Grading urothelial carcinoma with probe-based confocal laser endomicroscopy during flexible cystoscopy.

PURPOSE: Urothelial bladder cancer (UCB) care requires frequent follow-up cystoscopy and surgery. Confocal laser endomicroscopy (CLE) is a probe-based optical technique that can provide real-time microscopic evaluation with the potential for outpatient grading of UCB. This study aims to investigate the diagnostic accuracy and interobserver variability for the grading of UCB with CLE during flexible cystoscopy (fCLE). METHODS: Participants scheduled for transurethral resection of papillary bladder tumors were prospectively included for intra-operative fCLE. Exclusion criteria were flat lesions, fluorescein allergy or pregnancy. Two independent observers evaluated fCLE, classifying tumors as low- or high-grade urothelial carcinoma (LGUC/HGUC) or benign. Interobserver agreement was calculated with Cohens kappa (κ) and diagnostic accuracy with 2 × 2 tables. Histopathology was the reference test. RESULTS: Histopathology of 34 lesions revealed 14 HGUC, 14 LGUC and 6 benign tumors. Diagnostic yield for fCLE was 80-85% with a κ of 0.75. Respectively, sensitivity, specificity, NPV and PPV were: for benign tumors 0-20%, 96-100%, unmeasureable-50% and 87%, for LGUC 57-64%, 41-58%, 44-53% and 54-69% and for HGUC 38-57%, 56-68%, 38-57% and 56-68%, with an interobserver agreement of κ 0.61. CONCLUSION: fCLE is currently insufficient to grade UCB.

Therapeutic prostate cancer interventions: a systematic review on pubic arch interference and needle positioning errors.

INTRODUCTION: This study focuses on the quantification of and current guidelines on the hazards related to needle positioning in prostate cancer treatment: (1) access restrictions to the prostate gland by the pubic arch, so-called Pubic Arch Interference (PAI) and (2) needle positioning errors. Next, we propose solution strategies to mitigate these hazards. METHODS: The literature search was executed in the Embase, Medline ALL, Web of Science Core Collection*, and Cochrane Central Register of Controlled Trials databases. RESULTS: The literature search resulted in 50 included articles. PAI was reported in patients with various prostate volumes. The level of reported PAI varied between 0 and 22.3 mm, depending on the patient's position and the measuring method. Low-Dose-Rate Brachytherapy induced the largest reported misplacement errors, especially in the cranio-caudal direction (up to 10 mm) and the largest displacement errors were reported for High-Dose-Rate Brachytherapy in the cranio-caudal direction (up to 47 mm), generally increasing over time. CONCLUSIONS: Current clinical guidelines related to prostate volume, needle positioning accuracy, and maximum allowable PAI are ambiguous, and compliance in the clinical setting differs between institutions. Solutions, such as steerable needles, assist in mitigating the hazards and potentially allow the physician to proceed with the procedure.This systematic review was performed in accordance with the PRISMA guidelines. The review was registered at Protocols.io (DOI: dx.doi.org/10.17504/protocols.io.6qpvr89eplmk/v1).

Advanced optical imaging techniques for bladder cancer detection and diagnosis: a systematic review.

