BACKGROUND AND OBJECTIVE:Prostate-specific membrane-antigen positron emission tomography (PSMA-PET) has transformed management of prostate cancer biochemical recurrence (BCR) with higher diagnostic accuracy than previous imaging modalities. 64Cu-SAR-bisPSMA PET/computed tomography (CT) (64Cu-bisPSMA) is a bivalent-PSMA-peptide with 12.7-hr half-life. The study objective was detection rate (per-patient) comparison between 64Cu-bisPSMA and 68GaPSMA-11 PET/CT (68Ga-PSMA) in BCR post radical prostatectomy (RP) (NCT06907641). METHODS:This prospective imaging trial enrolled 50 participants with BCR (PSA 0.2-0.75 ng/ml). 64Cu-bisPSMA (1 and 24 hr) and 68Ga-PSMA were acquired within 3-wk. Images were prospectively reported, and triple read for concordance. Management impact was evaluated after 68Ga-PSMA and 64Cu-bisPSMA. A reference standard (RS) for accuracy included biopsy, targeted treatment response (no androgen deprivation therapy), PSA increase/decrease on observation or repeat imaging (64Cu-bisPSMA). The primary endpoint was mean per-participant lesional difference. Paired t tests and mixed-effects Poisson regression assessed lesion number differences between scans. KEY FINDINGS AND LIMITATIONS:Median prostate specific antigen (PSA) was 0.43 (interquartile range: 0.31-0.63). Mean per-participant lesions were higher in 64Cu-bisPSMA (1.26) versus 68GaPSMA (0.48), difference 0.78 (95% CI: 0.52-1.04), ratio 2.63 (95% CI: 1.64-4.20) (p < 0.0001). At a per-participant level 78% (39/50) were positive on 24-hr 64Cu-bisPSMA compared to 36% (18/50) on 68GaPSMA. Management changed between scans in 22/50 (44%). 64Cu-bisPSMA were triple concordant in 84% (42/50) and 68Ga-PSMA reads in 80% (40/50). RS-true positive was 71% (24/34) versus 29% (10/34) and RS-false negative rate was 21% (7/34) versus 65% (22/34) for 64Cu-bisPSMA versus 68Ga-PSMA, respectively. CONCLUSION AND CLINICAL IMPLICATIONS:64Cu-bisPSMA-PET/CT identifies a higher number of disease recurrences than 68Ga PSMA-PET/CT with substantial management impact and a high RS true positive rate in men with BCR post RP.

Background Prostate cancer (PCa) exhibits significant ancestry-related disparity. While men of African ancestry experience higher overall mortality rates, this difference is most pronounced in Sub-Saharan Africa and for grade group 1 (GG1) disease, alluding to ancestry-specific biology. Despite this health disparity, African-relevant and prostate tumour GG1 inclusive data, specifically transcriptomic data, is lacking. In turn, this raises significant concerns with regards to adopting Eurocentric models to classify and manage assumed indolent disease for African men. The risk - suboptimal treatment decisions. Methods Using a single technical and analytical pipeline, we generated total RNA sequencing data from fresh-frozen prostate tissue for 68 Black South African (40 GG1-PCa, 28 non-PCa) and 48 Australian European men (all GG1-PCa), performing ancestry-specific differential gene expression and pathway analysis. Sourcing public data enabled limited African American inclusive The Cancer Genome Atlas cross-validation (13 of 61 GG1-PCa), while Pan Prostate Cancer Group European ancestral data provided for deeper cross-ancestral comparative analyses (106 GG1-PCa, 17 non-PCa). Results Identifying 5,652 differentially expressed genes between African and European ancestral GG1 tumours ( p < 0.05), including top-ranked PCa tumour suppressor genes DUSP1, JUN, FOS , and JUNB downregulated in African tumours. In turn, six metabolic and six immune-related pathways showed significant African-specific negative enrichment. Concordantly, cell type analysis showed significantly lower immune, stromal, and angiogenesis scores in African over European-derived GG1 tumours. Inclusion of African American GG1 data showed pathway over gene-level ancestry-specific concordance, with significant negative enrichment verification for oxidative phosphorylation, fatty acid metabolism and glycolysis. Compared to and irrespective of PCa status, our African tissues showed a 4.9-fold increase in differential gene expression in PSA-high versus PSA-low tissues. Notably, cell type clustering revealed 29% of PSA-high non-PCa tissues exhibited cancer-like profiles, indicating potential occult disease. Conclusions Revealing substantial transcriptomic divergence from European ancestral GG1 tumours, we identify African-specific transcriptomic features that may contribute to outcome disparities in this under-appreciated clinical group. Our study highlights not only a critical shortcoming in providing equitable PCa care for African men, but it also raises major concerns with regards to managing and treating African men using European-developed criteria.

