Publications by authors named "David Elashoff"

411 Publications

Impact of Perceived Stress During the SARS-CoV-2 Pandemic on Rheumatoid Arthritis Patients' Disease Activity: An Online Survey.

J Clin Rheumatol 2022 Jun 3. Epub 2022 Jun 3.

Department of Medicine, University of California-Los Angeles, Los Angeles, CA.

Introduction/objectives: Psychological stress worsens rheumatoid arthritis (RA) disease activity, and the COVID-19 pandemic has increased stress/anxiety in rheumatic patients. The purpose of this study was to determine if stress during the COVID-19 pandemic specifically impacts RA disease activity as reported by the patient.

Method: This was a cross-sectional COVID-19 RA survey study. University of California, Los Angeles rheumatology clinic patients were emailed a link to a survey in July and November 2020. The 30-question survey pertained to COVID-19-related stress, RA disease activity, and demographics. For the survey responders, anti-cyclic citrullinated antibody, rheumatoid factor, and age were extracted from the electronic health record. Analyses were performed to examine the association between the 4-item Perceived Stress Scale (PSS-4) and other COVID-19-related stress measures with the Routine Assessment of Patient Index Data 3 (RAPID3).

Results: A total of 1138/5037 subjects completed the emailed survey (22.6% response rate). When examining responses across RAPID3 categories (near remission, low, moderate, and high disease severity), there were significant increases in PSS-4 and other stress variables. Multiple linear regression models showed that PSS-4, financial stress, age, seropositivity, disease duration, and Black race were independently associated with worsened RAPID3 scores, when controlling for other confounding factors.

Conclusions: This study suggests that stress overall negatively impacts RAPID3, and Black RA patients have higher RAPID3 scores during the COVID-19 pandemic. Despite colossal efforts to combat the pandemic, RA patients currently suffer from stress/anxiety, and methods to mitigate these psychological effects are needed.
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http://dx.doi.org/10.1097/RHU.0000000000001861DOI Listing
June 2022

Improved outcomes in rheumatoid arthritis with obesity after a weight loss intervention: randomized trial.

Rheumatology (Oxford) 2022 May 28. Epub 2022 May 28.

University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.

Objective: To examine whether a weight loss intervention program improves rheumatoid arthritis (RA) disease activity and/or musculoskeletal ultrasound synovitis measures in obese RA patients.

Methods: We conducted a proof-of-concept, 12-week, single-blind, randomized controlled trial of obese RA patients (BMI ≥ 30) with DAS28 ≥ 3.2 and with evidence of power Doppler synovitis. Forty patients were randomized to the diet intervention(N = 20) or control group(N = 20). Diet intervention consisted of a hypocaloric diet of 1,000-1,500 kcal/day and high protein meal replacements. Co-primary outcomes included change in DAS28 and PDUS34. Clinical disease activity, imaging, biomarkers, adipokines, and patient reported outcomes were monitored throughout the trial. Recruitment terminated early. All analyses were based on intent-to-treat for a significance level of 0.05.

Results: The diet intervention group lost an average 9.5 kg/patient, while the control group lost 0.5 kg (p< 0.001). RAPID3 improved, serum leptin decreased, and serum adiponectin increased significantly within the diet group and between the groups (all p< 0.03). DAS28 decreased, 5.2→4.2 within the diet group (p< 0.001)(-0.51 ([95%CI; -1.01, 0.00], p= 0.056, between groups). HAQ-DI improved significantly within the diet group (p< 0.04)(p= 0.065 between group). Ultrasound measures and the multi-biomarker disease activity score did not differ between groups (PDUS34 -2.0 [95%CI; -7.00, 3.1], p= 0.46 between groups).

Conclusion: Obese RA patients on the diet intervention achieved weight loss. There were significant between group improvements for RAPID3, adiponectin, and leptin levels, and positive trends for DAS28 and HAQ-DI. Longer-term, larger weight loss studies are needed to validate these findings, and will allow for further investigative work to improve the clinical management of obese RA patients.

Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02881307.
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http://dx.doi.org/10.1093/rheumatology/keac307DOI Listing
May 2022

DNA Methylation-Based Prediction of Post-operative Atrial Fibrillation.

