Matteo Droghetti

The EMBARK trial demonstrated improved survival with enzalutamide plus androgen deprivation therapy (ADT) in non-metastatic hormone-sensitive prostate cancer patients with high-risk biochemical recurrence (BCR), although staged using conventional imaging. Given the higher sensitivity of PSMA-PET, many of these patients could harbor metastatic disease. We retrospectively analyzed 587 patients with first BCR after radical treatment who underwent PSMA-PET. Patients were stratified according to EMBARK criteria for high-risk BCR. 169 patients (29%) met EMBARK criteria. They more often showed PSMA-PET positivity for any localization (82% vs 39%; p < 0.001) and metastatic disease (46% vs 15%; p < 0.001). Median PSA was higher and PSA doubling-time (PSADT) shorter (2.23 vs 0.43 ng/mL; 4.3 vs 9 months). Most High-risk BCR patients have a positive PSMA-PET, and many of these harbor metastatic disease at molecular imaging. Given the survival benefit from intensified systemic treatment with ARPI in this cohort, how to best combine systemic therapy with PSMA-PET guided metastases-directed-treatments remains an important future area of research.

Background: Thanks to the improved accuracy of multiparametric Magnetic Resonance Imaging (mpMRI) to detect and localize the dominant index lesion on prostate cancer (PCa), the concept of minimally invasive focal treatments (FT) has gained popularity. Nevertheless, although high-quality evidence that FT has favorable functional outcomes, definitive proof of its oncological effectiveness compared to standard treatments remains underreported. Objective: This study aims to explore the efficacy, safety, oncologic and functional outcomes of different type of FT for PCa. Evidence acquisition: A non-systematic literature review was conducted by searching on PubMed “prostate cancer” AND “focal treatment” OR “HIFU” OR “irreversible electroporation” OR “cryoablation” OR “focal laser ablation.” Overall, 22 articles published in English literature from 2018 to 2023 describing FT techniques for PCa were included. Evidence synthesis: Related to the field ablated, focal therapies include hemiablation (half gland), focal ablation (zonal-base) or targeted therapy (lesion-based). FT modalities can be categorized in thermal and non-thermal energy: thermal energy techniques include high-intensity focused ultrasound (HIFU), cryotherapy, radiofrequency ablation (RFA), and focal laser ablation (FLA). Focal brachytherapy, irreversible electroporation (IRE), and vascular-targeted photodynamic therapy (VTP) are classified as non-thermal ablation. Each focal ablative treatments could be promising alternative to conventional radical therapies to treat PCa in term of mid-term oncologic and functional outcomes, however, limited data are available in comparison with standardized radical treatments. HIFU and Cryo are the most studied techniques and seem to be superior to radical treatments in term of functional outcomes despite associated with higher recurrence and retreatment rate. Conclusions: Current evidences of oncologic and functional outcomes of FT are based mainly on retrospective, non-comparative and single center studies. Thus, none of the focal therapies available should be considered safe alternative to standardized treatments in routine practice and should be offered only for well selected PCa patients with low or at least favorable-intermediate risk disease, unfit for radical options.

Objectives: To explore the factors affecting the lymph node metastasis (LNM) detection performance of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) and to evaluate its prognostic value for biochemical recurrence after radical prostatectomy (RP). Methods: Patients who had intermediate- or high-risk prostate cancer and underwent robot-assisted (RA)RP between 2017 and 2021 were included. Initial lymph node staging was carried out using PSMA PET/CT. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were calculated. A cut-off value for LNM tumor deposit size that maximizes specificity was investigated and a post hoc specificity analysis was carried out. In survival analysis for biochemical progression-free survival (bPFS) after RP, Kaplan–Meier curves of molecular imaging (mi)N0 and miN1 patients were compared using the log-rank test and separate Cox regression models were developed to reveal the significance of PSMA PET/CT staging in pre- and post-surgery settings. Results: In 583 patients with a prevalence of pathology-proven LNM of 27.4%, overall sensitivity, specificity, PPV, and NPV of PSMA PET/CT per patient were 26.3% [95%CI 18.9–35.5], 93.9% [95%CI 84.9–100], 61.8% [95%CI 44.5–83.5], and 77.1% [95%CI 69.7–85.1], respectively. PSMA PET/CT showed a better sensitivity as LNM tumor deposit size increased (p = 0.003 OR 2.4 [95%CI 1.3–4.4]) and a better specificity in pT3-4 tumors (96.1%) versus pT2 (91.1%, p = 0.024 OR 2.7 [95%CI 1.1–6.3]). After adjustment according to 5.5 mm LNM tumor deposit size, which showed the best discriminative performance (AUC: 0.905 [95%CI 0.804–1.000, p < 0.001]), overall sensitivity tripled (90.2%, p < 0.001). The 1-year bPFS was 56.0% and 83.3% for miN1 and miN0 patients, respectively (p < 0.001). Whereas miN0pN1 was not, miN1pN1 disease was independently associated with decreased bPFS (HR:2.1 95%CI 1.3–3.4, p < 0.001). Conclusions: PSMA PET/CT has a lymph node tumor burden-dependent and cohort-driven diagnostic ability but consequently a strong independent prognostic value for predicting biochemical recurrence after RARP.

