Matthijs Jv Scheltema

Objectives: To 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 Methods: Between 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 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. Results: Patient 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. Conclusions: Irreversible 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.

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 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.

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.

Objectives: 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). Materials and Methods: Men with primary high-risk Pca (≥cT3a, international society of urological pathology (ISUP) Grade Group ≥3 or PSA of ≥ 15 ng/mL) with potential lymph node metastasis (Briganti nomogram risk >10% or on preoperative imaging) were enrolled onto the study. Patients underwent a staging ⁶⁸Ga-PSMA PET/CT. Pre-operatively a ^99mTc-labelled PSMA ligand (^99mTc PSMA I&S; 500 MBq) was administrated followed by single-photon emission/CT(SPECT). A RARP including extended pelvic lymph node dissection was performed, with intraoperative tracing of PSMA-avid tissues using a prototype DROP-IN gamma probe. Resected specimens were also measured ex-vivo. Histopathological 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 of 68 years and PSA of 9.15 ng/ml. The majority of patients harboured ISUP 5 PCa (75%) and had avid lymph nodes on pre-operative PSMA PET (64%). The DROP-IN probe aided resection of PSMA-avid (out-of-template) lymph nodes and residual disease at the prostate bed. 11 metastatic lymph nodes were identified by the probe that were not observed on pre-operative ⁶⁸Ga-PSMA PET/CT. Of the 74 extraprostatic tissue specimens that were resected, 22 (29.7%) contained PCa. The sensitivity, specificity, PPV and NPV (95% confidence interval) of inpatient use of the gamma probe was 76% (53-92%), 69% (55-81%), 50% and 88%, respectively. Ex-vivo, the diagnostic accuracy was superior, 76% (53-92%), 96% (87-99%), 89% and 91%, respectively. Of the missed lymph nodes in-vivo (n = 5) and ex-vivo (n = 5), 90% were micrometastasis (≤3mm). No complications occurred greater than Clavien-Dindo Grade I. 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 ePLND. Further improvement of the detector technology may optimize the capabilities of robot-assisted ^99mTc-based PSMA-radioguided surgery.

Background: To report the feasibility, oncological and functional outcomes of salvage robot-assisted radical prostatectomy (sRARP) for recurrent prostate cancer (PCa) after irreversible electroporation (IRE). Methods: This was a retrospective analysis of patients who underwent sRARP by a single high-volume surgeon after IRE treatment in our institution. Surgical complications, oncological and functional outcomes were assessed. Results: 15 patients with at least 12 months follow up were identified out of the 234 men who underwent primary IRE between 2013 and 2019. The median [IQR] age was 68 (62–70) years. The median [IQR] time from focal IRE to sRARP was 42 (21–57) months. There were no rectal, bladder or ureteric injuries. The T-stage was pT2 in 9 (60%) patients and pT3a in 6 (40%) patients. Only one (7%) patient had a positive surgical margin. At a median [IQR] follow up of 22 (16–32) months no patient had a biochemical recurrence (PSA > 0.2). All 15 patients were continent (pad-free) by 6 months and 9 (60%) patients had erections sufficient for intercourse with or without PDE5 inhibitors. No predisposing factors were identified for predicting erectile dysfunction after sRARP. Conclusions: In patients with recurrent or residual significant PCa after focal IRE ablation it is feasible to obtain good functional and oncological outcomes with sRARP. Our results demonstrate that good outcomes can be achieved with sRARP, when respecting close monitoring post-IRE, good patient selection and surgical experience. The limitations of this study are that it is a small series, with short follow up and a lack of standardised quality of life instruments.