OBJECTIVES: To systematically assess the current available literature concerning advanced optical imaging methods for the detection and diagnosis of bladder cancer (BCa), focusing particularly on the sensitivity and specificity of these techniques. METHODS: First a scoping search was performed to identify all available optical techniques for BCa detection and diagnosis. The optical imaging techniques used for detecting BCa are: the Storz professional image enhancement system (IMAGE1 S), narrow-band imaging (NBI), photoacoustic imaging (PAI), autofluorescence imaging (AFI), photodynamic diagnosis (PDD), and scanning fibre endoscopy (SFE). The staging and grading techniques for BCa are: optical coherence tomography (OCT), confocal laser endomicroscopy (CLE), Raman spectroscopy, endocytoscopy, and non-linear optical microscopy (NLO). Then a systematic literature search was conducted using MEDLINE, EMBASE and Web of Science from inception to 21 November 2023. Articles were screened and selected by two independent reviewers. Inclusion criteria were: reporting on both the sensitivity and specificity of a particular technique and comparison to histopathology, and in the case of a detection technique comparison to white light cystoscopy (WLC). RESULTS: Out of 6707 articles, 189 underwent full-text review, resulting in 52 inclusions. No articles met criteria for IMAGE1 S, PAI, SFE, Raman spectroscopy, and endocytoscopy. All detection techniques showed higher sensitivity than WLC, with NBI leading (87.8-100%). Overall, detection technique specificity was comparable to WLC, with PDD being most specific (23.3-100%). CLE and OCT varied in sensitivity and specificity, with OCT showing higher specificity for BCa diagnosis, notably for carcinoma in situ (97-99%) compared to CLE (62.5-81.3%). NLO demonstrated high sensitivity and specificity (90-97% and 77-100%, respectively) based on limited data from two small ex vivo studies. CONCLUSIONS: Optical techniques with the most potential are PDD for detecting and OCT for staging and grading BCa. Further research is crucial to validate their integration into routine practice and explore the value of other imaging techniques.

Transperineal laser ablation of the prostate as a treatment for benign prostatic hyperplasia and prostate cancer: The results of a Delphi consensus project.

Objective: To evaluate transperineal laser ablation (TPLA) with Echolaser® (Echolaser® TPLA, Elesta S.p.A., Calenzano, Italy) as a treatment for benign prostatic hyperplasia (BPH) and prostate cancer (PCa) using the Delphi consensus method. Methods: Italian and international experts on BPH and PCa participated in a collaborative consensus project. During two rounds, they expressed their opinions on Echolaser® TPLA for the treatment of BPH and PCa answering online questionnaires on indications, methodology, and potential complications of this technology. Level of agreement or disagreement to reach consensus was set at 75%. If the consensus was not achieved, questions were modified after each round. A final round was performed during an online meeting, in which results were discussed and finalized. Results: Thirty-two out of forty invited experts participated and consensus was reached on all topics. Agreement was achieved on recommending Echolaser® TPLA as a treatment of BPH in patients with ample range of prostate volume, from <40 mL (80%) to >80 mL (80%), comorbidities (100%), antiplatelet or anticoagulant treatment (96%), indwelling catheter (77%), and strong will of preserving ejaculatory function (100%). Majority of respondents agreed that Echolaser® TPLA is a potential option for the treatment of localized PCa (78%) and recommended it for low-risk PCa (90%). During the final round, experts concluded that it can be used for intermediate-risk PCa and it should be proposed as an effective alternative to radical prostatectomy for patients with strong will of avoiding urinary incontinence and sexual dysfunction. Almost all participants agreed that the transperineal approach of this organ-sparing technique is safer than transrectal and transurethral approaches typical of other techniques (97% of agreement among experts). Pre-procedural assessment, technical aspects, post-procedural catheterization, pharmacological therapy, and expected outcomes were discussed, leading to statements and recommendations. Conclusion: Echolaser® TPLA is a safe and effective procedure that treats BPH and localized PCa with satisfactory functional and sexual outcomes.

The association between patient and disease characteristics, and the risk of disease progression in patients with prostate cancer on active surveillance.