Front Cardiovasc Med 2022 10;9:837725. Epub 2022 May 10.

Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and post-operative atrial fibrillation (POAF) is a major healthcare burden, contributing to an increased risk of stroke, kidney failure, heart attack and death. Genetic studies have identified associations with AF, but no molecular diagnostic exists to predict POAF based on pre-operative measurements. Such a tool would be of great value for perioperative planning to improve patient care and reduce healthcare costs. In this pilot study of epigenetic precision medicine in the perioperative period, we carried out bisulfite sequencing to measure DNA methylation status in blood collected from patients prior to cardiac surgery to identify biosignatures of POAF.

Methods: We enrolled 221 patients undergoing cardiac surgery in this prospective observational study. DNA methylation measurements were obtained from blood samples drawn from awake patients prior to surgery. After controlling for clinical and methylation covariates, we analyzed DNA methylation loci in the discovery cohort of 110 patients for association with POAF. We also constructed predictive models for POAF using clinical and DNA methylation data. We subsequently performed targeted analyses of a separate cohort of 101 cardiac surgical patients to measure the methylation status solely of significant methylation loci in the discovery cohort.

Results: A total of 47 patients in the discovery cohort (42.7%) and 43 patients in the validation cohort (42.6%) developed POAF. We identified 12 CpGs that were statistically significant in the discovery cohort after correcting for multiple hypothesis testing. Of these sites, 6 were amenable to targeted bisulfite sequencing and chr16:24640902 was statistically significant in the validation cohort. In addition, the methylation POAF prediction model had an AUC of 0.79 in the validation cohort.

Conclusions: We have identified DNA methylation biomarkers that can predict future occurrence of POAF associated with cardiac surgery. This research demonstrates the use of precision medicine to develop models combining epigenomic and clinical data to predict disease.
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http://dx.doi.org/10.3389/fcvm.2022.837725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127230PMC
May 2022

Physical Activity Behavior of Patients at a Skilled Nursing Facility: Longitudinal Cohort Study.

JMIR Mhealth Uhealth 2022 May 23;10(5):e23887. Epub 2022 May 23.

Center for Smart Health, University of California, Los Angeles, Los Angeles, CA, United States.

Background: On-body wearable sensors have been used to predict adverse outcomes such as hospitalizations or fall, thereby enabling clinicians to develop better intervention guidelines and personalized models of care to prevent harmful outcomes. In our previous work, we introduced a generic remote patient monitoring framework (Sensing At-Risk Population) that draws on the classification of human movements using a 3-axial accelerometer and the extraction of indoor localization using Bluetooth low energy beacons, in concert. Using the same framework, this paper addresses the longitudinal analyses of a group of patients in a skilled nursing facility. We try to investigate if the metrics derived from a remote patient monitoring system comprised of physical activity and indoor localization sensors, as well as their association with therapist assessments, provide additional insight into the recovery process of patients receiving rehabilitation.

Objective: The aim of this paper is twofold: (1) to observe longitudinal changes of sensor-based physical activity and indoor localization features of patients receiving rehabilitation at a skilled nursing facility and (2) to investigate if the sensor-based longitudinal changes can complement patients' changes captured by therapist assessments over the course of rehabilitation in the skilled nursing facility.

Methods: From June 2016 to November 2017, patients were recruited after admission to a subacute rehabilitation center in Los Angeles, CA. Longitudinal cohort study of patients at a skilled nursing facility was followed over the course of 21 days. At the time of discharge from the skilled nursing facility, the patients were either readmitted to the hospital for continued care or discharged to a community setting. A longitudinal study of the physical therapy, occupational therapy, and sensor-based data assessments was performed. A generalized linear mixed model was used to find associations between functional measures with sensor-based features. Occupational therapy and physical therapy assessments were performed at the time of admission and once a week during the skilled nursing facility admission.

Results: Of the 110 individuals in the analytic sample with mean age of 79.4 (SD 5.9) years, 79 (72%) were female and 31 (28%) were male participants. The energy intensity of an individual while in the therapy area was positively associated with transfer activities (β=.22; SE 0.08; P=.02). Sitting energy intensity showed positive association with transfer activities (β=.16; SE 0.07; P=.02). Lying down energy intensity was negatively associated with hygiene activities (β=-.27; SE 0.14; P=.04). The interaction of sitting energy intensity with time (β=-.13; SE 0.06; P=.04) was associated with toileting activities.

