In the United States, African American (AA) men have a 2.4 times higher mortality rate due to prostate cancer than White men. The multifactorial causes of the racial disparities in prostate cancer ...involve various social determinants of health, socioeconomic status, and access to healthcare. However, emerging evidence also suggests that circadian rhythm disruption (CRD) contributes to prostate cancer, and AA men may be more susceptible to developing CRDs. Circadian rhythms play a significant role in metabolism, hormone secretion, and sleep/wake cycles. Disruption in these circadian rhythms can be caused by airplane travel/jetlag, night shift work, exposure to light, and neighborhood noise levels, which can contribute to sleep disorders and chronic conditions such as obesity, diabetes, cardiovascular disease, and depression. The drivers of the racial disparities in CRD include night shift work, racial discrimination, elevated stress, and residing in poor neighborhoods characterized by high noise pollution. Given the increased vulnerability of AA men to CRDs, and the role that CRDs play in prostate cancer, elucidating the clock-related prostate cancer pathways and their behavior and environmental covariates may be critical to better understanding and reducing the racial disparities in prostate cancer.
One of the central goals of human genetics is to discover the genes and pathways driving human traits. To date, most of the common risk alleles discovered through genome-wide association studies ...(GWAS) map to nonprotein-coding regions. Because of our relatively poorer understanding of this part of the genome, the functional consequences of trait-associated variants pose a considerable challenge. To identify the genes through which risk loci act, we hypothesized that the risk variants are regulatory elements. For each of 12 known risk polymorphisms, we evaluated the correlation between risk allele status and transcript abundance for all annotated protein-coding transcripts within a 1-Mb interval. A total of 103 transcripts were evaluated in 662 prostate tissue samples normal (n = 407) and tumor (n = 255) from 483 individuals European Americans (n = 233), Japanese (n = 127), and African Americans (n = 123). In a pooled analysis, 4 of the 12 risk variants were strongly associated with five transcripts (NUDT11 , MSMB , NCOA4 , SLC22A3 , and HNF1B) in histologically normal tissue (P ≤ 0.001). Although associations were also observed in tumor tissue, they tended to be more attenuated. Previously, we showed that MSMB and NCOA4 participate in prostate cancer pathogenesis. Suppressing the expression of NUDT11 , SLC22A3 , and HNF1B influences cellular phenotypes associated with tumor-related properties in prostate cancer cells. Taken together, the data suggest that these transcripts contribute to prostate cancer pathogenesis.
Prostate cancer (PCa) incidence, morbidity, and mortality rates are significantly impacted by racial disparities. Despite innovative therapeutic approaches and advancements in prevention, men of ...African American (AA) ancestry are at a higher risk of developing PCa and have a more aggressive and metastatic form of the disease at the time of initial PCa diagnosis than other races. Research on PCa has underlined the biological and molecular basis of racial disparity and emphasized the genetic aspect as the fundamental component of racial inequality. Furthermore, the lower enrollment rate, limited access to national-level cancer facilities, and deferred treatment of AA men and other minorities are hurdles in improving the outcomes of PCa patients. This review provides the most up-to-date information on various biological and molecular contributing factors, such as the single nucleotide polymorphisms (SNPs), mutational spectrum, altered chromosomal loci, differential gene expression, transcriptome analysis, epigenetic factors, tumor microenvironment (TME), and immune modulation of PCa racial disparities. This review also highlights future research avenues to explore the underlying biological factors contributing to PCa disparities, particularly in men of African ancestry.Prostate cancer (PCa) incidence, morbidity, and mortality rates are significantly impacted by racial disparities. Despite innovative therapeutic approaches and advancements in prevention, men of African American (AA) ancestry are at a higher risk of developing PCa and have a more aggressive and metastatic form of the disease at the time of initial PCa diagnosis than other races. Research on PCa has underlined the biological and molecular basis of racial disparity and emphasized the genetic aspect as the fundamental component of racial inequality. Furthermore, the lower enrollment rate, limited access to national-level cancer facilities, and deferred treatment of AA men and other minorities are hurdles in improving the outcomes of PCa patients. This review provides the most up-to-date information on various biological and molecular contributing factors, such as the single nucleotide polymorphisms (SNPs), mutational spectrum, altered chromosomal loci, differential gene expression, transcriptome analysis, epigenetic factors, tumor microenvironment (TME), and immune modulation of PCa racial disparities. This review also highlights future research avenues to explore the underlying biological factors contributing to PCa disparities, particularly in men of African ancestry.
