PSMA-PET follow-up to assess response in patients not receiving PSMA therapy: Is there value beyond localization of disease?

Introduction: Prostate Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) is routinely used for the staging of patients with prostate cancer, but data on response assessment are sparse and primarily stem from metastatic castration-resistant prostate cancer (mCRPC) patients treated with PSMA radioligand therapy. Still, follow-up PSMA-PET is employed in earlier disease stages in case of clinical suspicion of disease persistence, recurrence or progression to decide if localized or systemic treatment is indicated. Therefore, the prognostic value of PSMA-PET derived tumor volumes in earlier disease stages (i.e., hormone-sensitive prostate cancer (HSPC) and non-[177Lu]Lu-PSMA-617 (LuPSMA) therapy castration resistant prostate cancer (CRPC)) are evaluated in this manuscript. Methods: A total number of 73 patients (6 primary staging, 42 HSPC, 25 CRPC) underwent two (i.e., baseline and follow-up, median interval: 379 days) whole-body [68Ga]Ga-PSMA-11 PET/CT scans between Nov 2014 and Dec 2018. Analysis was restricted to non-LuPSMA therapy patients. PSMA-PETs were retrospectively analyzed and primary tumor, lymph node-, visceral-, and bone metastases were segmented. Body weight-adjusted organ-specific and total tumor volumes (PSMAvol: sum of PET volumes of all lesions) were measured for baseline and follow-up. PSMAvol response was calculated as the absolute difference of whole-body tumor volumes. High metastatic burden (>5 metastases), RECIP 1.0 and PSMA-PET Progression Criteria (PPP) were determined. Survival data were sourced from the cancer registry. Results: The average number of tumor lesions per patient on the initial PET examination was 10.3 (SD 28.4). At baseline, PSMAvol was strongly associated with OS (HR 3.92, p <0.001; n = 73). Likewise, response in PSMAvol was significantly associated with OS (HR 10.48, p < 0.005; n = 73). PPP achieved significance as well (HR 2.19, p <0.05, n = 73). Patients with hormone sensitive disease and poor PSMAvol response (upper quartile of PSMAvol change) in follow-up had shorter outcome (p < 0.05; n = 42). PSMAvol in bones was the most relevant parameter for OS prognostication at baseline and for response assessment (HR 31.11 p < 0.001; HR 32.27, p < 0.001; n = 73). Conclusion: PPP and response in PSMAvol were significantly associated with OS in the present heterogeneous cohort. Bone tumor volume was the relevant miTNM region for OS prognostication. Future prospective evaluation of the performance of organ specific PSMAvol in more homogeneous cohorts seems warranted.

Near-infrared fluorescence lymph node template region dissection plus backup lymphadenectomy in open radical cystectomy for bladder cancer using an innovative handheld device: A single center experience.

BACKGROUND: The extent of pelvic lymphadenectomy (PLND) as part of radical cystectomy (RC) for bladder cancer (BC) remains unclear. Sentinel-based and lymphangiographic approaches could lead to reduced morbidity without sacrificing oncologic safety. OBJECTIVE: To evaluate the feasibility and diagnostic value of fluorescence-guided template sentinel region dissection (FTD) using a handheld near-infrared fluorescence (NIRF) camera in open radical cystectomy. DESIGN, SETTING, AND PARTICIPANTS: After peritumoral cystoscopic injection of indocyanine green (ICG) 21 patients underwent open RC with FTD due to BC between June 2019 and June 2021. Intraoperatively, the FIS-00 Hamamatsu Photonics® NIRF camera was used to identify and resect fluorescent template sentinel regions (FTRs) followed by extended pelvic lymphadenectomy (ePLND) as oncological back-up. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: Descriptive analysis of positive and negative results per template region. RESULTS AND LIMITATIONS: FTRs were identified in all 21 cases. Median time (range) from ICG injection to fluorescence detection was 75 (55-125) minutes. On average (SD), 33.4 (9.6) lymph nodes were dissected per patient. Considering template regions as the basis of analysis, 67 (38.3%) of 175 resected regions were NIRF-positive, with 13 (7.4%) regions harboring lymph node metastases. We found no metastatic lymph nodes in NIRF-negative template regions. Outside the standard template, two NIRF-positive benign nodes were identified. CONCLUSION: The concept of NIRF-guided FTD proved for this group all lymph node metastases to be found in NIRF-positive template regions. Pending validation in a larger collective, resection of approximately 40% of standard regions may be sufficient and may result in less morbidity.