PURPOSE: The objective of this study was to identify and assess patient and disease characteristics associated with an increased risk of disease progression in men with prostate cancer on active surveillance. METHODS: We studied patients with low-risk (ISUP GG1) or favorable intermediate-risk (ISUP GG2) PCa. All patients had at least one repeat biopsy. Disease progression was the primary outcome of this study, based on pathological upgrading. Univariate and multivariate Cox proportional hazard analyses were used to evaluate the association between covariates and disease progression. RESULTS: In total, 240 men were included, of whom 198 (82.5%) were diagnosed with low-risk PCa and 42 (17.5%) with favorable intermediate-risk PCa. Disease progression was observed in 42.9% (103/240) of men. Index lesion > 10 mm (HR = 2.85; 95% CI 1.74-4.68; p < 0.001), MRI (m)T-stage 2b/2c (HR = 2.52; 95% CI 1.16-5.50; p = 0.02), highest PI-RADS score of 5 (HR 3.05; 95% CI 1.48-6.28; p = 0.002) and a higher PSA level (HR 1.06; 95% CI 1.01-1.11; p = 0.014) at baseline were associated with disease progression on univariate analysis. Multivariate analysis showed no significant baseline predictors of disease progression. CONCLUSION: In AS patients with low-risk or favorable intermediate-risk PCa, diameter of index lesion, MRI (m)T-stage, height of the PI-RADS score and the PSA level at baseline are significant predictors of disease progression to first repeat biopsy.

Transperineal laser ablation as treatment for benign prostatic obstruction: Safety, feasibility and functional outcomes-A pilot study.

Background: Standard surgical treatment for lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO) requires anaesthesia and hospitalization. Transperineal laser ablation (TPLA) is a novel minimally invasive treatment for BPO, which has been performed using local anaesthetics and conscious sedation. Objectives: The aim of this study is to assess safety, feasibility and functional outcomes of TPLA for the treatment of LUTS in men fit also for standard surgery. Methods: This prospective, multicentre, interventional pilot study included 20 patients. Eligible patients were men ≥40 years of age, with urodynamically proven bladder outlet obstruction, a peak urinary flow of 5-15 mL/s and a prostate volume of 30-120 cc. All subjects underwent Soractelite™ TPLA using the Echolaser® X4 system. Two to four fibres were placed in the prostate, whereafter laser light induced coagulative necrosis. Twelve months of follow-up included uroflowmetry, an ultrasound of the prostate and PROMs (IPSS and IIEF). Results: Twenty patients were treated with TPLA using local anaesthetics and optional sedation. Sixteen patients were treated in an outpatient setting, using only local anaesthetics in 12 of them; four were treated in the operating room, whereof two under general anaesthesia. No device related adverse events occurred, nor did any grade ≥3 adverse events during follow-up. Post-TPLA, 10 men continued spontaneous voiding, and 10 men developed a urinary retention treated by a temporary indwelling catheter for 15.2 ± 3.5 days. At 12 months, Qmax improved from 9.7 ± 3.5 to 14.9 ± 6.0 (p = 0.015), IPSS improved from 21.3 ± 5.2 to 10.9 ± 5.5 (p < 0.0001), QoL improved from 4.9 ± 0.9 to 1.9 ± 1.1 (p < 0.0001), IIEF-15 total score remained stable and 11/13 patients (85%) preserved antegrade ejaculation. Conclusions: TPLA is a safe and feasible treatment for men with LUTS due to BPO. TPLA can be performed in an outpatient setting under only local anaesthetics. Functional and quality of life outcomes improved significantly at 12 months, and erectile function remained stable.

Diagnostic liquid biopsy biomarkers in renal cell cancer.

The clinical presentation of renal cell cancer (RCC) is shifting towards incidental and early detection, creating new challenges in RCC diagnosis. Overtreatment might be reduced with the development of new diagnostic biomarkers to distinguish benign from malignant small renal masses (SRMs). Differently from tissue biopsies, liquid biopsies are obtained from a patient's blood or urine and, therefore, are minimally invasive and suitable for longitudinal monitoring. The most promising types of liquid biopsy biomarkers for RCC diagnosis are circulating tumour cells, extracellular vesicles (EVs) and cell-free DNA. Circulating tumour cell assays have the highest specificity, with low processing time and costs. However, the biological characteristics and low sensitivity limit the use of these markers in SRM diagnostics. Cell-free DNA might complement the diagnosis of high-volume RCC, but the potential for clinical application in SRMs is limited. EVs have the highest biological abundance and the highest sensitivity in identifying low-volume disease; moreover, the molecular characteristics of these markers make EVs suitable for multiple analytical applications. Thus, currently, EV assays have the greatest potential for diagnostic application in RCC (including identification of SRMs). All these liquid biomarkers have potential in clinical practice, pending validation studies. Biomarker implementation will be needed to also improve characterization of RCC subtypes. Last, diagnostic biomarkers might be extended to prognostic or predictive applications.