This interim analysis of a multicentre implementation trial (n = 200) evaluated a multimodal artificial intelligence biomarker's impact on shared short-term androgen deprivation therapy (ST-ADT) decisions in intermediate-risk prostate cancer (IR-PC). Biomarker testing altered 27.5% (CI: 21.4-34.2%) of final decisions. ST-ADT use significantly decreased: 70.3% (CI: 58.5-80.3%) of patients initially electing ST-ADT changed to 'NO', versus a 2.4% (CI: 0.5-6.8%) shift to 'YES' (p < 0.001). Decision changes were significantly greater in unfavourable versus favourable IR-PC (35% v 4%; p < 0.001). These interim findings demonstrate a significant shift toward de-escalation.

Abstract Background Kataegis, the focal hypermutation of single base positions in tumour genomes, has received little attention with regards to prostate cancer (PCa) molecular features, tumour evolution and associated clinical presentation. Most notably, the impact of this phenomenon is yet to be explored across ancestral lineages representing the extremities of PCa presentation and outcomes, with men of African ancestry disproportionately disadvantaged. The purpose of this study is to address the knowledge gap through African inclusive multi-ancestral interrogation. Methods We assessed for ancestrally shared and unique molecular, evolutionary and clinical features of kataegis in 669 multi-ancestral whole PCa genomes. Access to raw whole-genome sequenced data allowed for direct single-pipeline comparative analysis between 109 southern African and 57 European derived treatment naïve high-risk-biased primary tumours (74% and 88%) with paired blood samples, further assessed against publicly available 207 Asian high-risk-leaning comparative (65%) and 296 European low-risk-biased alternative (79%) resources. Comparisons between ancestries and risk groups were through Wilcoxon’s rank sum test and Fisher’s exact tests, with P values adjusted by false discovery rate. Results Confirming relatively low burdens, we found kataegis to be significantly associated with genomic instability, cancer drivers, and clinical adversity across ancestries (false discovery rate = $$\:7.44\times\:{10}^{-6}-0.04$$ ). Notably, kataegis-postive tumours were associated with elevated prostate-specific antigen levels at presentation in African (false discovery rate = $$\:1.66\times\:{10}^{-3}$$ ) and higher risk for metastatic progression in European patients (Kaplan-Meier estimator, $$\:P=0.03$$ ). Enrichment of APOBEC’s context preferences showed more attribution from APOBEC3B than APOBEC3A. Further through analyses of evolution and structural variant (SV) co-occurrence, commonly the ancestry agnostic SV-associated kataegis predominated in the clonal evolutionary state, while the less common the SV-independent kataegis ( $$\:P=0.03$$ ) and subclonal kataegis ( $$\:P=1.67\times\:{10}^{-3}$$ ) showed African specificity. Conclusions We found kataegis-positivity to be associated with poor PCa presentation and prognosis, irrespective of patient ancestry. Kataegis-related genomic instability occurring early and late during African derived tumourigenesis, may partly explain the heightened tumour and clinical heterogeneity observed for patients of African ancestry.

Active surveillance (AS) delays or avoids unnecessary treatment-related side effects for early localised non-aggressive prostate cancer (PCa) through monitoring with regular prostate-specific antigen (PSA) testing, digital rectal examination (DRE), magnetic resonance imaging (MRI) and prostate biopsy. Whilst baseline MRI has prognostic value and is increasingly used for disease monitoring, molecular biomarkers could be an adjunct to refine risk stratification and disease prognostication [2]. Unlike tissue-based genomic classifiers such as Decipher (Veracyte) and Prolaris CCP (Myriad), blood-based molecular testing for example cell-free RNA (cfRNA) offers minimally invasive real-time monitoring. Moreover, cfRNA may yield genetic information shed from different cell populations within the tumour microenvironment, as well as the host circulation, expanding the opportunities for biomarker discovery. Here, we test the feasibility of whole transcriptome profiling of cfRNAs from the blood of PCa patients under AS, exploring differences between patients with stable disease (SD), and progression to radical prostatectomy (RP).

