Response to RL-225Ac in prostate cancer: Effect of prior treatment with RL-177Lu: A systematic review of the literature.

BACKGROUND: Targeted radionuclide therapy with Actinium-225-labeled prostate-specific membrane antigen agents (225Ac-PSMA) is currently being studied in clinical trials for patients with metastatic castration-resistant prostate cancer (mCRPC). Compared to ß-emitting therapeutic radionuclides, alpha-emitters (e.g., 225Ac) have a significantly higher linear energy transfer and significantly shorter range. As a result, alpha emitters could be expected to improve efficacy and reduce bystander toxicity. This systematic literature review was conducted to evaluate the impact of sequencing of 177Lu-PSMA and 225Ac-PSMA targeted radionuclide therapy (TRT) in mCRPC. METHODS: The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The searches were made using relevant keywords in the PubMed, Scopus, and Web of Science databases, and articles up to August 22, 2022, were included. Publications were excluded if they were duplicate publications, wrong study or publication format, or discussing a topic out of scope. Data on efficacy, toxicity, and health-related quality of life were extracted from the individual articles. The I2 index was used to measure the extent of heterogeneity amongst studies. In the studies that reported subgroup outcomes according to the prior status on 177Lu-PSMA TRT, pooled estimates of the main outcomes were generated through descriptive analysis. Quality assessment was performed using the Newark-Ottawa-scale. RESULTS: The study included 12 articles; 1 series was performed prospectively. In total, data of 329 patients were analyzed. About 40.1% (n = 132) of the included men were pretreated with 177Lu-PSMA TRT. Seven studies, including data of 212 individuals, were eligible for quantitative analysis based on reporting outcomes of the subgroups according to their prior status on 177Lu-PSMA TRT. >25% PSA decline after 225Ac-PSMA TRT was lower in individuals who received prior 177Lu-PSMA TRT (pooled median 42.7%) compared to those who did not (pooled median 15.4%). The pooled medians of the reported median progression-free survival and overall survival for pretreated versus not pretreated individuals was 4.3 versus 14.3 months and 11.1 versus 9.2 months, respectively. However, the outcomes for each individual study were reported inconsistently (I2 = 99.9%). None of the included studies stratified the report of adverse events or changes in health-related quality of life for the subgroups. CONCLUSIONS: 225Ac-PSMA TRT is an experimental treatment for men with mCRPC. There is limited data available from high-quality trials but so far PSMA-targeted TRT has demonstrated a low morbidity profile. Our review revealed that there is a possible decrease in efficacy of targeted alpha-particle therapy if individuals previously were exposed to 177Lu-PSMA TRT. However, the level of evidence is low. The underlying mechanism by which 177Lu-PSMA TRT might trigger possible radioresistance as well as randomized controlled trials are required to establish the therapeutic efficacy and safety of 225-Ac-PSMA TRT in men refractory to 177Lu-PSMA TRT.

Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic castration-resistant prostate cancer receiving prostate-specific membrane antigen targeted radionuclide therapy.

BACKGROUND: Neutrophil count:lymphocyte count ratio (NLR) may be a prognostic factor for men with advanced prostate cancer. We hypothesized that it is associated with prostate-specific antigen (PSA) response and survival in men treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT). METHODS: Data of 180 men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in sequential prospective radionuclide clinical trials from 2002 to 2021 (utilizing 177Lu-J591, 90Y-J591, 177Lu-PSMA-617, or 225Ac-J591) were retrospectively analyzed. We used a logistic regression to determine the association between NLR and ≥50% PSA decline (PSA50) and a Cox proportional hazards model to investigate the association between NLR and overall survival (OS). RESULTS: A total of 94 subjects (52.2%) received 177Lu-J591, 51 (28.3%) 177Lu-PSMA-617, 28 (15.6%) 225Ac-J591, and 7 (3.9%) 90Y-J591. The median NLR of 3.75 was used as cut-off (low vs. high NLR; n = 90, respectively). On univariate analysis, NLR was not associated with PSA50 (HR 1.08; 95% confidence interval [CI] 0.99-1.17, p = 0.067). However, it was associated with worse OS (hazard ratio [HR] 1.06, 95% CI 1.02-1.09, p = 0.002), also after controlling for circulating tumor cell count and cancer and leukemia group B risk group (HR 1.05; 95% CI 1.003-1.11, p = 0.036). Men with high NLR were at a higher hazard of death from all causes (HR 1.43, 95% CI 1.05-1.94, p = 0.024). CONCLUSIONS: NLR provides prognostic information in the setting of patients with mCRPC receiving treatment with PSMA-TRT.