Reliable Visualization of the Treatment Effect of Transperineal Focal Laser Ablation in Prostate Cancer Patients by Magnetic Resonance Imaging and Contrast-enhanced Ultrasound Imaging.

Background: Transperineal focal laser ablation (TPLA) treatment for prostate cancer (PCa) is an experimental focal ablative therapy modality with low morbidity. However, a dosimetry model for TPLA is lacking. Objective: To determine (1) the three-dimensional (3D) histologically defined ablation zone of single- and multifiber TPLA treatment for PCa correlated with magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) and (2) a reliable imaging modality of ablation zone volumetry. Design setting and participants: This was a prospective, multicenter, and interventional phase I/II pilot study with an ablate-and-resect design. TPLA was performed in 12 patients with localized prostate cancer divided over four treatment regimens to evaluate potential variation in outcomes. Intervention: TPLA was performed approximately 4 wk prior to robot-assisted radical prostatectomy (RARP) in a daycare setting using local anesthesia. Outcome measurements and statistical analysis: Four weeks after TPLA, ablation zone volumetry was determined on prostate MRI and CEUS by delineation and segmentation into 3D models and correlated with whole-mount RARP histology using the Pearson correlation index. Results and limitations: Twelve office-based TPLA procedures were performed successfully under continuous transrectal ultrasound guidance using local perineal anesthesia. No serious adverse events occurred. A qualitative analysis showed a clear demarcation of the ablation zone on T2-weighted MRI, dynamic contrast-enhanced MRI, and CEUS. On pathological evaluation, no remnant cancer was observed within the ablation zone. Ablation zone volumetry on CEUS and T2-weighted MRI compared with histology had a Pearson correlation index of r = 0.94 (95% confidence interval [CI] 0.74-0.99, p < 0.001) and r = 0.93 (95% CI 0.73-0.98, p < 0.001), respectively. Conclusions: CEUS and prostate MRI could reliably visualize TPLA ablative effects after minimally invasive PCa treatment with a high concordance with histopathological findings and showed no remnant cancer. Patient summary: The treatment effects of a novel minimally invasive ablation therapy device can reliably be visualized with radiological examinations. These results will improve planning and performance of future procedures.

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

Added Clinical Value of 18F-FDG-PET/CT to Stage Patients With High-Risk Non-Muscle Invasive Bladder Cancer Before Radical Cystectomy.

