The Role of Baseline Prostate-specific Antigen Value Prior to Age 60 in Predicting Lethal Prostate Cancer: Analysis of a Contemporary North American Cohort.

BACKGROUND AND OBJECTIVE: Studies evaluating the role of baseline midlife prostate-specific antigen (PSA) as a predictor of development and progression of prostate cancer relied predominately on cohorts from the pre-PSA screening introduction era. The aim of our study was to examine the role of baseline PSA prior to the age of 60 yr as a predictor of developing lethal prostate cancer using a contemporary North American cohort. METHODS: Our cohort included all men aged 40-59 yr who received their first PSA through our health system between the years 1995 and 2019. Patients were divided into four categories based on age: 40-44, 45-49, 50-54, and 55-59 yr. Baseline PSA was the predictor of interest. Lethal disease was defined as death from prostate cancer or development of metastatic disease either at diagnosis or during follow-up. Cancer-specific mortality and overall mortality were obtained by linking our database to the Michigan Vital Records registry. Competing-risk regression was used to evaluate the association between PSA and lethal prostate cancer. KEY FINDINGS AND LIMITATIONS: A total of 129067 men met the inclusion criteria during the study period. The median follow-up for patients free from cancer was 7.4 yr. For men aged 40-44, 45-49, 50-54, and 55-59 yr, the estimated rates of lethal prostate cancer at 20 yr were 0.02%, 0.14%, 0.33%, and 0.51% in men with PSA

Impact of Prostate-Specific Antigen Screening Pattern on Prostate Cancer Mortality Among Non-Hispanic Black and Non-Hispanic White Men: A Large, Urban Health System Cohort Analysis.

PURPOSE: Randomized studies assessing the effect of PSA screening on mortality in non-Hispanic Black (NHB) men are lacking. We aimed to assess the association between PSA screening and survival among NHB men in comparison to non-Hispanic White (NHW) men in a racially diverse real-world North American population. MATERIALS AND METHODS: The study cohort included 6378 men who self-identified as NHB or NHW and were diagnosed with prostate cancer (PCa). Patients received PSA screening and subsequent PCa treatment and follow-up at our institution. Patients were sorted based on PSA testing intensity for the 5 years prior to diagnosis, as follows: never, some (<1 test/y), and annual testing (1 test/y). The primary outcome was risk of prostate cancer-specific mortality (PCSM). Competing risk cumulative incidence curves estimated PCSM rates. Competing risk regression analyses examined the impact of PSA testing on PCSM. An interaction term was incorporated to assess the impact of race on the outcome. RESULTS: Median (IQR) age and PSA at diagnosis were 67 (60-73) years and 5.8 (4.4-9.6) ng/mL, respectively, and 2929 (46%) men were NHB (Kruskal-Wallis P values < .001). Annual PSA testing was more frequent in NHW (5%) than in NHB (3%) men (χ2 P value < .001). On cumulative incidence analysis, in the never, some, and annual PSA testing groups, the 10-year PCSM was respectively 12.3%, 5.8%, and 4.6% in NHW and 18.5%, 7%, and 1.2% in NHB patients (Gray's test P values < .001). At CCR, PSA screening rate was associated with more favorable PCSM rates (HR: 0.47; 95% CI 0.33-0.68; P < .001). The interaction term for race did not show statistical significance (P = .2). CONCLUSIONS: PSA testing was associated with a reduced risk of PCSM in both NHB and NHW men diagnosed with PCa. Additionally, the positive impact of the screening rate seemed to be independent of race.

Patient-Derived Conditionally Reprogrammed Cells in Prostate Cancer Research.