In this large, diverse population of men with newly diagnosed unfavourable intermediate- to very-high-risk prostate cancer, 18F-rhPSMA-7.3 positron emission tomography/computed tomography was shown ...to be well tolerated and to provide clinically useful information regarding the identification of both N1 and M1 disease prior to surgery.
Radiohybrid (rh) 18F-rhPSMA-7.3 is a novel high-affinity prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for prostate cancer (PCa) imaging.
To evaluate the diagnostic performance and safety of 18F-rhPSMA-7.3 in newly diagnosed PCa patients planned for prostatectomy.
Data on 18F-rhPSMA-7.3 were reported from the phase 3 prospective, multicentre LIGHTHOUSE study (NCT04186819).
Patients underwent positron emission tomography/computed tomography (PET/CT) 50–70 min after an injection of 296 MBq 18F-rhPSMA-7.3. Images were interpreted locally and by three blinded independent readers. The coprimary endpoints were patient-level sensitivity and specificity for the detection of pelvic lymph node (PLN) metastases, validated using histopathology at PLN dissection. Prespecified statistical thresholds (lower bounds of 95% confidence interval CI) were set at 22.5% for sensitivity and 82.5% for specificity.
Of 372 patients screened, 352 had evaluable 18F-rhPSMA-7.3-PET/CT and 296 (99 33% with unfavourable intermediate-risk UIR and 197 67% with high-/very-high-risk VHR PCa) subsequently underwent surgery. As per the independent reads, 23–37 (7.8–13%) patients had 18F-rhPSMA-7.3–positive PLN. Seventy (24%) patients had one or more positive PLNs on histopathology. The sensitivity for PLN detection was 30% (95% CI, 19.6–42.1%) for reader 1, 27% (95% CI, 17.2–39.1%) for reader 2, and 23% (95% CI, 13.7–34.4%) for reader 3, not meeting the prespecified threshold. Specificity was 93% (95% CI, 88.8–95.9%), 94% (95% CI, 89.8–96.6%), and 97% (95% CI, 93.7–98.7%), respectively, exceeding the threshold for all readers. Specificity was high (≥92%) across both risk stratifications. Sensitivity was higher among high-risk/VHR (24–33%) than among UIR (16–21%) patients. Extrapelvic (M1) lesions were reported for 56–98/352 (16–28%) patients who underwent 18F-rhPSMA-7.3-PET/CT irrespective of surgery. Verification of these (predominantly by conventional imaging) gave a verified detection rate of 9.9–14% (positive predictive value, 51–63%). No serious adverse events were observed.
Across all risk stratifications, 18F-rhPSMA-7.3-PET/CT had high specificity, meeting the specificity endpoint. The sensitivity endpoint was not met, although higher sensitivity was noted among high-risk/VHR than among UIR patients. Overall, 18F-rhPSMA-7.3-PET/CT was well tolerated, and identified N1 and M1 disease prior to surgery in newly diagnosed PCa patients.
In order to select the most appropriate treatment for patients with prostate cancer, it is critical to diagnose the disease burden accurately at initial diagnosis. In this study, we investigated a new diagnostic imaging agent in a large population of men with primary prostate cancer. We found it to have an excellent safety profile and to provide clinically useful information regarding the presence of disease beyond the prostate.
African-American men in the USA have a higher incidence of and mortality from prostate cancer (PCa), with a longstanding debate about the cause for these worse outcomes. This review examines ...differences in tumour biology and socioeconomics for African-American and Non-Hispanic White (NHW) men to answer the question 'why AA men face higher risks for lethal PCa' and draw a management consensus to redress the imbalance.
Recent evidence from over the past 2 years suggests the reasons why African-American men face a higher risk of lethal PCa are multifactorial, with contributions from differences in tumour biology as well as socioeconomic and healthcare access factors. Regarding tumour biology, genomic and transcriptome profiling suggests African-American men have upregulated expression of genes related to inflammatory pathways with downregulation of DNA repair genes. In contrast, NHW men have higher DNA repair pathways and metabolic pathways involving glycolysis and cell cycle activity. In addition, epidemiological evidence suggests equal healthcare access ensures equal PCa specific outcomes, implying African-American men's disease is not inherently more lethal. However, differences in tumour biology remain, which may explain specific differences in PCa incidence and the clinical findings of African-American men's increased response to immunotherapy and radiotherapy in recent trials.
