Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Robotic Renal Vein Bypass: A Novel Technique for Treating a Challenging Case of Nutcracker Syndrome.

This case report highlights the successful application of a robotic-assisted surgical approach in managing Nutcracker syndrome. The patient, a 36-year-old female presented with severe symptoms and underwent robotic left renal vein transposition after failing conservative management. The procedure was performed through a minimally invasive approach utilizing the Da Vinci robotic system™ which offers enhanced visualization and precision. However, challenges arose during the renal vein anastomosis due to tension and poor flow through the transposition, requiring two revisions with a bovine pericardial patch. Ultimately, an 8 mm ringed PTFE bypass was anastomosed from the distal left renal vein to the Inferior Vena Cava. Despite these challenges, the patient experienced a successful outcome with complete symptom resolution of this complicated pathology.

Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer.

BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC. PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests. RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+. CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2.

The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 39.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared with non-MPUC were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor-suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

Genomic Profiles and Clinical Outcomes of Penile Squamous Cell Carcinoma With Elevated Tumor Mutational Burden.

Importance: Tumor mutational burden (TMB) is a putative biomarker of efficacy for immune checkpoint inhibitor (ICI) therapies of solid tumors, but not specifically for penile squamous cell carcinoma (PSCC). Objective: To characterize biomarker features and ICI therapy outcomes associated with high TMB in PSCC in the routine clinical practice setting. Design, Setting, and Participants: In this cohort study, 397 PSCC cases were analyzed to identify genomic alterations in more than 300 cancer-associated genes and genomic signatures, including TMB, using a hybrid capture-based comprehensive genomic profiling assay. Tumor mutational burden was categorized as low (<10 mutations per megabase [mut/Mb]), high (10-19 mut/Mb), or very high (≥20 mut/Mb). Germline status of genetic alterations was predicted using a validated somatic-germline computational method. Clinical outcomes of patients with metastatic PSCC receiving first-line ICI were abstracted using the deidentified nationwide Clinico-Genomic Database (CGDB) from January 1, 2011, through December 31, 2022. Exposure: Comprehensive genomic profiling was performed using FoundationOne and FoundationOne CDx assays from Foundation Medicine Inc. Main outcomes and measures: The spectrum of genetic alterations by TMB level in PSCC, the percentage of germline genetic alterations, and the outcome (overall survival with routine clinical treatment) by TMB of chemotherapy-naive patients with PSCC who received ICI treatment up front were assessed in this descriptive study. Results: Among 397 patients (median [IQR] age, 65 [54-73] years; 266 [67.0%] of European, 83 [20.9%] of admixed American, and 34 [8.5%] of African or other genomic ancestry), the median (IQR) age (eg, 65 [53-73] years for low TMB vs 68 [61-78] years for TMB ≥10 mut/Mb) and genomic ancestry distribution (eg, European 228 of 339 [67.3%] for low TMB vs 38 of 58 [65.5%] for TMB ≥10 mut/Mb) were similar between TMB subgroups. There were 339 PSCC cases (85.4%) with low TMB, 40 cases (10.1%) with high TMB, and 18 cases (4.5%) with very high TMB. Comparisons of TMB of 10 mut/Mb or higher vs low TMB showed an enrichment of genetic alterations in PIK3CA (48.3% vs 18.3%; P < .001) and KMT2D (29.3% vs 7.7%; P < .001) and less frequent genetic alterations in CDKN2A (25.9% vs 45.7%; P = .05). Most genetic alterations did not co-occur. Human papillomavirus identification was more frequent as TMB increased: 28.3% for low TMB, 50.0% for high, and 72.2% for very high. In total, 95 of 1377 genetic alterations (6.9%) were germline. Of 10 patients identified from the CGDB receiving frontline ICIs, median (IQR) follow-up was 9.9 months. Four patients had overall survival with clinical treatment of more than 12 months, including 2 of 3 patients with TMB of 10 mut/Mb or higher. Conclusions and Relevance: In this cohort study of advanced metastatic PSCC based on TMB levels, significant differences were observed for biomarkers in nearly 15% of patients with a TMB of 10 mut/Mb or higher. Germline testing and ICI-based therapy should be integrated into the management of selected PSCC cases.

Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer.

Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic domain and causes apoptosis in renal cancer. We further demonstrated that PP5 interacts with FADD, RIPK1, and caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic apoptosis. Our data suggests that PP5 promotes renal cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacologic inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal cancer.

The Current Role of Lymph Node Dissection in Nonmetastatic Localized Renal Cell Carcinoma.

PURPOSE: To explore the current role of lymph node dissection (LND) in the management of nonmetastatic localized renal cell carcinoma (RCC). BACKGROUND: There is currently no proven benefit of LND in the setting of RCC, and its role remains controversial because of conflicting evidence. Patients who may benefit from LND are those at greatest risk of nodal disease, but the tools used to predict nodal involvement are limited due to unpredictable retroperitoneal lymphatics. The indications, templates, and extent of LND are also not standardized, adding to the ambiguity of current guidelines surrounding its use. EVIDENCE ACQUISITION: A PubMed search of the literature from January 2017 to December 2022 was conducted using the search terms "renal cell carcinoma" or "renal cancer" in combination with "lymph node dissection" or "lymphadenectomy". Case studies and editorials were excluded, whereas studies investigating the therapeutic effect of LND were classified as either demonstrating a benefit or no benefit. References of the studies and review articles were also searched for notable studies and findings that were outside the five-year literature search. The studies in this review were restricted to the English language. RESULTS: Only a number of studies in recent years have found an association between the extent of LND and increased survival. Most studies do not indicate an associated benefit, and some even suggest a negative effect on survival. Most of these studies are retrospective. CONCLUSION: The therapeutic value of LND in RCC is still unclear, and although prospective data are needed, its declining rates and emerging new therapies make this unlikely. A better understanding of renal lymphatics and improved detection of nodal disease may help determine the role of LND in nonmetastatic localized RCC.

Adjuvant therapy for renal cell carcinoma in 2023: hopes and disappointments.

PURPOSE: It is known that 30% of clear cell renal cell carcinomas (ccRCC) will develop progressive disease after surgical treatment. These patients with high-risk ccRCC require adjuvant therapy after nephrectomy or resection of metastases. The article presents an overview of the results of recent studies in adjuvant therapy. METHODS: We analyzed the results of randomized trials of targeted therapy and checkpoint inhibitors in high-risk ccRCC patients. RESULTS: Targeted therapy did not significantly reduce this risk or/and did not affect overall survival. Three randomized studies investigating nivolumab, ipilimumab, and atezolizumab in the adjuvant setting also failed without improving disease-free survival. Pembrolizumab had a significant impact on the disease-free survival in the entire population, with the greatest effect in patients after metastasectomy, but mature overall survival data are not yet available. CONCLUSIONS: In conclusion, it must be noted that, at present, it has not been possible to achieve magnificent success in adjuvant therapy of RCC in patients at high risk of relapse after surgical treatment. There remains hope for adjuvant pembrolizumab, which has been used for high-risk population including patients with removed metastases who may benefit more from therapy.

Chylous Ascites After Robot-Assisted Laparoscopic Donor Nephrectomy: Is Early Surgical Intervention Necessary?

OBJECTIVES: Chylous ascites is a rare complication that may occur after living donor nephrectomy. The continuous loss of lymphatics, which carries a high risk of morbidity, may ensue in possible immunodeficiency and protein-calorie malnutrition. Here, we presented patients who developed chylous ascites after robotassisted living donor nephrectomy and reviewed the current literature of therapeutic strategies for chylous ascites. MATERIALS AND METHODS: We reviewed the medical records of 424 laparoscopic living donor nephrectomies performed at a single transplant center; among these, we studied the records of 3 patients who developed chylous ascites following robot-assisted living donor nephrectomy. RESULTS: Among 438 living donor nephrectomies, 359 (81.9%) were laparoscopic and 77 (18.1%) were by robotic assistance. In the 3 cases highlighted in our study, patient 1 did not respond to conservative therapy, which consisted of diet optimization, total parenteral nutrition, and octreotide (somatostatin). Patient 1 subsequently underwent robotic-assisted laparoscopy with suture ligation and clipping of leaking lymphatic vessels, allowing the chylous ascites to subside. Patient 2 similarly did not respond to conservative treatment and developed ascites. Despite initial improvement after wound interrogation and drainage, patient 2 had continued symptoms, resulting in diagnostic laparoscopy and repair of leaky channels leading to the cisterna chyli. Patient 3 developed chylous ascites 4 weeks postoperatively and received ultrasonographic-guided paracentesis by interventional radiology, with results showing an aspirate consistent with chyle. The patient's diet was optimized, allowing for initial improvement and eventual return to normal diet. CONCLUSIONS: Our case series and literature review demonstrate the importance of early surgical intervention after failed conservative management for resolution of chylous ascites in patients after robotassisted donor laparoscopic nephrectomy.