Prostate cancer (PCa) remains a leading cause of mortality among American men, with metastatic and recurrent disease posing significant therapeutic challenges due to a limited comprehension of the underlying biological processes governing disease initiation, dormancy, and progression. The conventional use of PCa cell lines has proven inadequate in elucidating the intricate molecular mechanisms driving PCa carcinogenesis, hindering the development of effective treatments. To address this gap, patient-derived primary cell cultures have been developed and play a pivotal role in unraveling the pathophysiological intricacies unique to PCa in each individual, offering valuable insights for translational research. This review explores the applications of the conditional reprogramming (CR) cell culture approach, showcasing its capability to rapidly and effectively cultivate patient-derived normal and tumor cells. The CR strategy facilitates the acquisition of stem cell properties by primary cells, precisely recapitulating the human pathophysiology of PCa. This nuanced understanding enables the identification of novel therapeutics. Specifically, our discussion encompasses the utility of CR cells in elucidating PCa initiation and progression, unraveling the molecular pathogenesis of metastatic PCa, addressing health disparities, and advancing personalized medicine. Coupled with the tumor organoid approach and patient-derived xenografts (PDXs), CR cells present a promising avenue for comprehending cancer biology, exploring new treatment modalities, and advancing precision medicine in the context of PCa. These approaches have been used for two NCI initiatives (PDMR: patient-derived model repositories; HCMI: human cancer models initiatives).

Race has no impact on prostate cancer-specific mortality, when comparing patients with similar risk of other-cause mortality: An analysis of a population-based cohort.

BACKGROUND: Other-cause mortality (OCM) can serve as a surrogate for access-to-care. The authors sought to compare prostate cancer-specific mortality (PCSM) in Black versus White men matched based on their calculated OCM risk. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for Black and White men diagnosed with prostate cancer between 2004 to 2009, to collect long-term follow-up. A Cox regression was used to calculate the OCM risk using all available covariates. This calculated OCM risk was used to construct a 1:1 propensity score matched (PSM) cohort. Then, a competing-risks multivariable tested the impact of race on PCSM. RESULTS: A total of 94,363 patients were identified, with 19,398 Black men and 74,965 White men. The median (IQR) follow-up was 11.3 years (9.8-12.8). In the unmatched-cohort at 10-years, PCSM and OCM were 5.5% versus 3.5% and 13.8% versus 8.4% in non-Hispanic Black (NHB) versus non-Hispanic White (NHW) patients (all p < .0001). The standardized mean difference was <0.15 for all covariates, indicating a good match. In the matched cohort at 10-years, OCM was 13.6% and 10.0% in NHB versus NHW (p < .0001), whereas the PCSM was 5.3% versus 4.7% (p < .01). On competing-risks multivariable analysis on PCSM, Black men had a hazard ratio of 1.08 (95% confidence interval, 0.98-1.20) compared to White men with a p = .13. CONCLUSIONS: The results of this study showed similar PCSM in Black and White patients, when matched with their calculated OCM risk. This report is the first to indicate at a population-based level that race has no impact on PCSM. PLAIN LANGUAGE SUMMARY: Prostate cancer is a very common cancer among men and it is associated with health disparities that disproportionately impact Black men compared to White men. There is an on-going discussion of whether disparities between these two groups stem from genetic or environmental factors. This study sought to examine if matching based on overall health status, a proxy for the impact of social determinants of health, mitigated significant differences in outcomes. When matched using risk of death from any cause other than prostate cancer, Black and White men had no significant differences in prostate cancer death.

Testing the external validity of the POUT III trial (adjuvant platnium-based chemotherapy in upper tract urothelial carcinoma) in a North American cohort.

OBJECTIVE: The European POUT III randomized controlled trial provided level-one evidence that adjuvant platinum-based chemotherapy is the standard of care following nephroureterectomy (RNU) for locally invasive or node-positive upper tract urothelial carcinoma. We aim to assess this European randomized controlled trial's generalizability (external validity) to a North American cohort, using a nationwide database. MATERIALS AND METHODS: To compare trial patients with those seen in real-world practice, we simulated the trial inclusion criteria using data from the National Cancer Database (NCDB). We identified patients with histologically confirmed transitional cell carcinoma who underwent RNU. The available demographic characteristics of the NCDB cohort were compared with the POUT III trial cohort using Chi-squared test. RESULTS: The NCDB cohort (n = 3,380) had a significantly higher proportion of older patients (age ≥ 80: 23.5% vs. 5%), and more males (68% vs. 56.2%) than the POUT cohort (Table 1, both p < 0.001). Additionally, the rate of advanced nodal disease was higher in the NCDB (N1 9.6%, N2 9.3%) than in the POUT (N1 6%, N2 3%) cohort (p < 0.001). A more extensive lymph node dissection was performed in NCDB vs. POUT patients (node≥10 10.9% vs. 3%, p < 0.001). Sensitivity analysis removing all subjects with a Charlson Comorbidity Index > 0 did not change the significance of any results. CONCLUSIONS: While the primary disease stage was similar, the rate of advanced nodal disease was significantly higher in NCDB, which might be explained partially by the more extensive lymph node dissection performed in the latter. These differences warrant caution when applying the POUT III findings to North American patients.