INTRODUCTION AND OBJECTIVES: 18F-fluorodeoxyglucose positron-emission tomography-computed tomography (FDG-PET/CT) is increasingly used in the preoperative staging of patients with muscle-invasive bladder cancer. The clinical added value of FDG-PET/CT in high-risk non-muscle invasive bladder cancer (NMIBC) is unknown. In this study, the value of FDG-PET/CT in addition to contrast enhanced (CE)-CT was evaluated in high-risk NMIBC before radical cystectomy (RC). MATERIALS AND METHODS: This is a retrospective analysis of consecutive patients with high risk and very-high risk urothelial NMIBC scheduled for RC in a tertiary referral center between 2011 and 2020. Patients underwent staging with CE-CT (chest and abdomen/pelvis) and FDG-PET/CT. We assessed the clinical disease stage before and after FDG-PET/CT and the treatment recommendation based on the stage before and after FDG-PET/CT. The accuracy of CT and FDG-PET/CT for identifying metastatic disease was defined by the receiver-operating curve using a reference-standard including histopathology/cytology (if available), imaging and follow-up. RESULTS: A total of 92 patients were identified (median age: 71 years). In 14/92 (15%) patients, FDG-PET/CT detected metastasis (12 suspicious lymph nodes and 4 distant metastases). The disease stage changed in 11/92 (12%) patients based on additional FDG-PET/CT findings. FDG-PET/CT led to a different treatment in 9/92 (10%) patients. According to the reference standard, 25/92 (27%) patients had metastases. The sensitivity, specificity and accuracy of FDG-PET/CT was 36%, 93% and 77% respectively, versus 12%, 97% and 74% of CE-CT only. The area under the ROC curve was 0.643 for FDG-PET/CT and 0.545 for CT, P = .036. CONCLUSION: The addition of FDG-PET/CT to CE-CT imaging changed the treatment in 10% of patients and proved to be a valuable diagnostic tool in a selected subgroup of NMIBC patients scheduled for RC.

Effect of Focal vs Extended Irreversible Electroporation for the Ablation of Localized Low- or Intermediate-Risk Prostate Cancer on Early Oncological Control: A Randomized Clinical Trial.

Importance: Focal ablative irreversible electroporation (IRE) is a therapy that treats only the area of the tumor with the aim of achieving oncological control while reducing treatment-related functional detriment. Objective: To evaluate the effect of focal vs extended IRE on early oncological control for patients with localized low- and intermediate-risk prostate cancer. Design, Setting, and Participants: In this randomized clinical trial conducted at 5 centers in Europe, men with localized low- to intermediate-risk prostate cancer were randomized to receive either focal or extended IRE ablation. Data were collected at baseline and at regular intervals after the procedure from June 2015 to January 2020, and data were analyzed from September 2021 to July 2022. Main Outcomes and Measures: Oncological outcome as indicated by presence of clinically significant prostate cancer (International Society of Urological Pathology grade ≥2) on transperineal template-mapping prostate biopsy at 6 months after IRE. Descriptive measures of results from that biopsy included the number and location of positive cores. Results: A total of 51 and 55 patients underwent focal and extended IRE, respectively. Median (IQR) age was 64 years (58-67) in the focal ablation group and 64 years (57-68) in the extended ablation group. Median (IQR) follow-up time was 30 months (24-48). Clinically significant prostate cancer was detected in 9 patients (18.8%) in the focal ablation group and 7 patients (13.2%) in the extended ablation group. There was no significant difference in presence of clinically significant prostate cancer between the 2 groups. In the focal ablation group, 17 patients (35.4%) had positive cores outside of the treated area, 3 patients (6.3%) had positive cores in the treated area, and 5 patients (10.4%) had positive cores both in and outside of the treated area. In the extended group, 10 patients (18.9%) had positive cores outside of the treated area, 9 patients (17.0%) had positive cores in the treated area, and 2 patients (3.8%) had positive cores both in and outside of the treated area. Clinically significant cancer was found in the treated area in 5 of 48 patients (10.4%) in the focal ablation group and 5 of 53 patients (9.4%) in the extended ablation group. Conclusions and Relevance: This study found that focal and extended IRE ablation achieved similar oncological outcomes in men with localized low- or intermediate-risk prostate cancer. Because some patients with intermediate-risk prostate cancer are still candidates for active surveillance, focal therapy may be a promising option for those patients with a high risk of cancer progression. Trial Registration: ClinicalTrials.gov Identifier: NCT01835977.

Sequencing of Androgen-Deprivation Therapy of Short Duration With Radiotherapy for Nonmetastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials.

PURPOSE: The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT). MATERIALS AND METHODS: Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality. RESULTS: Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points (P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT. CONCLUSION: ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

A Multicenter, Randomized, Single-blind, 2-Arm Intervention Study Evaluating the Adverse Events and Quality of Life After Irreversible Electroporation for the Ablation of Localized Low-intermediate Risk Prostate Cancer.