Artificial Intelligence-Based PTEN Loss Assessment as an Early Predictor of Prostate Cancer Metastasis After Surgery: A Multicenter Retrospective Study.

Phosphatase and tensin homolog (PTEN) loss is associated with adverse outcomes in prostate cancer and can be measured via immunohistochemistry. The purpose of the study was to establish the clinical application of an in-house developed artificial intelligence (AI) image analysis workflow for automated detection of PTEN loss on digital images for identifying patients at risk of early recurrence and metastasis. Postsurgical tissue microarray sections from the Canary Foundation (n = 1264) stained with anti-PTEN antibody were evaluated independently by pathologist conventional visual scoring (cPTEN) and an automated AI-based image analysis pipeline (AI-PTEN). The relationship of PTEN evaluation methods with cancer recurrence and metastasis was analyzed using multivariable Cox proportional hazard and decision curve models. Both cPTEN scoring by the pathologist and quantification of PTEN loss by AI (high-risk AI-qPTEN) were significantly associated with shorter metastasis-free survival (MFS) in univariable analysis (cPTEN hazard ratio [HR], 1.54; CI, 1.07-2.21; P = .019; AI-qPTEN HR, 2.55; CI, 1.83-3.56; P < .001). In multivariable analyses, AI-qPTEN showed a statistically significant association with shorter MFS (HR, 2.17; CI, 1.49-3.17; P < .001) and recurrence-free survival (HR, 1.36; CI, 1.06-1.75; P = .016) when adjusting for relevant postsurgical clinical nomogram (Cancer of the Prostate Risk Assessment [CAPRA] postsurgical score [CAPRA-S]), whereas cPTEN does not show a statistically significant association (HR, 1.33; CI, 0.89-2; P = .2 and HR, 1.26; CI, 0.99-1.62; P = .063, respectively) when adjusting for CAPRA-S risk stratification. More importantly, AI-qPTEN was associated with shorter MFS in patients with favorable pathological stage and negative surgical margins (HR, 2.72; CI, 1.46-5.06; P = .002). Workflow also demonstrated enhanced clinical utility in decision curve analysis, more accurately identifying men who might benefit from adjuvant therapy postsurgery. This study demonstrates the clinical value of an affordable and fully automated AI-powered PTEN assessment for evaluating the risk of developing metastasis or disease recurrence after radical prostatectomy. Adding the AI-qPTEN assessment workflow to clinical variables may affect postoperative surveillance or management options, particularly in low-risk patients.

Does a prior cancer diagnosis impact PSA testing? Results from the National Health Interview Survey.

INTRODUCTION: Prostate-specific antigen (PSA) testing remains a controversial issue. However, most urological guidelines recommend PSA testing in men aged 55-69 through a shared decision-making process with the patient. The impact of prior cancer diagnosis on PSA testing is not well-known. To compare PSA testing in men aged 55-69 years with and without a history of cancer (excluding prostate cancer patients). MATERIALS AND METHODS: Utilizing the National Health Interview Survey (NHIS), a retrospective cross-sectional study during the year 2018 was carried out. Multivariable logistic regression analysis was implemented to demonstrate potential associations with PSA testing and assess the association of cancer history. RESULTS: A total of 2,892 men aged 55-69 years from the NHIS survey who met the inclusion criteria were analyzed. A total of 308 (10.7%) men had a history of cancer (non-prostate). Men with a cancer history had a higher number of PSA tests and more recent testing than men with no previous cancer history. On multivariable analysis, men who were previously diagnosed with cancer had a higher likelihood of undergoing PSA testing compared to men with no history of cancer (OR: 1.87, 95% CI 1.39-2.52, p < 0.0001). CONCLUSIONS: Our data suggest that men aged 55-69 with a history of cancer are more likely to undergo PSA testing than men with no cancer history.

