Recruitment strategies and consent rates in a national prospective colorectal cancer screening cohort: results from year 1 of the Voyage Study.

OBJECTIVE: To identify the optimal incentive protocol for maximising participation while managing study costs during the Voyage trial. DESIGN: Prospective cohort (Voyage trial) of colorectal cancer (CRC) incidence and mortality outcomes in individuals screened with multitarget stool DNA (mt-sDNA) served as the population. A subset was randomised to receive postage stamps as a pre-consent incentive, or as a post-consent incentive after completion of the consent and questionnaire. Descriptive statistics from year 1 are reported. RESULTS: During year 1 of the Voyage trial, a total of 600 258 individuals with mt-sDNA orders received at Exact Sciences Laboratories were randomly selected and invited to participate. Of those, 26 429 (4.4%) opted in, 14 365 of whom (54.3%) consented. The opt-in and consent samples were similar to the target population with respect to sex but differed by geographic residence and age (p<0.001). For the embedded incentive experiment, 2333 were randomised to the pre-incentive arm, while 2342 were randomised to the post-incentive arm. Overall consent rate in the incentive trial was 56.4% (60.9% for the pre-consent incentive arm (1421/2333) vs 52.0% for the post-consent incentive arm (1217/2342), p<0.001). Cost reduction was observed for the pre-consent incentive group, and higher response rates were seen among older versus younger individuals. CONCLUSIONS: Pre-consent incentive option was associated with a higher participation rate and lower costs and was used for the remainder of study recruitment. CRC incidence and mortality vary with age; thus, adjusting for differential participation by age and region will be important in analyses of Voyage data. TRIAL REGISTRATION NUMBER: NCT04124406.

Well-Child Visits for Early Detection and Management of Maternal Postpartum Hypertensive Disorders.

Importance: Innovative approaches are needed to address the increasing rate of postpartum morbidity and mortality associated with hypertensive disorders. Objective: To determine whether assessing maternal blood pressure (BP) and associated symptoms at time of well-child visits is associated with increased detection of postpartum preeclampsia and need for hospitalization for medical management. Design, Setting, and Participants: This is a pre-post quality improvement (QI) study. Individuals who attended the well-child visits between preimplementation (December 2017 to December 2018) were compared with individuals who enrolled after the implementation of the QI program (March 2019 to December 2019). Individuals were enrolled at an academic pediatric clinic. Eligible participants included birth mothers who delivered at the hospital and brought their newborn for well-child check at 2 days, 2 weeks, and 2 months. A total of 620 individuals were screened in the preintervention cohort and 680 individuals were screened in the QI program. Data was analyzed from March to July 2022. Exposures: BP evaluation and preeclampsia symptoms screening were performed at the time of the well-child visit. A management algorithm-with criteria for routine or early postpartum visits, or prompt referral to the obstetric emergency department-was followed. Main Outcome and Measures: Readmission due to postpartum preeclampsia. Comparisons across groups were performed using a Fisher exact test for categorical variables, and t tests or Mann-Whitney tests for continuous variables. Results: A total of 595 individuals (mean [SD] age, 27.2 [6.1] years) were eligible for analysis in the preintervention cohort and 565 individuals (mean [SD] age, 27.0 [5.8] years) were eligible in the postintervention cohort. Baseline demographic information including age, race and ethnicity, body mass index, nulliparity, and factors associated with increased risk for preeclampsia were not significantly different in the preintervention cohort and postintervention QI program. The rate of readmission for postpartum preeclampsia differed significantly in the preintervention cohort (13 individuals [2.1%]) and the postintervention cohort (29 individuals [5.6%]) (P = .007). In the postintervention QI cohort, there was a significantly earlier time frame of readmission (median [IQR] 10.0 [10.0-11.0] days post partum for preintervention vs 7.0 [6.0-10.5] days post partum for postintervention; P = .001). In both time periods, a total of 42 patients were readmitted due to postpartum preeclampsia, of which 21 (50%) had de novo postpartum preeclampsia. Conclusions and Relevance: This QI program allowed for increased and earlier readmission due to postpartum preeclampsia. Further studies confirming generalizability and mitigating associated adverse outcomes are needed.

