversible electroporation (IRE) using transperineal or transrectal template ± targeted biopsies. DESIGN, SETTING, AND PARTICIPANTS: A retrospective international multicenter study of men with biopsy-proven PCa, treated with focal IRE, and followed by mpMRI (index-test) and template biopsies (reference-test) between February 2013 and January 2021, was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of mpMRI were calculated for in- and outfield residual disease based on two definitions of significant PCa: University College London (UCL) 1-International Society of Urological Pathology (ISUP) ≥3 or ISUP ≥1 with maximum cancer core length (MCCL) ≥6 mm, and UCL2-ISUP ≥2 or ISUP ≥1 with MCCL ≥4 mm. RESULTS AND LIMITATIONS: A total of 303 patients from five focal therapy centers were treated with primary IRE. The final analysis was performed on 217 men (median age 67, median prostate-specific antigen 6.2, 81% ISUP 2/3) who underwent both mpMRI and template biopsies. Multiparametric MRI missed 38/57 (67%) positive biopsy locations (UCL1) in 22 patients. Sensitivity, specificity, PPV, and NPV of mpMRI to detect whole gland residual disease (UCL1) were 43.6% (95% confidence interval [CI]: 28-59), 80.9% (95% CI: 75-86), 33.3% (95% CI: 21-47), and 86.7% (95% CI: 81-91), respectively. Based on UCL2, sensitivity, specificity, PPV, and NPV were 35.8% (95% CI: 25-48), 82.0% (95% CI: 75-88), 47.1% (95% CI: 34-61), and 74.1% (95% CI: 67-80), respectively. Limitations are the retrospective nature and short follow-up. CONCLUSIONS: The diagnostic accuracy of mpMRI to detect residual clinically significant PCa following IRE was low. Follow-up template biopsies should be performed, regardless of mpMRI results. PATIENT SUMMARY: We investigated the accuracy of magnetic resonance imaging (MRI) to detect residual prostate cancer after treatment with irreversible electroporation. The accuracy of MRI is insufficient, and we emphasize the importance of confirmatory prostate biopsies.

Robot-Assisted Prostate-Specific Membrane Antigen-Radioguided Surgery in Primary Diagnosed Prostate Cancer.

The objective of this study was to evaluate the safety and feasibility of 99mTc-based prostate-specific membrane antigen (PSMA) robot-assisted-radioguided surgery to aid or improve the intraoperative detection of lymph node metastases during primary robot-assisted radical prostatectomy (RARP) for prostate cancer (PCa). Methods: Men with primary high-risk PCa (≥ cT3a, International Society of Urological Pathology (ISUP) grade group ≥ 3 or prostate-specific antigen of ≥ 15 ng/mL) with potential lymph node metastasis (Briganti nomogram risk > 10% or on preoperative imaging) were enrolled in the study. Patients underwent staging 68Ga-PSMA PET/CT scanning. Preoperatively, a 99mTc-labeled PSMA ligand (99mTc PSMA I&S; 500 MBq) was administered followed by SPECT/CT. A RARP including extended pelvic lymph node dissection was performed, with intraoperative tracing of PSMA-avid tissues using a prototype DROP-IN γ-probe. Resected specimens were also measured ex vivo. Histopathologic concordance with probe findings was evaluated. A radiotracer count of ≥ 1.5 times the background reference (in vivo), and ≥ 10 (absolute count) in the ex vivo setting, was considered positive. Results: Twelve patients were included (median age, 68 y, and prostate-specific antigen, 9.15 ng/mL). Most of the patients harbored ISUP 5 PCa (75%) and had avid lymph nodes on preoperative PSMA PET (64%). The DROP-IN probe aided resection of PSMA-avid (out-of-template) lymph nodes and residual disease at the prostate bed. Eleven metastatic lymph nodes were identified by the probe that were not observed on preoperative 68Ga-PSMA PET/CT. Of the 74 extraprostatic tissue specimens that were resected, 22 (29.7%) contained PCa. The sensitivity, specificity, positive predictive value, and negative predictive value of inpatient use of the γ-probe were 76% (95% CI, 53%-92%), 69% (95% CI, 55%-81%), 50%, and 88%, respectively. Ex vivo, the diagnostic accuracy was superior: 76% (95% CI, 53%-92%), 96% (95% CI, 87%-99%), 89%, and 91%, respectively, for sensitivity, specificity, positive predictive value, and negative predictive value. Of the missed lymph nodes in vivo (n = 5) and ex vivo (n = 5), 90% were micrometastasis (≤3 mm). No complications greater than Clavien-Dindo Grade I occurred. Conclusion: Robot-assisted 99mTc-based PSMA-radioguided surgery is feasible and safe in the primary setting, optimizing the detection of nodal metastases at the time of RARP and extended pelvic lymph node dissection. Further improvement of the detector technology may optimize the capabilities of robot-assisted 99mTc-based PSMA-radioguided surgery.

