Cartilage is a dense connective tissue with limited self-repair capabilities. Mesenchymal stem cell (MSC) laden hydrogels are commonly used for fibrocartilage and articular cartilage tissue engineering, however they typically lack the mechanical integrity for implantation into high load bearing environments. This has led to increased interested in 3D bioprinting of cell laden hydrogel bioinks reinforced with stiffer polymer fibres. The objective of this study was to compare a range of commonly used hydrogel bioinks (agarose, alginate, GelMA and BioINK™) for their printing properties and capacity to support the development of either hyaline cartilage or fibrocartilage in vitro. Each hydrogel was seeded with MSCs, cultured for 28 days in the presence of TGF-β3 and then analysed for markers indicative of differentiation towards either a fibrocartilaginous or hyaline cartilage-like phenotype. Alginate and agarose hydrogels best supported the development of hyaline-like cartilage, as evident by the development of a tissue staining predominantly for type II collagen. In contrast, GelMA and BioINK (a PEGMA based hydrogel) supported the development of a more fibrocartilage-like tissue, as evident by the development of a tissue containing both type I and type II collagen. GelMA demonstrated superior printability, generating structures with greater fidelity, followed by the alginate and agarose bioinks. High levels of MSC viability were observed in all bioinks post-printing (∼80%). Finally we demonstrate that it is possible to engineer mechanically reinforced hydrogels with high cell viability by co-depositing a hydrogel bioink with polycaprolactone filaments, generating composites with bulk compressive moduli comparable to articular cartilage. This study demonstrates the importance of the choice of bioink when bioprinting different cartilaginous tissues for musculoskeletal applications.

Background: Although there are considerable racial and ethnic disparities in prostate cancer incidence and mortality in the United States and globally, clinical trials often do not reflect disease incidence across racial and ethnic subgroups. This study aims to comprehensively review the reporting of race and ethnicity data and the representation of race and ethnicity across prostate cancer treatment-, prevention-, and screening-based clinical trials.Methods: Seventy-two global phase III and IV prevention, screening, and treatment prostate cancer clinical trials with enrollment start dates between 1987 and 2016 were analyzed in this study, representing a total of 893,378 individual trial participants. Availability and representation of race and ethnicity data by trial funding type, temporal changes in the racial/ethnic diversity of participants, and geographic representation of countries were assessed.Results: Of the 72 trials analyzed, 59 (81.9%) had available race data, and 11 (15.3%) of these trials additionally reported ethnicity. Of the trials reporting data, participants were overwhelmingly white men (with the highest proportion in U.S. nonpublicly funded trials), comprising over 96% of the study population. The proportion of white participants in prostate cancer clinical trials has remained at over 80% since 1990. Geographically, Africa and the Caribbean were particularly underrepresented with only 3% of countries included.Conclusions: Trial participants continue to be majority white despite the known racial disparities in prostate cancer clinical outcomes.Impact: Current and future trials must use novel recruitment strategies to ensure enrollment of underrepresented men. Targeting the inclusion of African and Caribbean medical centers is crucial to achieve equity in representation.

Prostate cancer disproportionately affects racial and ethnic minority populations. Reasons for disparate outcomes among minority patients are multifaceted and complex, involving factors at the patient, provider, and system levels. Although advancements in our understanding of disease biology have led to novel therapeutics for men with advanced prostate cancer, including the introduction of biomarker-driven therapeutics, pivotal translational studies and clinical trials are underrepresented by minority populations. Despite attempts to bridge the disparities gap, there remains an unmet need to expand minority engagement and participation in clinical trials to better define the impact of therapy on efficacy outcomes, quality of life, and role of biomarkers in diverse patient populations. The IRONMAN registry (ClinicalTrials.gov identifier: NCT03151629 ), a global, prospective, population-based study, was borne from this unmet medical need to address persistent gaps in our knowledge of advanced prostate cancer. Through integrated collection of clinical outcomes, patient-reported outcomes, epidemiologic data, and biospecimens, IRONMAN has the goal of expanding our understanding of how and why prostate cancer outcomes differ by race and ethnicity. To this end, the Diversity Working Group of the IRONMAN registry has developed informed strategies for site selection, recruitment, engagement and retention, and trial design and eligibility criteria to ensure broad inclusion and needs awareness of minority participants. In concert with systematic strategies to tackle the complex levels of disparate care, our ultimate goal is to expand minority engagement in clinical research and bridge the disparities gap in prostate cancer care.

Background: Inflammation and focal atrophy are common features adjacent to prostate tumors. Limited evidence exists on whether these features have prognostic significance.Methods: In the Health Professionals Follow-Up Study and Physicians' Health Study, we studied 1,035 men diagnosed with prostate cancer. A genitourinary pathologist centrally reviewed tumor and normal areas of hematoxylin and eosin slides from prostate cancer specimens for the presence of acute and chronic inflammation, and four subtypes of focal atrophy. Cox proportional hazards models adjusted for potential confounders were used to estimate HRs and 95% confidence intervals (CI) for the association of these features with lethal prostate cancer, defined as development of metastatic disease or death during follow-up.Results: During a median of 12 years of follow-up, 153 men developed lethal prostate cancer. A total of 84% of men had histologic evidence of chronic inflammation and 30% had acute inflammation. Both chronic and acute inflammation were inversely associated with lethal prostate cancer in age-and lifestyle-adjusted models. Chronic inflammation remained inversely associated with lethal prostate cancer after additionally adjusting for prognostic clinical features (HR ¼ 0.45; 95% CI, 0.30-0.69 for mild and HR ¼ 0.51; 95% CI, 0.33-0.80 for moderate to severe). None of the atrophic lesions were associated with lethal prostate cancer.Conclusions: Our data suggest that the presence of inflammation, particularly chronic inflammation, in prostate cancer tissue is associated with better prognosis among patients with prostate cancer.Impact: This is the largest prospective cohort study to examine the association between inflammation, focal atrophy, and lethal prostate cancer.