The effect of reef morphology on coral recruitment at multiple spatial scales.

Coral reefs are in decline worldwide, making it increasingly important to promote coral recruitment in new or degraded habitat. Coral reef morphology-the structural form of reef substrate-affects many aspects of reef function, yet the effect of reef morphology on coral recruitment is not well understood. We used structure-from-motion photogrammetry and airborne remote sensing to measure reef morphology (rugosity, curvature, slope, and fractal dimension) across a broad continuum of spatial scales and evaluated the effect of morphology on coral recruitment in three broadcast-spawning genera. We also measured the effect of other environmental and biotic factors such as fish density, adult coral cover, hydrodynamic larval import, and depth on coral recruitment. All variables combined explained 72% of coral recruitment in the study region. Coarse reef rugosity and curvature mapped at ≥2 m spatial resolution-such as large colonies, knolls, and boulders-were positively correlated with coral recruitment, explaining 22% of variation in recruitment. Morphology mapped at finer scales (≤32 cm resolution) was not significant. Hydrodynamic larval import was also positively related to coral recruitment in Porites and Montipora spp., and grazer fish density was linked to significantly lower recruitment in all genera. In addition, grazer density, reef morphology, and hydrodynamic import had differential effects on coral genera, reflecting genus-specific life history traits, and model performance was lower in gonochoric species. Overall, coral reef morphology is a key indicator of recruitment potential that can be detected by remote sensing, allowing potential larval sinks to be identified and factored into restoration actions.

The Role of Individual-Level Socioeconomic Status on Nursing Home Placement Accounting for Neighborhood Characteristics.

OBJECTIVE: Independent living is desirable for many older adults. Although several factors such as physical and cognitive functions are important predictors for nursing home placement (NHP), it is also reported that socioeconomic status (SES) affects the risk of NHP. In this study, we aimed to examine whether an individual-level measure of SES is associated with the risk of NHP after accounting for neighborhood characteristics. DESIGN: A population-based study (Olmsted County, Minnesota, USA). SETTING AND PARTICIPANTS: Older adults (age 65+ years) with no prior history of NHP. METHODS: Electronic health records (EHR) were used to identify individuals with any NHP between April 1, 2012 (baseline date) and April 30, 2019. Association between the (HOUsing-based index of SocioEconomic Status (HOUSES) index, an individual-level SES measure based on housing characteristics of current residence, and risk of NHP was tested using random effects Cox proportional hazard model adjusting for area deprivation index (ADI), an aggregated SES measure that captures neighborhood characteristics, and other pertinent confounders such as age and chronic disease burden. RESULTS: Among 15,031 older adults, 3341 (22.2%) experienced NHP during follow-up period (median: 7.1 years). At baseline date, median age was 73 years old with 55% female persons, 91% non-Hispanic Whites, and median number of chronic conditions of 4. Accounting for pertinent confounders, the HOUSES index was strongly associated with risk of NHP (hazard ratio 1.89; 95% confidence interval 1.66‒2.15 for comparing the lowest vs highest quartiles), which was not influenced by further accounting for ADI. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that an individual-level SES measure capturing current individual-specific socioeconomic circumstances plays a significant role for predicting NHP independent of neighborhood characteristics where they reside. This study suggests that older adults who are at higher risk of NHP can be identified by utilizing the HOUSES index and potential individual-level intervention strategies can be applied to reduce the risk for those with higher risk.

Untapped policy avenues to protect coral reef ecosystems.

Coral reefs are experiencing severe decline, and urgent action is required at local and global scales to curb ecosystem loss. Establishing new regulations to protect corals, however, can be time consuming and costly, and it is therefore necessary to leverage existing legal instruments, such as policies originally designed to address terrestrial rather than marine activities, to prevent coral reef degradation. Focusing on the United States, but drawing on successful examples worldwide, we present actionable pathways to increase coral protections under legislation that was originally designed to advance clean freshwater, safe drinking water, and emergency management. We identify specific legal policies and procedures (e.g., industrial permit limits, nonpoint source management incentives, and floodplain restoration programs) that can curb coral reef pollution and can be extended to other countries with similar regulations in place. Coral reef practitioners should consider a broad array of currently underused, actionable, and intersecting environmental policies that can be applied to mitigate coral stress.

Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment.

We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study.We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC).At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4-4.5) or long-term (median 29 months; range 23.5-41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders. IMPLICATIONS: Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.

Screening Postoperative Hemoglobin after Robot-Assisted Radical Prostatectomy-Frequently Used, but Is It Necessary?

INTRODUCTION: Robot-assisted radical prostatectomy is associated with low rates of postoperative transfusion and hemorrhage. At our institution the decision to obtain screening hemoglobin testing after uncomplicated robot-assisted radical prostatectomy is left to surgeon discretion. It is unknown whether this testing represents high value care. We assessed the prevalence and clinical utility of hemoglobin testing after uncomplicated robot-assisted radical prostatectomy. METHODS: We retrospectively reviewed patients undergoing robot-assisted radical prostatectomy between 2002 and 2016. Patients transfused intraoperatively were excluded. Demographic and perioperative data were reviewed. In patients requiring blood transfusion and/or with hemorrhage clinical signs/symptoms of anemia were reviewed. The primary endpoint was rate of routine postoperative hemoglobin testing. Secondary endpoints included rates of postoperative transfusion and hemorrhage, rates of signs/symptoms of anemia in patients transfused postoperatively and/or with hemorrhage. RESULTS: A total of 3,405 patients were identified of whom 73.8% (2,514) underwent postoperative hemoglobin testing. Mean change relative to preoperative hemoglobin was -2.7±1.0 gm/dl with 10.2% (256) and 3.5% (87) experiencing a decrease in hemoglobin 4 gm/dl or greater and postoperative hemoglobin 10 gm/dl or less, respectively. Of patients undergoing at least 1 postoperative hemoglobin test subsequent testing was prompted for 13.4% (337). Of patients transfused (1.7%, 58) and/or with postoperative hemorrhage (1.5%, 48) with records available for review (46), 95.7% (44) had clinical signs/symptoms of anemia. CONCLUSIONS: Our results suggest that routine hemoglobin testing after uncomplicated prostatectomy should be performed when clinically indicated rather than as routine practice.

Nontuberculous Mycobacteria Show Differential Infectivity and Use Phospholipids to Antagonize LL-37.

Comparisons of infectivity among the clinically important nontuberculous mycobacteria (NTM) species have not been explored in great depth. Rapid-growing mycobacteria, including Mycobacterium abscessus and M. porcinum, can cause indolent but progressive lung disease. Slow-growing members of the M. avium complex are the most common group of NTM to cause lung disease, and molecular approaches can now distinguish between several distinct species of M. avium complex including M. intracellulare, M. avium, M. marseillense, and M. chimaera. Differential infectivity among these NTM species may, in part, account for differences in clinical outcomes and response to treatment; thus, knowing the relative infectivity of particular isolates could increase prognostication accuracy and enhance personalized treatment. Using human macrophages, we investigated the infectivity and virulence of nine NTM species, as well as multiple isolates of the same species. We also assessed their capacity to evade killing by the antibacterial peptide cathelicidin (LL-37). We discovered that the ability of different NTM species to infect macrophages varied among the species and among isolates of the same species. Our biochemical assays implicate modified phospholipids, which may include a phosphatidylinositol or cardiolipin backbone, as candidate antagonists of LL-37 antibacterial activity. The high variation in infectivity and virulence of NTM strains suggests that more detailed microbiological and biochemical characterizations are necessary to increase our knowledge of NTM pathogenesis.

Impact of metabolic syndrome on functional outcomes and complications of surgical treatment of prostate cancer.