To assess the oncological outcomes of sentinel-node dissection during radical prostatectomy according to nodal location in comparison to extended pelvic lymph node dissection. Prospectively collected data of clinically node negative patients that underwent prostatectomy and extended lymph node dissection with or without sentinel-node from 2013 to January 2023 was retrospectively analyzed. The primary endpoint was to assess oncological outcomes on the whole population. Kaplan-Meier curves were used to depict biochemical and clinical recurrence free survival. Multivariable Cox regression models assessed the impact of nodal location on SPECT on oncological outcomes. Adjustment for case mix included: pathological T stage, ISUP grade group, initial PSA, nodal burden, age at surgery and surgical margin status. Secondarily, a propensity score match was performed according to age at surgery, PSA, biopsy ISUP, clinical T stage and Briganti risk of nodal invasion. Survival and regression analyses were than performed also in the matched population. 55.8% patients had at least one sentinel node outside of lymph node dissection template at SPECT/CT. Log-rank test showed comparable 36-months biochemical (P = .3) and clinical recurrence-free survival (P = .6) among patients with sentinel-node inside template, outside template or ePLND alone. At Cox regression, sentinel-node location outside template was associated with lower hazard of metastases (HR 0.62; P = .04) in the overall cohort, while in the matched cohort benefits were observed only for biochemical recurrence (HR 0.57; P = .001). Wider nodal resection boundaries outside "classic" template, driven by sentinel node procedure, have a positive impact on oncological outcomes in selected patient.

Introduction: Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed by normal prostatic tissue. Therefore, molecular imaging targeting PSMA (PSMA-PET) has gained particular interest and diffusion for PCa staging and restaging. Several factors may affect PSMA-PET results, and many tools have been proposed to improve patient selection. Furthermore, PSMA expression is not homogeneous among different tissues and within the prostate itself. The aims of this study were to evaluate immunohistochemistry (IHC) features of prostate biopsy samples and to assess their correlation with whole-mount specimens and PSMA-PET parameters.Methods: We included consecutive high-risk PCa patients who underwent PSMA-PET for staging proposal at our institution from January 2022 to December 2022. The PET parameters selected were SUVmax, total volume (TV), and total lesion activity (TL). Each patient underwent multiparametric MRI (mpMRI) and fusion-targeted prostate biopsy prior to surgery. IHC analyses were performed on the index lesion cores. IHC visual score (VS) (1, 2, 3) and visual pattern (VP) (membranous, cytoplasmic, and combined) and the percentage of PSMA-negative tumor areas (PSMA%neg) within biopsy cores were evaluated.Results: Forty-three patients who underwent robotic radical prostatectomy after PSMA-PET were available for analyses. Concordance between VS and VP at biopsy and final pathology showed a Cohen’s kappa coefficient of 0.39 and 0.38, respectively. Patients with PSMA%neg p = 0.3) and PSMA-TL (p = 0.9) according to VS at biopsy, while median SUVmax was higher in patients with VS 3 (p = 0.04). Higher SUVmax was associated with membranous and combined VP expression (p = 0.008). No difference emerged between patients with PSMA%neg 20% on biopsy cores in terms of SUVmax, PSMA-TL, and PSMA-TV (p = 0.5, p = 0.5, and p = 0.9 respectively).Conclusions: We found a correlation between IHC VS and VP on targeted biopsy cores and SUVmax at PSMA-PET. However, the correlation between the IHC parameters of biopsy cores and final pathology was not as high as expected. Nevertheless, the presence of PSMA%neg <20% seems to have a better concordance in terms of visual score.