Transperineal vs. transrectal biopsy to reduce postinterventional sepsis.

PURPOSE OF REVIEW: Prostate biopsy is commonly performed in men suspected to have prostate cancer. It has traditionally been performed using a transrectal approach, but transperineal prostate biopsy has been increasingly adopted in part because of its lower associated infectious risk. We review recent studies evaluating the rate of potentially life-threatening post-biopsy sepsis and potential preventive strategies. RECENT FINDINGS: After performing a comprehensive literature search, 926 records were screened and 17 studies published in 2021 or 2022 were found to be relevant. Studies varied in periprocedural perineal and transrectal preparation, antibiotic prophylaxis, and definition of sepsis. The sepsis rates after transperineal ultrasound-guided versus transrectal ultrasound-guided biopsy ranged between 0 and 1 versus 0.4 and 9.8%. Mixed efficacy was found for the topical application of antiseptics before transrectal biopsy to decrease postprocedural sepsis. Promising strategies include the use of topical rectal antiseptics before transrectal prostate biopsy and using a rectal swab to guide the antibiotic selection and the route of the biopsy. SUMMARY: The transperineal approach to biopsy is increasingly used because of lower associated sepsis rates. Our review of the recent literature supports this practice pattern change. Hence, transperineal biopsy should be offered as an option to all men.

Thyroid and androgen receptor signaling are antagonized by µ-Crystallin in prostate cancer.

Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3'-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein µ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRα/TRß) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen-mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.

The prognostic impact of tumour NSD2 expression in advanced prostate cancer.

Purpose: To assess the prognostic significance of the nuclear receptor binding SET protein 2 (NSD2), a co-activator of the NFkB-pathway, on tumour progression in patients with advanced prostate cancer (PCa).Methods: We retrospectively assessed NSD2 expression in 53 patients with metastatic and castration-resistant PCa. Immunohistochemical staining for NSD2 was carried out on specimen obtained from palliative resection of the prostate. Univariable and multivariable analyses were performed to assess the association between NSD2 expression and PCa progression.Results: Of the 53 patients, 41 had castration-resistant PCa and 48 men had metastases at time of tissue acquisition. NSD2 expression was increased in tumour specimen from 42 patients (79.2%). In univariable Cox regression analyses, NSD2 expression was associated with PSA progression, progression on imaging and overall survival (p = 0.04, respectively). In multivariable analyses, NSD2 expression did not retain its association with these endpoints.Conclusions: NSD2 expression is abnormal in almost 80% of patients with advanced PCa. Expression levels of this epigenetic regulator are easily detected by immunohistochemistry while this biomarker exhibited prognostic value for PCa progression and death in univariable analysis. Further studies on NSD2 involvement in PCa proliferation, progression, metastasis and resistance mechanisms are needed.

Prognostic Value of Concomitant Carcinoma In Situ in the Radical Cystectomy Specimen: A Systematic Review and Meta-Analysis.