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.

PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Which Patients with Prostate Cancer and Lymph Node Uptake at Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography/Computerized Tomography Scan Are at a Higher Risk of Prostate-specific Antigen Persistence After Radical Prostatectomy? Identifying Indicators of Systemic Disease by Integrating Clinical, Magnetic Resonance Imaging, and Functional Imaging Parameters.

BACKGROUND: The role of local therapies including radical prostatectomy (RP) in prostate cancer (PCa) patients with clinical lymphadenopathies on prostate-specific membrane antigen (PSMA) positron emission tomography/computerized tomography (PET/CT) has scarcely been explored. Limited data are available to identify men who would benefit from RP; on the contrary, those more likely to benefit already have systemic disease. OBJECTIVE: We aimed to assess the predictors of prostate-specific antigen (PSA) persistence in surgically managed PCa patients with lymphadenopathies on a PSMA PET/CT scan by integrating clinical, magnetic resonance imaging (MRI), and PSMA PET/CT parameters. DESIGN, SETTING, AND PARTICIPANTS: We identified 519 patients treated with RP and extended lymph node dissection, and who received preoperative PSMA PET between 2017 and 2022 in nine referral centers. Among them, we selected 88 patients with nodal uptake at preoperative PSMA PET (miTxN1M0). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PSA persistence, defined as a PSA value of ≥0.1 ng/ml at the first measurement after surgery. Multivariable logistic regression models tested the predictors of PSA persistence. Covariates consisted of biopsy International Society of Urological Pathology (ISUP) grade group, clinical stage at MRI, and number of positive spots at a PET/CT scan. A regression tree analysis stratified patients into risk groups based on preoperative characteristics. RESULTS AND LIMITATIONS: Overall, lymph node invasion (LNI) was detected in 63 patients (72%) and 32 (36%) experienced PSA persistence after RP. At multivariable analyses, having more than two lymph nodal positive findings at PSMA PET, seminal vesicle invasion (SVI) at MRI, and ISUP grade group >3 at biopsy were independent predictors of PSA persistence (all p < 0.05). At the regression tree analysis, patients were stratified in four risk groups according to biopsy ISUP grade, number of positive findings at PET/CT, and clinical stage at MRI. The model depicted good discrimination at internal validation (area under the curve 78%). CONCLUSIONS: One out of three miN1M0 patients showed PSA persistence after surgery. Patients with ISUP grade 2-3, as well as patients with organ-confined disease at MRI and a single or two positive nodal findings at PET are those in whom RP may achieve the best oncological outcomes in the context of a multimodal approach. Conversely, patients with a high ISUP grade and extracapsular extension or SVI or more than two spots at PSMA PET should be considered as potentially affected by systemic disease upfront. PATIENT SUMMARY: Our novel and straightforward risk classification integrates currently available preoperative risk tools and should, therefore, assist physician in preoperative counseling of men candidates for radical treatment for prostate cancer with positive lymph node uptake at prostate-specific membrane antigen positron emission tomography.

Prediction models of incontinence and sexual function one year after radical prostatectomy based on data from 20 164 prostate cancer patients.