Association of Age with Non-muscle-invasive Bladder Cancer: Unearthing a Biological Basis for Epidemiological Disparities?

BACKGROUND: Age disparity in patients with non-muscle-invasive bladder cancer (NMIBC) exists. Whether this is due to differences in adequate cancer care or tumour biology is unclear. OBJECTIVE: To investigate age disparities in NMIBC using the Surveillance, Epidemiology, and End Results (SEER)-Medicare and UROMOL datasets. DESIGN, SETTING, AND PARTICIPANTS: The SEER-Medicare data were used to identify patients with clinical stage Ta, Tis, and T1 NMIBC between 2005 and 2017 (n = 32 225). Using the UROMOL cohort (n = 834), age disparities across transcriptomic, genomic, and spatial proteomic domains were assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For the SEER-Medicare data, multivariable competing-risk regression was used to examine the association between age and recurrence, progression, and bladder cancer-specific mortality (BCSM). For the UROMOL cohort, multivariable general linear model and multinomial logistic regression were performed to evaluate the association between age and tumour biology. RESULTS AND LIMITATIONS: An analysis of the SEER-Medicare cohort revealed 5-yr recurrence rates of 55.2%, 57.4%, and 58.9%; 5-yr progression rates of 25.6%, 29.2%, and 36.9%; and 5-yr BCSM rates of 3.9%, 5.8%, and 11.8% in patients aged 66-70, 71-80, and ≥81 yr, respectively. After multivariable adjustment, age ≥81 yr was associated with a higher risk of recurrence (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.03-1.12; p = 0.001), progression (HR 1.32, p < 0.001), and BCSM (HR 2.58, p < 0.001). UROMOL2021 transcriptomic class 2a was most frequently observed in patients with advanced age (34.0% in ≥76 yr vs 21.6% in ≤65 yr; p = 0.004), a finding confirmed on multivariable analysis (risk ratio [RR] 3.86, p = 0.002). UROMOL2021 genomic class 3 was observed more frequently in patients aged ≥76 yr (4.9% vs 24.2%; p = 0.001). Limitations include the definitions used for recurrence and progression, which may lead to under- or overestimation of true rates. CONCLUSIONS: Among SEER-Medicare patients with NMIBC, advanced age is associated with inferior oncological outcomes. These results reflect age-related molecular biological differences observed across transcriptomic and genomic domains, providing further evidence that innate tumour biology contributes to observed disparities in NMIBC outcomes. PATIENT SUMMARY: Older patients with non-muscle-invasive bladder cancer have worse oncological outcomes than younger patients. Some of this age disparity may be due to differences in tumour biology.

Comparison of patient background between a real-world North American cohort and the Göteborg-2 trial.

OBJECTIVES: To analyze the generalizability of the Göteborg-2 findings to a North American cohort. METHODS: We replicated the Göteborg-2 inclusion criteria in our Henry Ford Health (HFH) cohort, by identifying all patients 50-60 years old who had a PSA test from 2013 to 2018. The first PSA within the study period was considered PSA at entry, and included in the analysis. Chi-square test was used to compare categorical variables between the Göteborg-2 and HFH cohort, with a particular focus on Black men, who were also analyzed separately. RESULTS: The HFH patients included in the cohort were 49 456, of which 8562 were Black. In patients within the entire HFH cohort, HFH Black cohort, Göteborg Reference cohort, and Göteborg Experimental cohort, the rate of PSA ≥3 ng/mL was, respectively, 6.8%, 10.2%, 6.8%, and 6.6%. The rate of biopsy performed was, respectively, 1.8%, 4.1%, 5.8%, and 2.5%. PCa was found in, respectively, 1.4%, 3.0%, 2.3%, and 1.5%; Gleason score 3 + 3 in, respectively, 0.5%, 0.8%, 1.2%, and 0.6%; Gleason score > 3 + 3 in, respectively, 0.9%, 2.2%, 1.1%, and 0.9%. CONCLUSIONS: Our cohort had a lower biopsy rate and a lower incidence of non-csPCa diagnosis than both Göteborg cohorts, while still maintaining the same incidence of csPCa. This implies that the benefits of reducing non-csPCa diagnosis, as observed in the Experimental Göteborg cohort, are not necessarily replicable in U.S. "real-world practice" patients. Also noteworthy, we had a significantly higher percentage of Black men, who showed more aggressive disease.

