Community-based health events provide an opportunity to increase knowledge, awareness, and screening for acute and chronic diseases among individuals living in a socioeconomically diverse community. Because there are limited reports of such events, here we describe our ten-year experience of annual men’s health fairs. This retrospective study of the Michigan Institute of Urology Foundation evaluated Men’s Health Events held in Detroit, Michigan, from 2012 to 2021. Over 10 years, 11,129 men were screened and > 100,000 screenings were performed. The majority of the attendees were African-American men (61

Supplemental Table 1. Overall cohort characteristics of AAPC whole exome sequencing cohort (n=102) Supplemental Table 2. Clinical and pathological characteristics of AAPC WES discovery cohort (n=102) Supplemental Table 3. Comparison of numbers of tumors by Gleason grade between the TCGA and AAPC cohorts Supplemental Table 4. Germline pathogenic variants in genes in the DNA repair pathway and list of 20 DNA repair genes assessed in targeted analysis Supplemental Table 5. Alteration file of somatic variants detected in the AAPC WES discovery cohort (n=102) Supplemental Table 6. Focal deletion and amplification peaks and genes located within peaks by GISTIC2.0 analysis of AAPC WES cohort Supplemental Table 7. ERF deletions and mutations in prostate tumors of the Weill Cornell Precision Medicine cohort Supplemental Table 8. Clinical and pathological characteristics of AAPC targeted sequencing extension cohort Supplemental Table 9. List of genes and intronic regions targeted with hybrid capture bait set used for AAPC extension cohort Supplemental Table 10. Alteration file of somatic variants detected in the AAPC extension cohort (n=90) using the targeted sequencing panel Supplemental Table 11. ERF mutation frequencies across published prostate cancer cohorts Supplemental Table 12. Germline ERF variant detected in the AAPC WES cohort Supplemental Table 13. Mutations in cytochrome P450 genes in the AAPC exome discovery cohort Supplemental Table 14. ERF oligonucleotides used for RNA in situ hybridization Supplemental Table 15. Gene sets shERF_VCAP_UP_LnCAP_UP_overlap_UP and shERF_vs_CNTRL.LHSAR_UP Supplemental Table 16. Tumor purity estimates for AAPC exome discovery cohort

PDF file - 114K, Suppl Table 1 - List of the 517 genes whose expression was measured by DASL microarray analysis of RNA from FFPE specimens. Supplemental Table 2. Mean difference and t-test p-value between the computed DDCt from EAM minus the computed DDCt from AAM from the validation sample of 16 AAM and 16 EAM. Supplemental Figure 1. Plot of the first 2 principal components, computed from all 517 genes on 163 patient tumor samples (80 AAM, 83 EAM) with the corresponding matched normal samples.

Abstract Background Altered DNA damage response (DDR) has emerged as an important mechanism for the development of aggressive prostate cancer among men of European ancestry but not other ancestry groups. Because common mechanisms for aggressive disease are expected, we explored a large panel of DDR genes and pathways to demonstrate that DDR alterations contribute to development of aggressive prostate cancer in both African American and European American men. Methods We performed a case-case study of 764 African American and European American men with lethal or indolent prostate cancer treated at 4 US hospitals. We calculated carrier frequencies of germline pathogenic or likely pathogenic sequence variants within 306 DDR genes, summarized by DDR pathway, and compared lethal cases against indolent cases using 2-sided Fisher’s exact tests. Secondary analysis examined if carrier frequencies differed by ancestry. Results Lethal cases were more likely to carry a pathogenic sequence variant in a DDR gene compared with indolent cases (18.5% vs 9.6%, P = 4.30 × 10−4), even after excluding BRCA2 (14.6% vs 9.6%, P = .04). The carrier frequency was similar among lethal cases of African (16.7% including and 15.8% excluding BRCA2) and lethal cases of European (19.3% including and 14.2% excluding BRCA2) ancestry. Three DDR pathways were statistically significantly associated with lethal disease: homologous recombination (P = .003), Fanconi anemia (P = .002), and checkpoint factor (P = .02). Conclusions Our findings suggest that altered DDR is an important mechanism for aggressive prostate cancer not only in men of European but also of African ancestry. Therefore, interrogation of entire DDR pathways is needed to fully characterize and better define genetic risk of lethal disease.