BACKGROUND: Incontinence and sexual dysfunction are long-lasting side effects after surgical treatment (radical prostatectomy, RP) of prostate cancer (PC). For an informed treatment decision, physicians and patients should discuss expected impairments. Therefore, this paper firstly aims to develop and validate prognostic models that predict incontinence and sexual function of PC patients one year after RP and secondly to provide an online decision making tool. METHODS: Observational cohorts of PC patients treated between July 2016 and March 2021 in Germany were used. Models to predict functional outcomes one year after RP measured by the EPIC-26 questionnaire were developed using lasso regression, 80-20 splitting of the data set and 10-fold cross validation. To assess performance, R2, RMSE, analysis of residuals and calibration-in-the-large were applied. Final models were externally temporally validated. Additionally, percentages of functional impairment (pad use for incontinence and firmness of erection for sexual score) per score decile were calculated to be used together with the prediction models. RESULTS: For model development and internal as well as external validation, samples of 11 355 and 8 809 patients were analysed. Results from the internal validation (incontinence: R2 = 0.12, RMSE = 25.40, sexual function: R2 = 0.23, RMSE = 21.44) were comparable with those of the external validation. Residual analysis and calibration-in-the-large showed good results. The prediction tool is freely accessible: https://nora-tabea.shinyapps.io/EPIC-26-Prediction/. CONCLUSION: The final models showed appropriate predictive properties and can be used together with the calculated risks for specific functional impairments. Main strengths are the large study sample (> 20 000) and the inclusion of an external validation. The models incorporate meaningful and clinically available predictors ensuring an easy implementation. All predictions are displayed together with risks of frequent impairments such as pad use or erectile dysfunction such that the developed online tool provides a detailed and informative overview for clinicians as well as patients.

Enfortumab Vedotin in Metastatic Urothelial Carcinoma: Survival and Safety in a European Multicenter Real-world Patient Cohort.

Background: Treatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials. Objective: To analyze the efficacy and safety of EV in a cohort of real-world patients. Design setting and participants: Retrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards. Outcome measurements and statistical analysis: Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results and limitations: The median age for the 125 eligible patients was 66 yr (range 31-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 for 76.0%, 2-4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20-12.80) and median PFS was 5.0 mo (95% confidence interval 4.34-5.67). For patients with ECOG PS of 0-1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up. Conclusions: Administration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC. Patient summary: Enfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment.

Intraoperative Molecular Positron Emission Tomography Imaging for Intraoperative Assessment of Radical Prostatectomy Specimens.

In this prospective two-center feasibility study, we evaluate the diagnostic value of intraoperative ex vivo specimenPET/CT imaging of radical prostatectomy (RP) and lymphadenectomy specimens. Ten patients with high-risk prostate cancer underwent clinical prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) preoperatively on the day of surgery. Six patients received 68Ga-PSMA-11 and four 18F-PSMA-1007. Radioactivity of the resected specimen was measured again using a novel specimenPET/CT device (AURA10; XEOS Medical, Gent, Belgium) developed for intraoperative margin assessment. All index lesions of staging multiparametric magnetic resonance imaging could be visualized. Overall, specimenPET/CT correlated well with conventional PET/CT regarding detection of suspicious tracer foci (Pearson coefficient 0.935). In addition, specimenPET/CT demonstrated all lymph node metastases detected on conventional PET/CT (n = 3), as well as three previously undetected lymph node metastases. Importantly, all positive or close (<1 mm) surgical margins could be visualized in agreement with histopathology. In conclusion, specimenPET/CT enables detection of PSMA-avid lesions and warrants further investigation to tailor RP, based on a good correlation with final pathology. Future trials will prospectively compare ex vivo specimenPET/CT with a frozen section analysis for the detection of positive surgical margins and assessment of biochemical recurrence-free survival. Patient summary: In this report, we examined prostatectomy and lymphadenectomy specimens for suspicious positron emission tomography (PET) signals after preoperative tracer injection. It was found that in all cases, a good signal could be visualized, with a promising correlation of surface assessment compared with histopathology. We conclude that specimenPET imaging is feasible and may help improve oncological outcomes in the future.

Identification of the Optimal Candidates for Nodal Staging with Extended Pelvic Lymph Node Dissection Among Prostate Cancer Patients Who Underwent Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography. External Validation of the Memorial Sloan Kettering Cancer Center and Briganti Nomograms and Development of a Novel Tool.

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

Cumulative sum analysis (CUSUM) for evaluating learning curve (LC) of robotic-assisted laparoscopic partial nephrectomy (RALPN).