Conclusions: This study demonstrates that a combination of indoor localization and physical activity tracking produces a series of features, a subset of which can provide crucial information to the story line of daily and longitudinal activity patterns of patients receiving rehabilitation at a skilled nursing facility. The findings suggest that detecting physical activity changes within locations may offer some insight into better characterizing patients' progress or decline.
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http://dx.doi.org/10.2196/23887DOI Listing
May 2022

Integrated Multiomics Analysis of Salivary Exosomes to Identify Biomarkers Associated with Changes in Mood States and Fatigue.

Int J Mol Sci 2022 May 9;23(9). Epub 2022 May 9.

The Drug Discovery Lab, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, CA 90095, USA.

Fatigue and other deleterious mood alterations resulting from prolonged efforts such as a long work shift can lead to a decrease in vigilance and cognitive performance, increasing the likelihood of errors during the execution of attention-demanding activities such as piloting an aircraft or performing medical procedures. Thus, a method to rapidly and objectively assess the risk for such cognitive fatigue would be of value. The objective of the study was the identification in saliva-borne exosomes of molecular signals associated with changes in mood and fatigue that may increase the risk of reduced cognitive performance. Using integrated multiomics analysis of exosomes from the saliva of medical residents before and after a 12 h work shift, we observed changes in the abundances of several proteins and miRNAs that were associated with various mood states, and specifically fatigue, as determined by a Profile of Mood States questionnaire. The findings herein point to a promising protein biomarker, phosphoglycerate kinase 1 (PGK1), that was associated with fatigue and displayed changes in abundance in saliva, and we suggest a possible biological mechanism whereby the expression of the PGK1 gene is regulated by miR3185 in response to fatigue. Overall, these data suggest that multiomics analysis of salivary exosomes has merit for identifying novel biomarkers associated with changes in mood states and fatigue. The promising biomarker protein presents an opportunity for the development of a rapid saliva-based test for the assessment of these changes.
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http://dx.doi.org/10.3390/ijms23095257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105576PMC
May 2022

Oncologic Outcomes of Multi-Institutional Minimally Invasive Inguinal Lymph Node Dissection for Melanoma Compared with Open Inguinal Dissection in the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II).

Ann Surg Oncol 2022 May 2. Epub 2022 May 2.

Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Minimally invasive inguinal lymphadenectomy (MILND) is safe and feasible, but limited data exist regarding oncologic outcomes.

Methods: This study performed a multi-institutional retrospective cohort analysis of consecutive MILND performed for melanoma between January 2009 and June 2016. The open ILND (OILND) comparative cohort comprised patients enrolled in the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) between December 2004 and March 2014.The pre-defined primary end point was the same-basin regional nodal recurrence, calculated using properties of binomial distribution. Time to events was calculated using the Kaplan-Meier method. The secondary end points were overall survival, progression-free survival, melanoma-specific survival (MSS), and distant metastasis-free survival (DMFS).

Results: For all the patients undergoing MILND, the same-basin regional recurrence rate was 4.4 % (10/228; 95 % confidence interval [CI], 2.1-7.9 %): 8.2 % (4/49) for clinical nodal disease and 3.4 % (6/179) for patients with a positive sentinel lymph node (SLN) as the indication. For the 288 patients enrolled in MSLT-II who underwent OILND for a positive SLN, 17 (5.9 %) had regional node recurrence as their first event. After controlling for ulceration, positive LN count and positive non-SLNs at the time of lymphadenectomy, no difference in OS, PFS, MSS or DMFS was observed for patients with a positive SLN who underwent MILND versus OILND.

Conclusion: This large multi-institutional experience supports the oncologic safety of MILND for melanoma. The outcomes in this large multi-institutional experience of MILND compared favorably with those for an OILND population during similar periods, supporting the oncologic safety of MILND for melanoma.
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http://dx.doi.org/10.1245/s10434-022-11758-zDOI Listing
May 2022

Prediction of Sudden Cardiac Death Manifesting With Documented Ventricular Fibrillation or Pulseless Ventricular Tachycardia.