The 2022 WHO classification of urinary and male genital tumors introduced several novel kidney entities exhibiting eosinophilic/oncocytic features with specific mutational backgrounds. Thus, molecular techniques, such as next-generation sequencing (NGS), became more commonly used for their evaluation. We studied 12 low-grade oncocytic tumors (LOT) of the kidney (from 11 patients), identified in a cohort of 210 eosinophilic/oncocytic renal tumors, diagnosed in our institution between October 2019 and May 2023, which represented 5.7% (12/210) of all eosinophilic/oncocytic renal tumors during this period. We reviewed their clinicopathologic, histologic, and immunohistochemical features, as well as their mutational profiles. We also reviewed the literature on NGS-derived data of LOT, by selecting papers in which LOT diagnosis was rendered according to the criteria proposed initially. Median age was 65 years (mean: 63.5; range 43–79) and median tumor size was 2.0 cm (mean: 2.2; range: 0.9–3.1). All tumors were positive for PAX8, CK7, and GATA3, and negative or focally positive for CD117/KIT. We found the following gene mutations: MTOR ((6/11), 54.5%)), TSC1 ((2/11), 18.2%)), and 1 had both NOTCH1 and NOTCH4 ((1/11), 9.1%)). Wild-type status was found in 2/11 (18.2%) patients and one tumor was not analyzable. A review of 8 previous studies that included 79 LOTs revealed frequent mutations in the genes that regulate the mammalian target of rapamycin (mTOR) pathway: MTOR (32/79 (40.5%)), TSC1 (21/79 (26.6%)), and TSC2 (9/79 (11.4%)). Other mutated genes included PIK3CA, NF2, and PTEN, not typically known to affect the mTOR pathway, but potentially acting as upstream and downstream effectors. Our study shows that LOT is increasingly diagnosed in routine practice when applying the appropriate diagnostic criteria. We also confirm that the mTOR pathway is strongly implicated in the pathogenesis of this tumor mainly through MTOR, TCS1, and TSC2 mutations, but other genes could also be involved in the pathway activation, especially in LOTs without “canonical” mutations.

Purpose The aim of this study was to reveal the association between the other-cause mortality (OCM) and post-radical prostatectomy (RP) salvage radiotherapy (sRT) in men with prostate cancer (PCa). Methods A retrospective study was carried out with patients who had PCa and underwent RP ± sRT in a high-volume cancer center between 2005 and February 2019. Data from 1955 patients were subjected to a 1:1 matching for age, initial PSA, pathological (p)T/N stages, and ISUP score, which yielding 439 RP + RT (group 1) vs 439 RP-only cases (group 2), without any residual difference. Primary and secondary endpoints of the study were OCM and cancer-specific mortality (CSM). Kaplan–Meier, log-rank, and cox regression tests were used for purpose of the study. Results The median follow-up time after RP was 5.3 years (interquartile range: 4.0–7.3). After matching, of all deaths that occurred during the study period, 16 in group 1 and 35 in group 2 were attributed to other causes (p = 0.006). 5-year OCM rate of patients who received sRT (1.2%) was significantly lower compared to patients that underwent RP-only (4.4%, p < 0.001). 19 versus 16 patients died of PCa, respectively (p = 0.61). There was no CSM risk difference between groups (p = 0.29). Older patients had an increased risk of OCM (hazard ratio [HR]:1.10 [95%CI 1.05–1.17], p < 0.001) and post-RP RT was associated with lower OCM (HR: 0.28 [95%CI 0.15–0.51], p < 0.001) in multivariable model. pT/N stages and ISUP score were strongly associated with CSM, but not with OCM. Conclusion OCM was not higher in patients who had sRT with or without ADT. Excess OCM in favor of RP-only patients may be cautiously explained with higher-performance status/life expectancy of patients who selected for RT after RP in our cohort.