INTRODUCTION:Patients with mCSPC experience a longer overall survival with treatment intensification by addition of novel hormonal therapy (NHT) or docetaxel to androgen deprivation vs androgen deprivation alone. Real-world data report, however, that nearly half of mCSPC patients do not receive treatment intensification. In this study, treatment patterns and utilization of treatment intensification in mCSPC patients were described using the IQVIA Anonymized Patient Longitudinal Data, a dataset of fully adjudicated pharmacy and medical claims. PATIENTS AND METHODS:Reports on first line (1L) treatment patterns were obtained for years 2015 to 2021. Medicaid, Medicare, Medicare part D, cash transactions, and commercial data were included for years 2012 to 2021. RESULTS:Nationwide, of 66,844 men with newly diagnosed mCSPC since 2015, on average 25% were prescribed NHT, and another 12% were prescribed chemotherapy. No differences were noted in treatment patterns based on U.S. regions and/or rural vs. urban communities. The disparity was observed in prescribing patterns between oncology and urology providers. Oncology providers prescribed 1L NHT on average 32% of the time, while urology providers did so 12% of the time. Furthermore, oncology providers prescribed chemotherapy on average 20% of the time, resulting in 52% of men with mCSPC receiving treatment intensification as 1L therapy. Patients' age group, community or health insurance did not account for the disparity between the 2 specialties. CONCLUSION:Both medical oncology and urology providers need to improve their treatment intensification efforts for men with mCSPC to increase their patients' overall survival.

ContextMen of African ancestry have demonstrated markedly higher rates of prostate cancer mortality than men of other races and ethnicities around the world. In fact, the highest rates of prostate cancer mortality worldwide are found in the Caribbean and Sub-Saharan West Africa, and among men of African descent in the USA. Addressing this inequity in prostate cancer care and outcomes requires a focused research approach that creates durable solutions to address the structural, social, environmental, and health factors that create racial disparities in care and outcomes.ObjectiveTo introduce a conceptual model for evaluating racial inequities in prostate cancer care to facilitate the development of translational research studies and interventions.Evidence acquisitionA collaborative review of literature relevant to racial inequities in prostate cancer care and outcomes was performed. Existing literature was used to highlight various components of the conceptual model to inform future research and interventions toward equitable care and outcomes.Evidence synthesisRacial inequities in prostate cancer outcomes are driven by a series of structural and social determinants of health that impact exposures, mediators, and outcomes. Social determinants of equity, such as laws/policies, economic systems, and structural racism, affect the inequitable access to environmental and neighborhood exposures, in addition to health care access. Although the incidence disparity remains problematic, various studies have demonstrated parity in outcomes when social and health factors, such as access to equitable care, are normalized. Few studies have tested interventions to reduce inequities in prostate cancer among Black men.ConclusionsWorldwide, men of African ancestry demonstrate worse outcomes in prostate cancer, a phenomenon driven largely by social factors that inform biologic, environmental, and health care risks. A conceptual model was presented that organizes the many factors that influence prostate cancer incidence and mortality. Within that framework, we must understand the current state of inequities in clinical prostate cancer practice, the optimal state of what equitable practice would be, and how achieving equity in prostate cancer care balances costs, benefits, and harms. More robust characterization of the sources of prostate cancer inequities should inform testing of ambitious and innovative interventions as we work toward equity in care and outcomes.Patient summaryMen of African ancestry demonstrate the highest rates of prostate cancer mortality, which may be reduced through social interventions. We present a framework for formalizing the identification of the drivers of prostate cancer inequities to facilitate the development of interventions and trials to eradicate them.