PURPOSE: Our goal was to evaluate the effect of focal vs extended irreversible electroporation on side effects, patient-reported quality of life, and early oncologic control for localized low-intermediate risk prostate cancer patients. MATERIALS AND METHODS: Men with localized low-intermediate risk prostate cancer were randomized to receive focal or extended irreversible electroporation ablation. Quality of life was measured by International Index of Erectile Function, Expanded Prostate Cancer Index Composite questionnaire, and International Prostate Symptom Score. RESULTS: A total of 51 and 55 patients underwent focal and extended irreversible electroporation, respectively. The median follow-up time was 30 months. Rates of erectile dysfunction and rates of adverse events were similar between the 2 groups at 3 months. The focal ablation group seemed to have better International Index of Erectile Function scores at 3 months; it also had a better Expanded Prostate Cancer Index Composite-sexual function score than the extended ablation group across time that was close to statistical significance (mean difference 1.4; 95% CI -0.13 to 2.9, P = .073). There were no significant differences between the 2 groups in other quality-of-life measures. Upon prostate biopsy at 6 months, the rate of residual clinically significant prostate cancer (Gleason ≥3 + 4) was 18.8% and 13.2% in the focal and extended irreversible electroporation groups, respectively, without significant differences. CONCLUSIONS: Focal and extended irreversible electroporation ablation had similar safety profile, urinary function, and oncologic outcomes in men with localized low-intermediate risk prostate cancer. In addition, focal ablation demonstrated superior erectile function outcome over extended irreversible electroporation in the first 3-6 months.

Perturbation of Copper Homeostasis Sensitizes Cancer Cells to Elevated Temperature.

Temporary elevation of tumor temperature, also known as hyperthermia, is a safe and well-tolerated treatment modality. The efficacy of hyperthermia can be improved by efficient thermosensitizers, and various candidate drugs, including inhibitors of the heat stress response, have been explored in vitro and in animal models, but clinically relevant thermosensitizers are lacking. Here, we employ unbiased in silico approaches to uncover new mechanisms and compounds that could be leveraged to increase the thermosensitivity of cancer cells. We then focus on elesclomol, a well-performing compound, which amplifies cell killing by hyperthermia by 5- to 20-fold in cell lines and outperforms clinically applied chemotherapy when combined with hyperthermia in vitro. Surprisingly, our findings suggest that the thermosensitizing effects of elesclomol are independent of its previously reported modes of action but depend on copper shuttling. Importantly, we show that, like elesclomol, multiple other copper shuttlers can thermosensitize, suggesting that disturbing copper homeostasis could be a general strategy for improving the efficacy of hyperthermia.

Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).

CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.

An optimized prostate biopsy strategy in patients with a unilateral lesion on prostate magnetic resonance imaging avoids unnecessary biopsies.