PURPOSE: We investigated the prognostic impact of concomitant carcinoma in situ in radical cystectomy specimens. MATERIALS AND METHODS: We performed a systematic review and meta-analysis using MEDLINE®, Scopus®, Web of Science™ and The Cochrane Library to identify eligible studies published until October 2017. Studies were eligible for analysis if they compared patients with concomitant carcinoma in situ in radical cystectomy specimens for bladder cancer to patients without concomitant carcinoma in situ to determine its value to prognosticate overall mortality, recurrence-free survival, cancer specific mortality and ureteral involvement using multivariable analysis. The protocol for this systematic review was registered in PROSPERO (Prospective Register of Systematic Reviews, CRD42018086539) and is available in full on the University of York website. RESULTS: Overall 23 studies published between 2006 and 2017 including a total of 20,647 patients were selected for the systematic review and meta-analysis. Concomitant carcinoma in situ was reported in 39.4% of radical cystectomy specimens. In studies analyzing all patients the presence of concomitant carcinoma in situ was not associated with overall mortality (pooled HR 0.92, 0.77-1.10), recurrence-free survival (pooled HR 1.06, 0.99-1.13) or cancer specific mortality (pooled HR 1.00, 0.93-1.07). It was associated with ureteral involvement (pooled OR 4.51, 2.59-7.84). On subanalysis of studies restricted to patients with organ confined bladder cancer at radical cystectomy concomitant carcinoma in situ was associated with worse recurrence-free survival (pooled HR 1.57, 1.12-2.21) and cancer specific mortality (pooled HR 1.51, 1.001-2.280). CONCLUSIONS: Concomitant carcinoma in situ is significantly associated with ureteral involvement in patients treated with radical cystectomy. In patients with organ confined disease concomitant carcinoma in situ in the radical cystectomy specimen is a prognosticator of recurrence-free survival and cancer specific mortality.

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591.

PURPOSE: Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225. METHODS: Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of 225Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D. RESULTS: Radiochemistry and animal studies were favorable. Thirty-two patients received 225Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%). CONCLUSION: To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of 225Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.

Application of the ERAS guidelines in pediatric urological surgery: a systematic review.

INTRODUCTION: Consensus for Enhanced Recovery After Surgery (ERAS) in pediatrics has been achieved in neonatal intestinal surgery, yet it is not widely utilized in pediatric urology. We investigated the application of ERAS guidelines in pediatric urology, and determined its effects given the available level of evidence supporting the ERAS protocol in children. EVIDENCE ACQUISITION: A systematic literature review including series providing adoption of fast-track recovery protocols for pediatric urology procedures was carried out. Main outcome measures were study characteristics, adherence to the 19 ERAS items, complication rates and length of hospital stay. Sub-group analysis by surgery type (hypospadias versus major surgery) was performed. EVIDENCE SYNTHESIS: Nine series with data from 1272 surgical pediatric cases were included. An enhanced recovery pathway was applied in 67.3% of the reports. Two series included patients undergoing hypospadias repair and ERAS items were insufficiently reported. Studies including children undergoing major procedures mentioned a median of 15 ERAS items, yet applied a median of 11 items. Median compliance rate was 88.9% (range 50-100). More ERAS guideline items were reported (applied or mentioned) in the most recently published studies. CONCLUSIONS: There is limited reporting and use of the ERAS guidelines in urologic surgery particularly in hypospadias repair; whilst in major surgery in children, adherence and compliance rates vary widely. In more recent series there was an increase in ERAS items that have been mentioned and applied. Future research is needed to identify barriers and to overcome them in order to fully adopt and benefit from the ERAS pathway.

Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis.

Localized prostate cancer is frequently composed of multiple spatially distinct tumors with significant inter- and intra-tumoral molecular heterogeneity. This genomic diversity gives rise to many competing clones that may drive the biological trajectory of the disease. Previous large-scale sequencing efforts have focused on the evolutionary process in metastatic prostate cancer, revealing a potential clonal progression to castration resistance. However, the clonal origin of synchronous lymph node (LN) metastases in primary disease is still unknown. Here, we perform multi-region, targeted next generation sequencing and construct phylogenetic trees in men with prostate cancer with synchronous LN metastasis to better define the pathologic and molecular features of primary disease most likely to spread to the LNs. Collectively, we demonstrate that a combination of histopathologic and molecular factors, including tumor grade, presence of extra-prostatic extension, cellular morphology, and oncogenic genomic alterations are associated with synchronous LN metastasis.

Intermediate Grade Prostate Cancer and Risk for Adverse Pathology Radical Prostatectomy: Implications for Partial Gland Ablation Case Selection.