JACC Clin Electrophysiol 2022 04 30;8(4):411-423. Epub 2022 Mar 30.

Department of Emergency Medicine, Oregon Health and Science University, Portland, Oregon, USA.

Objectives: This study aimed to develop a novel clinical prediction algorithm for avertable sudden cardiac death.

Background: Sudden cardiac death manifests as ventricular fibrillation (VF)/ ventricular tachycardia (VT) potentially treatable with defibrillation, or nonshockable rhythms (pulseless electrical activity/asystole) with low likelihood of survival. There are no available clinical risk scores for targeted prediction of VF/VT.

Methods: Subjects with out-of-hospital sudden cardiac arrest presenting with documented VF or pulseless VT (33% of total cases) were ascertained prospectively from the Portland, Oregon, metro area with population ≈1 million residents (n = 1,374, 2002-2019). Comparisons of lifetime clinical records were conducted with a control group (n = 1,600) with ≈70% coronary disease prevalence. Prediction models were constructed from a training dataset using backwards stepwise logistic regression and applied to an internal validation dataset. Receiver operating characteristic curves (C statistic) were used to evaluate model discrimination. External validation was performed in a separate, geographically distinct population (Ventura County, California, population ≈850,000, 2015-2020).

Results: A clinical algorithm (VFRisk) constructed with 13 clinical, electrocardiogram, and echocardiographic variables had very good discrimination in the training dataset (C statistic = 0.808; [95% CI: 0.774-0.842]) and was successfully validated in internal (C statistic = 0.776 [95% CI: 0.725-0.827]) and external (C statistic = 0.782 [95% CI: 0.718-0.846]) datasets. The algorithm substantially outperformed the left ventricular ejection fraction (LVEF) ≤35% (C statistic = 0.638) and performed well across the LVEF spectrum.

Conclusions: An algorithm for prediction of sudden cardiac arrest manifesting with VF/VT was successfully constructed using widely available clinical and noninvasive markers. These findings have potential to enhance primary prevention, especially in patients with mid-range or preserved LVEF.
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http://dx.doi.org/10.1016/j.jacep.2022.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034059PMC
April 2022

Effects of Primary Kidney Disease Etiology on Renal Osteodystrophy in Pediatric Dialysis Patients.

JBMR Plus 2022 Apr 8;6(4):e10601. Epub 2022 Apr 8.

Department of Pediatrics David Geffen School of Medicine at the University of California Los Angeles CA USA.

Congenital diseases of the kidney and urinary tract (CAKUT) and glomerulonephritis are the main causes of chronic kidney disease (CKD) in children. Although renal osteodystrophy (ROD) and indices of mineral metabolism have been characterized in dialyzed children, the impact of primary kidney disease on ROD is unknown. We performed a cross-sectional study of bone biopsies performed in 189 pediatric dialysis patients aged 12.6 ± 5.4 years. Patients were classified into three groups according to primary kidney disease: CAKUT ( = 82), hereditary ( = 22), or glomerular disease ( = 85). Serum concentrations of calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 25(OH) vitamin D were measured at the time of biopsy. Fibroblast growth factor 23 (FGF23) levels were measured in a subset of 59 patients. Levels of calcium, phosphate, PTH, and 25(OH) vitamin D were similar across groups. CAKUT patients had higher serum ALP and lower C-terminal FGF23 levels. Bone turnover and bone volume parameters did not differ across groups. However, osteoid volume (OV/BV), osteoid surface (OS/BS), and osteoid maturation time (OMT) were highest in the CAKUT group and lowest in the hereditary group. Multiple regression analysis revealed that calcium, phosphate, ALP, and PTH were independently associated with OV/BV and osteoid thickness (O.Th). PTH was an independent factor affecting bone formation rate. The relationship between CKD etiology and bone histomorphometric variables was abrogated after adjustment for biochemical parameters in the multivariable models. Overall, bone histology differed according to CKD etiology in the unadjusted analysis; however, this association could not be confirmed independently of biochemical parameters. Although CAKUT patients had a greater mineralization defect with elevated serum ALP levels, longitudinal studies will be needed to elucidate mediation pathways that might be involved in the complex interplay of CKD-mineral bone disease (MBD). © 2022 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009101PMC
April 2022

Variability in Donor-Derived Cell-Free DNA Scores to Predict Mortality in Heart Transplant Recipients - A Proof-of-Concept Study.

