Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer.

Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2-12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.

Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.

BACKGROUND: Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs). METHODS: Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score. RESULTS: Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001). CONCLUSIONS: In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.

Diagnosis and management of neuroendocrine prostate cancer.

BACKGROUND: Although most patients with prostate cancer (PC) respond to initial androgen deprivation therapy (ADT), castration-resistant disease invariably develops. Progression to treatment-emergent neuroendocrine PC (t-NEPC) represents a unique mechanism of resistance to androgen receptor (AR)-targeted therapy in which lineage plasticity and neuroendocrine differentiation induce a phenotypic switch from an AR-driven adenocarcinoma to an AR-independent NEPC. t-NEPC is characterized by an aggressive clinical course, increased resistance to AR-targeted therapies, and a poor overall prognosis. METHODS: This review provides an overview of our current knowledge of NEPC, with a focus on the unmet needs, diagnosis, and clinical management of t-NEPC. RESULTS: Evidence extrapolated from the literature on small cell lung cancer or data from metastatic castration-resistant PC (mCRPC) cohorts enriched for t-NEPC suggests an increased sensitivity to platinum-based chemotherapy. However, optimal strategies for managing t-NEPC have not been established, and prospective clinical trial data are limited. Intertumoral heterogeneity within a given patient, as well as the lack of robust molecular or clinical biomarkers for early detection, often lead to delays in diagnosis and prolonged treatment with suboptimal strategies (i.e., conventional chemohormonal therapies for mCRPC), which may further contribute to poor outcomes. CONCLUSIONS: Recent advances in genomic and molecular classification of NEPC and the development of novel biomarkers may facilitate an early diagnosis, help to identify promising therapeutic targets, and improve the selection of patients most likely to benefit from NEPC-targeted therapies.

Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models. METHODS: Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression. RESULTS: Common adverse effects included rash (31.7% Grades 1-2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1-2), diarrhoea (37% Gr 1-2), and hypertension (17% Gr 1-2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D. CONCLUSIONS: The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02833883.

Large remodeling of the Myc-induced cell surface proteome in B cells and prostate cells creates new opportunities for immunotherapy.

MYC is a powerful transcription factor overexpressed in many human cancers including B cell and prostate cancers. Antibody therapeutics are exciting opportunities to attack cancers but require knowledge of surface proteins that change due to oncogene expression. To identify how MYC overexpression remodels the cell surface proteome in a cell autologous fashion and in different cell types, we investigated the impact of MYC overexpression on 800 surface proteins in three isogenic model cell lines either of B cell or prostate cell origin engineered to have high or low MYC levels. We found that MYC overexpression resulted in dramatic remodeling (both up- and down-regulation) of the cell surfaceome in a cell type-dependent fashion. We found systematic and large increases in distinct sets of >80 transporters including nucleoside transporters and nutrient transporters making cells more sensitive to toxic nucleoside analogs like cytarabine, commonly used for treating hematological cancers. Paradoxically, MYC overexpression also increased expression of surface proteins driving cell turnover such as TNFRSF10B, also known as death receptor 5, and immune cell attacking signals such as the natural killer cell activating ligand NCR3LG1, also known as B7-H6. We generated recombinant antibodies to these two targets and verified their up-regulation in MYC overexpression cell lines and showed they were sensitive to bispecific T cell engagers (BiTEs). Our studies demonstrate how MYC overexpression leads to dramatic bidirectional remodeling of the surfaceome in a cell type-dependent but functionally convergent fashion and identify surface targets or combinations thereof as possible candidates for cytotoxic metabolite or immunotherapy.

Cardiovascular Health of Middle-Aged U.S. Adults by Income Level, 1999 to March 2020 : A Serial Cross-Sectional Study.