PURPOSE: Using nationally representative data, we determined the likelihood of adverse pathology at radical prostatectomy (RP) to better inform case selection for partial gland ablation (PGA). MATERIALS AND METHODS: We identified men with clinically localized GG2 (n = 106,048) and GG3 (n = 55,488) prostate cancer on biopsy from 2010 through 2019 who subsequently underwent RP. Men with GG2 were stratified as unfavorable and favorable per NCCN guidelines. RP adverse pathology was defined as upgrading to GG4-5, pT3-4, or nodal involvement (pN1), respectively. Logistic regression determined factors associated with adverse pathology, and the Cochran-Armitage Test was used to evaluate temporal trends. RESULTS: Men with biopsy GG3 vs. GG2 experienced significant upgrading (11.3% vs. 3.6%, P < .001), more EPE (26.9% vs. 21.1%), SVI (11.9% vs. 5.3%), and pN1 (4.3% vs. 1.6%), all P < .001. When comparing unfavorable vs. favorable GG2, men experienced more EPE (25.3% vs. 16.5%), SVI (7.2% vs. 3%), and pN1 (2.2% vs. 0.8%), all P < .001. In adjusted analysis, age, Hispanic race, PSA > 10 ng/mL, and ≥ 50% positive biopsy cores were associated with adverse pathology (all P < .001). The likelihood of RP adverse pathology for men with biopsy GG3 increased significantly during the study period from 38.8% in 2010 to 47.3% in 2019 (P < .001). CONCLUSION: Approximately 40% of men with GG3 and more than 30% with unfavorable GG2 prostate cancer harbor adverse pathology that may not be curable by PGA. Given MRI often understages prostate cancer, our findings have significant implications for optimizing PGA case selection and cancer control outcomes.

α-Labeling of J591, an Antibody Targeting Prostate-Specific Membrane Antigen: The Technique and Considerations from the First Dedicated Production Lab at an Academic Institution in the United States.

The protein expression of the prostate-specific membrane antigen correlates with unfavorable or aggressive histologic features of prostate cancer, resulting in use as a diagnostic PET imaging radiotracer and therapeutic target. Here, we discuss the methods to develop 225Ac-DOTA-J591, an α-labeled compound targeting an extracellular epitope of prostate-specific membrane antigen, which is currently being studied in early clinical trials. In addition, we review quality control, radiation safety measures, and clinical considerations before administration of this radioimmunotherapeutic agent.

Partial-gland Cryoablation Outcomes for Localized Prostate Cancer in Patients with Magnetic Resonance Imaging (MRI)-visible and MRI-invisible Lesions.

Background: Expert consensus recommends treatment of magnetic resonance imaging (MRI)-visible prostate cancer (PCa). Outcomes of partial-gland ablation (PGA) for MRI-invisible PCa remain unknown. Objective: To compare recurrence-free survival, adverse events, and health-related quality of life (HRQoL) outcomes following cryoablation of MRI-visible vs invisible PCa. Design setting and participants: We analyzed data for 75 men who underwent cryoablation therapy between January 2017 and January 2022. PCa identified on MRI-targeted and/or adjacent systematic biopsy cores was defined as MRI-visible, whereas PCa identified on systematic biopsy beyond the targeted zone was defined as MRI-invisible. Outcome measurements and statistical analysis: The primary outcome was recurrence at 12 mo after PGA, defined as the presence of clinically significant PCa (grade group [GG] ≥2) on surveillance biopsy. Adverse events were captured using the Clavien-Dindo classification and HRQoL was captured using the Expanded Prostate Cancer Index-Clinical Practice (EPIC-CP) tool. Results and limitations: Of the 58 men treated for MRI-visible and 17 treated for MRI-invisible lesions, 51 (88%) and 16 (94%), respectively, had at least one surveillance biopsy performed. There were no statistically significant differences in age, race, body mass index, biopsy GG, prostate-specific antigen, prostate volume, or treatment extent between the MRI-visible and MRI-invisible groups. Median follow-up was 44 mo (interquartile range 17-54) and did not significantly differ between the groups. The recurrence rate at 12 mo did not significantly differ between the groups (MRI-visible 39%, MRI-invisible 19%; p = 0.2), and log-rank survival analysis demonstrated no significant difference in recurrence-free survival (p = 0.15). Adverse event rates did not significantly differ (MRI-visible 29%, MRI-invisible 53%; p = 0.092); no man in the MRI-visible group had a Clavien-Dindo grade ≥III complication, while one subject in the MRI-invisible group had a Clavien-Dindo grade III complication. Median EPIC-CP urinary and sexual function scores were similar for the two groups at baseline and at 12 mo after PGA. Study limitations include the retrospective design and small sample size. Conclusions: We observed similar cancer control, adverse event, and HRQoL outcomes for MRI-visible versus MRI-invisible PCa in the first comparison of partial-gland cryoablation. Longer follow-up and external validation of our findings are needed to inform patient selection for PGA for MRI-invisible PCa. Patient summary: Patients with prostate cancer lesions that are not visible on magnetic resonance imaging (MRI) scans who undergo partial gland ablation may have similar treatment outcomes compared to patients with cancer lesions that are visible on MRI.