Robotic-assisted laparoscopic partial nephrectomy (RALPN) is becoming a standard treatment for localized renal tumors worldwide. Data on the learning curve (LC) of RALPN are still insufficient. In the present study, we have attempted to gain further insight in this area by evaluating the LC using cumulative summation analysis (CUSUM). A series of 127 robotic partial nephrectomies were performed by two surgeons at our center between January 2018 and December 2020. CUSUM analysis was used to evaluate LC for operative time (OT). The different phases of surgical experience were compared in terms of perioperative parameters and pathologic outcomes. In addition, multivariate linear regression analysis was used to confirm the results of the CUSUM analysis by adjusting the phases of surgical experience for the other confounding factors that may affect OT. The median age of patients was 62 years, mean BMI was 28, and mean tumor size was 32 mm. Tumor complexity was classified as low, intermediate, and high risk according to the PADUA score in 44%, 38%, and 18%, respectively. The mean OT was 205 min, and trifecta was achieved in 72.4%. According to the CUSUM diagram, the LC of OT was divided into three phases: initial learning phase (18 cases), plateau phase (20 cases), and mastery phase (subsequent cases). The mean OT was 242, 208, and 190 min in the first, second, and third phases, respectively (P < 0.001). Surgeon experience phases were significantly associated with OT in multivariate analysis considering other preoperative and operative parameters. Surgical outcome was comparable between the three phases in terms of complications and achievement of trifecta; hospital stay was shorter in the mastery phase than in the first 2 phases (4 days vs 5 days, P = 0.02). The LC for RALPN is divided into 3 performance phases with CUSUM. Mastery of surgical technique was achieved after performing 38 cases. The initial learning phase of RALPN has no negative impact on surgical and oncologic outcomes .

Metastatic Prostate Cancer-A Review of Current Treatment Options and Promising New Approaches.

Androgen deprivation therapy (ADT) alone has been the standard of care for many years in men with metastatic prostate cancer. Due to the limited survival under this monotherapy, many new treatment options have been developed in the last few years. Regarding hormone-sensitive prostate cancer, combination therapies of two or three agents of ADT, androgen receptor signaling inhibitors (ARSI) and chemotherapy have been established and led to a significant benefit in overall survival. Additionally, in patients with metastatic castration-resistant prostate cancer, there are many new therapeutic approaches. Chemotherapy alone has been the standard of care in this situation. In the last years, some new therapeutic options have been developed, which led to an improved survival after progression under chemotherapy. These therapies include ARSI, PARP inhibitors and Lu-PSMA radioligand therapy. The use of a bispecific T-cell engager (BiTE) in this setting is a new promising therapeutic approach, which has not been established as standard of care yet. The role of immunotherapy in prostate cancer is still under investigation. Overall, many new treatment options make prostate cancer therapy a challenging and promising field.

Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.

PURPOSE: The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). EXPERIMENTAL DESIGN: Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4-negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts. RESULTS: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001). CONCLUSIONS: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377.

Immune-Checkpoint-Inhibitor Therapy-Principles and Relevance of Biomarkers for Pathologists and Oncologists.

Immune-checkpoint-inhibitor (ICI) therapy has been one of the major advances in the treatment of a variety of advanced or metastatic tumors in recent years. Therefore, ICI-therapy is already approved in first-line therapy for multiple tumors, either as monotherapy or as combination therapy. However, there are relevant differences in approval among different tumor entities, especially with respect to PD-L1 testing. Different response to ICI-therapy has been observed in the pivotal trials, so PD-L1 diagnostic testing is used for patient selection. In addition to PD-L1 testing of tumor tissue, liquid biopsy provides a noninvasive way to monitor disease in cancer patients and identify those who would benefit most from ICI-therapy. This overview focuses on the use of ICI-therapy and how it relates to common and potential future biomarkers for patient-directed treatment planning.

18F-PSMA Cerenkov Luminescence and Flexible Autoradiography Imaging in a Prostate Cancer Mouse Model and First Results of a Radical Prostatectomy Feasibility Study in Men.