BACKGROUND: Although cardiovascular mortality has increased among middle-aged U.S. adults since 2011, how the burden of cardiovascular risk factors has changed for this population by income level over the past 2 decades is unknown. OBJECTIVE: To evaluate trends in the prevalence, treatment, and control of cardiovascular risk factors among low-income and higher-income middle-aged adults and how social determinants contribute to recent associations between income and cardiovascular health. DESIGN: Serial cross-sectional study. SETTING: NHANES (National Health and Nutrition Examination Survey), 1999 to March 2020. PARTICIPANTS: Middle-aged adults (aged 40 to 64 years). MEASUREMENTS: Age-standardized prevalence of hypertension, diabetes, hyperlipidemia, obesity, and cigarette use; treatment rates for hypertension, diabetes, and hyperlipidemia; and rates of blood pressure, glycemic, and cholesterol control. RESULTS: The study population included 20 761 middle-aged adults. The prevalence of hypertension, diabetes, and cigarette use was consistently higher among low-income adults between 1999 and March 2020. Low-income adults had an increase in hypertension over the study period (37.2% [95% CI, 33.5% to 40.9%] to 44.7% [CI, 39.8% to 49.5%]) but no changes in diabetes or obesity. In contrast, higher-income adults did not have a change in hypertension but had increases in diabetes (7.8% [CI, 5.0% to 10.6%] to 14.9% [CI, 12.4% to 17.3%]) and obesity (33.0% [CI, 26.7% to 39.4%] to 44.0% [CI, 40.2% to 47.7%]). Cigarette use was high and stagnant among low-income adults (33.2% [CI, 28.4% to 38.0%] to 33.9% [CI, 29.6% to 38.3%]) but decreased among their higher-income counterparts (18.6% [CI, 13.5% to 23.7%] to 11.5% [CI, 8.7% to 14.3%]). Treatment and control rates for hypertension were unchanged in both groups (>80%), whereas diabetes treatment rates improved only among the higher-income group (58.4% [CI, 44.4% to 72.5%] to 77.4% [CI, 67.6% to 87.1%]). Income-based disparities in hypertension, diabetes, and cigarette use persisted in more recent years even after adjustment for insurance coverage, health care access, and food insecurity. LIMITATION: Sample size limitations could preclude detection of small changes in treatment and control rates. CONCLUSION: Over 2 decades in the United States, hypertension increased in low-income middle-aged adults, whereas diabetes and obesity increased in their higher-income counterparts. Income-based disparities in hypertension, diabetes, and smoking persisted even after adjustment for other social determinants of health. PRIMARY FUNDING SOURCE: National Institutes of Health.

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

Differential responses to taxanes and PARP inhibitors in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer.

BACKGROUND: PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions. METHODS: mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy. RESULTS: Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35). CONCLUSIONS: Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas.

BACKGROUND: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. PRIMARY ENDPOINT: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.

Health care and harm reduction provider perspectives on treating older adults who use non-medical opioids: a qualitative study set in Chicago.

BACKGROUND: Opioid overdose death rates are increasing for adults aged 55 and older, with especially high rates in large urban areas. In parallel, admissions to treatment programs for older adults using illicit substances are increasing as well. Despite these trends, there is a lack of information about older adults who use non-medical opioids (NMO) and even less knowledge about their health and service encounters. Conducted in Chicago, Illinois, this qualitative study explores the perspectives of health care and harm reduction service providers who work with older adults using non-medical opioids. METHODS: The study used snowball sampling to locate participants with expertise in working with older adults who use non-medical opioids. In total, we conducted 26 semi-structured interviews from September 2021-August 2022. We explored questions regarding participants' perceptions of older adult opioid use patterns, comorbidities, and involvement in harm reduction outreach and opioid use disorder treatment. RESULTS: Many of the providers we interviewed consider older adults who use NMO as a distinct population that employ unique use behaviors with the intent to protect them from opioid overdose. However, these same unique behaviors may potentiate their risk for overdose in today's climate. Providers report initial encounters that are not care seeking for opioid use and primarily oriented around health conditions. Older adults who use non-medical opioids are seen as complex patients due to the need to diagnostically untangle symptoms of substance use from co-morbidities and conditions associated with aging. Treatment for this population is also viewed as complicated due to the interactions between aging, comorbidities, and substance use. Providers also noted that older adults who use NMO have use behaviors that make them less visible to outreach and treatment service providers, potentially putting them at increased risk for overdose and health conditions associated with opioid use. CONCLUSIONS: Findings from this study are intended to inform future research on care provision for older adults who use non-medical opioids and may be especially applicable to large urban reas with histories of opioid use dating back to earlier drug epidemics of the 1970s, 1980s, and 1990s.

Diabetes Screening by Race and Ethnicity in the United States: Equivalent Body Mass Index and Age Thresholds.