You have accessJournal of UrologyProstate Cancer: Markers (MP60)1 Sep 2021MP60-05 MOLECULAR PROFILING OF PROSTATE CANCER REVEALS INCREASED INFLAMMATORY MARKERS AND POOR CLINICAL OUTCOMES IN AFRICAN AMERICAN COMPARED TO EUROPEAN AMERICAN MEN Udit Singhal, Srinivas Nallandhighal, Susan Bolton, Mark Farha, Judith Strangl-Kremser, Ganesh Palapattu, Aliccia Bollig-Fischer, Aaron Udagar, Isaac Powell, and Simpa Salami Udit SinghalUdit Singhal , Srinivas NallandhighalSrinivas Nallandhighal , Susan BoltonSusan Bolton , Mark FarhaMark Farha , Judith Strangl-KremserJudith Strangl-Kremser , Ganesh PalapattuGanesh Palapattu , Aliccia Bollig-FischerAliccia Bollig-Fischer , Aaron UdagarAaron Udagar , Isaac PowellIsaac Powell , and Simpa SalamiSimpa Salami View All Author Informationhttps://doi.org/10.1097/JU.0000000000002095.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: African American men (AAM) with prostate cancer (PCa) often harbor more aggressive disease compared to European American men (EAM). However, the underlying cause for disparities in PCa outcomes is controversial. We performed gene expression analysis to characterize differences in tumor biology in AAM and EAM with PCa and assess the impact on outcomes. METHODS: Microarray analyses using 1,507 probes were performed to assess the expression of 517 genes in PCa radical prostatectomy (RP) specimens from 270 AAM and 369 EAM from 1991-1996. The primary endpoint was biochemical recurrence (BCR) and secondary endpoint was PCa-specific mortality (PCSM). Cox proportional hazard regression analyses were performed adjusting for age, pre-treatment PSA, Gleason grade group (GG), and T-stage. Differential Gene Expression (DEG) analysis was performed using the limma R package, with correction for multiple comparisons using the Benjamini-Hochberg procedure (false-discovery rate (FDR) of <0.05 considered significant). Gene Set Enrichment Analysis (GSEA) was performed to identify enriched hallmark pathways using R package fgsea. RESULTS: The median age of AAM and EAM was 64 (IQR 56-72) and 62 (IQR 54-70) years, respectively. A total of 66 (24%) AAM and 67 (18%) EAM developed BCR (p=0.002; median follow up 10.5 and 13.8 years, respectively). Sixteen men experienced PCSM in each group (5.9% and 4.3% in AAM and EAM, respectively; p=0.080). Interestingly, among those with GG1-2 disease, AAM were more likely to develop BCR than EAM (HR 2.3, 95% CI 1.3–4, p=0.004). However, the BCR risk was not significantly different between AAM and EAM with GG3-5 disease (p=0.370). DEG and GSEA revealed upregulation of inflammation, TNF-alpha signaling, apoptosis, androgen response, and epithelial to mesenchymal transition, among other pathways, in AAM compared to EAM (Figure 1; FDR <0.05). CONCLUSIONS: AAM with GG1-2 PCa had a higher incidence of BCR compared with EAM following RP, suggesting a more aggressive biologic behavior in AAM in early disease. The molecular profile of PCa in AAM is different from that in EAM, with inflammation playing a prominent role. Prognostic gene signatures accounting for these biological differences are needed to facilitate better disease management. Source of Funding: N/A © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1042-e1043 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Udit Singhal More articles by this author Srinivas Nallandhighal More articles by this author Susan Bolton More articles by this author Mark Farha More articles by this author Judith Strangl-Kremser More articles by this author Ganesh Palapattu More articles by this author Aliccia Bollig-Fischer More articles by this author Aaron Udagar More articles by this author Isaac Powell More articles by this author Simpa Salami More articles by this author Expand All Advertisement Loading ...

Pro-inflammatory cytokine and chemokines genes drive prostate cancer progression and metastasis: molecular mechanism update and the science that underlies racial disparity. comprehensive review article.Isaac J. Powell, S. Chinni, S.S. Reddy, Alexander Zaslavsky, Navnath Gavande Introduction: In 2013 we reported that with the use of bioinformatics and ingenuity pathway network analysis we were able to identify functional driver genes that were differentially expressed among a large population of African American men (AAM) and European American men (EAM). Pro-inflammatory cytokine genes were found to be more interactive and more expressed among AAM and have been found to be functional drivers of aggressive prostate cancer (CaP) and aggressiveness in other solid tumors. We examined these genes and biological pathways initiated by these cytokines in primary CaP tissue.Method We unravel the gene network and identified biologic pathways that impacted activation of the androgen receptor, mesenchymal epithelial transition (invasion) and chemokines associated with metastasis in the CaP tissue from 639 radical prostatectomy specimens.Results Biologic pathways identified by unraveling pro-inflammatory genes from our network, more expressed among AAM compared to EAM, were tumor necrosis factor (TNF), IL1b, IL6, and IL8. IL6 and IL8 are downstream of TNF activity and are known activators of androgen receptor and through mediators promote CaP cell proliferation. TNF and IL1b mediate tumor cell invasiveness through the activation of MMP (matrix metalloproteinase) which down regulates E-Cadherin to initiate epithelial mesenchymal transition which allows cells to become invasive in the microenvironment. Ultimately our network analysis indicates that TNF and IL1b activate CXCR4 receptor on CaP cells, which facilitates metastatic progression reportedly by binding to CXCL12 on lipid rafts and tumor implantation in the bone marrow.Conclusion Our retrospective biologic mechanistic model reveals a set of pro-inflammatory cytokines and chemokines that drive CaP aggressiveness, tumor heterogeneity, progression and metastasis. A prospective multi-institutional study needs to be conducted for clinical validation as well consideration of targeted therapy. (C) 2020 Elsevier Inc. All rights reserved.