Regardless of racial differences in disease outcomes and the factors causing them, African-American and NHW men seem to have diseases unique to their ancestry. This supports the exploration of personalized PCa treatment approaches, leveraging translational basic science research to uncover these differences and devise specific individualized methods therapeutic regimes to address them.
The COVID-19 pandemic exploits existing inequalities in social determinants of health (SDOH) in disease burden and access to healthcare. Few studies have examined these emerging disparities using ...indicators of SDOH.
To evaluate predictors of COVID-19 test positivity, morbidity, and mortality and their implications for inequalities in SDOH and for future policies and health care improvements.
A cross sectional analysis was performed on all patients tested for COVID-19 on the basis of symptoms with either a history of travel to at risk regions or close contact with a confirmed case, across the Mount Sinai Health System (MSHS) up until April 26th 2020.
Primary outcome was death from COVID-19 and secondary outcomes were test positivity, and morbidity (e.g., hospitalization and intubation caused by COVID-19).
Of 20,899 tested patients, 8,928 tested positive, 1,701 were hospitalized, 684 were intubated, and 1,179 died from COVID-19. Age, sex, race/ethnicity, New York City borough (derived from first 3 digits of zip-code), and English as preferred language were significant predictors of test positivity, hospitalization, intubation and COVID-19 mortality following multivariable logistic regression analyses.
People residing in poorer boroughs were more likely to be burdened by and die from COVID-19. Our results highlight the importance of integrating comprehensive SDOH data into healthcare efforts with at-risk patient populations.
Complex immune evasion mechanisms and lack of biomarkers predicting responsiveness to immune checkpoint blockade therapies compromise immunotherapy's therapeutic efficacy for patients with prostate ...cancer. The authors review established and nominated immune evasion mechanisms in prostate cancer and discuss how the precise treatment strategies can be developed to improve efficacy of immunotherapy.
•Prostate cancer diagnosis is subject to inter-pathologist variability.•Artificial intelligence can assuage pain points by streamlining diagnosis.•Artificial intelligence is evolving to diagnose, ...grade, and predict outcomes.•Challenges remain before wide-scale autonomous prostate cancer diagnosis.
The diagnosis of prostate cancer (PCa) depends on the evaluation of core needle biopsies by trained pathologists. Artificial intelligence (AI) derived models have been created to address the challenges posed by pathologists’ increasing workload, workforce shortages, and variability in histopathology assessment. These models with histopathological parameters integrated into sophisticated neural networks demonstrate remarkable ability to identify, grade, and predict outcomes for PCa. Though the fully autonomous diagnosis of PCa remains elusive, recently published data suggests that AI has begun to serve as an initial screening tool, an assistant in the form of a real-time interactive interface during histological analysis, and as a second read system to detect false negative diagnoses. Our article aims to describe recent advances and future opportunities for AI in PCa histopathology.
Abstract Although prostate cancer (PCa) is the second leading cause of cancer death among men worldwide, not all men diagnosed with PCa will die from the disease. A critical challenge, therefore, is ...to distinguish indolent PCa from more advanced forms to guide appropriate treatment decisions. We used Enhanced Reduced Representation Bisulfite Sequencing, a genome-wide high-coverage single-base resolution DNA methylation method to profile seven localized PCa samples, seven matched benign prostate tissues, and six aggressive castration-resistant prostate cancer (CRPC) samples. We integrated these data with RNA-seq and whole-genome DNA-seq data to comprehensively characterize the PCa methylome, detect changes associated with disease progression, and identify novel candidate prognostic biomarkers. Our analyses revealed the correlation of cytosine guanine dinucleotide island (CGI)-specific hypermethylation with disease severity and association of certain breakpoints (deletion, tandem duplications, and interchromosomal translocations) with DNA methylation. Furthermore, integrative analysis of methylation and single-nucleotide polymorphisms (SNPs) uncovered widespread allele-specific methylation (ASM) for the first time in PCa. We found that most DNA methylation changes occurred in the context of ASM, suggesting that variations in tumor epigenetic landscape of individuals are partly mediated by genetic differences, which may affect PCa disease progression. We further selected a panel of 13 CGIs demonstrating increased DNA methylation with disease progression and validated this panel in an independent cohort of 20 benign prostate tissues, 16 PCa, and 8 aggressive CRPCs. These results warrant clinical evaluation in larger cohorts to help distinguish indolent PCa from advanced disease.
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