Urothelial Bladder Cancer: Genomic Alterations in Fibroblast Growth Factor Receptor.

BACKGROUND AND OBJECTIVE: Genomic alterations in fibroblast growth factor receptor (FGFR) genes have been linked to a reduced response to immune checkpoint inhibitors. Some of the immune microenvironment of urothelial bladder cancer (UBC) could be distorted because of the inhibition of interferon signaling pathways. We present a landscape of FGFR genomic alterations in distorted UBC to evaluate the immunogenomic mechanisms of resistance and response. METHODS: There were 4035 UBCs that underwent hybrid, capture-based comprehensive genomic profiling. Tumor mutational burden was determined in up to 1.1 Mbp of sequenced DNA and microsatellite instability was determined in 114 loci. Programmed death ligand expression in tumor cells was assessed by immunohistochemistry (Dako 22C3). RESULTS: The FGFR tyrosine kinases were altered in 894 (22%) UBCs. The highest frequency of alterations was in FGFR genomic alterations with FGFR3 at 17.4% followed by FGFR1 at 3.7% and FGFR2 at 1.1%. No FGFR4 genomic alterations were identified. The age and sex distribution were similar in all groups. Urothelial bladder cancers that featured FGFR3 genomic alterations were associated with lower driver genomic alterations/tumors. 14.7% of the FGFR3 genomic alterations were FGFR3 fusions. Other findings included a significantly higher frequency of ERBB2 amplification in FGFR1/2-altered UBCs compared with FGFR3-altered UBCs. Urothelial bladder cancers with FGFR3 genomic alterations also had the highest frequency of the activating mTOR pathway. FGFR3-altered UBCs also featured significantly higher frequencies of biomarkers associated with a lack of response to immune checkpoint inhibitors including a lower tumor mutational burden, lower programmed death-ligand 1 expression, and higher frequencies of genomic alterations in MDM2. Also linked to IO drug resistance, CDKN2A/B loss and MTAP loss were observed at a higher frequency in FGFR3-driven UBC. CONCLUSIONS: An increased frequency of genomic alterations is observed in UBC FGFR. These have been linked to immune checkpoint inhibitor resistance. Clinical trials are needed to evaluate UBC FGFR-based biomarkers prognostic of an immune checkpoint inhibitor response. Only then can we successfully incorporate novel therapeutic strategies into the evolving landscape of UBC treatment.

Comparative Genomic Landscape of Urothelial Carcinoma of the Bladder Among Patients of East and South Asian Genomic Ancestry.

BACKGROUND: Despite the low rate of urothelial carcinoma of the bladder (UCB) in patients of South Asian (SAS) and East Asian (EAS) descent, they make up a significant portion of the cases worldwide. Nevertheless, these patients are largely under-represented in clinical trials. We queried whether UCB arising in patients with SAS and EAS ancestry would have unique genomic features compared to the global cohort. METHODS: Formalin-fixed, paraffin-embedded tissue was obtained for 8728 patients with advanced UCB. DNA was extracted and comprehensive genomic profiling was performed. Ancestry was classified using a proprietary calculation algorithm. Genomic alterations (GAs) were determined using a 324-gene hybrid-capture-based method which also calculates tumor mutational burden (TMB) and determines microsatellite status (MSI). RESULTS: Of the cohort, 7447 (85.3%) were EUR, 541 (6.2%) were AFR, 461 (5.3%) were of AMR, 74 (0.85%) were SAS, and 205 (2.3%) were EAS. When compared with EUR, TERT GAs were less frequent in SAS (58.1% vs. 73.6%; P = .06). When compared with non-SAS, SAS had less frequent GAs in FGFR3 (9.5% vs. 18.5%, P = .25). TERT promoter mutations were significantly less frequent in EAS compared to non-EAS (54.1% vs. 72.9%; P < .001). When compared with the non-EAS, PIK3CA alterations were significantly less common in EAS (12.7% vs. 22.1%, P = .005). The mean TMB was significantly lower in EAS vs. non-EAS (8.53 vs. 10.02; P = .05). CONCLUSIONS: The results from this comprehensive genomic analysis of UCB provide important insight into the possible differences in the genomic landscape in a population level. These hypothesis-generating findings require external validation and should support the inclusion of more diverse patient populations in clinical trials.