Study protocol for a prospective, multi-centered randomized controlled trial comparing pelvic fascia-sparing radical prostatectomy with conventional robotic-assisted prostatectomy: The PARTIAL trial.

BACKGROUND: Pelvic fascia-sparing robotic-assisted radical prostatectomy (PFS-RARP) is a novel approach that spares the endopelvic fascia ventral to the prostate. The preservation of more native structures compared to conventional robotic-assisted radical prostatectomy (RARP) may lead to faster recovery of urinary function, fewer penile changes, and decreased inguinal hernia sequelae, but may have a higher risk for positive surgical margins and poorer cancer control. However, high-level evidence is absent. The PARTIAL trial is a surgical randomized controlled trial (RCT) aiming to bridge this evidence gap (NCT05155501). METHODS: We describe a prospective RCT with a projected enrollment of 600 men randomized to PFS-RARP vs. RARP. The primary outcome is cancer control (positive surgical margins and prostate-specific antigen failure) and secondary outcomes include health-related quality of life pertaining to urinary and sexual function, decision regret, and adverse events (30-day complications, inguinal hernias, penile shortening, and Peyronie's disease). The anticipated duration of trial participation is 24 months. Study participation is incentivized with the use of innovative methodologies such as a novel, two-stage informed consent and a validated web-based interface to monitor patient-reported symptoms and empower individuals to improve their recovery. CONCLUSION: If PFS-RARP is non-inferior to RARP in terms of cancer control and has better functional outcomes, it should be the surgical standard of care for men with localized prostate cancer. Using the innovative two-stage consent process, completion of the trial will not only provide much needed evidence on one of the most common cancer surgeries but also insight on improving surgical RCT methodology. Trial status This trial is registered at ClinicalTrials.gov (NCT05155501; first posted on December 13, 2021); Institutional approval number: WCM IRB # 21-07023781, BRANY's initial approval event ID # 186333. The trial is not yet recruiting.

Analysis of the Tumor Immune Microenvironment (TIME) in Clear Cell Renal Cell Carcinoma (ccRCC) Reveals an M0 Macrophage-Enriched Subtype: An Exploration of Prognostic and Biological Characteristics of This Immune Phenotype.

There is a need to optimize the treatment of clear cell renal cell carcinoma (ccRCC) patients at high recurrence risk after nephrectomy. We sought to elucidate the tumor immune microenvironment (TIME) of localized ccRCC and understand the prognostic and predictive characteristics of certain features. The discovery cohort was clinically localized patients in the TCGA-Kidney Renal Clear Cell Carcinoma (KIRC) project (n = 382). We identified an M0 macrophage-enriched cluster (n = 25) in the TCGA-KIRC cohort. This cluster's median progression-free survival (PFS) and overall survival (OS) were 40.4 and 45.3 months, respectively, but this was not reached in the others (p = 0.0003 and <0.0001, respectively). Gene set enrichment (GSEA) analysis revealed an enrichment of epithelial to mesenchymal transition and cell cycle progression genes within this cluster, and these patients also had a lower predicted response to immune checkpoint blockade (ICB) (4% vs. 20-34%). An M0-enriched cluster (n = 9) with shorter PFS (p = 0.0006) was also identified in the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort (n = 94). Through this characterization of the TIME in ccRCC, a cluster of patients defined by enrichment in M0 macrophages was identified that demonstrated poor prognosis and lower predicted ICB response. Pending further validation, this signature can identify localized ccRCC patients at high risk of recurrence after nephrectomy and who may require therapeutic approaches beyond ICB monotherapy.