Intraoperative identification of positive resection margins (PRMs) in high-risk prostate cancer (PC) needs improvement. Cerenkov luminescence imaging (CLI) with 68Ga-PSMA-11 is promising, although limited by low residual activity and artificial signals. Here, we aimed to assess the value of CLI and flexible autoradiography (FAR) with 18F-PSMA-1007. Methods: Mice bearing subcutaneous PSMA-avid RM1-PGLS tumors were administered 18F-PSMA-1007, and PET/CT was performed. After the animals had been killed, organs were excised and measured signals in CLI and FAR CLI were correlated with tracer activity concentrations (ACs) obtained from PET/CT. For clinical assessment, 7 high-risk PC patients underwent radical prostatectomy immediately after preoperative 18F-PSMA PET/CT. Contrast-to-noise ratios (CNRs) were calculated for both imaging modalities in intact specimens and after incision above the index lesion. Results: In the heterotopic in vivo mouse model (n = 5), CLI did not detect any lesion. FAR CLI detected a distinct signal in all mice, with a lowest AC of 7.25 kBq/mL (CNR, 5.48). After incision above the index lesion of the prostate specimen, no increased signal was observed at the cancer area in CLI. In contrast, using FAR CLI, a signal was detectable in 6 of 7 patients. The AC in the missed index lesion was 1.85 kBq/mL, resulting in a detection limit of at least 2.06 kBq/mL. Histopathology demonstrated 2 PRMs, neither of which was predicted by CLI or FAR CLI. Conclusion: 18F-PSMA FAR CLI was superior to CLI in tracer-related signal detectability. PC was could be visualized in radical prostatectomy down to 2.06 kBq/mL. However, the detection of PRMs was limited. Direct anatomic correlation of FAR CLI is challenging because of the scintillator overlay.

Detection of Clinically Significant Prostate Cancer Using Targeted Biopsy with Four Cores Versus Target Saturation Biopsy with Nine Cores in Transperineal Prostate Fusion Biopsy: A Prospective Randomized Trial.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) and targeted biopsy (TB) facilitate accurate detection of clinically significant prostate cancer (csPC). However, it remains unclear how targeted cores should be applied for accurate diagnosis of csPC. OBJECTIVE: To assess csPC detection rates for two target-directed MRI/transrectal ultrasonography (TRUS) fusion biopsy approaches, conventional TB and target saturation biopsy (TS). DESIGN, SETTING, AND PARTICIPANTS: This was a prospective single-center study of outcomes for transperineal MRI/TRUS fusion biopsies for 170 men. Half of the men (n = 85) were randomized to conventional TB with four cores per lesion and half (n = 85) to TS with nine cores. Biopsies were performed by three experienced board-certified urologists. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PC and csPC (International Society of Urological Pathology grade group ≥2) detection rates for systematic biopsy (SB), TB, and TS were analyzed using McNemar's test for intrapatient comparisons and Fisher's exact test for TS versus TB. A combination of targeted biopsy (TS or TB) and SB served as the reference. RESULTS AND LIMITATIONS: According to the reference, csPC was diagnosed for 57 men in the TS group and 36 men in the TB group. Of these, TS detected 57/57 csPC cases and TB detected 33/36 csPC cases (p = 0.058). Detection of Gleason grade group 1 disease was 10/12 cases with TS and 8/17 cases with TB (p = 0.055). In addition, TS detected 97% of 63 csPC lesions, compared to 86% with TB (p = 0.1). Limitations include the single-center design, the limited generalizability owing to the transperineal biopsy route, the lack of central review of pathology and radical prostatectomy correlation, and uneven distributions of csPC prevalence, Prostate Imaging-Reporting and Data System (PI-RADS) 5 lesions, men with two or more PI-RADS ≥3 lesions, and prostate-specific antigen density between the groups, which may have affected the results. CONCLUSIONS: In our study, rates of csPC detection did not significantly differ between TS and TB. PATIENT SUMMARY: In this study, we investigated two targeted approaches for taking prostate biopsy samples after observation of suspicious lesions on prostate scans. We found that the rates of detection of prostate cancer did not significantly differ between the two approaches.

Risk and predictors of adverse pathology after radical prostatectomy in patients diagnosed with IUSP 1-2 prostate cancer at MRI-targeted biopsy: a multicenter analysis.