BACKGROUND: Metabolic syndrome (MetS) has a negative impact on functional recovery and complications after many surgical procedures. AIM: To assess the role of Mets on functional outcomes and complications after radical prostatectomy (RP) for prostate cancer. PATIENTS AND METHODS: Complete data were collected from 5758 patients, undergoing RP at a single referral centers in a 10-year period and the presence of MetS before surgery was ascertained in 17.7% of them using a modified version of the IDF-AHA/NHLBI criteria. Outcomes included 1-year continence and potency rates, early (≤90 days) and late (>90 days) complications. RESULTS: Postoperative continence (no pads) was significantly less likely in MetS patients (75.4% vs 82.6%, P < .01), despite no difference in preoperative continence. Erections with or without therapy were reached in 55.8% of non-MetS and 41.8% of MetS patients (P < .01), in this case a significant difference in preoperative function was seen. No differences in early and late complications, except for wound infections (5.8% vs 3.9%, P < .01) were observed. CONCLUSIONS: In the present study RP was safe from the complications standpoint in MetS patients, but the presence of the syndrome was a significant risk factor for post-RP incontinence and impotence.

A Prospective Correlation of Tissue Histopathology With Nucleic Acid Yield in Metastatic Castration-Resistant Prostate Cancer Biopsy Specimens.

OBJECTIVE: To determine histopathologic, exome, and transcriptome nucleic acid material yield from prospectively collected metastatic tissue biopsy specimens in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial metastatic site core needle biopsies after study activation on May 17, 2013. Multiple cores were obtained, and from each core, 1- to 2-mm segments were separated and formalin fixed for histopathologic examination. Tumor purity was determined for DNA and RNA from the rest of the biopsy specimen. RNA quality was assessed by calculation of an RNA integrity number and a DV200 score. RESULTS: A total of 89 patients underwent 172 uniformly processed core needle biopsies (89 on visit 1 and 83 on visit 2) between May 30, 2013, and September 10, 2015. Metastatic sites biopsied included bone (131), lymph nodes (31), liver (5), lung (3), and pelvic soft tissues (2). Of the 172 biopsy specimens, 85 (49%) had at least one of the multiple cores positive for tumor on histopathologic examination (53 of 88 [60%] from visit 1 and 32 of 83 [39%] from visit 2; P=.006). Metastatic carcinoma was observed in 50 of 130 bone lesion specimens (38%), compared to 35 of 41 nonbone specimens (85%) (P<.001). More than 10% tumoral DNA purity was observed in 89% and 80% of visit 1 and visit 2 biopsy specimens, respectively. Similarly, more than 10% tumor RNA purity was observed in 79% of visit 1 vs 59% for visit 2 (P=.008). In all, 134 of 172 procedures (78%) yielded tumor material either by histopathologic or nucleic acid purity analysis. CONCLUSION: This study found that biopsy specimens from mCRPC sites yield adequate histopathologic, exome, and transcriptome material in most, but not all, cases. This finding has relevance for future genome sequencing studies on the introduction of targeted therapeutic agents. TRIAL REGISTRATION: clinicaltrials.gov Identifier: 01953640.

Role of Metabolic Syndrome on Perioperative and Oncological Outcomes at Radical Prostatectomy in a Low-risk Prostate Cancer Cohort Potentially Eligible for Active Surveillance.