Objectives:This work aimed to report real-world outcomes from the use of SBRT to treat ADT naïve, PSMA-detected oligometastatic prostate cancer (OPCa) and to assess disease and treatment characteristics in this heterogeneous population intersect or impact treatment response. Subjects and Methods:This retrospective single-institution study examined PSMA-PET-detected oligometastases (n = 1-5) in ADT-naïve OPCa patients, treated with metastasis-directed therapy (MDT) using SBRT delivered via MRI- or CT-guided linear accelerator. Primary endpoint was biochemical progression free survival (PSA ≥ 25% if baseline <2 ng/mL or ≥2 ng/mL from nadir if baseline ≥ 2 ng/mL, start of systemic therapy, death). Secondary endpoints included time to PSA progression, time to next intervention, ADT-free survival. Univariate and multivariate analyses were conducted for prognostic factors associated with bPFS, time to PSA progression and PSA50 response. Baseline clinical and treatment characteristics, PSA responses and local failure rates were analysed. Those with castrate-resistant disease, prior systemic therapy or interval follow-up of <6 weeks were excluded. Results:Sixty-seven patients treated from January 2019 to August 2024 were analysed with a median follow-up of 18.8 months. Ninety-three oligometastatic lesions were treated; 55.3% were treated for nodal disease, 38.8% bone and 5% with lung disease. All lesions were PSMA-detected with median SUVmax 6.3. Median bPFS was 22.1 m; TTNI was 28.8 m. Lower initial T stage and longer duration from OPCa diagnosis to MDT were associated with prolonged bPFS. Lower T stage and PSA doubling time >3 m at MDT were associated with prolonged time to PSA progression. Median PSA fall was 68.9%; PSA 50% response was observed in 55.2%. Twenty-nine patients (43%) had a complete metabolic response after MDT. Median ADT-free survival was not reached. Conclusions:MDT in PSMA-PET-detected OPCa can provide clinically meaningful disease control in a subset of patients. This study supports this approach but warrants continued prospective study and exploration into the castrate-resistant setting.

OBJECTIVES:To provide a contemporary statement on focal therapy (FT) for localised prostate cancer (PCa) from an international and diverse group of physicians treating localised PCa, with the aim of overcoming the limitations of previous consensus statements, which were restricted to early adopters, and to offer direction regarding the various aspects of FT application that are currently not well defined. MATERIALS AND METHODS:The FocAL therapy CONsensus (FALCON) project began with a 154-item online survey, developed following a steering committee discussion and literature search. Invitations to participate were extended to a large, diverse group of professionals experienced in PCa management. From 2022 to 2023, a Delphi consensus study consisting of three online rounds was conducted using the Modified Delphi method. A 1-9 Likert scale was used for the survey, which was followed by an in-person expert meeting. The threshold for achieving consensus was set at 70% agreement/disagreement. Six main aspects of FT were covered: (i) patient selection; (ii) energy source selection; (iii) treatment approach; (iv) treatment evaluation and follow-up; (v) treatment cost and accessibility; and (vi) future perspectives. RESULTS:Of 246 initial participants, 148 (60%) completed all three rounds. Based on participant feedback, 27 new statements were added in the second round, and 33 questions related to personal expertise, for which consensus was not necessary, were excluded. After the third and final round, consensus had not been reached for 69 items. These items were discussed at the in-person meeting, resulting in a consensus of 57 additional items. Consensus was finally not reached on 12 items. Given the volume of data, the voting outcomes are summarised in this article, with a detailed breakdown presented in the form of figures and tables. CONCLUSIONS:The FALCON project delivered a significant consensus on the approach to FT for localised PCa. Additionally, it highlighted gaps in our knowledge that may provide guidance for future research.

Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline testing guidelines exclude for Africans. Established that structural variations (SVs) are major contributors to human disease and prostate tumourigenesis, their role is under-appreciated in familial and therapeutic testing. Utilising clinico-methodologically matched deep-sequenced whole-genome data for 113 African versus 57 European PCa patients, we interrogate 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identify 15 potentially pathogenic SVs representing 12.4% African and 7.0% European patients, of which 72% and 86% met germline testing standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair MLH1 and BARD1 and tumour suppressors FOXP1, WASF1 and RB1. Representing only a fraction of the vast African diaspora, this study raises considerations with respect to the contribution of kilo-to-mega-base rare variants to PCa pathogenicity and African-associated disparity.

