From Detection to Cure - Emerging Roles for Urinary Tumor DNA (utDNA) in Bladder Cancer.

PURPOSE OF REVIEW: This review sought to define the emerging roles of urinary tumor DNA (utDNA) for diagnosis, monitoring, and treatment of bladder cancer. Building from early landmark studies the focus is on recent studies, highlighting how utDNA could aid personalized care. RECENT FINDINGS: Recent research underscores the potential for utDNA to be the premiere biomarker in bladder cancer due to the constant interface between urine and tumor. Many studies find utDNA to be more informative than other biomarkers in bladder cancer, especially in early stages of disease. Points of emphasis include superior sensitivity over traditional urine cytology, broad genomic and epigenetic insights, and the potential for non-invasive, real-time analysis of tumor biology. utDNA shows promise for improving all phases of bladder cancer care, paving the way for personalized treatment strategies. Building from current research, future comprehensive clinical trials will validate utDNA's clinical utility, potentially revolutionizing bladder cancer management.

The Elusive Horizon: Biomarkers in Urothelial Carcinoma.

Urinary tests for circulating tumor DNA have potential for accurate discrimination of bladder cancer from other common inflammatory processes. Efforts are still needed to determine whether these tests can differentiate between cancer and field cancerization and to demonstrate clinical benefit in prospective trials.

Distance to Treatment With Radical Cystectomy in a Rural State: Long Car Rides, Equivalent Outcomes.

INTRODUCTION: Radical cystectomy is a complex surgery with better outcomes reported when performed at high-volume centers. This may lead to patients traveling farther for care. We examined the impact of travel distance on clinical outcomes. METHODS: A total of 220 patients undergoing radical cystectomy from 2015-2021 were retrospectively reviewed. Distance traveled to the treatment center by patient zip codes was classified as <12.5 miles, 12.5-49.9 miles, and ≥50 miles. Multivariable logistic regression was used to assess complications, readmissions, 90-day mortality, and length of stay by distance traveled. Time to treatment based on distance traveled was compared. RESULTS: A total of 220 patients underwent radical cystectomy with complete 90-day follow-up. Of the patients 38.6% (85/220) were readmitted; 62.5% (53/85) presented to the treatment center or were transferred. All patients readmitted to an outside hospital traveled ≥12.5 miles (P < .001). Patients with high-grade complications were likely to be transferred to the treatment center with only 23.7% (9/38) definitively managed by outside hospital. Patients traveling >12.5 miles with low-grade complications were more likely to be managed at an outside hospital (57.5%, P = .01). There was no difference in time to initiation of neoadjuvant chemotherapy (P = .99) or time to radical cystectomy following neoadjuvant chemotherapy (P = .23) by distance traveled. For 49 muscle-invasive bladder cancer patients proceeding directly to surgery without neoadjuvant chemotherapy, time from diagnosis to radical cystectomy was increased if traveling >12.5 miles (P = .04). CONCLUSIONS: Increased travel distance did not impact early postoperative outcomes. Distance traveled may impact access to care, such as time to surgery or location of readmission to the treatment center postoperatively.

Prostate Specific Antigen Testing Behaviors for Prostate Cancer Screening Among U.S. Immigrants: A Cross-sectional Analysis Using the National Health Interview Survey.

PURPOSE: Immigrants constitute 14% of the U.S. population, and this group is especially vulnerable to poor health care access. Prior research demonstrates U.S. immigrants have low rates of guideline-concordant breast and colorectal screening, but prostate cancer screening has not previously been evaluated. We sought to characterize screening behaviors among U.S. immigrants and to consider possible mechanisms to enhance PSA-based screening for this population. MATERIALS AND METHODS: Data were obtained from the 2010, 2013, 2015, and 2018 National Health Interview Survey reports, which were the recent survey years that included questions about PSA testing. Complex samples logistic regression was performed to assess the relationship between immigrant-specific characteristics including region of birth, citizenship status, length of residence within the U.S., English language proficiency, and history of PSA testing. RESULTS: There were 22,997 survey respondents; 3,257 were foreign-born and 19,740 were U.S.-born. Rates of PSA testing were much lower among the foreign-born population compared to the U.S.-born population (43% vs 60%). Citizenship status, length of residence in the U.S. for more than 15 years, and English proficiency were directly linked to increased rates of PSA testing. There was significant variability in PSA testing among immigrant subgroups and Asian immigrants had the lowest rate of PSA testing. Annual physician visits and English language proficiency were associated with increased PSA testing among the U.S. immigrant population. CONCLUSIONS: Immigrants have relatively low rates of PSA testing. Improving health care utilization and language services may help to narrow the gap in guideline-concordant prostate cancer screening between immigrants and nonimmigrants.

PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry.

BACKGROUND: Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. Men of African ancestry are at an increased risk of PrCa; however, current polygenic risk score (PRS) models are based on European ancestry groups and may not be broadly applicable. The objective of this study was to construct an African ancestry-specific PrCa PRS (PRState) and evaluate its performance. METHODS: African ancestry group of 4,533 individuals in ELLIPSE consortium was used for discovery of African ancestry-specific PrCa SNPs. PRState was constructed as weighted sum of genotypes and effect sizes from genome-wide association study (GWAS) of PrCa in African ancestry group. Performance was evaluated using ROC-AUC analysis. RESULTS: We identified African ancestry-specific PrCa risk loci on chromosomes 3, 8, and 11 and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60-0.63] and 0.65 [0.64-0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program (MVP), demonstrating improved prediction of PrCa and metastatic PrCa in individuals of African ancestry. CONCLUSIONS: African ancestry-specific PRState improves PrCa prediction in African ancestry groups in ELLIPSE consortium and MVP. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRSs and identifies African ancestry-specific variants for use in future studies.

Ureteroscopy with thulium fiber laser lithotripsy results in shorter operating times and large cost savings.

PURPOSE: Prolonged ureteroscopy (URS) is associated with complications including ureteral perforation, stricture, and urosepsis. As laser lithotripsy is one of the most common urologic procedures, small cost savings per case can have a large financial impact. This retrospective study was designed to determine if Thulium fiber laser (TFL) lithotripsy decreases operative time and costs compared to standard Holmium:YAG (Ho:YAG) lithotripsy without pulse modulation. METHODS: A retrospective review of URS with laser lithotripsy was conducted for 152 cases performed from August 2020 to January 2021. Variables including cumulative stone size, location, chemical composition, prior ureteral stenting, and ureteral access sheath use were recorded for each case. A cost benefit analysis was performed to show projected cost savings due to potentially decreased operative times. RESULTS: Compared to Ho:YAG, use of TFL resulted in an average decrease of 12.9 min per case (p = .021, 95% CI [2.03-23.85]). In subgroup analysis of cases with cumulative stone diameter less than 15 mm, the difference was 14.0 min (p = .007, CI [3.95-23.95]). For cases less than 10 mm, the mean difference was 17.3 min in favor of TFL (p = .002, 95% CI [6.89-27.62]). This ~ 13 min reduction in operative time resulted in saving $440/case in direct operating room costs giving our institution a range of $294,000 to $381,900 savings per year. CONCLUSIONS: TFL has a significantly shorter operative time and decreased cost when compared to the standard Ho:YAG for equivalent kidney stone and patient characteristics. Longer term follow up is needed to see if recurrence rates are affected.

National Recommendations against Prostate Specific Antigen Screening versus Statewide Medicaid Expansion Initiatives: A Battle of the Titans.

PURPOSE: Medicaid expansion under the Patient Protection and Affordable Care Act occurred almost concurrently with 2012 U.S. Preventive Services Task Force recommendations against prostate specific antigen screening. Here the relative influence on prostate specific antigen screening rates by 2 concurrent and opposing system-level policy initiatives is investigated: improved access to care and change in clinical practice guidelines. MATERIALS AND METHODS: Behavioral Risk Factor Surveillance System data from years 2012 to 2018 were analyzed for trends in self-reported prostate specific antigen screening and insurance coverage. Subanalyses included state Medicaid expansion status and respondent federal poverty level. Multivariable logistic regression was performed to evaluate factors associated with prostate specific antigen screening. RESULTS: From 2012 to 2018 prostate specific antigen screening predominantly declined with a notable exception of an increase of 7.3% for men at <138% federal poverty level between 2011 and 2013 in early expansion states. Initial increases did not continue, and screening trends mirrored those of nonexpansion states by 2018. Notably, 2014 planned expansions states did not follow this trend with minimal change between 2015 and 2017 compared to declines in early expansion states and nonexpansion states (-0.4% vs -6.7% and -8.6%, respectively). CONCLUSIONS: Medicaid expansion was associated with increased rates of insured men at <138% federal poverty level from 2012 to 2018 in early expansion states. In this group, initial increases in prostate specific antigen screening were not durable and followed the trend of reduced screening seen across the United States. In planned expansions states the global drop in prostate specific antigen screening from 2016 to 2018 was offset in men at <138% federal poverty level by expanding access to care. Nonexpansion states showed a steady decline in prostate specific antigen screening rates. This suggests that policy such as U.S. Preventive Services Task Force recommendations against screening competes with and often outmatches access to care.