Front Immunol 2022 18;13:825108. Epub 2022 Feb 18.

Deng Advanced Heart Failure Research Laboratory, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, United States.

Background: Over the last decade, expanding use of molecular diagnostics in heart transplantation has allowed implementation of non-invasive surveillance strategies for monitoring allograft health. The commercially available HeartCare platform combines the AlloMap gene expression profiling assay and the AlloSure donor-derived cell-free DNA test (dd-cfDNA). Beyond their established use for assessment of rejection, evidence is building for predictive utility, with the longitudinal AlloMap Variability score previously shown to correlate with the risk of future rejection, graft dysfunction, re-transplantation, or death. In this single-center, retrospective pilot study, we evaluated the performance of a novel AlloSure Variability metric in predicting mortality in a cohort of heart transplant recipients.

Methods: Seventy-two adult heart transplant recipients with at least 3 concurrent AlloMap/AlloSure results were included. Demographic, clinical, imaging, and laboratory parameters were captured. Variability was defined as the standard deviation of longitudinal AlloMap/AlloSure results. A Cox multivariable adjusted proportional hazards model was used to evaluate the variability metrics as predictors of mortality. Associations between AlloMap/AlloSure variability and donor specific antibody (DSA) status were also assessed.

Results: A total of 5 patients (6.9%) died during a median follow-up of 480 days. In a univariate Cox proportional hazards model, higher AlloSure variability (HR 1.66, 95%CI 1.14 - 2.41), but not AlloMap variability or the cross-sectional AlloSure/AlloMap results was associated with increased mortality risk. Longitudinal AlloSure variability was also higher among patients with both preformed DSA and those developing DSA.

Conclusion: Our results suggest that increased variability of dd-cfDNA in heart transplant patients is associated with both mortality risk and the presence of donor specific antibodies. These findings highlight the added value of longitudinal data in the interpretation of AlloMap/AlloSure scores in this population and open the door to larger studies investigating the utility of these metrics in shaping post-transplant clinical care paradigms.
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http://dx.doi.org/10.3389/fimmu.2022.825108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895247PMC
May 2022

Sentinel lymph node melanoma metastases: Assessment of tumor burden for clinical prediction of outcome in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).

Eur J Surg Oncol 2022 Jun 12;48(6):1280-1287. Epub 2022 Feb 12.

John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA; The Angeles Clinic and Research Institute, Los Angeles, USA; Cedars Sinai Medical Center, Los Angeles, CA, USA.

Purpose: As clinical management decisions in patients with Stage III melanoma have become more complex, precise pathologic characterization of sentinel lymph node (SLN) metastases has become critical to guide management. The extent of SLN involvement correlates with risk of adverse outcomes, but reported methods of disease quantification vary. We examined SLN metastases from patients participating in an international clinical trial and compared several methods of tumor burden quantification.

Methods: SLNs from 146 node-positive patients in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) were centrally-reviewed and characterized by number of tumor-positive nodes, percent nodal area tumor replacement, maximum dimension of largest metastasis, tumor penetrative depth, number of tumor foci, metastasis microanatomic location, and extracapsular extension. These data were analyzed for correlation with non-SLN metastasis and melanoma-specific survival (MSS).

Results: The median number of tumor-involved SLNs was 1. The median maximum metastasis dimension was 1.11 mm. Median SLN area involvement was 1.5%. Tumor burden measures were highly correlated with each other. Factors associated with non-SLN metastasis by univariable analysis were primary tumor ulceration and extent of metastases. Tumor thickness, ulceration, non-SLN metastasis and multiple measures of SLN tumor burden were significantly related to MSS on univariable analysis. After multivariable adjustment, number of involved SLNs (p = 0.05) and percent nodal area tumor replacement (p = 0.02) were independent predictors of MSS.