Enhancing Recovery After Major Bladder Cancer Surgery: Comprehensive Review and Assessment of Application of the Enhanced Recovery After Surgery Guidelines.

Radical cystectomy with pelvic lymphadenectomy and urinary diversion is the standard treatment for patients diagnosed with localized muscle-invasive bladder cancer. Enhanced recovery after surgery (ERAS) is a multimodal perioperative care pathway comprising recommendations on different items with variable evidence that are aimed at improving outcomes. This review provides an overview of the application of specific elements of the ERAS guidelines. Forty-eight series were identified through our literature search. The studies reported a median of 16 out of the 22 ERAS steps (72.7%). The elements were applied in 79.3% of cases (interquartile range 61.1-85%) if mentioned in the studies, decreasing to 73.5% in the postoperative period. PATIENT SUMMARY: Guidelines on enhanced recovery after surgery recommend steps to follow and cover all areas of the patient's journey through the surgical process. We looked at the application of the elements for patients with bladder cancer. We found inconsistent reporting and use.

The impact of lymphovascular invasion in patients treated with radical nephroureterectomy for upper tract urothelial carcinoma: An extensive updated systematic review and meta-analysis.

Patients with upper tract urothelial carcinoma (UTUC) often have a delayed diagnosis and by then, present with advanced disease which has been shown to be associated with lymphovascular invasion (LVI). It has been suggested to be involved in the metastatic cascade of the disease. In this review, we provide an extensive up-to-date summary of the current knowledge about the prognostic impact of LVI in patients undergoing radical nephroureterectomy (RNU). A systematic search of PubMed/MEDLINE, Scopus, EMBASE, and Web of Science for all reports published from 2010 through 2021 was performed. We performed pooled analyses of hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) of series that evaluated LVI as a prognostic factor in adults with UTUC who underwent RNU. The assessed oncological outcomes were disease recurrence, cancer-specific and overall survival. A meta-regression analysis was used to explore potential heterogeneity. A total of 58 series met the eligibility criteria for qualitative and quantitative synthesis. We included 29,829 patients, ranging from 101 to 2492 per study. All series were retrospective. LVI was present in 7,818 patients (26.2%). The median age of the patients was 69 years and the median follow-up was 40 months. In 40 of 58 studies (68.9%), adjuvant chemotherapy was given. The pooled HRs show that LVI predicts a greater risk of recurrence of the disease (pooled HR 1.43, 95% CI: 1.31-1.55, P = 0.000; I2 = 76.3%), and decreases cancer-specific survival (pooled HR 1.53, 95% CI: 1.41-1.66, P = 0.000; I2 = 72.3%) and overall survival (HR 1.56, 95% CI 1.45-1.69, P = 0.000; I2 = 62.9%). It can be concluded that LVI is a common histologic pattern in surgical specimen in patients undergoing RNU for UTUC. LVI predicts a greater risk of recurrence and mortality, thus it should be carefully assessed in clinical practice to determine prognosis, and for optimal decision-making within the concept of personalized therapies.

Molecular Characterization of Clear Cell Renal Cell Carcinoma Reveals Prognostic Significance of Epithelial-mesenchymal Transition Gene Expression Signature.