BACKGROUND: Racial/ethnic minority populations in the United States have increased rates of diabetes compared with White populations. The 2021 guidelines from the U.S. Preventive Services Task Force recommend diabetes screening for adults aged 35 to 70 years with a body mass index (BMI) of 25 kg/m2 or greater. OBJECTIVE: To determine the BMI threshold for diabetes screening in major racial/ethnic minority populations with benefits and harms equivalent to those of the current diabetes screening threshold in White adults. DESIGN: Cross-sectional study. SETTING: NHANES (National Health and Nutrition Examination Survey), 2011 to 2018. PARTICIPANTS: Nonpregnant U.S. adults aged 18 to 70 years (n = 19 335). MEASUREMENTS: A logistic regression model was used to estimate diabetes prevalence at various BMIs for White, Asian, Black, and Hispanic Americans. For each racial/ethnic minority group, the equivalent BMI threshold was defined as the BMI at which the prevalence of diabetes in 35-year-old persons in that group is equal to that in 35-year-old White adults at a BMI of 25 kg/m2. Ranges were estimated to account for the uncertainty in prevalence estimates for White and racial/ethnic minority populations. RESULTS: Among adults aged 35 years with a BMI of 25 kg/m2, the prevalence of diabetes in Asian Americans (3.8% [95% CI, 2.8% to 5.1%]), Black Americans (3.5% [CI, 2.7% to 4.7%]), and Hispanic Americans (3.0% [CI, 2.1% to 4.2%]) was significantly higher than that in White Americans (1.4% [CI, 1.0% to 2.0%]). Compared with a BMI threshold of 25 kg/m2 in White Americans, the equivalent BMI thresholds for diabetes prevalence were 20 kg/m2 (range, <18.5 to 23 kg/m2) for Asian Americans, less than 18.5 kg/m2 (range, <18.5 to 23 kg/m2) for Black Americans, and 18.5 kg/m2 (range, <18.5 to 24 kg/m2) for Hispanic Americans. LIMITATION: Sample size limitations precluded assessment of heterogeneity within racial/ethnic groups. CONCLUSION: Among U.S. adults aged 35 years or older, offering diabetes screening to Black Americans and Hispanic Americans with a BMI of 18.5 kg/m2 or greater and Asian Americans with a BMI of 20 kg/m2 or greater would be equivalent to screening White adults with a BMI of 25 kg/m2 or greater. Using screening thresholds specific to race/ethnicity has the potential to reduce disparities in diabetes diagnosis. PRIMARY FUNDING SOURCE: Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology.

Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance.

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.

Cardiovascular Risk Factor Prevalence, Treatment, and Control in US Adults Aged 20 to 44 Years, 2009 to March 2020.

Importance: Declines in cardiovascular mortality have stagnated in the US over the past decade, in part related to worsening risk factor control in older adults. Little is known about how the prevalence, treatment, and control of cardiovascular risk factors have changed among young adults aged 20 to 44 years. Objective: To determine if the prevalence of cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, obesity, and tobacco use), treatment rates, and control changed among adults aged 20 to 44 years from 2009 through March 2020, overall and by sex and race and ethnicity. Design, Setting, and Participants: Serial cross-sectional analysis of adults aged 20 to 44 years in the US participating in the National Health and Nutrition Examination Survey (2009-2010 to 2017-March 2020). Main Outcomes and Measures: National trends in the prevalence of hypertension, diabetes, hyperlipidemia, obesity, and smoking history; treatment rates for hypertension and diabetes; and blood pressure and glycemic control in those receiving treatment. Results: Among 12 924 US adults aged 20 to 44 years (mean age, 31.8 years; 50.6% women), the prevalence of hypertension was 9.3% (95% CI, 8.1%-10.5%) in 2009-2010 and 11.5% (95% CI, 9.6%-13.4%) in 2017-2020. The prevalence of diabetes (from 3.0% [95% CI, 2.2%-3.7%] to 4.1% [95% CI, 3.5%-4.7%]) and obesity (from 32.7% [95% CI, 30.1%-35.3%] to 40.9% [95% CI, 37.5%-44.3%]) increased from 2009-2010 to 2017-2020, while the prevalence of hyperlipidemia decreased (from 40.5% [95% CI, 38.6%-42.3%] to 36.1% [95% CI, 33.5%-38.7%]). Black adults had high rates of hypertension across the study period (2009-2010: 16.2% [95% CI, 14.0%-18.4%]; 2017-2020: 20.1% [95% CI, 16.8%-23.3%]), and significant increases in hypertension were observed among Mexican American adults (from 6.5% [95% CI, 5.0%-8.0%] to 9.5% [95% CI, 7.3%-11.7%]) and other Hispanic adults (from 4.4% [95% CI, 2.1%-6.8%] to 10.5% [95% CI, 6.8%-14.3%]), while Mexican American adults had a significant rise in diabetes (from 4.3% [95% CI, 2.3%-6.2%] to 7.5% [95% CI, 5.4%-9.6%]). The percentage of young adults treated for hypertension who achieved blood pressure control did not significantly change (from 65.0% [95% CI, 55.8%-74.2%] in 2009-2010 to 74.8% [95% CI, 67.5%-82.1%] in 2017-2020], while glycemic control among young adults receiving treatment for diabetes remained suboptimal throughout the study period (2009-2010: 45.5% [95% CI, 27.7%-63.3%]) to 2017-2020: 56.6% [95% CI, 39.2%-73.9%]). Conclusions and Relevance: In the US, diabetes and obesity increased among young adults from 2009 to March 2020, while hypertension did not change and hyperlipidemia declined. There was variation in trends by race and ethnicity.

