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Background: Although the therapeutic role of extended pelvic lymph node dissection (ePLND) in patients with prostate cancer (PCa) is still under debate, this procedure is recommended for staging purposes in selected cases. Nomograms for predicting lymph node invasion (LNI) do not account for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, which is characterized by a high negative predictive value for nodal metastases., Objective: To externally validate models predicting LNI in patients with miN0M0 PCa at PSMA PET and to develop a novel tool in this setting., Design, Setting, and Participants: Overall, 458 patients with miN0M0 disease undergoing radical prostatectomy (RP) and ePLND at 12 centers between 2017 and 2022 were identified., Outcome Measurements and Statistical Analyses: Available tools were externally validated using calibration plots, the area under the receiver operating characteristic curve (AUC), and decision curve analyses to assess calibration, discrimination, and the net benefit. A novel coefficient-based model was developed, internally validated, and compared with available tools., Results and Limitations: Overall, 53 patients (12%) had LNI. The AUC was 69% for the Briganti 2012, 64% for the Briganti 2017, 73% for the Briganti 2019, and 66% for the Memorial Sloan Kettering Cancer Center nomogram. Multiparametric magnetic resonance imaging stage, biopsy grade group 5, the diameter of the index lesion, and the percentage of positive cores at systematic biopsy were independent predictors of LNI (all p ≤ 0.04). Internal cross-validation confirmed a coefficient-based model with AUC of 78%, better calibration, and a higher net benefit in comparison to the other nomograms assessed. Use of a 5% cutoff would have spared 47% ePLND procedures (vs 13% for the Briganti 2019 nomogram) at the cost of missing only 2.1% LNI cases . The lack of central review of imaging and pathology represents the main limitation., Conclusions: Tools for predicting LNI are associated with suboptimal performance for men with miN0M0 PCa. We propose a novel model for predicting LNI that outperforms available tools in this population., Patient Summary: Tools currently used to predict lymph node invasion (LNI) in prostate cancer are not optimal for men with negative node findings on PET (positron emission tomography) scans, leading to a high number of unnecessary extended pelvic lymph node dissection (ePLND) procedures. A novel tool should be used in clinical practice to identify candidates for ePLND to reduce the risk of unnecessary procedures without missing LNI cases., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Family history (FH) of prostate cancer (PCa) is associated with an increased risk of PCa and adverse disease features. However, whether patients with localized PCa and FH could be considered for active surveillance (AS) remains controversial., Objective: To assess the association between FH and reclassification of AS candidates, and to define predictors of adverse outcomes in men with positive FH., Design, Setting, and Participants: Overall, 656 patients with grade group (GG) 1 PCa included in an AS protocol at a single institution were identified., Outcome Measurements and Statistical Analysis: Kaplan-Meier analyses assessed the time to reclassification (GG ≥2 and GG ≥3 at follow-up biopsies) overall and according to FH status. Multivariable Cox regression tested the impact of FH on reclassification and identified the predictors among men with FH. Men treated with delayed radical prostatectomy (n = 197) or external-beam radiation therapy (n = 64) were identified, and the impact of FH on oncologic outcomes was assessed., Results and Limitations: Overall, 119 men (18%) had FH. The median follow-up was 54 mo (interquartile range 29-84 mo), and 264 patients experienced reclassification. The 5-yr reclassification-free survival rate was 39% versus 57% for FH versus no FH (p = 0.006), and FH was associated with reclassification to GG ≥2 (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.19-2.15, p = 0.002). In men with FH, the strongest predictors of reclassification were prostate-specific antigen (PSA) density (PSAD), high-volume GG 1 (≥33% of cores involved or ≥50% of any core involved), and suspicious magnetic resonance imaging (MRI) of the prostate (HRs 2.87, 3.04, and 3.87, respectively; all p < 0.05). No association between FH, adverse pathologic features, and biochemical recurrence was observed (all p > 0.05)., Conclusions: Patients with FH on AS are at an increased risk of reclassification. Negative MRI, low disease volume, and low PSAD identify men with FH and a low risk of