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Background: How 5-alpha reductase inhibitor (5-ARI) use influences prostate cancer mortality is unclear. The objective of this study was to determine whether men taking 5-ARIs with regular healthcare access have increased prostate cancer mortality. Methods: We undertook two analyses in the Health Professionals Follow-up Study examining 5-ARI use, determined by biennial questionnaires, and prostate cancer. A cohort analysis followed 38,037 cancer-free men for prostate cancer incidence from 1996 through January 2017 and mortality through January 2019. A case-only analysis followed 4,383 men with localized/locally advanced prostate cancer for mortality over a similar period. Hazard ratios (HR) and 95% confidence intervals were calculated for prostate cancer incidence and mortality. Results: Men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Over 20 years of follow-up, 509 men developed lethal disease (metastases or prostate cancer death). Among men initially free from prostate cancer, 5-ARI use was not associated with developing lethal disease (HR 1.02, 0.71-1.46), but was associated with reduced rates of overall and localized disease (HR 0.71, 0.60-0.83). Among men diagnosed with prostate cancer, there was no association between 5-ARI use and cancer-specific (HR 0.78, 0.48-1.27) or overall survival (HR 0.88, 0.72-1.07). Conclusions: Men using 5-ARIs were less likely to be diagnosed with low-risk prostate cancer, without increasing long-term risk of lethal prostate cancer or cancer-specific death after diagnosis. Impact: Our results provide evidence that 5-ARI use is safe with respect to prostate cancer mortality in the context of regular healthcare access.

Background: Racial disparities in prostate cancer incidence and mortality rates are considerable. We previously found in the Health Professionals Follow-up Study (HPFS) that African-American men had an 80% higher prostate cancer risk than White men. With 21 additional years of follow-up and four-fold increase in cases, we undertook a contemporary analysis of racial differences in prostate cancer incidence and mortality in HPFS. Methods: For 47,679 men, we estimated HRs and 95% confidence intervals (CI) for the association between race and risk of prostate cancer through 2016 using Cox proportional hazards regression. Multivariable models (mHR) were adjusted for lifestyle, diet, family history, and PSA screening collected on biennial questionnaires. Results: 6,909 prostate cancer cases were diagnosed in White, 89 in African-American, and 90 in Asian-American men. African-Americans had higher prostate cancer incidence (mHR = 1.31; 95% CI, 1.06–1.62) and mortality (mHR = 1.67; 95% CI, 1.00–2.78), and lower PSA screening prevalence than White men. The excess risk was greater in the pre-PSA screening era (HR = 1.68; 95% CI, 1.14–2.48) than the PSA screening era (HR = 1.20; 95% CI, 0.93–1.56). Asian-Americans had lower prostate cancer risk (mHR = 0.74; 95% CI, 0.60–0.92), but similar risk of fatal disease compared with white men. Conclusions: Racial differences in prostate cancer incidence and mortality in HPFS are not fully explained by differences in lifestyle, diet, family history, or PSA screening. Impact: Additional research is necessary to address the disproportionately higher rates of prostate cancer in African-American men.

69 Background: While population-based estimates of advanced prostate cancer survivors are lacking, an estimated 180,000 men in the US are living with metastatic prostate cancer. Their survivorship experience is distinct from localized patients as they suffer quality of life detriments both due to the severity of disease and its therapies. We examined quality-of-life indictors among men in the IRONMAN global registry of advanced prostate cancer. Methods: IRONMAN (International Registry of Men with Advanced Prostate Cancer) is a population-based prospective study of men with newly diagnosed advanced, metastatic hormone-sensitive (mHSPC) and castration-resistant prostate cancer (CRPC) enrolled from 16 countries. We report data from first 1865 men enrolled, 1567 who completed a baseline Patient Reported Outcome Measure (PROM) in the US (N=581), Canada (N=245), Spain (N=166), UK (N=204), Australia (N=126), Switzerland (N=88), Sweden (N=70), Ireland (N=46), and Brazil (N=41). PROMs are collected at baseline and every three months using electronic (90%) or paper versions of validated questionnaires. Results: The cohort includes 1,128 men with mHSPC and 737 with CRPC. Based on self-report, 9% of men overall (18% in the US) are Black and 83% are white (78% in the US). Sleep problems were common among men at enrollment, with 59% of men reporting problems with insomnia. The prevalence was similarly high among men with mHSPC or CRPC disease. Ten percent of men reported that pain substantially interfered with daily activities, and 24% reported pain had some effect. Physical functioning was high among both mHSPC (median 93.3, 80-100) and CRPC (median 86.7, 73.3-100) patients based on EORTC QLQ-30. Global health status was similar between the two groups (median 75, 58.3 - 83.3). More than 25% of men reported some cognitive impairment at baseline. Financial difficulties due to the disease and treatment were quite high, ranging from 12% in Sweden, 16% in Canada and Spain, 34% in the US, and 46% in Brazil. Conclusions: Men with advanced prostate cancer experience a range of quality of life detriments which impair overall health. While at baseline, many of these measures were similar among men with mHSPC and CRPC, we will continue to monitor these over time to examine changes in quality of life associated with disease progression and treatments. A longer-term goal is to identify opportunities for intervention to improve quality of life and potentially improve survival. Clinical trial information: NCT03151629.