Medicare eligibility and healthcare access, affordability, and financial strain for low- and higher-income adults in the United States: A regression discontinuity analysis.

BACKGROUND: US policymakers are debating whether to expand the Medicare program by lowering the age of eligibility. The goal of this study was to determine the association of Medicare eligibility and enrollment with healthcare access, affordability, and financial strain from medical bills in a contemporary population of low- and higher-income adults in the US. METHODS AND FINDINGS: We used cross-sectional data from the National Health Interview Survey (2019) to examine the association of Medicare eligibility and enrollment with outcomes by income status using a local randomization-based regression discontinuity approach. After weighting to account for survey sampling, the low-income group consisted of 1,660,188 adults age 64 years and 1,488,875 adults age 66 years, with similar baseline characteristics, including distribution of sex (59.2% versus 59.7% female) and education (10.8% versus 12.5% with bachelor's degree or higher). The higher-income group consisted of 2,110,995 adults age 64 years and 2,167,676 adults age 66 years, with similar distribution of baseline characteristics, including sex (40.0% versus 49.4% female) and education (41.0% versus 41.6%). The share of adults age 64 versus 66 years enrolled in Medicare differed within low-income (27.6% versus 87.8%, p < 0.001) and higher-income groups (8.0% versus 85.9%, p < 0.001). Medicare eligibility at 65 years was associated with a decreases in the percentage of low-income adults who delayed (14.7% to 6.2%; -8.5% [95% CI, -14.7%, -2.4%], P = 0.007) or avoided medical care (15.5% to 5.9%; -9.6% [-15.9%, -3.2%], P = 0.003) due to costs, and a larger decrease in the percentage who were worried about (66.5% to 51.1%; -15.4% [-25.4%, -5.4%], P = 0.003) or had problems (33.9% to 20.6%; -13.3% [-23.0%, -3.6%], P = 0.007) paying medical bills. In contrast, there were no significant associations between Medicare eligibility and measures of cost-related barriers to medication use. For higher-income adults, there was a large decrease in worrying about paying medical bills (40.5% to 27.5%; -13.0% [-21.4%, -4.5%], P = 0.003), a more modest decrease in avoiding medical care due to cost (3.5% to 0.6%; -2.9% [-5.3%, -0.5%], P = 0.02), and no significant association between eligibility and other measures of healthcare access and affordability. All estimates were stronger when examining the association of Medicare enrollment with outcomes for low and higher-income adults. Additional analyses that adjusted for clinical comorbidities and employment status were largely consistent with the main findings, as were analyses stratified by levels of educational attainment. Study limitations include the assumption adults age 64 and 66 would have similar outcomes if both groups were eligible for Medicare or if eligibility were withheld from both. CONCLUSIONS: Medicare eligibility and enrollment at age 65 years were associated with improvements in healthcare access, affordability, and financial strain in low-income adults and, to a lesser extent, in higher-income adults. Our findings provide evidence that lowering the age of eligibility for Medicare may improve health inequities in the US.

DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms.

INTRODUCTION: Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis. METHODS: This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the potential for therapeutic targeting of DLL3, and ongoing studies of DLL3-targeting therapies. Classification, incidence, pathogenesis, and current management of NEN are reviewed to provide biological context and illustrate the unmet clinical needs. DISCUSSION: DLL3 is overexpressed in many NENs, implicated in tumor progression, and is typically associated with poor clinical outcomes, particularly in patients with NEC. Targeted therapies using DLL3 as a homing beacon for cytotoxic activity mediated via several different mechanisms (eg, antibody-drug conjugates, T-cell engager molecules, CAR-Ts) have shown promising clinical activity in small-cell lung cancer (SCLC). DLL3 may be a clinically actionable target across NEN. CONCLUSIONS: Current treatment options for NEN do not provide sustained responses. DLL3 is expressed on the cell surface of many NEN types and is associated with poor clinical outcomes. Initial clinical studies targeting DLL3 therapeutically in SCLC have been promising, and additional studies are expanding this approach to the broader group of NEN.