BACKGROUND:Androgen deprivation therapy (ADT) improves outcomes in men undergoing definitive radiotherapy for prostate cancer but carries significant toxicities. Clinical parameters alone are insufficient to accurately identify patients who will derive the most benefit, highlighting the need for improved patient selection tools to minimize unnecessary exposure to ADT's side effects while ensuring optimal oncological outcomes. The ArteraAI Prostate Test, incorporating a multimodal artificial intelligence (MMAI)-driven digital histopathology-based biomarker, offers prognostic and predictive information to aid in this selection. However, its clinical utility in real-world settings has yet to be measured prospectively. METHODS:This multicentre implementation trial aims to collect real-world data on the use of the previously validated Artera MMAI-driven prognostic and predictive biomarkers in men with intermediate-risk prostate cancer undergoing curative radiotherapy. The prognostic biomarker estimates the 10-year risk of metastasis, while the predictive biomarker determines the likely benefit from short-term ADT (ST-ADT). A total of 800 participants considering ST-ADT in conjunction with curative radiotherapy will be recruited from multiple Australian centers. Eligible patients with intermediate-risk prostate cancer, as defined by the National Comprehensive Cancer Network, will be asked to participate. The primary endpoint is the percentage of patients for whom testing led to a change in the shared ST-ADT recommendation, analyzed using descriptive statistics and McNemar's test comparing recommendations before and after biomarker testing. Secondary endpoints include the impact on quality of life and 5-year disease control, assessed through linkage with the Prostate Cancer Outcomes Registry. The sample size will be re-evaluated at an interim analysis after 200 patients. DISCUSSION:ASTuTE will determine the impact of a novel prognostic and predictive biomarker on shared decision-making in the short term, and both quality of life and disease control in the medium term. If the biomarker demonstrates a significant impact on treatment decisions, it could lead to more personalized treatment strategies for men with intermediate-risk prostate cancer, potentially reducing overtreatment and improving quality of life. A potential limitation is the variability in clinical practice across different centers inherent in real-world studies. TRIAL REGISTRATION:Australian New Zealand Clinical Trials Registry, ACTRN12623000713695p. Registered 5 July 2023.

ObjectivesTo prospectively compare systemic anti‐tumour immune responses induced by irreversible electroporation (IRE) and robot‐assisted radical prostatectomy (RARP) in patients with localised intermediate‐risk prostate cancer (PCa).Patients and MethodsBetween February 2021 and June 2022, before and after treatment (at 5, 14 and 30 days) peripheral blood samples of 30 patients with localised PCa were prospectively collected. Patient inclusion criteria were: International Society of Urological Pathologists Grade 2–3, clinical cancer stage ≤T2c, prostate‐specific antigen level <20 ng/mL). Patients were treated with IRE (n = 20) or RARP (n = 10). Frequency and activation status of lymphocytic and myeloid immune cell subsets were determined using flow cytometry. PCa‐specific T‐cell responses to prostatic acid phosphatase (PSAP) and cancer testis antigen (New York oesophageal squamous cell carcinoma 1 [NY‐ESO‐1]) were determined by interferon‐γ enzyme‐linked immunospot assay (ELISpot). Repeated‐measures analysis of variance and two‐sided Student's t‐tests were used to compare immune responses over time and between treatment cohorts.ResultsPatient and tumour characteristics were similar between the cohorts except for age (median 68 years [IRE] and 62 years [RARP], P = 0.01). IRE induced depletion of systemic regulatory T cells (P = 0.0001) and a simultaneous increase in activated cytotoxic T‐lymphocyte antigen 4 (CTLA‐4)+ cluster of differentiation (CD)4+ (P < 0.001) and CD8+ (P = 0.032) T cells, consistent with reduction of systemic immune suppression allowing for effector T‐cell activation, peaking 14 days after IRE. Effects were positively correlated with tumour volume/ablation size. Accordingly, IRE induced expansion of PSAP and/or NY‐ESO‐1 specific T‐cell responses in four of the eight immune competent patients. Temporarily increased activated myeloid derived suppressor cell frequencies (P = 0.047) were consistent with transient immunosuppression after RARP.ConclusionsIrreversible electroporation induces a PCa‐specific systemic immune response in patients with localised PCa, aiding conversion of the tumour microenvironment into a more immune permissive state. Therapeutic efficacy might be further enhanced by combination with CTLA‐4 checkpoint inhibition, potentially opening up a new synergistic treatment paradigm for high‐risk localised or (oligo)metastatic disease.

Kataegis, the focal hypermutation of single base substitutions (SBS) in tumour genomes, has received little attention with respect to prostate cancer (PCa) associated molecular and clinical features. Most notably, data is lacking with regards to this tumour evolutionary phenomenon and PCa racial disparities, with African men disproportionately impacted. Here through comparison between African (n = 109) and non-African (n = 79) whole genome sequenced treatment naïve primary tumours, using a single analytical workflow we assessed for shared and unique features of kataegis. Linking kataegis to aggressive presentation, structural variant burden and copy number loss, we attributed APOBEC3 activity through higher rates of SBS2 to high-risk African tumours. While kataegis positive African patients presented with elevated prostate specific antigen levels, their tumours showed evolutionary unique trajectories marked by increased subclonal and structural variant-independent kataegis. The potential to exacerbate tumour heterogeneity emphases the significance of continued exploration of biological behaviours and environmental exposures for African patients.