reclassification. Nonetheless, sample size and wide CIs entail caution in drawing conclusions based on these results., Patient Summary: We tested the impact of family history in men on active surveillance for localized prostate cancer. A significant risk of reclassification, but not adverse oncologic outcomes after deferred treatment, prompts the need for cautious discussion with these patients, without precluding initial expectant management., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The optimal definition and prognostic significance of persistently elevated prostate-specific antigen (PSA) after salvage lymph node dissection (sLND) for node-only recurrent prostate cancer (PCa) remain unknown., Objective: To assess the definition and clinical implications of persistently elevated PSA after sLND for node-only recurrent PCa after radical prostatectomy., Design, Setting, and Participants: The study included 579 patients treated with sLND at 11 high-volume centers between 2000 and 2016., Outcome Measurements and Statistical Analysis: We assessed the linear relationship between the first PSA after sLND and death from PCa. Different definitions of PSA persistence were included in a multivariable model predicting cancer-specific mortality (CSM) after surgery to identify the best cutoff value. We investigated the association between PSA persistence and oncologic outcomes using multivariable regression models. Moreover, the effect of early androgen deprivation therapy (ADT) after sLND was tested according to PSA persistence status and estimated risk of CSM., Results and Limitations: We found an inverse relationship between the first PSA after sLND and the probability of cancer-specific survival. PSA persistence defined as first postoperative PSA ≥0.3 ng/ml provided the best discrimination accuracy (C index 0.757). According to this cutoff, 331 patients (57%) experienced PSA persistence. The median follow-up for survivors was 48 mo (interquartile range 27-74). After adjusting for confounders, men with persistently elevated PSA had higher risk of clinical recurrence (hazard ratio [HR] 1.61), overall mortality (HR 2.20), and CSM (HR 2.59; all p < 0.001) after sLND. Early ADT administration after sLND improved survival only for patients with PSA persistence after surgery (HR 0.49; p = 0.024). Similarly, when PSA persistence status was included in multivariable models accounting for pathologic features, early ADT use after sLND was beneficial only for patients with a predicted risk of CSM at 5 yr of >10%., Conclusions: PSA persistence after sLND independently predicts adverse prognosis, with the best discrimination accuracy for CSM provided by a definition of PSA ≥ 0.3 ng/ml. We showed that when stratifying patients by final pathology results and PSA persistence status, early ADT use after sLND was beneficial only for patients with PSA persistence or with a calculated 5-yr risk of CSM of >10%, which could be useful as we await results from ongoing prospective trials., Patient Summary: We found that for patients with prostate cancer who had lymph nodes removed after their cancer recurred, persistently elevated prostate-specific antigen (PSA) levels predict poorer prognosis. We showed that a PSA level of ≥0.3 ng/ml provides the best accuracy in identifying patients with worse prognosis. This may help to improve risk stratification after lymph node removal and allow physicians to optimize treatment strategies after surgery., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Prostate cancer (PCa) is the second most common cancer among men worldwide. Urinary, bowel, and sexual function, as well as hormonal symptoms and health-related quality of life (HRQoL), were prioritised by patients and professionals as part of a core outcome set for localised PCa regardless of treatment type., Objective: To systematically review the measurement properties of patient-reported outcome measures (PROMs) used in localised PCa and recommend PROMs for use in routine practice and research settings., Evidence Acquisition: The psychometric properties of PROMs measuring functional and HRQoL domains used in randomised controlled trials including patients with localised PCa were assessed according to the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) methodology. MEDLINE and Embase were searched to identify publications evaluating psychometric properties of the PROMs. The characteristics and methodological quality of the studies included were extracted, tabulated, and assessed according to the COSMIN criteria., Evidence Synthesis: Overall, 27 studies evaluating psychometric properties of the Expanded Prostate Cancer Index Composite (EPIC), University of California-Los Angeles Prostate