Clinical translation of hyperpolarized 13 C pyruvate and urea MRI for simultaneous metabolic and perfusion imaging.

PURPOSE: The combined hyperpolarized (HP) 13 C pyruvate and urea MRI has provided a simultaneous assessment of glycolytic metabolism and tissue perfusion for improved cancer diagnosis and therapeutic evaluation in preclinical studies. This work aims to translate this dual-probe HP imaging technique to clinical research. METHODS: A co-polarization system was developed where [1-13 C]pyruvic acid (PA) and [13 C, 15 N2 ]urea in water solution were homogeneously mixed and polarized on a 5T SPINlab system. Physical and chemical characterizations and toxicology studies of the combined probe were performed. Simultaneous metabolic and perfusion imaging was performed on a 3T clinical MR scanner by alternatively applying a multi-slice 2D spiral sequence for [1-13 C]pyruvate and its downstream metabolites and a 3D balanced steady-state free precession (bSSFP) sequence for [13 C, 15 N2 ]urea. RESULTS: The combined PA/urea probe has a glass-formation ability similar to neat PA and can generate nearly 40% liquid-state 13 C polarization for both pyruvate and urea in 3-4 h. A standard operating procedure for routine on-site production was developed and validated to produce 40 mL injection product of approximately 150 mM pyruvate and 35 mM urea. The toxicology study demonstrated the safety profile of the combined probe. Dynamic metabolite-specific imaging of [1-13 C]pyruvate, [1-13 C]lactate, [1-13 C]alanine, and [13 C, 15 N2 ]urea was achieved with adequate spatial (2.6 mm × 2.6 mm) and temporal resolution (4.2 s), and urea images showed reduced off-resonance artifacts due to the JCN coupling. CONCLUSION: The reported technical development and translational studies will lead to the first-in-human dual-agent HP MRI study and mark the clinical translation of the first HP 13 C MRI probe after pyruvate.

Improving multiparametric MR-transrectal ultrasound guided fusion prostate biopsies with hyperpolarized 13 C pyruvate metabolic imaging: A technical development study.

PURPOSE: To develop techniques and establish a workflow using hyperpolarized carbon-13 (13 C) MRI and the pyruvate-to-lactate conversion rate (kPL ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies. METHODS: The integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized 13 C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of kPL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T2 -weighted anatomic images. Abdominal radiologists identified 13 C research biopsy targets based on the general recommendation of focal lesions with kPL >0.02(s-1 ), and created a targeting report for each study. Urologists conducted transrectal ultrasound-guided MR fusion biopsies, including the standard 1 H-mpMRI targets as well as 12-14 core systematic biopsies informed by the research 13 C-kPL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk. RESULTS: This study demonstrated the safety and technical feasibility of integrating hyperpolarized 13 C metabolic targeting into routine 1 H-mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate-specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13 C-kPL targeting, and scan-to-biopsy time was 2 weeks. Median number of 13 C targets was 1 (range: 1-2) per patient, measuring 1.0 cm (range: 0.6-1.9) in diameter, with a median kPL of 0.0319 s-1 (range: 0.0198-0.0410). CONCLUSIONS: This proof-of-concept work demonstrated the safety and feasibility of integrating hyperpolarized 13 C MR biomarkers to the standard mpMRI workflow to guide MR-transrectal ultrasound fusion biopsies.

In Vivo Profiling with 18F-YJH08 Reveals Diverse Tissue Patterns of Antagonist/Glucocorticoid Receptor Interactions.

Demonstrating target engagement in vivo is an important milestone in drug development, both to establish on target, on tissue interactions but also to identify potentially undesirable off tissue binding. The glucocorticoid receptor (GR) is a long-studied yet vexing drug target that has recently re-emerged as a potential druggable driver of many solid tumor types including breast and prostate cancer, and several antagonists are currently in early phase clinical trials. Since GR is also ubiquitously expressed in normal tissues, understanding antagonist/GR interactions in normal tissues and tumor is crucial to defining a therapeutic index. Herein, we demonstrate that the GR radioligand 18F-YJH08 can map drug/GR engagement in vivo. Profiling target engagement in vivo showed that the GR antagonists RU486 (mifepristone) and CORT125281 engaged GR in fewer normal tissues compared to ORIC-101 or the agonist dexamethasone. Furthermore, 18F-YJH08 detected GR in human prostate cancer tumor models and measured receptor binding by RU486. In summary, these data show for the first time that antagonist/GR interactions can be measured in vivo with 18F-YJH08, a finding with clinical relevance as GR antagonists and 11C-YJH08 are currently in clinical trials.