Disparities Associated with Shared Decision-making in Prostate Cancer Screening.

BACKGROUND: Prostate cancer screening guidelines recommend shared decision-making (SDM) regarding prostate-specific antigen (PSA) testing. However, it is unclear who undergoes SDM and whether any disparities exist. OBJECTIVE: To examine sociodemographic differences in participation of SDM and its association with PSA testing in prostate cancer screening. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cross-sectional study was conducted among men aged 45-75 yr undergoing PSA screening, using the 2018 National Health Interview Survey database. The evaluated sociodemographic features included age, race, marital status, sexual orientation, smoking status, working status, financial difficulty, US geographic regions, and cancer history. Questions regarding self-reported PSA testing and whether respondents discussed its advantages and disadvantages with their healthcare provider were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Our primary outcome was to evaluate the possible associations between various sociodemographic factors and undergoing PSA screening and SDM. We used multivariable logistic regression analyses to detect potential associations. RESULTS AND LIMITATIONS: A total of 59596 men were identified, of whom 5605 answered the question regarding PSA testing, with 2288 (40.6%) undergoing PSA testing. Of these men, 39.5% (n = 2226) discussed the advantages and 25.6% (n = 1434) discussed the disadvantages of PSA testing. On a multivariable analysis, older (odds ratio [OR] 1.092; 95% confidence interval [CI] 1.081-1.103, p < 0.001) and married (OR 1.488; 95% CI 1.287-1.720, p < 0.001) men were more likely to undergo PSA testing. Although Black men were more likely to discuss PSA advantages (OR 1.421; 95% CI 1.150-1.756, p = 0.001) and disadvantages (OR 1.554; 95% CI 1.240-1.947, p < 0.001) than White men, this did not correlate with higher rates of PSA screening (OR 1.086; 95% CI 0.865-1.364, p = 0.477). The lack of important clinical data remains a limitation. CONCLUSIONS: Overall, SDM rates were low. Older and married men had an increased likelihood of SDM and PSA testing. Despite higher rates of SDM, Black men had similar rates of PSA testing to White men. PATIENT SUMMARY: We evaluated sociodemographic differences in shared decision-making (SDM) in prostate cancer screening using a large national database. We found that SDM had varying results in different sociodemographic groups.

Comprehensive Genomic Profiling of NF2-Mutated Kidney Tumors Reveals Potential Targets for Therapy.

Genomic alterations (GA) in NF2 tumor-suppressor gene have been associated with aggressive behavior in kidney tumors. We used comprehensive genomic profiling (CGP) to evaluate the frequencies of NF2 GA in histologic subtypes of kidney tumors and co-occurring GA in other genes and biomarkers. Advanced kidney tumors included 1875 clear cell (ccRCC), 405 papillary (pRCC), 108 chromophobe (chRCC), 171 sarcomatoid (sRCC), 61 collecting duct (cdRCC), 49 medullary (mRCC), 134 unclassified (uRCC), 906 urothelial carcinoma of renal pelvis (UC), and 147 Wilms tumors underwent hybrid-capture based CGP to evaluate all classes of GA. 192 (4.9%) of kidney tumors featured NF2 GA which were predominantly structural variant mutations (89%), followed by copy number alterations (9%). Gender and age were similar between NF2-mutant (NF2mut) and NF2-wild type (NF2wt) cohorts with male preponderance. NF2 GA frequency was highest in cdRCC (30%), sRCC (21%), uRCC (15%), and pRCC (12%) while lowest in ccRCC (3%), UC (3%) Wilms tumor (1%), and chRCC (0%). NF2 mutational status was associated with loss of Ch 22 (P < .001). NF2mut RCC harbored co-occurring GA including CDKN2A, CDKN2B, SETD2, and BAP1. VHL, PBRM1, PTEN, and FGFR3 GA were significantly more frequent in NF2wt than in NF2mut tumors. MTOR pathway GAs were uncommon in NF2mut tumors. No NF2 mutated RCC featured MSI-high or high TMB. sRCC was associated with high PD-L1 expression. PD-L1 SP142 tumoral (P = .04) and immune cells (P = .013) were more frequent in NF2mut as compared to NF2wt group. Among histologic subtypes of RCC, cdRCC, sRCC, pRCC, and uRCC are enriched in NF2 GA. Co-occurrent GA in CDKN2A/B, SETD2, and BAP1 may represent potential therapeutic targets. Higher level of PD-L1 expression in NF2mut cohort suggests that these tumors might be sensitive to immune checkpoint inhibitor therapies.