Purpose: The introduction of magnetic resonance imaging (MRI)-targeted biopsy (TBx) besides systematic prostate biopsies has resulted in a discussion on what the optimal prostate biopsy strategy is. The ideal template has high sensitivity for clinically significant prostate cancer (csPCa), while reducing the detection rate of clinically insignificant prostate cancer (iPCa). This study evaluates different biopsy strategies in patients with a unilateral prostate MRI lesion. Methods: Retrospective subgroup analysis of a prospectively managed database consisting of patients undergoing prostate biopsy in two academic centres. Patients with a unilateral lesion (PI-RADS ⩾ 3) on MRI were included for analysis. The primary objective was to evaluate the diagnostic performance for different biopsy approaches compared with bilateral systematic prostate biopsy (SBx) and TBx. Detection rates for csPCa (ISUP ⩾ 2), adjusted csPCa (ISUP ⩾ 3) and iPCa (ISUP = 1) were determined for SBx alone, TBx alone, contralateral SBx combined with TBx and ipsilateral SBx combined with TBx. A subgroup analysis was performed for biopsy-naive patients. Results: A total of 228 patients were included from October 2015 to September 2021. Prostate cancer (PCa) detection rate of combined SBx and TBx was 63.5% for csPCa, 35.5% for adjusted csPCa, and 14% for iPCa. The best performing alternative biopsy strategy was TBx and ipsilateral SBx, which reached a sensitivity of 98.6% (95% CI: 95.1-99.6) for csPCa and 98.8% (95% CI: 96.3-99.9) for adjusted csPCa, missing only 1.4% of csPCa, while reducing iPCa detection by 15.6% compared with SBx and TBx. TBx or SBx alone missed a significant amount of csPCa, with sensitivities of 90.3% (95% CI: 84.4-94.2) and 86.8% (95% CI: 80.4-91.4) for csPCa. Subgroup analysis on biopsy-naive patients showed similar results as the overall group. Conclusion: This study shows that performing TBx with ipsilateral SBx and omitting contralateral SBx is the optimal biopsy strategy in patients with a unilateral MRI lesion. With this strategy, a very limited amount of csPCa is missed and iPCa detection is reduced.

Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. OBJECTIVE: To determine the safety of iCRT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. INTERVENTION: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). RESULTS AND LIMITATIONS: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. CONCLUSIONS: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. PATIENT SUMMARY: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials.

Image-guided in-Vivo Needle-Based Confocal Laser Endomicroscopy in the Prostate: Safety and Feasibility Study in 2 Patients.

Purpose: To assess the safety and technical feasibility of in-vivo needle-based forward-looking confocal laser endomicroscopy in prostate tissue. Methods: For this feasibility study, 2 patients with a suspicion of prostate cancer underwent transperineal needle-based confocal laser endomicroscopy during ultrasound-guided transperineal template mapping biopsies. After intravenous administration of fluorescein, needle-based confocal laser endomicroscopy imaging was performed with a forward-looking probe (outer diameter 0.9 mm) in 2 trajectories during a manual push-forward and pullback motion. A biopsy was taken in a coregistered parallel adjacent trajectory to the confocal laser endomicroscopy trajectory for histopathologic comparison. Peri- and postprocedural adverse events, confocal laser endomicroscopy device malfunction and procedural failures were recorded. Needle-based confocal laser endomicroscopy image quality assessment, image interpretation, and histology were performed by an experienced confocal laser endomicroscopy rater and uro-pathologist, blinded to any additional information. Results: In both patients, no peri- and post-procedural adverse events were reported following needle-based confocal laser endomicroscopy. No confocal laser endomicroscopy device malfunction nor procedural failures were reported. Within 1.5 min after intravenous administration of fluorescein, needle-based confocal laser endomicroscopy image quality was sufficient for interpretation for at least 14 min, yielding more than 5000 confocal laser endomicroscopy frames per patient. The pullback confocal laser endomicroscopy recordings and most of the push-forward recordings almost only visualized erythrocytes, being classified as non-representative. During the push-forward recordings, prostate tissue was occasionally visualized in single frames, insufficient for histopathologic comparison. Prostate carcinoma was identified by biopsy in one patient (Gleason score 4 + 3 = 7, >50%), while the biopsy from the other patient showed no malignancy. Conclusion: Needle-based confocal laser endomicroscopy imaging of in-vivo prostate tissue with a forward-looking confocal laser endomicroscopy probe is safe without device malfunctions or procedural failures. Needle-based confocal laser endomicroscopy is technically feasible, but the acquired confocal laser endomicroscopy datasets are non-representative. The confocal laser endomicroscopy images' non-representative nature is possibly caused by bleeding artifacts, movement artifacts and a lack of contact time with the tissue of interest. A different confocal laser endomicroscopy probe or procedure might yield representative images of prostatic tissue.