Receipt of Survivorship Care Plans and Self-Reported Health Status among Patients with Genitourinary Malignancy.

PURPOSE: Implementation of survivorship care plans has been emphasized as a key component to improving care for cancer survivors. Our objective was to determine the prevalence of survivorship care plan receipt for survivors of genitourinary malignancy including kidney, prostate and bladder cancer, and evaluate whether receipt was associated with a measurable health benefit. MATERIALS AND METHODS: Data from the Behavioral Risk Factor Surveillance System Cancer Survivorship modules in 2012, 2014, 2016 and 2017 were analyzed. The proportion of patients with bladder, kidney or prostate cancer receiving a survivorship care plan was calculated. Complex samples multivariable logistic regressions were performed to determine the association of survivorship care plan receipt with sociodemographic variables, and assess the relationship between survivorship care plan receipt and self-reported health status (general, physical and mental). RESULTS: Survivorship care plan distribution increased from 27.5% in 2012 to 39.5% in 2017. Patients with low income, less formal education and extremes of age were less likely to receive a survivorship care plan. Those receiving a survivorship care plan were less likely to report poor physical health (OR 0.70, CI 0.52-0.96, p=0.026). Subanalysis showed a similar result for physical health of patients with prostate cancer (OR 0.68, CI 0.48-0.96, p=0.030) and general health of patients with kidney cancer (OR 0.37, CI 0.19-0.75, p=0.006). CONCLUSIONS: Distribution of survivorship care plans to genitourinary malignancy survivors has increased since 2012 in response to advocacy from national organizations. Nonetheless, utilization is low and there is heterogeneity in the populations likely to receive a survivorship care plan. There is a measurable association between survivorship care plans and improved health status but further study is needed to determine causality.

Substrate-Differentiated Transition States of SET7/9-Catalyzed Lysine Methylation.

Transition state stabilization is essential for rate acceleration of enzymatic reactions. Despite extensive studies on various transition state structures of enzymes, an intriguing puzzle is whether an enzyme can accommodate multiple transition states (TSs) to catalyze a chemical reaction. It is experimentally challenging to study this proposition in terms of the choices of suitable enzymes and the feasibility to distinguish multiple TSs. As a paradigm with the protein lysine methyltransferase (PKMT) SET7/9 paired with its physiological substrates H3 and p53, their TSs were solved with experimental kinetic isotope effects as computational constraints. Remarkably, SET7/9 adopts two structurally distinct TSs, a nearly symmetric SN2 and an extremely early SN2, for H3K4 and p53K372 methylation, respectively. The two TSs are also different from those previously revealed for other PKMTs. The setting of multiple TSs is expected to be essential for SET7/9 and likely other PKMTs to act on broad substrates with high efficiency.

Kinetic isotope effects reveal early transition state of protein lysine methyltransferase SET8.

Protein lysine methyltransferases (PKMTs) catalyze the methylation of protein substrates, and their dysregulation has been linked to many diseases, including cancer. Accumulated evidence suggests that the reaction path of PKMT-catalyzed methylation consists of the formation of a cofactor(cosubstrate)-PKMT-substrate complex, lysine deprotonation through dynamic water channels, and a nucleophilic substitution (SN2) transition state for transmethylation. However, the molecular characters of the proposed process remain to be elucidated experimentally. Here we developed a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) method and corresponding mathematic matrix to determine precisely the ratios of isotopically methylated peptides. This approach may be generally applicable for examining the kinetic isotope effects (KIEs) of posttranslational modifying enzymes. Protein lysine methyltransferase SET8 is the sole PKMT to monomethylate histone 4 lysine 20 (H4K20) and its function has been implicated in normal cell cycle progression and cancer metastasis. We therefore implemented the MS-based method to measure KIEs and binding isotope effects (BIEs) of the cofactor S-adenosyl-l-methionine (SAM) for SET8-catalyzed H4K20 monomethylation. A primary intrinsic 13C KIE of 1.04, an inverse intrinsic α-secondary CD3 KIE of 0.90, and a small but statistically significant inverse CD3 BIE of 0.96, in combination with computational modeling, revealed that SET8-catalyzed methylation proceeds through an early, asymmetrical SN2 transition state with the C-N and C-S distances of 2.35-2.40 Å and 2.00-2.05 Å, respectively. This transition state is further supported by the KIEs, BIEs, and steady-state kinetics with the SAM analog Se-adenosyl-l-selenomethionine (SeAM) as a cofactor surrogate. The distinct transition states between protein methyltransferases present the opportunity to design selective transition-state analog inhibitors.