OBJECTIVE:To review the literature on salvage treatments after focal therapy (FT) for prostate cancer (PCa). MATERIALS AND METHODS:A non-systematic literature review was conducted on PubMed, Scopus, and Web of Science up to March 15, 2024, for studies that assessed salvage treatment outcomes in patients with recurrent PCa after primary FT. Original prospective and retrospective studies with more than 10 patients were included. Reviews, editorial comments, conference abstracts, and studies focusing solely on whole-gland treatments were excluded. RESULTS:Twenty-one studies with a total of 1012 patients were included. The most reported salvage treatments were salvage radical prostatectomy followed by re-do ablation therapy. Only one study evaluated salvage radiation therapy. Except for one prospective study, all studies were retrospective. Oncological outcomes showed acceptable biochemical recurrence rates. Functional outcomes varied, with significant impacts observed on erectile function across modalities, though continence rates were less impacted. Complications were generally low across all treatment options. CONCLUSION:Salvage treatment post-primary FT is feasible, safe, and has reasonable oncologic outcomes. However, significant declines in sexual function are common, while continence is comparatively less affected. The literature primarily consists of retrospective studies; hence, future research should focus on large-scale prospective evaluations to better define treatment protocols and improve patient outcomes.

Background: Preoperative assessment of the probability of pelvic lymph-node meta-static disease (pN1) is required to identify patients with prostate cancer (PCa) who are candidates for extended pelvic lymph-node dissection (ePLND).Objective: To develop a novel intuitive prognostic nomogram for predicting pathological lymph-node (pN) status in contemporary patients with primary diagnosed localized PCa, using preoperative clinical and histopathological parameters, magnetic resonance imaging (MRI), and prostate-specific membrane antigen (PSMA) positron emission tomography (PET).Design, setting, and participants: In total, 700 eligible patients who underwent robot -assisted radical prostatectomy and ePLND were included in the model-building cohort. The external validation cohort consisted of 305 surgically treated patients. Logistic regression with backward elimination was used to select variables for the Amsterdam-Brisbane-Sydney nomogram.Outcome measurements and statistical analysis: Performance of the final model was evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision-curve analyses. Models were subsequently validated in an external population.Results and limitations: The Amsterdam-Brisbane-Sydney nomogram included initial prostate-specific antigen value, MRI T stage, highest biopsy grade group (GG), biopsy technique, percentage of systematic cores with clinically significant PCa (GG >= 2), and lymph-node status on PSMA-PET. The AUC for predicting pN status was 0.81 (95% confidence interval [CI] 0.78-0.85) for the final model. On external validation, the Amsterdam-Brisbane-Sydney nomogram showed superior discriminative ability to the Briganti-2017 and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms (AUC 0.75 [95% CI 0.69-0.81] vs 0.67 [95% CI 0.61-0.74] and 0.65 [95% CI 0.58-0.72], respectively; p < 0.05), and similar discriminative ability to the Briganti-2019 nomogram (AUC 0.78 [95% CI 0.71-0.86] vs 0.80 [95% CI 0.73-0.86]; p = 0.76). The Amsterdam-Brisbane -Sydney nomogram showed excellent calibration on external validation, with an increased net benefit at a threshold probability of >= 4%.Conclusions: The validated Amsterdam-Brisbane-Sydney nomogram performs superior to the Briganti-2017 and MSKCC nomograms, and similar to the Briganti-2019 nomogram. Furthermore, it is applicable in all patients with newly diagnosed unfavorable intermediate-and high-risk PCa.Patient summary: We developed and validated the Amsterdam-Brisbane-Sydney nomogram for the prediction of prostate cancer spread to lymph nodes before surgery. This nomogram performs similar or superior to all presently available nomograms.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology.