BACKGROUND: Metabolic syndrome (MetS) is considered a potential risk factor for adverse outcomes after radical prostatectomy (RP). Furthermore, studies about the effect of MetS on low-risk prostate cancer (PCa) and its implications in active surveillance (AS) are limited. OBJECTIVE: To investigate the role of MetS (using International Diabetes Federation-American Heart Association/National Heart, Lung, and Blood Institute criteria) on perioperative and oncological outcomes after RP in low-risk PCa and in a subgroup potentially eligible for AS. DESIGN, SETTING, AND PARTICIPANTS: A total of 3662 patients treated with RP for low-risk PCa and further stratified as very low risk (VLR) PCa-prostate-specific antigen density of ≤0.15ng/ml/cm3, ≤2 cores involved, and no core with >50% cancer involvement-at a tertiary referral hospital were identified. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes analyzed were pathological outcomes, perioperative complications, biochemical failure (BCF), and overall survival. Pathological outcomes and complications were analyzed with logistic regression models. Kaplan-Meier curves and Cox proportional hazards models were used to analyze survival outcomes. RESULTS AND LIMITATIONS: In univariate/multivariate analyses, MetS was associated with upgrading and positive surgical margins in the entire cohort, upgrading only in the VLR group. In Kaplan-Meier analysis, MetS patients had a higher rate of overall death (p<0.0001) and BCF (p=0.03) for MetS patients. In the VLR group, no differences were found for BCF (p=0.064). Further, in Cox proportional hazards models, MetS was not associated with BCF (hazard ratio=1.23; 95% confidence interval [CI]=0.95-1.60, p=0.12). MetS patients had a higher rate of complications compared with non-MetS patients (23.7% vs 19.7%; p=0.01). In multivariate analysis, MetS was associated with a higher rate of complications (odds ratio=1.24, 95% CI=1.04-1.49, p=0.018) but did not impact the rate of major ones. This study is limited by its retrospective design. CONCLUSIONS: In low-risk PCa treated with RP but potentially eligible for AS, MetS impacted perioperative and pathological outcomes, suggesting further study of MetS in patients undergoing AS. PATIENT SUMMARY: Metabolic syndrome negatively impacts perioperative and pathological outcomes in low-risk prostate cancer patients treated with radical prostatectomy but potentially eligible for active surveillance, in a large American single-center cohort. These findings suggest the need for a more cautious approach to low-risk prostate cancer in patients with metabolic syndrome.

Impact of metabolic syndrome on oncologic outcomes at radical prostatectomy.

PURPOSE: The associations between metabolic syndrome (MetS) and prostate cancer (CaP) outcomes following radical prostatectomy (RP) are not clear. This study aims to understand the role of MetS in influencing oncological outcomes at RP. MATERIALS AND METHODS: Patients who underwent RP for CaP at our institution from 2000 to 2010 were identified; MetS prior to RP was ascertained with a modified version of the IDF-AHA/NHLBI using ICD-9 codes. Histopathological outcomes included surgical margins, pathological stage, and Gleason score (GS) upgrading. Long-term outcomes included biochemical recurrence (BCR), local recurrence, systemic progression, and CaP-specific mortality. Multivariable adjusted logistic regression and Cox proportional hazards regression assessed the association between MetS status and histopathological and long-term outcomes, respectively. RESULTS: Of 8,504 RP patients, 1,054 (12.4%) had MetS at the time of RP. MetS patients were older, had higher biopsy GS, but lower pre-op prostatic specific antigen (PSA), higher pathological GS, and larger prostate volume. Adjusted logistic regression suggested an association between MetS and positive margins (odds ratio [OR] = 1.22, P = 0.025) and GS upgrading (OR = 1.28, P = 0.002). There was evidence of an increased risk of local recurrence (hazard ratio [HR] = 1.33, P = 0.037) and CaP-specific mortality (HR = 1.58, P < 0.001) for MetS patients. There was no evidence to suggest an association with BCR or systemic progression. CONCLUSION: Men with MetS are at higher risk of GS upgrade and positive surgical margins at surgery, local recurrence, and CaP-specific mortality. Pathological stage, BCR, and systemic progression were not associated with MetS. Our data may be useful in patients' counseling, especially when active surveillance is an option.

Assessing the Impact of a Professional Development Program for Physician Assistant Program Directors.

PURPOSE: The growth of physician assistant (PA) programs nationally has stretched the available capacity of experienced PA program directors. To address this need, a professional developmental program was designed to provide new program directors with the knowledge, skills, and resources necessary to succeed in the role. This study sought to characterize the impact of program attendance over time. Data were collected from individuals representing 5 cohorts that participated in the annual Physician Assistant Education Association New Program Directors Retreat between 2011 and 2015. METHODS: An electronic survey was developed and sent to all 5 cohorts (n = 139). Anonymous responses were collected and quantitative data were analyzed in the aggregate and also by year of participation. Qualitative data were analyzed, and a thematic analysis was conducted. Results were compared with baseline data collected during the program registration process and with published national data on program director characteristics. RESULTS: Seventy-five program participants completed the survey, for a response rate of 57%. Program director stability, educational achievement, and involvement in leadership and service activities were found to be positive outcomes for individuals who had participated in the professional development program. CONCLUSION: Survey respondents reported positive outcomes after attending a professional development program; these outcomes are consistent with research on similar programs published in the literature. Our findings suggest that new program directors who participated in this professional development program not only derived career-stabilizing benefits but also succeeded in creating supportive peer networks while gaining greater confidence in their new academic role.