At Nature Reviews Urology, we have pledged to strive towards improving diversity in our field. As a step towards this goal, this Viewpoint presents the experiences of 10 Black urologists. Their stories illustrate the importance of perseverance and emphasize the essential role of community and mentorship to raise up our peers and colleagues, to support and encourage Black urologists and lead to a more diverse field of urology in the future.

Purpose: Prostate cancer is the most common cancer in males, but also exhibits a ∼1.5-2-fold higher incidence in African American men compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ∼33 % of the familial risk. A portion of the undefined risk may be due to rare susceptibility variants. The African American Hereditary Prostate Cancer (AAHPC) Study, established in 1997, enrolled 77 AA families from seven clinical sites across the United States (Ann Epidemiol, 2000). The aim of this study is to identify rare, predictive, deleterious variants through exome sequencing of 99 cases from 26 families selected from the AAHPC families (2 to 3 affected men sequenced per family) and three female 1000 Genome controls. Methods: To explore the contribution of rare variation in coding regions of 38 known cancer-causing genes to prostate cancer risk (PCa), we sequenced the exomes of 99 AAHPC cases at a mean coverage of 30x. Post-variant calling quality control (QC) was implemented using Golden Helix SVS 8 software with filters set for removal of variants with Read Depth >10, Quality Score >10, and Quality Score: Read Depth Ratio > 0.5. Mendelian inconsistency was checked using PLINK. Prioritization of all candidate genes/variants were evaluated using online databases including 1000 Genomes and ANNOVAR for non-reference allele frequency and predictions of functional impact. Conclusions. Through exome sequencing of 99 AAHPC cases and 3 female 1000 Genome controls, we identified 37 non-synonymous single nucleotide variants that are considered damaging by at least one predictive scoring tool in our 38 candidate genes. However, most of these variants were common and thus unlikely to be causal. We observed three rare variants that were considered damaging by three predictive scoring tools in two known PCa genes, PCNT and ZFHX3. These 3 variants were each observed in a single different family (in 1 of 3 affected individuals). Interesting rare candidate variants (MAF ≤ 0.01) rs190517526 & rs114692729 were found in known cancer susceptibility loci (CD82 and EZH2). The CD82 variant was observed in all 3 sequenced affecteds in one family and the EZH2 variant was observed in 2 of 3 sequenced affecteds in a different family. These predicted damaging variants in these four genes represent potentially novel causal candidates for some of the 26 AAHPC families sequenced here. Future work will carefully analyze the remainder of the genome in the other 21 sequenced families including planned sequencing of additional family members. Citation Format: Deyana D. Lewis, Shukmei Wong, Angela S. Baker, Isaac Powell, John D. Carpten, Joan E. Bailey-Wilson, Cheryl Cropp. Rare candidate variants shared among affected family members in the African American Hereditary Prostate Cancer Study families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4240.