You have accessJournal of UrologyProstate Cancer: Localized: Ablative Therapy II (PD39)1 May 2024PD39-02 FOCAL THERAPY CONSENSUS: RECOMMENDATIONS OF A DELPHI INITIATIVE TO CONSOLIDATE PARTIAL GLAND ABLATION IN LOCALIZED PROSTATE CANCER Lara Rodriguez-Sanchez, Robert Reiter, Alejandro Rodriguez, Petr Macek, Pilar Laguna, Alberto Bossi, Eva Comperat, Luca Lunelli, Anita Mitra, George Schade, Georg Salomon, Peter Ka-Fung Chiu, Aiman Haider, Gaelle Fiard, José Luis Dominguez-Escrig, Bernardino Miñana, Marc Emberton, Phillip Stricker, Fernando Bianco, Anna Lantz, Theo de Reijke, Rafael Sanchez-Salas, and Falcon Consensus group Lara Rodriguez-SanchezLara Rodriguez-Sanchez , Robert ReiterRobert Reiter , Alejandro RodriguezAlejandro Rodriguez , Petr MacekPetr Macek , Pilar LagunaPilar Laguna , Alberto BossiAlberto Bossi , Eva ComperatEva Comperat , Luca LunelliLuca Lunelli , Anita MitraAnita Mitra , George SchadeGeorge Schade , Georg SalomonGeorg Salomon , Peter Ka-Fung ChiuPeter Ka-Fung Chiu , Aiman HaiderAiman Haider , Gaelle FiardGaelle Fiard , José Luis Dominguez-EscrigJosé Luis Dominguez-Escrig , Bernardino MiñanaBernardino Miñana , Marc EmbertonMarc Emberton , Phillip StrickerPhillip Stricker , Fernando BiancoFernando Bianco , Anna LantzAnna Lantz , Theo de ReijkeTheo de Reijke , Rafael Sanchez-SalasRafael Sanchez-Salas , and Falcon Consensus group View All Author Informationhttps://doi.org/10.1097/01.JU.0001008924.16121.42.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Focal Therapy (FT) for Prostate Cancer (PCa) has been accepted for evaluation under prospective registry assessment. Although improved functional outcomes are proven, long-term oncological results are awaited and there is no final consensus on the implementation of FT. Previously available consensus was limited to include experts' opinions on FT only. We aimed to conduct a consensus meeting, amongst a large group of PCa treatment physicians to propose a comprehensive approach for FT implementation. METHODS: A 154-item questionnaire was built following a stirring committee discussion and a literature search. From 2022 to 2023 the authors then performed three rounds of a Delphi Consensus (University of Liverpool, Comet Initiative Manager), using a 1-9 Likert scale with an "Unable to rate" option, followed by a face-to-face expert meeting. Six main areas of interest were covered including, 1) Patient selection, 2) Energy selection, 3) Treatment approach, 4) Treatment evaluation and follow-up, 5) Treatment cost and accessibility 6) Future perspectives. Respondents were invited to add new items during rounds 1 and 2. RESULTS: Out of the initial 254 participants; 148 (56%) completed the three Delphi rounds among the 181 statements considered in the second round (27 new statements); 33 questions related to personal expertise were excluded from subsequent rounds. After the third and final online round, 69 items did not reach a consensus. They were re-discussed, resulting in a consensus (n=57), and a consensus on uncertainty (n=12). A final list of statements was derived from the approved and discussed items, with the addition of generated statements, to provide guidance on FT. CONCLUSIONS: FALCON statements have provided an unprecedented comprehensive consensus guideline on implementing FT. Research efforts in FT could be guided by FALCON information. Source of Funding: The Falcon project has been supported by AngioDynamics © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e813 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Lara Rodriguez-Sanchez More articles by this author Robert Reiter More articles by this author Alejandro Rodriguez More articles by this author Petr Macek More articles by this author Pilar Laguna More articles by this author Alberto Bossi More articles by this author Eva Comperat More articles by this author Luca Lunelli More articles by this author Anita Mitra More articles by this author George Schade More articles by this author Georg Salomon More articles by this author Peter Ka-Fung Chiu More articles by this author Aiman Haider More articles by this author Gaelle Fiard More articles by this author José Luis Dominguez-Escrig More articles by this author Bernardino Miñana More articles by this author Marc Emberton More articles by this author Phillip Stricker More articles by this author Fernando Bianco More articles by this author Anna Lantz More articles by this author Theo de Reijke More articles by this author Rafael Sanchez-Salas More articles by this author Falcon Consensus group More articles by this author Expand All Advertisement PDF downloadLoading ...