A comparison of prostate cancer prediction models in men undergoing both magnetic resonance imaging and transperineal biopsy: Are the models still relevant?

OBJECTIVE: To externally validate and compare the performance of the European Randomized Study of Screening for Prostate Cancer risk calculator 3/4 (ERSPC-RC3/4), the Prostate Biopsy Collaborative Group risk calculator (PBCG-RC) and the van Leeuwen model to determine which prediction model would perform the best in a contemporary Australian cohort undergoing transperineal (TP) biopsy. MATERIALS AND METHODS: A retrospective review identified all patients undergoing TP biopsy across two centres. Of the 797 patients identified, 373 had the data required to test all three risk calculators. The probability of high-grade prostate cancer, defined as International Society of Urological Pathology Grade Group >1, was calculated for each patient. For each prediction model discrimination was assessed using area under the receiver-operating characteristic curve (AUC), calibration using numerical and graphical summaries, and net benefit using decision curve analysis. RESULTS: Assessment of model discrimination for detecting high-grade prostate cancer showed AUCs of 0.79 (95% confidence interval [CI] 0.74-0.84) for the ERSPC-RC3/4, 0.81 (95% CI 0.77-0.86) for the van Leeuwen model, and 0.68 (95% CI 0.63-0.74) for the PBCG-RC, compared to 0.58 (95% CI 0.52-0.65) for prostate-specific antigen alone. The ERSPC-RC3/4 was the best calibrated in the moderate-risk range of 10-40%, whilst the van Leeuwen model was the best calibrated in the low-risk range of 0-10%. The van Leeuwen model demonstrated the greatest net benefit from 10% risk onwards, followed closely by the ERSPC-RC3/4 and then the PBCG-RC. CONCLUSION: The ERPSC-RC3/4 demonstrated good performance and was comparable to the van Leeuwen model with regard to discrimination, calibration and net benefit for an Australian population undergoing TP prostate biopsy. It is one of the most accessible risk calculators with an easy-to-use online platform, therefore, we recommend that Australian urologists use the ERSPC-RC3/4 to predict risk in the clinical setting.

Identifying prostate cancer in men with non-suspicious multi-parametric magnetic resonance imaging of the prostate.

BACKGROUND: To formulate clinical pathways for identifying clinically significant prostate cancer (csPC) and avoiding insignificant prostate cancer (isPC) in those without suspicious regions of interest on multi-parametric magnetic resonance imaging (mpMRI) of the prostate. METHODS: A retrospective review identified patients with negative mpMRI who underwent subsequent transperineal prostate biopsy across two centres. Patient characteristics and association with biopsy results were evaluated using univariate and multivariate regression analyses. RESULTS: A total of 144 patients were identified as having negative mpMRI and undergoing subsequent transperineal prostate biopsy; 18% (25/144) of the cohort were found to have csPC. Logistic regression analysis failed to identify statistically significant predictive factors. In this cohort, if all patients with prostate-specific antigen > 3.0 were biopsied the least amount of csPC is missed, at 20% (5/25) however all isPC would be diagnosed. The least amount of isPC is diagnosed with a biopsy threshold of >15% from the European Randomized Study of Screening for Prostate Cancer calculator with 20% (5/25) of isPC diagnoses made however only 10.5% (2/19) csPC would be diagnosed. A biopsy threshold of >5% risk reduces the number of csPC missed to 37% (7/19) however increases isPC diagnoses to 54% (13/24) of the population. CONCLUSION: False-negative rates of prostate MRI for csPC are significant within our cohort at 18%. The decision to biopsy should be made in conjunction with a risk profile acceptable by the patient and clinician. The current study demonstrates that there is a need to balance the risk of missing csPC and harm of diagnosing isPC.