Cancer Index (UCLA-PCI), European Organisation for Research and Treatment of Cancer (EORTC) quality of life core 30 (QLQ-C30) and prostate cancer 25 (QLQ-PR25) modules, International Index of Erectile Function (IIEF), and the 36-item (SF-36) and 12-item Short-Form health survey (SF-12) PROMs were identified and included in the systematic review. EPIC and EORTC QLQ-C30, a general module that assesses patients' physical, psychological, and social functions, were characterised by high internal consistency (Cronbach's α 0.46-0.96 and 0.68-0.94 respectively) but low content validity. EORTC QLQ-PR25, which is primarily designed to assess PCa-specific HRQoL, had moderate content validity and internal consistency (Cronbach's α 0.39-0.87). UCLA-PCI was characterised by moderate content validity and high internal consistency (Cronbach's α 0.21-0.94). However, it does not directly assess hormonal symptoms, whereas EORTC QLQ-PR25 does., Conclusion: The tools with the best evidence for psychometric properties and feasibility for use in routine practice and research settings to assess PROMs in patients with localised PCa were EORTC QLQ-C30 and QLQ-PR25. Since EORTC QLQ-C30 is a general module that does not directly assess PCa-specific issues, it should be adopted in conjunction with the QLQ-PR25 module., Patient Summary: We reviewed and appraised the measurement properties of patient-reported outcome measure questionnaires used for patients with localised prostate cancer. We found good evidence to suggest that two questionnaires (EORTC QLQ-C30 and QLQ-PR25) can be used to measure urinary, bowel, and sexual functions and health-related quality of life., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Context: The role of positron emission tomography/computed tomography (PET/CT) with prostate-specific membrane antigen (PSMA) in the primary staging for patients with prostate cancer (PCa) is still debated., Objective: To analyze published studies reporting the accuracy of PSMA PET/CT for detecting lymph node invasion (LNI) at pelvic lymph node dissection (PLND)., Evidence Acquisition: A search of PubMed/MEDLINE, Cochrane library's Central, EMBASE and Scopus databases, from inception to May 2021, was conducted. The primary outcome was to evaluate the sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of PSMA PET/CT in detecting LNI on a per-patient level. As a secondary outcome, NPV of PET PSMA was tested on a per-node-level analysis. Detection rates were pooled using random-effect models. Preplanned subgroup analyses tested the diagnostic accuracy after stratification for the preoperative risk group. PPV and NPV variation over LNI prevalence was evaluated. Only studies including extended PLND (ePLND) as the reference standard test were included., Evidence Synthesis: Twenty-seven studies, with a total of 2832 participants, were included in quantitative synthesis. The sensitivity, specificity, PPV, and NPV of PSMA PET/CT for LNI were, respectively, 58% (95% confidence interval [CI] 50-66%), 95% (95% CI 93-97%), 79% (95% CI 72-85%), and 87% (95% CI 84-89%), with overall moderate heterogeneity between studies. At bivariate analysis, the diagnostic accuracy of PSMA PET/CT estimated through summary receiver operating characteristic-derived area under the curve was 84% (95% CI 81-87%). On a per-node level, NPV of PET PSMA was 97% (95% CI 96-99%). At subgroup analyses, according to preoperative risk groups, sensitivity, specificity, PPV, and NPV were 51%, 93%, 73%, and 81%, respectively, in high-risk patients. Over the LNI prevalence range of 5-40%, PPV increased from 59% to 91%, while NPV decreased from 99% to 84%., Conclusions: PSMA PET/CT scan provides promising accuracy in the field of primary nodal staging for PCa. The high NPV in men with a lower risk of LNI might be clinically useful to reduce the number of unnecessary PLND procedures performed. Conversely, in high-risk patients, negative PSMA PET/CT cannot replace staging ePLND., Patient Summary: In this systematic review and meta-analysis, we demonstrated that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) scan may optimize the primary nodal staging and surgical management of prostate cancer patients candidate to radical prostatectomy. The high negative predictive value in men with a lower risk of lymph node invasion might be clinically useful for reducing the number of useless pelvic lymph node dissection (PLND) procedures performed. Conversely, in high-risk patients, negative PSMA PET/CT cannot allow avoiding of PLND., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: The variability of the positive predictive value (PPV) represents a significant factor affecting the diagnostic performance of