Serum chromogranin-A-based prognosis in metastatic castration-resistant prostate cancer.

OBJECTIVE: To determine the prognostic value of serum chromogranin-A (CGA) in a two-cohort study of men with metastatic castrate resistant prostate cancer (mCRPC) and to compare with circulating tumor cells (CTCs)-based prognosis. PATIENTS AND METHODS: A two-cohort-based evaluation for serum CGA for prognostication in CRPC stage was performed using a screening cohort of 256 men with mCRPC and an independent validation cohort of 92 men with mCRPC. In both cohorts, men receiving proton pump inhibitors and those with non-castrate levels of testosterone (>50 ng/dl) were excluded. Serum CGA was measured in a homogeneous automated immunofluorescent assay using time-resolved amplified cryptate emission. In the validation cohort, CTC enumeration was also performed using the FDA-cleared CELLSEARCH® CTC test. Cox proportional hazard regression models were used for prognostic association of serum CGA and CTC counts with overall survival. RESULTS: In the screening cohort, 200 men were eligible for analysis. The median serum CGA was 100.3 ng/mL (interquartile range: 67-161.3) and 34/200 were above the reference range. In the subset of men with Gleason scores ≥ 8, elevated CGA was associated with shorter overall survival [hazard ratio (HR) 2.19, p = 0.017]. In the validation cohort for 71 men eligible for analysis, the median serum CGA was 90 ng/mL (interquartile range: 55-156) and 31/71 patients had an elevated CGA. 51% of patients had a Gleason score ≥ 8 and 66/71 patients had CTCs enumerated with 26/66 with a CTC count ≥ 5 per 7.5 ml blood sample (unfavorable). Both elevated serum CGA (HR: 1.91, p = 0.043) and unfavorable CTC counts (HR: 2.97, p = 0.0012) were adversely associated with overall survival and patients with ≥ 5 CTCs and elevated serum CGA had the shortest overall survival (HR: 3.76, p = 0.008). CONCLUSION: Elevated serum CGA was negatively associated with OS in men with mCRPC. Serum CGA represents a prognostic biomarker that may complement CTC enumeration.

Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients.

BACKGROUND: The prognostic significance of plasma cell-free DNA (cfDNA) androgen receptor amplification (ARamp) in metastatic castration-resistant prostate cancer (mCRPC) compared with circulating tumor cell (CTC) counts is not known. METHODS: As part of correlative aims of a prospective study in mCRPC, concurrent and serial collections of plasma and CTCs were performed. Specimen collections were performed at baseline after progression on androgen deprivation therapy and then 12 weeks later. QuantStudio3D digital PCR system was used to determine plasma cfDNA AR copy number variations and Cell search assay for enumerating CTC counts. Association of baseline cfDNA ARamp status/CTC counts with overall survival (OS) (primary goal) was evaluated using Kaplan-Meier method and log-rank test (p ≤ 0.05 for significance) and receiver operator curves (ROCs) for ARamp status and CTC counts ≥5. A multivariate analysis was performed using Cox regression models that included ARamp, CTC counts, and other clinical factors. RESULTS: ARamp was detected in 19/70 patients at baseline. At the time of analysis, 28/70 patients had died (median follow-up 806 days; interquartile range: 535-966). ARamp was associated with poor OS (2-year OS of 35% in ARamp vs. 71% in non-ARamp; log-rank p value ≤0.0001). Baseline CTC counts ≥5 (vs. <5) was also associated with poor survival (2-year OS of 44 vs. 74%; log-rank p = 0.001). ROC analysis demonstrated area under the curve of 0.66 for ARamp-based prognosis and 0.68 for CTC count-based prognosis (p = 0.84 for difference). The best two variables included for multivariable analysis were ARamp and CTC counts ≥5; however, the two-factor model was not significantly better than using ARamp alone for predicting survival (hazard ratio = 5.25; p = 0.0002). CONCLUSIONS: CTCs and plasma cfDNA ARamp were observed to have equal prognostic value in mCRPC. Larger cohorts that incorporate molecular and clinical factors are needed to further refine prognosis in CRPC.