PURPOSE: Although active surveillance (AS) is recommended for low- to favorable intermediate-risk prostate cancer (PCa), risk of upgrading at radical prostatectomy (RP) is not negligible. Available studies based on systematic transrectal ultrasound biopsy might not be applicable to contemporary cohorts diagnosed with MRI-targeted biopsy (TB). The aim of the present study is to explore rates and risk factors for adverse outcomes (AO) at RP in patients with ISUP ≤ 2 PCa detected at TB with concomitant systematic biopsy (SB). METHODS: Multicenter, retrospective analysis of 475 consecutive patients with ISUP ≤ 2 PCa at MRI-TB + SB is treated with RP. AO were defined as ISUP upgrading, adverse pathology (upgrading to ISUP ≥ 3 and/or ≥ pT3 at RP, and/or pN1) (AP) or biochemical recurrence (BCR) in men with follow-up (n = 327). RESULTS: The rate of ISUP upgrading, upgrading ≥ 3, and AP were 39%, 21%, and 43%. Compared to ISUP2, men with ISUP1 PCa had a higher rate of overall upgrading (27 vs. 67%, p < 0.001), but less upgrading to ≥ 3 (27 vs. 10%, p < 0.001). AP was more common when ISUP2 was detected with a combined MRI-TB + SB approach compared to considering TB (p = 0.02) or SB (p = 0.01) alone. PSA, PSA density, PI-RADS, ISUP at TB, overall biopsy ISUP and EAU classification were predictors of upgrading to ISUP ≥ 3 and AP. The 1 year BCR-free survival was 94% with no differences in BCR rates between subgroups. CONCLUSION: Upgrading in ISUP ≤ 2 PCa remains prevalent even in men diagnosed in the MRI era. The use of MRI-TB with concomitant SB allows for the accurate identification of ISUP2 PCa and predicts the risk of AO at RP.

[Current concepts for perioperative systemic therapy in advanced renal cell carcinoma]. / Aktuelle Konzepte für die perioperative Systemtherapie beim fortgeschrittenen Nierenzellkarzinom.

BACKGROUND: The incidence of renal cell carcinoma (RCC), one of the most common malignant tumors in Germany, continues to increase. Medical treatment is indicated in relapsed or metastatic disease. MATERIALS AND METHODS: The article is based on the content of the recent guidelines and a selective literature search. RESULTS: The use of the introduction of immune checkpoint inhibitors (ICI) and their combination with tyrosine kinase inhibitors (TKI) in particularly vulnerable patients has fundamentally changed the therapeutic landscape. The median overall survival was thus extended to > 40 months. However, until recently neither targeted nor conventional therapy could be established in (neo)adjuvant therapy. New data show survival benefit for patients at high risk of recurrence on adjuvant therapy with pembrolizumab. CONCLUSIONS: Currently only pembrolizumab is approved in adjuvant therapy in Germany. Further studies and a longer follow-up will help us in the future in the classification of therapy with ICI and its combination with TKI in localized RCC.

FDG-PET Positivity and Overall Survival in Renal Cell Carcinoma.

This cohort study examines positron emission tomography in renal cell carcinoma and its association with overall survival among adults.

High Pretreatment Serum PD-L1 Levels Are Associated with Muscle Invasion and Shorter Survival in Upper Tract Urothelial Carcinoma.

Programmed death ligand-1 (PD-L1) is an immune checkpoint molecule and a widely used therapeutic target in urothelial cancer. Its circulating, soluble levels (sPD-L1) were recently suggested to be associated with the presence and prognosis of various malignancies but have not yet been investigated in upper tract urothelial carcinoma (UTUC). In this study, we assessed sPD-L1 levels in 97 prospectively collected serum samples from 61 UTUC patients who underwent radical nephroureterectomy (RNU), chemotherapy (CTX), or immune checkpoint inhibitor (ICI) therapy. In addition to pretreatment samples, postoperative and on-treatment sPD-L1 levels were determined in some patients by using ELISA. In the RNU group, elevated preoperative sPD-L1 was associated with a higher tumor grade (p = 0.019), stage (p < 0.001) and the presence of metastasis (p = 0.002). High sPD-L1 levels were significantly associated with worse survival in both the RNU and CTX cohorts. sPD-L1 levels were significantly elevated in postoperative samples (p = 0.011), while they remained unchanged during CTX. Interestingly, ICI treatment caused a strong, 25-fold increase in sPD-L1 (p < 0.001). Our results suggest that elevated preoperative sPD-L1 level is a predictor of higher pathological tumor stage and worse survival in UTUC, which therefore may help to optimize therapeutic decision-making. The observed characteristic sPD-L1 flare during immune checkpoint inhibitor therapy may have clinical significance.