BACKGROUND: There is an ongoing need to develop prognostic biomarkers to improve the management of clear cell renal cell carcinoma (ccRCC). OBJECTIVE: To leverage enriched pathways in ccRCC to improve risk-stratification. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified two complementary discovery cohorts of patients with ccRCC who underwent (1) radical nephrectomy (RNx) with inferior vena cava tumor thrombectomy (patients = 5, samples = 24) and (2) RNx for localized disease and developed recurrence versus no recurrence (n = 36). Patients with localized ccRCC (M0) in The Cancer Genome Atlas (TCGA, n = 386) were used for validation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A differential expression gene (DEG) analysis was performed on targeted RNA next-generation sequencing data from both discovery cohorts. Using TCGA for validation, Kaplan-Meier survival analysis and multivariable Cox proportional hazard testing were utilized to investigate the prognostic impact of DEGs, cell cycle proliferation (CCP), and a novel epithelial-mesenchymal transition (EMT) score on progression-free (PFS) and disease-specific (DSS) survival. RESULTS AND LIMITATIONS: In the discovery cohorts, we observed overexpression of WT1 and CCP genes in the tumor thrombus versus the primary tumor, as well as in patients with recurrence versus those without recurrence. A hallmark pathway analysis demonstrated enrichment of the EMT- and CCP-related pathways in patients with high WT1 expression in the TCGA (validation) ccRCC cohort. CCP and EMT scores were derived in the validation cohort, which was stratified into four risk groups using Youden Index cut points: CCPlow/EMTlow, CCPlow/EMThigh, CCPhigh/EMTlow, and CCPhigh/EMThigh. The CCPhigh/EMThigh risk group was associated with the worst PFS and DSS (both p < 0.001). In a multivariable analysis, CCPhigh/EMThigh was independently associated with poor PFS and DSS (hazard ratio = 4.6 and 10.3, respectively; p < 0.001). CONCLUSIONS: We demonstrate the synergistic prognostic impact of EMT in tumors with a high CCP score. Our novel EMT score has the potential to improve risk stratification and provide potential novel therapeutic targets. PATIENT SUMMARY: Genes involved in epithelial-mesenchymal transition provides important prognostic information for patients with clear cell renal cell carcinoma.

Psoas Muscle Mass can Predict Postsurgical Outcomes in Patients Who Undergo Radical Cystectomy and Urinary Diversion Reconstruction.

OBJECTIVE: To morphometrically measure to muscle mass which may reflect physical components of frailty. Hence, we evaluated the association between L4 total psoas area (TPA) and operative outcome after radical cystectomy (RC) for bladder cancer. METHODS: In a retrospective single-center study, bladder cancer patients who underwent RC and urinary diversion between 2007 and 2012 were enrolled. TPA was evaluated in the cross-sectional imaging. The psoas muscles were normalized with the height. Male patients with a psoas mass index ≤7.4 cm2/m2 and female patients with a psoas mass index ≤5.2 cm2/m2 were classified as sarcopenic. Outcome measures were 30- and 90-day readmission and complications, and survival. Multivariable logistic and Cox proportional-hazards regression models were used to determine relevant predictors. RESULTS: The median age of the 441 participants and follow up time was 68 years (IQR 59-75) and 1.2 years (IQR 0.5-1.9), respectively. One hundred forty-three patients (32.4%) were sarcopenic. The 30-day readmission and the complication rates were 13.8% and 44.7%, respectively. The 90-day readmission and complication rates were 23.9% and 53.1%, respectively. The 1-year mortality rate was 11.6% (95%CI 8.7-15.4). Multivariable logistic regression analysis revealed an association between increased TPA and lower odds of 30-day complications after RC (OR 0.95, 95%CI 0.92-0.99, P = .02); similarly, an increase in TPA was of prognostic value, although not statistically significant in the multivariable model (P = .05) once adjusting for other patient factors. CONCLUSION: Sarcopenia predicted early complications and showed an informative trend for overall survival after RC, and thus may inform models predicting postsurgical outcomes.

Differential impact of radiation therapy after radical prostatectomy on recurrence patterns: an assessment using [68Ga]Ga-PSMA ligand PET/CT(MRI).