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.

Prostate Specific Antigen Screening on a Nationwide Level: Featuring the Contribution of Race and Life Expectancy in Decision Making.

BACKGROUND: Estimation of life expectancy (LE) is important for the relative benefit of prostate specific antigen (PSA) screening. Limited data exists regarding screening for Black men with extended LE. The aim of the current study was to assess temporal trends in screening in United States (US) Black men with limited vs. extended LE, using a nationally representative dataset. MATERIALS AND METHODS: Using the National Health Institution Survey (NHIS) 2000 to 2018, men aged ≥40 without prior history of prostate cancer (PCa) who underwent PSA screening in the last 12 months were stratified into limited LE (ie, LE <15 years) and extended LE (ie, LE≥15 years) using the validated Schonberg index. LE-stratified temporal trends in PSA screening were analyzed for all men, and then in Black men. Weighted multivariable analyses and dominance analyses identified the predictors of PSA screening. RESULTS: PSA screening declined over the study period both for all eligible men with limited and extended LE, particularly between NHIS 2008 and 2013 (27.9%-20.7% in the extended). Screening increased significantly in Black men with extended LE (17.6% in 2010-25.7% in 2018). However, LE was not an independent predictor of screening in the Black cohort. Prior recipient of colonoscopy (55%-57%) and visit to health care provider (24%-32%) were the most important determinants for screening. CONCLUSION: For US men with extended LE, only 1 in 4 receive PSA screening, with a decline over the study-period. Screening rates increased for Black men. However, these changes were not driven by LE consideration itself, but participation in other screenings and access to a provider.

Transfer of Knowledge on Pneumoconiosis Care Among Rural-Based Members of a Digital Community of Practice: Cross-Sectional Study.

BACKGROUND: Given the re-emergence of coal workers' pneumoconiosis in Appalachia and Mountain West United States, there is a tremendous need to train rural professionals in its multidisciplinary management. Since 2016, the Miners' Wellness TeleECHO (Extension for Community Health Outcomes) Program held by the University of New Mexico, Albuquerque, and Miners' Colfax Medical Center, Raton, New Mexico, provides structured longitudinal multidisciplinary telementoring to diverse professionals taking care of miners by creating a digital community of practice. Program sessions emphasize active learning through discussion, rather than didactic training. Professional stakeholder groups include respiratory therapists, home health professionals, benefits counselors, lawyers or attorneys, clinicians, and others. Rural-urban differences in knowledge transfer in such a community of practice, however, remain unknown. OBJECTIVE: We aim to evaluate the role of the rurality of the patient or client base in the transfer of knowledge to professionals caring for miners using the digital community of practice approach. METHODS: This is a cross-sectional study of 70 professionals participating in the Miners' Wellness TeleECHO Program between 2018 and 2019. Drawing insights from social network analysis, we examined the association between the rurality of participants' patient or client base and their self-reported receipt of knowledge. Our focal independent variable was the respondent's self-reported percentage of patients or clients who reside in rural areas. We measured knowledge transfer sources by asking participants if they received knowledge regarding the care of miners during and outside of TeleECHO sessions from each of the other participants. Our dependent variables included the number of knowledge sources, number of cross-stakeholder knowledge sources, number of same stakeholder knowledge sources, and range and heterogeneity of knowledge sources. RESULTS: Respondents, on average, identified 4.46 (SD 3.16) unique knowledge sources within the community, with a greater number of cross-stakeholder knowledge sources (2.80) than same stakeholder knowledge sources (1.72). The mean knowledge source range was 2.50 (SD 1.29), indicating that, on average, respondents received knowledge sources from roughly half of the 5 stakeholder groups. Finally, the mean heterogeneity of knowledge sources, which can range between 0 and 0.80, was near the midpoint of the scale at 0.44 (SD 0.30). Multivariable analyses revealed that as the rurality of patient or client bases increased, participants reported more knowledge sources overall, more knowledge sources from outside of their stakeholder groups, a higher knowledge source range, and greater heterogeneity of knowledge sources (P<.05 for all comparisons). CONCLUSIONS: Our findings suggest that participants who serve rural areas especially benefit from knowledge transfer within the TeleECHO community of practice. Additionally, the knowledge they receive comes from diverse information sources, emphasizing its multidisciplinary nature. Our results underscore the capacity of the TeleECHO model to leverage technology to promote rural health equity for miners.