Variation across operating sites in urinary and sexual outcomes after radical prostatectomy in localized and locally advanced prostate cancer.

PURPOSE: The extent of variation in urinary and sexual functional outcomes after radical prostatectomy (RPE) between prostate cancer (PC) operating sites remains unknown. Therefore, this analysis aims to compare casemix-adjusted functional outcomes (EPIC-26 scores incontinence, irritative/obstructive function and sexual function) between operating sites 12 months after RPE. MATERIALS AND METHODS: Analysis of a cohort of 7065 men treated with RPE at 88 operating sites (prostate cancer centers, "PCCs") between 2016 and 2019. Patients completed EPIC-26 and sociodemographic information surveys at baseline and 12 months after RPE. Survey data were linked to clinical data. EPIC-26 domain scores at 12 months after RPE were adjusted for relevant confounders (including baseline domain score, clinical and sociodemographic information) using regression analysis. Differences between sites were described using minimal important differences (MIDs) and interquartile ranges (IQR). The effects of casemix adjustment on the score results were described using Cohen's d and MIDs. RESULTS: Adjusted domain scores at 12 months varied between sites, with IQRs of 66-78 (incontinence), 89-92 (irritative/obstructive function), and 20-29 (sexual function). Changes in domain scores after casemix adjustment for sites ≥ 1 MID were noted for the incontinence domain (six sites). Cohen's d ranged between - 0.07 (incontinence) and - 0.2 (sexual function), indicating a small to medium effect of casemix adjustment. CONCLUSIONS: Variation between sites was greatest in the incontinence and sexual function domains for RPE patients. Future research will need to identify the factors contributing to this variation. TRIAL REGISTRY: The study is registered at the German Clinical Trial Registry ( https://www.drks.de/drks_web/ ) with the following ID: DRKS00010774.

Radiation Protection and Occupational Exposure on 68Ga-PSMA-11-Based Cerenkov Luminescence Imaging Procedures in Robot-Assisted Prostatectomy.

Cerenkov luminescence imaging (CLI) was successfully implemented in the intraoperative context as a form of radioguided cancer surgery, showing promise in the detection of surgical margins during robot-assisted radical prostatectomy. The present study was designed to provide a quantitative description of the occupational radiation exposure of surgery and histopathology personnel from CLI-guided robot-assisted radical prostatectomy after the injection of 68Ga-PSMA-11 in a single-injection PET/CT CLI protocol. Methods: Ten patients with preoperative 68Ga-PSMA-11 administration and intraoperative CLI were included. Patient dose rate was measured before PET/CT (n = 10) and after PET/CT (n = 5) at a 1-m distance for 4 patient regions (head [A], right side [B], left side [C], and feet [D]). Electronic personal dosimetry (EPD) was used for intraoperative occupational exposure (n = 10). Measurements included the first surgical assistant and scrub nurse at the operating table and the CLI imager/surgeon at the robotic console and encompassed the whole duration of surgery and CLI image acquisition. An estimation of the exposure of histopathology personnel was performed by measuring prostate specimens (n = 8) with a germanium detector. Results: The measured dose rate value before PET/CT was 5.3 ± 0.9 (average ± SD) µSv/h. This value corresponds to a patient-specific dose rate constant for positions B and C of 0.047 µSv/h⋅MBq. The average dose rate value after PET/CT was 1.04 ± 1.00 µSv/h. The patient-specific dose rate constant values corresponding to regions A to D were 0.011, 0.026, 0.024, and 0.003 µSv/h⋅MBq, respectively. EPD readings revealed average personal equivalent doses of 9.0 ± 7.1, 3.3 ± 3.9, and 0.7 ± 0.7 µSv for the first surgical assistant, scrub nurse, and CLI imager/surgeon, respectively. The median germanium detector-measured activity of the prostate specimen was 2.96 kBq (interquartile range, 2.23-7.65 kBq). Conclusion: Single-injection 68Ga-PSMA-11 PET/CT CLI procedures are associated with a reasonable occupational exposure level, if kept under 110 procedures per year. Excised prostate specimen radionuclide content was below the exemption level for 68Ga. Dose rate-based calculations provide a robust estimation for EPD measurements.