Prostate cancer is one of the most common cancers in men worldwide. Currently available diagnostic and prognostic tools for this disease, such as prostate specific antigen, suffer from lack of specificity and sensitivity, resulting in over- and misdiagnosis. Hence, there is an urgent need for clinically relevant biomarkers capable of distinguishing between aggressive and nonaggressive forms of prostate cancer to aid in stratification, management and therapeutic decisions. To address this unmet need, we investigated the patterns of expression of a panel of 68 plasma-derived microRNAs (miRNAs) in a cohort of African American (AA) and European American (EA) prostate cancer patients (n = 114). miRNA qPCR results were analyzed using in-depth statistical methods, and a bioinformatics analysis was conducted to identify potential targets of the differentially expressed miRNAs. Our data demonstrate that a new previously unreported circulating miRNA signature consisting of a combination of interacting miRNAs (miR-17/miR-192) and an independent miRNA (miR-181a) are capable of segregating aggressive and nonaggressive prostate cancer in both AA and EA patients. The interacting miRNAs outperformed independent miRNAs in identifying aggressiveness. Our results suggest that these circulating miRNAs may constitute novel biomarkers of prostate cancer aggressiveness in both races and warrant further investigation.

African American men (AAM) are at higher risk of being diagnosed with prostate cancer (PCa) and are at higher risk of dying from the disease compared to European American men (EAM). We sought to better understand PCa molecular diversity that may be underlying these disparities. We performed RNA-sequencing analysis on high-grade PCa to identify genes showing differential tumor versus noncancer adjacent tissue expression patterns unique to AAM or EAM. We observed that interleukin-6 (IL-6) was upregulated in the nonmalignant adjacent tissue in AAM, but in EAM IL-6 expression was higher in PCa tissue. Enrichment analysis identified that genes linked to the function of TP53 were overrepresented and downregulated in PCa tissue from AAM. These RNA-sequencing results informed our subsequent investigation of a diverse PCa cell line panel. We observed that PCa cell lines that are TP53 wild-type, which includes cell lines derived from AAM (MDA-PCa-2b and RC77T), did not express detectable IL-6 mRNA. IL-6 treatment of these cells downregulated wild-type TP53 protein and induced mRNA and protein expression of the epigenetic reader methyl CpG binding domain protein 2 (MBD2), specifically the alternative mRNA splicing variant MBD2_v2. Further investigation validated that upregulation of this short isoform promotes self-renewal and expansion of PCa cancer stem-like cells (CSCs). In conclusion, this report contributes to characterizing gene expression patterns in high-grade PCa and adjacent noncancer tissues from EAM and AAM. The results we describe here advance what is known about the biology associated with PCa race disparities and the molecular signaling of CSCs.