Novel synthetic lethality drug target in urothelial bladder cancer based on MTAP genomic loss.

BACKGROUND: When urothelial carcinoma of the bladder (UCB) presents or progresses to chemo-refractory metastatic disease, the search for new therapeutic targets is paramount. Targeting protein arginine methyltransferase 5 accumulation in tumors with methylthioadenosine phosphorylase (MTAP) genomic loss has been proposed as a new anti-tumor strategy. We evaluated the incidence of patients with MTAP loss and correlate to treatment-guiding targets and biomarkers. METHODS: Two thousand six hundred eighty-three cases of advanced UCB underwent hybrid-capture based comprehensive genomic profiling using the FDA-approved F1CDx assay to evaluate all classes of genomic alterations (GA) among 324 genes. Tumor mutational burden was determined on at least 0.8 Mbp of sequenced DNA and microsatellite instability was determined on at least 95 loci. RESULTS: 650 (24%) of UCB featured MTAP loss mutations (MTAP-). The gene and age distributions were similar in MTAP intact (MTAP+) and MTAP- UCB. MTAP- UCB contained higher GA/tumor frequency than MTAP+ UCB likely reflecting the frequent co-deletions of cyclin-dependent kinase inhibitor 2A/B. Of potential therapeutic targets, fibroblast growth factor receptor 3, and phosphatase and tensin homolog GA were more frequent in MTAP- UCB. In contrast, biomarkers of immunotherapy response, including higher frequencies of high tumor mutational burden and high programmed death-ligand 1 IHC staining, were observed in the MTAP+ UCB. CONCLUSIONS: When compared with MTAP+ UCB, MTAP- UCB differs in genomic signatures including an increase in potentially targetable alterations but a lower frequency of immunotherapy drug biomarkers. Thus, the genomic landscape in MTAP- UCB may play a role in the design of clinical trials incorporating combination treatment strategies when targeting protein arginine methyltransferase 5 in MTAP- tumors.

In Vivo Models for Prostate Cancer Research.

In 2022, prostate cancer (PCa) is estimated to be the most commonly diagnosed cancer in men in the United States-almost 270,000 American men are estimated to be diagnosed with PCa in 2022. This review compares and contrasts in vivo models of PCa with regards to the altered genes, signaling pathways, and stages of tumor progression associated with each model. The main type of model included in this review are genetically engineered mouse models, which include conditional and constitutive knockout model. 2D cell lines, 3D organoids and spheroids, xenografts and allografts, and patient derived models are also included. The major applications, advantages and disadvantages, and ease of use and cost are unique to each type of model, but they all make it easier to translate the tumor progression that is seen in the mouse prostate to the human prostate. Although both human and mouse prostates are androgen-dependent, the fact that the native, genetically unaltered prostate in mice cannot give rise to carcinoma is an especially critical component of PCa models. Thanks to the similarities between the mouse and human genome, our knowledge of PCa has been expanded, and will continue to do so, through models of PCa.

Understanding the Impact of Belzutifan on Treatment Strategies for Patients with VHL.

Belzutifan was recently approved for the management of Von Hippel-Lindau disease (VHL). Given the morbidity of recurrent treatment, systemic therapy to reduce or eliminate the need for surgery has been long-awaited. Herein, we sought to gain insight about future utilization by surveying VHL kidney cancer experts in the United States. A survey developed by members of the VHL Alliance (VHLA) Clinical Advisory Council was distributed to kidney cancer providers at VHLA and National Comprehensive Cancer Network (NCCN) centers. Surveys were administered on a secure web-based platform. A total of 60 respondents from 29 institutions participated. Urologists (50%) and medical oncologists (43%) represented the majority of participants. The majority (98%) of respondents anticipated that belzutifan's approval would significantly change the current treatment landscape. Most reported that therapy should be continuous (76%). There was a difference in willingness to prescribe belzutifan by specialty (38% of urologists vs 91% of medical oncologists (P = 0.02)). In individuals with renal tumors <3 cm, 36% would still recommend surveillance, while 36% would initiate belzutifan to prevent growth. In those with multifocal renal lesions and growth of a solitary tumor on belzutifan, 50% would proceed with only treatment of that site. In conclusion, VHL kidney cancer specialists anticipate a paradigm shift with the approval of belzutifan. Provider roles may change with movement away from surgical management. Opinions on treatment indications, such as when to initiate therapy and how to best salvage, vary widely and therefore collaborative efforts among experts may assist in the development of new clinical guidelines.