PURPOSE: To evaluate the differential impact of postoperative radiotherapy (RT) on recurrence patterns in patients treated with radical prostatectomy (RP) using [68Ga]Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA 11-PET). METHODS: We assessed 162 consecutive patients who experienced biochemical recurrence (BCR) after RP for nonmetastatic prostate cancer (PC). All had at least one positive lesion on imaging. No patient was on androgen deprivation therapy (ADT). Patients were categorized into those who had received adjuvant/salvage RT ± ADT and those who did not (RP only). Lesion- and patient-based analyses were performed. The impact of the radiation field was assessed. RESULTS: Overall, 57 BCR patients underwent RP only, 105 received postoperative RT. Median PSA was 1.01 ng/ml (IQR 0.58-2). In the lesion-based analysis, compared to the RP only patients, those who had received postoperative RT, had less lymph node (LN) recurrences distal to the common iliac bifurcation (35.2 vs. 57.9%, p = 0.05), but were more likely to harbor positive LNs proximal to the iliac bifurcation and in the presacral (34.2 vs. 12.3%, p = 0.002) areas as well as bone metastases (25.7 vs. 8.8%, p = 0.01). In the patient-based analysis, the patients with postoperative RT after RP had less recurrence in the pelvis only (pelvic LNs and/or prostate bed) (52.4 vs. 79%, p = 0.002), but were more likely to harbor extrapelvic recurrence (41.9 vs. 15.8%, p = 0.001). Patients who received RT to the prostate bed only had more recurrence to the pelvic LN only (54.2% vs. 23.4%, p = 0.002), but less extrapelvic recurrence (31.3 vs. 53.2%, p = 0.03) and less bone recurrence (16.7 vs. 36.2%, p = 0.031) compared to those patients, who received RT to the prostate bed and pelvic nodes. CONCLUSIONS: Postoperative radiation treatment alters the recurrence pattern in BCR patients after RP. Further prospective studies are needed to establish a decision tree for optimal imaging/management according to previous treatments.

Single-lesion Prostate-specific Membrane Antigen Protein Expression (PSMA) and Response to [177Lu]-PSMA-ligand Therapy in Patients with Castration-resistant Prostate Cancer.

Initial reports of a clinical response in patients treated with the radioligand [177Lu]-PSMA-617 for castration-resistant prostate cancer (CRPC) are promising, despite known inter- and intrapatient heterogeneity. In metastatic CRPC, we examined the association of baseline immunohistochemical (IHC) expression of prostate-specific membrane antigen (PSMA) in a single lesion and responsiveness to [177Lu]-PSMA-617 therapy, measured as the PSMA maximum standardized uptake value (SUVmax). Between 2015 and 2020, 19 patients with multiple metastases underwent single-lesion biopsy, [68Ga]-PSMA positron emission tomography (PET) imaging, and treatment with [177Lu]-PSMA-617. A monoclonal anti-PSMA antibody was used to semiquantitatively assess PSMA IHC in the biopsy specimen. Imaging evaluation of the biopsied single lesion and overall response was performed according to Positron Emission Tomography Response Criteria in Solid Tumors. The PSMA IHC histoscore correlated positively with pretreatment same-site PSMA SUVmax (r s = 0.6). Nine patients had imaging after three cycles of [177Lu]-PSMA-617 and were included in the lesion-specific analysis. Of these, five patients (55.6%) had an SUVmax response at the biopsy site, but three experienced overall progression. The histoscore was unable to predict the lesion-specific change in SUVmax (95% confidence interval [CI] -44.2 to 69.2) or PSA (95% CI-125.2 to 17.2). There was no correlation between single-lesion SUVmax and overall progression (r s = 0.1) on [68Ga]-PSMA PET imaging. Additional studies need to interrogate the clinical consequence of PSMA expression heterogeneity in metastases and the association with response to [177Lu]-PSMA-671. PATIENT SUMMARY: Treatment with a radioactive binding molecule called [177Lu]-PSMA-617 for men with prostate cancer resistant to castration (CRPC) is showing promise. We investigated the association between the presence of PSMA protein in metastatic lesions at biopsy and response to [177Lu]-PSMA-617 among men with metastatic CRPC. We found that assessment of PSMA presence at biopsy is not a reliable predictor of response to [177Lu]-PSMA-617. Additional studies are needed to better determine which CRPC metastatic sites will respond to this therapy.