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II1 Apr 2018MP64-15 PRO-INFLAMMATORY CYTOKINE GENES ARE DRIVERS OF PROSTATE CANCER PROGRESSION AND CASTRATE RESISTANT PROSTATE CANCER Isaac Powell, Aliccia Bollig-Fischer, and Elisabeth Heath Isaac PowellIsaac Powell More articles by this author , Aliccia Bollig-FischerAliccia Bollig-Fischer More articles by this author , and Elisabeth HeathElisabeth Heath More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2060AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Introduction: We reported functional driver genes and network interaction of race specific and differentially expressed genes by use of bioinformatics and ingenuity pathway analysis among a large population of African American men (AAM) and European American men (EAM) (Powell, I et al 2013, Cancer Epid Bio Prev.). When unraveling the network we identified multiple biological signaling pathways, parts of which reported elsewhere, but when put together, they activate directly or indirectly the androgen receptor and other pathways associated with invasiveness and metastasis. The drivers of these pathways are pro-inflammatory cytokines. We will present these signaling pathways from our interactive network. METHODS Method: In our initial microarray analysis from formalin fixed radical prostatectomy specimens, we examined 227 genes from 517 genes associated with PCa showing significantly greater expression in PCa from AAM and EAM, and a subset of these genes were identified by bioinformatics and the network from Ingenuity Pathway analysis to be functionally interrelated and driver genes. RESULTS Results: Pro-Inflammatory cytokines TNF (tumor necrosis factor) IL1B, IL6 and IL8 from our gene profile activated several intermediaries that interact and activate transcription factors in the nucleus, NFkB and TGFB included in our network . These factors bind to the promoter region of the androgen receptor and promote PCa cell proliferation (Zhang 2009,Cao 2015). Inflammatory cytokines TNF and IL1B up-regulate MMP9 (Matrix metalloproteinase 9) in the microenvironment which down regulates cell adhesion molecule E-Cadherin and allows tumors cells to become invasive (Zhang 1998, Canbay, 2015 ) Beta Catenin that is released into the cytoplasm after down regulation of E-Cadherin by MMP9 is translocated to the nucleus by IL8 (WNT pathway) (Tung-Yuan Lai, 2010). TNF and IL1B up regulate CXCR4 which facilitates movement of prostate cancer cells within the prostate and from the prostate to bone on lipid rafts (Han, 2001). These pro-inflammatory cytokines are more expressed among AAM. CONCLUSIONS Conclusion: These pro-inflammatory cytokines, the same cytokines identified in several other cancers and associated with aggressiveness and disease progression, are associated with PCa aggressiveness, disease progression and castrate resistant prostate cancer. These interactive pathways may become targets for therapy. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e856 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Isaac Powell More articles by this author Aliccia Bollig-Fischer More articles by this author Elisabeth Heath More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Active surveillance (AS) has emerged as the preferred management strategy for many men with prostate cancer (PC); however, insufficient longitudinal monitoring may increase the risk of poor outcomes. We sought to determine rates of patients becoming lost to follow-up (LTFU) and associated risk factors in a large AS cohort. The Michigan Urologic Surgery Improvement Collaborative (MUSIC) maintains a prospective registry of PC patients from 44 academic and community urology practices. Over a 6-yr period (2011-2017), we identified patients managed with AS. LTFU was defined as any 18-mo period where no pertinent surveillance testing was entered in the registry. With a median surveillance period of 32 mo, the estimated 2-yr LTFU-free probability calculated by Kaplan-Meier method was 90% (95% confidence interval [CI]=89-92%). Both African American race (hazard ratio [HR]: 2.77, 95% CI=1.81-4.24) and Charlson comorbidity index ≥1 (HR: 1.55, 95% CI=1.08-2.23) were independently associated with increased risk of LTFU. There was variability in rates of estimated 2-yr LTFU-free survival across MUSIC practices, ranging from 52% (95% CI=21-100%) to 99% (95% CI=97-100%), with a median of 96% (interquartile range: 94-98%), although this did not reach statistical significance (p=0.076). These data reveal opportunities for urology practices to identify systems to reduce rates of LTFU and improve the long-term safety of AS. PATIENT SUMMARY: With a median observation period of 32 mo, an estimated 10% of patients will be lost to follow-up at the 2 yr time point while on AS. African American men and generally unhealthy patients were at increased risk, and there was variability from one urology practice to another. There is ample opportunity to improve the quality of the performance of AS.