The telomere repetitive TTAGGG motif at the ends of chromosomes, serves to preserve genomic integrity and chromosomal stability. In turn, genomic instability is a hallmark of cancer-implicating telomere disturbance. Prostate cancer (PCa) shows significant ancestral disparities, with men of African ancestry at the greatest risk for aggressive disease and associated genomic instability. Yet, no study has explored the role of telomere length (TL) with respect to ancestrally driven PCa health disparities. Patient- and technically-matched tumour-blood whole genome sequencing data for 179 ancestrally defined treatment naive PCa patients (117 African, 62 European), we assessed for TL (blood and tumour) associations. We found shortened tumour TL to be associated with aggressive PCa presentation and elevated genomic instabilities, including percentage of genome alteration and copy number gains, in men of African ancestry. For European patients, tumour TL showed significant associations with PCa driver genes PTEN, TP53, MSH2, SETBP1 and DDX11L1, while shorter blood TL (< 3200 base pairs) and tumour TL (< 2861 base pairs) were correlated with higher risk for biochemical recurrence. Concurring with previous studies linking TL to PCa diagnosis and/or prognosis, for the first time we correlated TL differences with patient ancestry with important implications for future treatments targeting telomere dysfunction.

PURPOSE:The Prostate Imaging Reporting and Data System (PI-RADS) score is standard of care for clinically significant prostate cancer (csPCa) diagnosis. The PRIMARY score (prostate-specific membrane antigen [PSMA]-positron emission tomography [PET]/CT) also has high diagnostic accuracy for csPCa. This study aimed to develop an easily calculated combined (P) score for csPCa detection (International Society of Urological Pathology [ISUP] ≥2) incorporating separately read PI-RADS and PRIMARY scores, with external validation. MATERIALS AND METHODS:Two datasets of men with suspected PCa, no prior biopsy, recent MRI and 68Ga-PSMA-11-PET/CT, and subsequent transperineal biopsy were evaluated. These included the development sample (n = 291, 56% csPCa) a prospective trial and the validation sample (n = 227, 67% csPCa) a multicenter retrospective database. Primary outcome was detection of csPCa (ISUP ≥2), with ISUP ≥ 3 cancer detection a secondary outcome. Score performance was evaluated by area under the curve, sensitivity, specificity, and decision curve analysis. RESULTS:The 5-point combined (P) score was developed in a prospective dataset. In the validation dataset, csPCa was identified in 0%, 20%, 52%, 96%, and 100% for P score 1 to 5. The area under the curve was 0.93 (95% CI: 0.90-0.96), higher than PI-RADS 0.89 (95% CI: 0.85-0.93, P = .039) and PRIMARY score alone 0.84 (95% CI: 0.79-0.89, P < .001). Splitting scores at 1/2 (negative) vs 3/4/5 (positive), P score sensitivity was 94% (95% CI: 89-97) compared to PI-RADS 89% (95% CI: 83-93) and PRIMARY score 86% (95% CI: 79-91). For ISUP ≥ 3, P score sensitivity was 99% (95% CI: 95-100) vs 94% (95% CI: 88-98) and 92% (95% CI: 85-97) for PI-RADS and PRIMARY scores respectively. A maximum standardized uptake value > 12 (P score 5) was ISUP ≥ 2 in all cases with 93% ISUP ≥ 3. CONCLUSIONS:The P score is easily calculated and improves accuracy for csPCa over both PI-RADS and PRIMARY scores. It should be considered when PSMA-PET is undertaken for diagnosis.

Background The Illumina family of Infinium Methylation BeadChip microarrays has been widely used over the last 15 years for genome-wide DNA methylation profiling, including large-scale and population-based studies, due to their ease of use and cost effectiveness. Succeeding the popular HumanMethylationEPIC BeadChip (EPICv1), the recently released Infinium MethylationEPIC v2.0 BeadChip (EPICv2) claims to extend genomic coverage to more than 935,000 CpG sites. Here, we comprehensively characterise the reproducibility, reliability and annotation of the EPICv2 array, based on bioinformatic analysis of both manifest data and new EPICv2 data from diverse biological samples. Results We find a high degree of reproducibility with EPICv1, evidenced by comparable sensitivity and precision from empirical cross-platform comparison incorporating whole genome bisulphite sequencing (WGBS), and high correlation between technical sample replicates, including between samples with DNA input levels below the manufacturer’s recommendation. We provide a full assessment of probe content, evaluating genomic distribution and changes from previous array versions. We characterise EPICv2’s new feature of replicated probes and provide recommendations as to the superior probes. In silico analysis of probe sequences demonstrates that probe cross-hybridisation remains a significant problem in EPICv2. By mapping the off-target sites at single nucleotide resolution and comparing with WGBS we show empirical evidence for preferential off-target binding. Conclusions Overall, we find EPICv2 a worthy successor to the previous Infinium methylation microarrays, however some technical issues remain. To support optimal EPICv2 data analysis we provide an expanded version of the EPICv2 manifest to aid researchers in understanding probe design, data processing, choosing appropriate probes for analysis and for integration with methylation datasets from previous versions of the Infinium Methylation BeadChip.