The association of sexual orientation with prostate, breast, and cervical cancer screening and diagnosis.

PURPOSE: Data on heterogeneity in cancer screening and diagnosis rates among lesbians/gays and bisexuals (LGBs) is lacking. Recent studies showed that LGBs have decreased healthcare utilization compared to heterosexual counterparts. Few studies have examined how sexual orientation impacts cancer screening and prevalence. We, therefore, investigated the association between sexual orientation and prevalent sex-specific cancer including prostate (PCa), breast (BC), and cervical (CC) cancer. METHODS: This was a cross-sectional survey-based US study, including men and women aged 18 + from the Health Information National Trends Survey (HINTS) database between 2017 and 2019. The primary endpoint was individual-reported prostate, breast, and cervical cancer screening and prevalence rates among heterosexual and LGB men and women. Multivariable logistic regression analyses assessed association of various covariates with undergoing screening and diagnosis of these cancers. RESULTS: Overall, 4,441 and 6,333 heterosexual men and women, respectively, were compared to 225 and 213 LGB men and women, respectively. LGBs were younger and less likely to be screened for PCa, BC, and CC than heterosexuals. A higher proportion of heterosexual women than lesbian and bisexual women were screened for CC with pap smears (95.36% vs. 90.48% and 86.11%, p ≤ 0.001) and BC with mammograms (80.74% vs. 63.81% and 45.37%, p ≤ 0.001). Similarly, a higher proportion of heterosexual men than gay and bisexual men were screened for PCa with PSA blood tests (41.27% vs. 30.53% and 27.58%, p ≤ 0.001). CONCLUSION: There were more heterosexuals than LGBs screened for CC, BC, and PCa. However, no association between sexual orientation and cancer diagnosis was found. Healthcare professionals should be encouraged to improve cancer screening among LGBs.

Financial Toxicity and Its Association With Prostate and Colon Cancer Screening.

BACKGROUND: The term "financial toxicity" or "hardship" is a patient-reported outcome that results from the material costs of cancer care, the psychological impacts of these costs, and the coping strategies that patients use to deal with the strain that includes delaying or forgoing care. However, little is known about the impact of financial toxicity on cancer screening. We examined the effects of financial toxicity on the use of screening tests for prostate and colon cancer. We hypothesized that greater financial hardship would show an association with decreased prevalence of cancer screening. METHODS: This cross-sectional survey-based US study included men and women aged ≥50 years from the National Health Interview Survey database from January through December 2018. A financial hardship score (FHS) between 0 and 10 was formulated by summarizing the responses from 10 financial toxicity dichotomic questions (yes or no), with a higher score associated with greater financial hardship. Primary outcomes were self-reported occurrence of prostate-specific antigen (PSA) blood testing and colonoscopy for prostate and colon cancer screening, respectively. RESULTS: Overall, 13,439 individual responses were collected. A total of 9,277 (69.03%) people had undergone colonoscopies, and 3,455 (70.94%) men had a PSA test. White, married, working men were more likely to undergo PSA testing and colonoscopy. Individuals who had not had a PSA test or colonoscopy had higher mean FHSs than those who underwent these tests (0.70 and 0.79 vs 0.47 and 0.61, respectively; P≤.001 for both). Multivariable logistic regression models demonstrated that a higher FHS was associated with a decreased odds ratio for having a PSA test (0.916; 95% CI, 0.867-0.967; P=.002) and colonoscopy (0.969; 95% CI, 0.941-0.998; P=.039). CONCLUSIONS: Greater financial hardship is suggested to be associated with a decreased probability of having prostate and colon cancer screening. Healthcare professionals should be aware that financial toxicity can impact not only cancer treatment but also cancer screening.