You have accessJournal of UrologyProstate Cancer: Localized: Active Surveillance I1 Apr 2018MP12-11 RATES AND RISK FACTORS OF LOST TO FOLLOW UP IN PROSTATE CANCER PATIENTS MANAGED WITH ACTIVE SURVEILLANCE Kevin Ginsburg, Gregory Auffenberg, Ji Qi, Isaac Powell, James Montie, David Miller, Michael Cher, and For the Michigan Urological Surgery Improvement Collaborative Kevin GinsburgKevin Ginsburg More articles by this author , Gregory AuffenbergGregory Auffenberg More articles by this author , Ji QiJi Qi More articles by this author , Isaac PowellIsaac Powell More articles by this author , James MontieJames Montie More articles by this author , David MillerDavid Miller More articles by this author , Michael CherMichael Cher More articles by this author , and For the Michigan Urological Surgery Improvement CollaborativeFor the Michigan Urological Surgery Improvement Collaborative More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.398AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Active surveillance (AS) has emerged as an appropriate management strategy for many men with prostate cancer (PC), however insufficient monitoring may increase the risk of undesired outcomes. We evaluated a large AS cohort across diverse practices in Michigan to determine rates of loss to follow-up (LTFU) and associated risk factors. METHODS MUSIC maintains a prospective registry of PC patients from 44 academic and community urology practices within the state of Michigan. We identified all patients in the registry managed with AS from 2011-2015. We defined LTFU as any 18-month period where no pertinent surveillance information was identified in the medical record by trained data abstractors (i.e., no PSA, prostate CT/MRI, or prostate biopsy). LTFU events were stratified as either (1) prolonged loss to follow up (PLTFU): a LTFU event with no further data entered; or (2) insufficient follow up (IFU): a LTFU event followed by subsequent data. We fit multivariable logistic regression models and compared adjusted rates of LTFU events across MUSIC practices. RESULTS Of 2211 men enrolled on AS from 2011-2015, 217 (9.8%) had a LTFU event. Of these, 184 (8.3%) patients had PLTFU and 33 (1.5%) had IFU. African American (AA) patients were more likely than Caucasian patients to be LTFU (17.0% vs 7.4%, p<0.05). In multivariable analyses, both AA race (OR 2.36, 95% CI 1.42-3.92) and Charlson comorbidity index (CCI) of ≥1 (OR 1.53, 95% CI 1.03-2.27) were independently associated with an increased likelihood of LTFU. There was wide variability in rates of LTFU across MUSIC practices, ranging from 2.6% to 41.4% of patients entering AS, p<0.05 (Figure 1). CONCLUSIONS Nearly ten percent of men placed on AS become LTFU, representing suboptimal implementation of this management strategy. Patient-specific factors associated with being LTFU include AA race and higher burden of medical co-morbidity. Practice-level variability in LTFU may reveal opportunities to identify systems of care used in higher-performing practices that can reduce LTFU across all sites thereby improving the long-term safety of AS for men with early-stage PC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e139-e140 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Kevin Ginsburg More articles by this author Gregory Auffenberg More articles by this author Ji Qi More articles by this author Isaac Powell More articles by this author James Montie More articles by this author David Miller More articles by this author Michael Cher More articles by this author For the Michigan Urological Surgery Improvement Collaborative More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract In 2017 the US Preventive Services Task Force (USPSTF) reevaluated recommendation included support for screening men aged 55 to 69 years, but did not include African American men (AAM) because of lack of evidence. Their recommendation was based on evidence from a European study. However, in 2015 we reported (Powell et al., CEBP) that prostate cancer (PCa) survival among AAM was significantly worse than European American men (EAM) before PSA screening, but after the advent of PSA testing, 1995 to 2005, PCa survival was found to be similar among AAM compared to EAM. Another study reported that screening should begin for AAM at least nine years before EAM testing. Therefore AAM should begin PSA screening at approximately age 45 years. These studies were not included in the most recent USPSTF analysis. Even though survival is currently similar among AAM and EAM, the risk of PCa diagnosis has been reported to be 60% greater among AAM than other ethnicities and the mortality rate reported as 2 to 3 times greater among AAM than other ethnicities by SEER (Surveillance Epidemiology and End Results) analysis from 1973 to 2014. Our team at Wayne State University/Karmanos Cancer Institute has reported that PCa grows faster among AAM than among EAM based on our autopsy study, clinical data, and SEER data (CEBP, 2010). PCa starts at the same time among these groups but reaches distant disease at a 3 times greater proportion among AAM and at a younger age than EAM. This may account for much of the disproportionate mortality rate, but there are other factors that may contribute as well to such racial disparity of treatment. There is growing genetic and biologic evidence to support the disproportionate growth rate findings. Wallace et al. (Cancer Res 2008) reported that genes that facilitate PCa cell movement from the prostate gland to bone and are expressed in metastatic PCa tissue were greater among AAM than EAM. In 2013 we reported that genes associated with PCa are differentially expressed in AAM and EAM (Powell et al., CEBP). Functional driver genes more expressed among AAM were mostly proinflammatory cytokines, and those more expressed among EAM were lipid metabolism genes and ERG. It has been reported that proinflammatory genes are associated with aggressive PCa and activate transcription factors that activate the androgen receptor and cause PCa proliferation. They have other functions such as angiogenesis and being indirectly responsible for downregulation of cell adhesion molecules. They also play a role in several biologic pathways contributing to advanced disease. Further studies are needed such as validation of our data, comparison to other genetic panels, and identifying methods to personalize or individualize these genetic findings. Citation Format: Isaac J. Powell. Risk and appropriate screening of African-Americans for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA10.