Long-term Follow-up of a Matched Cohort Study Evaluating the Role of Adjuvant Radiotherapy for Organ-confined Prostate Cancer With a Positive Surgical Margin.

OBJECTIVE: To evaluate if adjuvant radiation therapy (ART) is associated with improved long-term oncologic outcomes for pT2N0R1 prostate cancer (PCa). METHODS: Men with pT2N0 PCa and a single positive surgical margin following radical prostatectomy and pelvic lymphadenectomy were identified (1987-1996). Men who received ART were matched 1:1 to men who did not receive ART based on age, year of surgery, Gleason score, preoperative prostate-specific antigen, site of positive surgical margin, and DNA ploidy. Biochemical recurrence (BCR), local recurrence, distant metastasis, and overall survival (OS) were compared between groups in time-to-event analyses. RESULTS: The cohort included 152 men (76 per group) with a median follow-up of 20 years (interquartile range 19,22). ART was associated with a lower cumulative incidence of BCR (25% vs 52%; P <.001) and local recurrence (3% vs 12%; P = .03), but no significant differences in cumulative incidence of distant metastasis (10% vs 7%; P = .44) or in probability of OS (56% vs 68%; P = .08) at 20 years. In competing risks models, receipt of ART was associated with reduced risks of BCR (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.23-0.70; P <.001) and local recurrence (HR = 0.21; 95% CI .05-0.98; P = .05), but not distant metastasis (HR = 1.56; 95% CI 0.51-4.75; P = .43). In the Cox model, ART was not associated with improved OS (HR = 1.56; 95% CI 0.94-2.57; P = .08). CONCLUSION: ART was associated with reduced risks of BCR and local recurrence for men with pT2N0R1 PCa. However, ART was not significantly associated with metastasis-free or OS benefits, as recurrences in these patients generally followed an indolent trajectory with 20 years of median follow-up.

Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance.

Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies.Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate.Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3' terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31-12.2; P = 0.02).Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC. Clin Cancer Res; 23(16); 4704-15. ©2017 AACR.

Associations Between Patient and Anthropometric Characteristics and Aromatase Inhibitor Discontinuation.

BACKGROUND: Toxicity can lead to noncontinuation of adjuvant endocrine therapy. We hypothesized that endocrine therapy-induced changes in grip strength would predict for early discontinuation of therapy because of musculoskeletal toxicity and would be associated with a patient's body mass index. PATIENTS AND METHODS: Postmenopausal women with breast cancer starting a new adjuvant endocrine therapy were enrolled in the present study. The patients were monitored for 12 months to assess their symptoms, endocrine therapy adherence and change in grip strength and baseline body mass index. The association between the change in grip strength and interval to discontinuation was assessed using a joint longitudinal and survival model. RESULTS: Of the 93 aromatase inhibitor (AI)-treated and 22 tamoxifen-treated patients, 40.9% and 9% discontinued endocrine therapy within 12 months because of toxicity, respectively (P = .019). A trend was seen toward a greater decrease in grip strength in the AI-treated patients over time (P = .055); however, the decrease was not significantly associated with the interval to discontinuation (P = .96). Receipt of an AI (hazard ratio, 5.49; P = .019) and baseline pain (hazard ratio, 1.19; P = .004) significantly decreased the interval to discontinuation. CONCLUSION: In contrast with the findings from previous reports, the change in grip strength in our study was not associated with the interval to discontinuation of AI therapy. Future research should focus on proactive treatment of patients at increased risk of AI intolerance, such as those with high levels of pre-existing pain.