multiparametric magnetic resonance imaging (mpMRI)., Objective: To analyze published studies reporting mpMRI PPV and the reasons behind the variability of clinically significant prostate cancer (csPCa) detection rates on targeted biopsies (TBx) according to Prostate Imaging Reporting and Data System (PI-RADS) version 2 categories., Evidence Acquisition: A search of PubMed, Cochrane library's Central, EMBASE, MEDLINE, and Scopus databases, from January 2015 to June 2020, was conducted. The primary and secondary outcomes were to evaluate the PPV of PI-RADS version 2 in detecting csPCa and any prostate cancer (PCa), respectively. Individual authors' definitions for csPCa and PI-RADS thresholds for positive mpMRI were accepted. Detection rates, used as a surrogate of PPV, were pooled using random-effect models. Preplanned subgroup analyses tested PPV after stratification for PI-RADS scores, previous biopsy status, TBx technique, and number of sampled cores. PPV variation over cancer prevalence was evaluated., Evidence Synthesis: Fifty-six studies, with a total of 16 537 participants, were included in the quantitative synthesis. The PPV of suspicious mpMRI for csPCa was 40% (95% confidence interval 36-43%), with large heterogeneity between studies (I 2 94%, p < 0.01). PPV increased according to PCa prevalence. In subgroup analyses, PPVs for csPCa were 13%, 40%, and 69% for, respectively, PI-RADS 3, 4, and 5 (p < 0.001). TBx missed 6%, 6%, and 5% of csPCa in PI-RADS 3, 4, and 5 lesions, respectively. In biopsy-naïve and prior negative biopsy groups, PPVs for csPCa were 42% and 32%, respectively (p = 0.005). Study design, TBx technique, and number of sampled cores did not affect PPV., Conclusions: Our meta-analysis underlines that the PPV of mpMRI is strongly dependent on the disease prevalence, and that the main factors affecting PPV are PI-RADS version 2 scores and prior biopsy status. A substantially low PPV for PI-RADS 3 lesions was reported, while it was still suboptimal in PI-RADS 4 and 5 lesions. Lastly, even if the added value of a systematic biopsy for csPCa is relatively low, this rate can improve patient risk assessment and staging., Patient Summary: Targeted biopsy of Prostate Imaging Reporting and Data System 3 lesions should be considered carefully in light of additional individual risk assessment corroborating the presence of clinically significant prostate cancer. On the contrary, the positive predictive value of highly suspicious lesions is not high enough to omit systematic prostate sampling., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The impact of positive surgical margins (PSMs) on the risk of metastases in prostate cancer (PCa) patients treated with radical prostatectomy (RP) is still debated., Objective: To identify PSM features associated with recurrence in a stage-by-stage analysis., Design, Setting, and Participants: A total of 1757 PCa patients treated with RP without neoadjuvant or adjuvant treatments between 2011 and 2017 were identified. Patients were stratified according to the presence of PSM and to margins characteristics in three groups: no versus favourable (single margin <3mm) versus unfavourable (≥3mm or multifocal margin) PSMs., Outcome Measurements and Statistical Analysis: Predictors of biochemical recurrence (BCR) and clinical recurrence (CR) were assessed using semiparametric Cox proportional hazard models., Results and Limitations: Overall, 285 (16%) patients had PSMs; 146 (51%) had a unifocal PSM, while 139 (49%) had a multifocal PSM. The median length of a PSM was 1mm. Overall, 120 (42%) versus 165 (58%) patients had favourable versus unfavourable PSMs. In patients with ≤pT3a and pathologic grade group ≤3 disease (n=1351), favourable (hazard ratio [HR]: 2.24; 95% confidence interval [CI]: 1.19-4.22) and unfavourable (HR: 2.68; 95% CI: 1.49-4.84) PSMs significantly increased the risk of BCR (p<0.01). However, they were not associated with CR (all p>0.05). Conversely, in patients with pT3b/4 and/or pathologic grade group 4-5 and/or pN1 (n=406), only an unfavourable PSM was associated with both BCR (HR: 2.96; 95% CI: 1.19-4.22) and CR (HR: 2.60; 95% CI: 1.07-6.30; all p≤0.04)., Conclusions: Although the presence of PSMs was associated with an increased risk of BCR in all stages, only men with adverse pathologic characteristics and an unfavourable PSM were at an increased risk of experiencing metastases as compared with their counterparts with no or a single margin shorter than 3mm., Patient Summary: In this study, we defined a new category of unfavourable positive surgical margins (namely, ≥3mm and/or multifocal), which confers a higher risk of developing metastasis in men with more aggressive pathologic features., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The prognostic role of multiparametric magnetic resonance imaging (mpMRI) and systematic biopsy in predicting biochemical recurrence (BCR) after radical prostatectomy (RP) in prostate cancer (PCa) patients has not been addressed yet., Objective: To develop a risk tool predicting BCR after RP in patients diagnosed with magnetic resonance imaging (MRI)-targeted biopsy., Design, Setting, and Participants: A total of 804 patients with a clinical suspicion of PCa and positive mpMRI diagnosed with MRI-targeted plus concomitant systematic biopsy treated with RP were identified., Outcome Measurements and Statistical Analyses: The outcome was represented by BCR defined as two prostate-specific antigen (PSA) values ≥0.2ng/ml after surgery. Multivariable Cox regression analyses assessed the predictors of BCR. A risk tool model based on imaging and biopsy parameters was developed and validated internally. The c-index, calibration plot, and decision curve analyses were used to assess discrimination, calibration, and the net benefit associated with its use in predicting BCR at 36 mo., Results and Limitations: Median (interquartile range) follow-up was 28 (25-29) mo, and 89 patients experienced BCR. The 36-mo BCR-free survival rate was 89%. The maximum diameter of the index lesion and seminal vesicle invasion (SVI) at mpMRI as well as the presence of clinically significant PCa at systematic biopsy (defined as a grade group of >2) were associated with BCR (all p≤0.03). A model based on PSA, Prostate Imaging Reporting and Data System score, SVI at mpMRI, diameter of the index lesion, grade group at MRI-targeted biopsy, and clinically significant PCa at systematic biopsy achieved the highest discrimination (77%) among all clinical models, as well as the European Association of Urology risk groups (62%) and the Cancer of the Prostate Risk Assessment (CAPRA) score (60%). This tool was characterized by excellent calibration at internal validation and the highest net benefit when predicting BCR for the threshold risk between 0% and 30%., Conclusions: The adoption of predictive models accounting for mpMRI and MRI-targeted biopsy-derived variables and concomitant systematic biopsy would improve clinicians' ability to identify patients at a higher risk of early recurrence after surgery., Patient Summary: The use of information obtained at multiparametric magnetic resonance imaging (mpMRI), and MRI-targeted and concomitant systematic biopsy would improve clinicians' ability to identify prostate cancer patients at a higher risk of experiencing early biochemical recurrence after surgery., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The quality of prostate biopsy is affected by sampling (does the urologist take cores from the right place?) and the histological evaluation (does the pathologist grade correctly?)., Objective: To evaluate the relative contribution of sampling and histological evaluation to the reliability of prostate biopsy in terms of concordance with grading of the surgical specimen., Design, Setting, and Participants: We identified 848 prostate cancer patients who underwent radical prostatectomy between 2015 and 2017 at our institution with external or internal biopsies. Since 2016, a dedicated uropathologist has reviewed all the biopsies sampled externally., Outcome Measurements and Statistical Analysis: We considered the discordance between biopsy and final pathology as a proxy for the quality of prostate biopsy, and calculated the corresponding discordance rate for each biopsy setting., Results and Limitations: We observed the highest rate of grade discordance for patients who had an external biopsy without internal review (66%). Biopsies both sampled and reviewed internally had the lowest discrepancy rate (39%; p<0.0001 compared to external biopsies). Biopsies sampled outside our institution and reviewed internally had an intermediate discordance rate (51%; p=0.003)., Conclusions: The quality of prostate biopsy is influenced by both sampling and evaluation. Highly experienced pathological evaluation of needle biopsies is crucial, but biopsy quality also strongly depends on the quality of the sampled material. Future studies should investigate the mechanism underlying discordance in sampling. Consideration should be given to regionalization of prostate biopsy., Patient Summary: The quality of prostate biopsy varies between specialist and community centers. We found that this variation is affected by both sampling (does the urologist take cores from the right place?) and histological evaluation (does the pathologist grade correctly?)., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)