PurposeThe aim of this study was to assess the use of magnetic resonance guided adaptive radiotherapy (MRgART) in the post-prostatectomy setting; comparing dose accumulation for our initial seven patients treated with fully adaptive workflow on the Unity MR-Linac (MRL) and with non-adaptive plans generated offline. Additionally, we analyzed toxicity in patients receiving treatment.MethodsSeven patients were treated with MRgART. The prescription was 70-72 Gy in 35-36 fractions. Patients were treated with an adapt to shape (ATS) technique. For each clinically delivered plan, a non-adaptive plan based upon the reference plan was generated and compared to the associated clinically delivered plan. A total of 468 plans were analyzed. Concordance Index of target and Organs at Risk (OARs) for each fraction with reference contours was analyzed. Acute toxicity was then assessed at six-months following completion of treatment with Common Terminology for Adverse Events (CTCAE) Toxicity Criteria.ResultsA total of 246 fractions were clinically delivered to seven patients; 234 fractions were delivered via MRgART and 12 fractions delivered via a traditional linear accelerator due to machine issues. Pre-treatment reference plans met CTV and OAR criteria. PTV coverage satisfaction was higher in the clinically delivered adaptive plans than non-adaptive comparison plans; 42.93% versus 7.27% respectively. Six-month CTCAE genitourinary and gastrointestinal toxicity was absent in most patients, and mild-to-moderate in a minority of patients (Grade 1 GU toxicity in one patient and Grade 2 GI toxicity in one patient).ConclusionsDaily MRgART treatment consistently met planning criteria. Target volume variability in prostate bed treatment can be mitigated by using MRgART and deliver satisfactory coverage of CTV whilst minimizing dose to adjacent OARs and reducing toxicity

The PRIMARY score is a 5-category scale developed to identify clinically significant intraprostate malignancy (csPCa) on 68Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT (68Ga-PSMA PET) using a combination of anatomic site, pattern, and intensity. Developed within the PRIMARY trial, the score requires evaluation in external datasets. This study aimed to assess the reproducibility and diagnostic accuracy of the PRIMARY score in a cohort of patients who underwent multiparametric MRI (mpMRI) and 68Ga-PSMA PET before prostate biopsy for the diagnosis of prostate cancer. Methods: In total, data from 242 men who had undergone 68Ga-PSMA PET and mpMRI before transperineal prostate biopsy were available for this ethics-approved retrospective study. 68Ga-PSMA PET and mpMRI data were centrally collated in a cloud-based deidentified image database. Six experienced prostate-focused nuclear medicine specialists were trained (1 h) in applying the PRIMARY score with 30 sample images. Six radiologists experienced in prostate mpMRI read images as per the Prostate Imaging-Reporting and Data System (PI-RADS), version 2.1. All images were read (with masking of clinical information) at least twice, with discordant findings sent to a masked third (or fourth) reader as necessary. Cohen κ was determined for both imaging scales as 5 categories and then collapsed to binary (negative and positive) categories (score 1 or 2 vs. 3, 4, or 5). Diagnostic performance parameters were calculated, with an International Society of Urological Pathology grade group of at least 2 (csPCa) on biopsy defined as the gold standard. Combined-imaging-positive results were defined as any PI-RADS score of 4 or 5 or as a PI-RADS score of 1-3 with a PRIMARY score of 3-5. Results: In total, 227 patients with histopathology, 68Ga-PSMA PET, and mpMRI imaging before prostate biopsy were included; 33% had no csPCa, and 67% had csPCa. Overall interrater reliability was higher for the PRIMARY scale (κ = 0.70) than for PI-RADS (κ = 0.58) when assessed as a binary category (benign vs. malignant). This was similar for all 5 categories (κ = 0.65 vs. 0.48). Diagnostic performance to detect csPCa was comparable between PSMA PET and mpMRI (sensitivity, 86% vs. 89%; specificity, 76% vs. 74%; positive predictive value, 88% vs. 88%; negative predictive value, 72% vs. 76%). Using combined imaging, sensitivity was 94%, specificity was 68%, positive predictive value was 86%, and negative predictive value was 85%. Conclusion: The PRIMARY score applied by first-user nuclear medicine specialists showed substantial interrater reproducibility, exceeding that of PI-RADS applied by mpMRI-experienced radiologists. Diagnostic performance was similar between the 2 modalities. The PRIMARY score should be considered when interpreting intraprostatic PSMA PET images.