No AccessJournal of UrologyLetter to the Editor/Errata1 Jan 2018Re: Pathological and Biochemical Outcomes among African-American and Caucasian Men with Low Risk Prostate Cancer in the SEARCH Database: Implications for Active Surveillance CandidacyM. S. Leapman, S. J. Freedland, W. J. Aronson, C. J. Kane, M. K. Terris, K. Walker, C. L. Amling, P. R. Carroll and M. R. Cooperberg J Urol 2016; 196: 1408–1414. Lance K. Heilbrun and Isaac J. Powell Lance K. HeilbrunLance K. Heilbrun More articles by this author and Isaac J. PowellIsaac J. Powell More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.08.102AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Re: Pathological and Biochemical Outcomes among African-American and Caucasian Men with Low Risk Prostate Cancer in the SEARCH Database: Implications for Active Surveillance Candidacy." The Journal of Urology, 199(1), pp. 305–306 References 1 : Multivariable Analysis: A Practical Guide for Clinicians and Public Health Researchers, 3rd ed. New York: Cambridge University Press2011: 88. Google Scholar 2 : Medical Biostatistics, 2nd ed. Boca Raton, Florida: Chapman and Hall/CRC2008: 533. Google Scholar 3 : Modern Regression Methods. New York: Wiley1996: 300. Google Scholar 4 : Applied Logistic Regression, 2nd ed. New York: Wiley2000: 138. Google Scholar © 2018 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 199Issue 1January 2018Page: 305-306 Advertisement Copyright & Permissions© 2018 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lance K. Heilbrun More articles by this author Isaac J. Powell More articles by this author Expand All Advertisement PDF downloadLoading ...

Background: African American men (AAM) have a 60% higher risk of being diagnosed with prostate cancer and a 2 to 3 times greater risk of dying from the disease compared to European American men (EAM). We previously reported evidence of molecular underpinnings for these disparities from high-throughput gene expression analysis of prostate cancer (PCa) specimens. The data showed that proinflammatory cytokine signaling factors, including IL6 and TGFB1, are significantly over-represented in PCa specimens from AAM. The limitation of that study, however, is that it did not investigate the potential molecular diversity for high-grade PCa, and it did not consider adjacent noncancer tissue. Methods: We conducted a pilot RNA-sequencing study of high-grade PCa, GS greater or equal to 7(4+3), and matched non-cancer adjacent prostate tissue specimens from AAM and EAM. We also studied the molecular biology of PCa cell lines derived from AAM and EAM tumors. Results: According to our genomic analysis, IL6 was once again relevant to our research, this time upregulated in PCa specimens from EAM, but also higher in the stromal compartment in AAM. Also, we noted that whether or not a PCa cell line expresses IL6 appears to be linked to TP53 mutation status. Moreover, cell lines derived from AAM (MDA-PCa-2b and RC77T), which are TP53 wild-type, did not express IL6 and showed an increased stem cell-like phenotype in response to IL6 treatment that was dose dependent. PCa cell lines that are TP53 mutant and expressed IL6 did not respond to exogenous IL6 treatment. We uncovered that in responsive PCa cell lines, IL6 treatment induced mRNA and protein expression of the epigenetic reader methyl CpG binding domain protein 2 (MBD2), more specifically the alternative mRNA splicing variant MBD2_v2. Further investigation validated that this short isoform promotes self-renewal and expansion of PCa stem cell-like cells. Conclusion: The outcomes suggest that there may be a dual nature for IL6 signaling in PCa that remains to be understood, yet contributes to the molecular diversity of high-grade prostate cancer and race disparities. Citation Format: Emily Girsch, Bin Bao, Cristina Mitrea, Wael A. Sakr, Gregory Dyson, Isaac Powell, Aliccia Bollig-Fischer. The role of epigenetic reader and alternative mRNA splicing variant MBD2_v2 in IL6 signaling in prostate cancer [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B58.

MicroRNAs (miRNAs) constitute short non-coding RNAs that can post-transcriptionally modulate the expression of many oncogenes and tumor suppressor genes engaged in key cellular processes. Deregulated serum miRNA signatures have been detected in various solid cancers including prostate cancer, suggesting that circulating miRNAs could function as non-invasive biomarkers of tumor emergence and progression. To determine whether serum miRNA expression levels are different between patients with aggressive and non-aggressive prostate cancer, we analyzed a panel of miRNAs from the blood of African American (AA) prostate cancer patients using a new recursive partitioning method that allows hypothesis testing of each split. We observed that both extrema of circulating miR-17, i.e. upregulation and downregulation, are associated with aggressive prostate cancer. A similar effect was observed in tumor samples from a separate dataset representing a different population of prostate cancer patients and in AA prostate cancer samples from the TCGA. The dual effect is consistent with the contradictory findings on the role of miR-17 in prostate cancer progression, whereby it controls important oncogenic and tumor-suppressive genes.