Admission Rates, Healthcare Utilization, and Inpatient Cost of Radiation Cystitis in the United States.

OBJECTIVE: To assess the incidence, cumulative healthcare burden, and financial impact of inpatient admissions for radiation cystitis (RC), while exploring practice differences in RC management between teaching and nonteaching hospitals. METHODS: We focused on 19,613 patients with a diagnosis of RC within the National Inpatient Sample (NIS) from 2008 to 2014. ICD-9 diagnosis and procedure codes were used. Complex-survey procedures were used to study the descriptive characteristics of RC patients and the procedures received during admission, stratified by hospital teaching status. Inflation-adjusted cost and cumulative annual cost were calculated for the study period. Multivariable logistic regression was used to study the impact of teaching status on the high total cost of admission. RESULTS: Median age was 76 (interquartile range 67-82) years. Most of the patients were males (73%; P < .001). 59,571 (61%) patients received at least one procedure, of which, 24,816 (25.5%) received more than one procedure. Median length of stay was 5days (interquartile range 2-9). Female patients and patients with a higher comorbidity score were more frequently treated at teaching hospitals. A higher proportion of patients received a procedure at a teaching hospital (64% vs 59%; P < .001). The inflation-adjusted cost was 9207 USD and was higher in teaching hospitals. The cumulative cost of inpatient treatment of RC was 63.5 million USD per year and 952.2 million USD over the study period. CONCLUSION: The incidence of RC-associated admissions is rising in the US. This disease is a major burden to US healthcare. The awareness of the inpatient economic burden and healthcare utilization associated with RC may have funding implications.

Impact of lymphovascular invasion on survival in surgically treated upper tract urothelial carcinoma: a nationwide analysis.

OBJECTIVES: To assess the prognostic ability of lymphovascular invasion (LVI) in upper tract urothelial carcinoma (UTUC) as a predictor of overall survival (OS) using a large North American cohort. PATIENTS AND METHODS: Our cohort included 5940 patients with clinical M0 UTUC who underwent a radical nephroureterectomy (RNU), between 2010 and 2016, within the National Cancer Database. The main variable of interest was LVI status, and its interaction with pathological nodal (pN) status. Kaplan-Meier curves were used to depict the OS also stratifying patients on LVI status. Cox regression analysis tested the impact of LVI status on OS after accounting for the available covariates. RESULTS: The median (interquartile range [IQR]) age at diagnosis was 71 (63-78) years and most patients had pathological T1 stage disease (48.6%). Nodal status was pN0, pN1 and pNx in 45.8%, 6.3% and 47.9%, respectively. Overall, 22.1% had LVI. The median (IQR) follow-up time was 32.6 (16.0-53.3) months. At the 5-year postoperative follow-up, the estimated OS rate was 28% in patients with LVI vs 66% in those without LVI (P < 0.001). When patients were stratified based on nodal status those rates were 32% vs 68% in pN0 patients (P < 0.001), 23% vs 30% in pN1 patients (P = 0.8), and 28% vs 65% in pNx patients (P < 0.001). On multivariable analysis, the presence of LVI was associated with less favourable OS (hazard ratio 1.79, 95% confidence interval 1.60-1.99; P < 0.001). CONCLUSION: Our study assessed the impact of LVI on OS in patients with UTUC in a large North American nationwide cohort. Our series, as the largest to date, indicate that LVI is associated with less favourable survival outcomes in patients with UTUC after RNU, and this variable could be used in counselling patients about their prognosis and might be a useful tool for future trials to risk-stratify patients.