Background: Prostate Specific Membrane Antigen-Positron Emission Tomography (PSMA-PET) is used to select recurrent prostate cancer (PCa) patients for metastases-directed therapy (MDT). We aimed to evaluate the oncologic outcomes of second-line PSMA-guided MDT in oligo-recurrent PCa patients. Methods: we performed a retrospective analysis of 113 recurrent PCa after previous radical prostatectomy and salvage therapies with oligorecurrent disease at PSMA-PET (≤3 lesions in N1/M1a-b) in three high-volume European centres. Patients underwent second-line salvage treatments: MDT targeted to PSMA (including surgery and/or radiotherapy), and the conventional approach (observation or Androgen Deprivation Therapy [ADT]). Patients were stratified according to treatments (MDT vs. conventional approach). Patients who underwent MDT were stratified according to stage in PSMA-PET (N1 vs. M1a-b). The primary outcome of the study was Progression-free survival (PFS). Secondary outcomes were Metastases-free survival (MFS) and Castration Resistant PCa free survival (CRPC-FS). Kaplan-Meier analyses assessed PFS, MFS and CRPC-FS. Multivariable Cox regression models identified predictors of progression and metastatic disease. Results: Overall, 91 (80%) and 22 (20%) patients were treated with MDT and the conventional approach, respectively. The median follow-up after PSMA-PET was 31 months. Patients who underwent MDT had a similar PFS compared to the conventional approach (p = 0.3). Individuals referred to MDT had significantly higher MFS and CRPC-FS compared to those who were treated with the conventional approach (73.5% and 94.7% vs. 30.5% and 79.5%; all p ≤ 0.001). In patients undergoing MDT, no significant differences were found for PFS and MFS according to N1 vs. M1a-b disease, while CRPC-FS estimates were significantly higher in patients with N1 vs. M1a-b (100% vs. 86.1%; p = 0.02). At multivariable analyses, age (HR = 0.96) and ADT during second line salvage treatment (HR = 0.5) were independent predictors of PFS; MDT (HR 0.27) was the only independent predictor of MFS (all p ≤ 0.04) Conclusion: Patients who underwent second-line PSMA-guided MDT experienced higher MFS and CRPC-FS compared to men who received conventional management.

PSMA-PET/CT is a suitable replacement for conventional imaging in the primary staging of PCa. The aim of this retrospective study was to assess the correlation between parameters discovered by PSMA PET/CT in primary staging and either prostate histopathology (pT) findings or PSMA-IHC expression in a cohort of biopsy-proven high-risk PCa candidates for surgery. Clinical information (age, iPSA-value, and grading group) and PSMA-PET/CT parameters (SUVmax, PSMA tumor volume [PSMA-TV], and total lesion [PSMA-TL]) were compared with pT (including histologic pattern, Gleason grade, and lymphovascular invasion [LVI]) and PSMA-IHC features, including visual quantification (VS) with a four-tiered score (0 = negative, 1+ = weak, 2+ = moderate, 3+ = strong), growth pattern (infiltrative vs expansive), and visual pattern (cytoplasmic vs membranous). In total, 44 patients were enrolled, with a median age of 67 (IQR 57-77); the median iPSA was 9.4 ng/dL (IQR 12.5-6.0). One patient (3%) was grading group (GG) 3, 27/44 (61%) were GG4, and 16/44 (36%) were GG5. PSMA-PET/CT detection rate for the presence of primary prostate cancer was 100%. Fused/poorly formed Gleason grade 4 features were predominant (22/44–50%); a cribriform pattern was present in 18/44 (41%) and acinar in 4/44 (9%). We found that lower PSMA-TVs were mostly related to acinar, while higher PSMA-TVs correlated with a higher probability to have a cribriform pattern (p-value 0.04). LVI was present in 21/44(48%) patients. We found that higher PSMA-TV and PSMA-TL are predictive of LVI p-value 0.002 and p-value 0.01, respectively. There was no correlation between PET-parameters and perineural invasion (PNI), probably because this was present in almost all the patients. Moreover, patients with high PSMA-TL values displayed the highest PSMA-IHC expression (VS3+) with a membranous pattern. In conclusion, PSMA-TV and PSMA-TL are predictors of a cribriform pattern and LVI. These conditions are mostly related to higher aggressiveness and worse outcomes.