Conclusion: Central review of MSLT-I pathology indicates that primary tumor and SLN tumor characteristics predict non-SLN metastasis and MSS. Percent nodal involvement was more powerfully prognostic than the more commonly used maximum dimension of largest metastasis.
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http://dx.doi.org/10.1016/j.ejso.2022.01.021DOI Listing
June 2022

A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial.

Pediatr Nephrol 2022 Mar 2. Epub 2022 Mar 2.

Department of Pediatrics, Division of Nephrology, David Geffen School of Medicine at UCLA and UCLA Mattel Children's Hospital, 10833 Le Conte Avenue, Los Angeles, CA, 90095, USA.

Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production-dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3-4 (ClinicalTrials.gov Identifier NCT04741646).
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http://dx.doi.org/10.1007/s00467-022-05492-7DOI Listing
March 2022

Effects of dietary omega-3 fatty acids on orthotopic prostate cancer progression, tumor associated macrophages, angiogenesis and T-cell activation-dependence on GPR120.

Prostate Cancer Prostatic Dis 2022 Jan 24. Epub 2022 Jan 24.

Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Background: The antiprostate cancer effects of dietary ω-3 fatty acids (FAs) were previously found to be dependent on host G-protein coupled receptor 120 (GPR120). Using an orthotopic tumor model and an ex-vivo model of bone marrow derived M2-like macrophages, we sought to determine if ω-3 FAs inhibit angiogenesis and activate T-cells, and if these effects are dependent on GPR120.

Methods: Gausia luciferase labeled MycCaP prostate cancer cells (MycCaP-Gluc) were injected into the anterior prostate lobe of FVB mice. After established tumors were confirmed by blood luminescence, mice were fed an ω-3 or ω-6 diet. Five weeks after tumor injection, tumor weight, immune cell infiltration and markers of angiogenesis were determined. An ex-vivo co-culture model of bone marrow derived M2-like macrophages from wild-type or GPR120 knockout mice with MycCap prostate cancer cells was used to determine if docosahexanoic acid (DHA, ω-3 FA) inhibition of angiogenesis and T-cell activation is dependent on macrophage GPR120.

Results: Feeding an ω-3 diet significantly reduced orthotopic MycCaP-Gluc tumor growth relative to an ω-6 diet. Tumors from the ω-3 group had decreased M2-like macrophage infiltration and decreased expression of angiogenesis factors. DHA significantly inhibited M2 macrophage-induced endothelial tube formation and reversed M2 macrophage-induced T-cell suppression, and these DHA effects were mediated, in part, by M2 macrophage GPR120.

Conclusion: Omega-3 FAs delayed orthotopic tumor growth, inhibited M2-like macrophage tumor infiltration, and inhibited M2-like macrophage-induced angiogenesis and T-cell suppression. Given the central role of M2-like macrophages in prostate cancer progression, GPR120-dependent ω-3 FA inhibition of M2-like macrophages may play an important role in prostate cancer therapeutics.
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http://dx.doi.org/10.1038/s41391-021-00440-2DOI Listing
January 2022

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

JAMA Oncol 2022 Mar 17;8(3):e216871. Epub 2022 Mar 17.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain.

Objective: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).

Design, Settings, And Participants: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021.

Exposures: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs).

Main Outcomes And Measures: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months).

Results: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01).

Conclusions And Relevance: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.
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http://dx.doi.org/10.1001/jamaoncol.2021.6871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778608PMC
March 2022

Comparison of Response to Definitive Radiotherapy for Localized Prostate Cancer in Black and White Men: A Meta-analysis.

JAMA Netw Open 2021 12 1;4(12):e2139769. Epub 2021 Dec 1.

Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Cleveland Medical Center, Cleveland, Ohio.

Importance: Black men have a 2-fold increased risk of dying from prostate cancer compared with White men. However, race-specific differences in response to initial treatment remain unknown.

Objective: To compare overall and treatment-specific outcomes of Black and White men with localized prostate cancer receiving definitive radiotherapy (RT).

Data Sources: A systematic search was performed of relevant published randomized clinical trials conducted by the NRG Oncology/Radiation Therapy Oncology Group between January 1, 1990, and December 31, 2010. This meta-analysis was performed from July 1, 2019, to July 1, 2021.

Study Selection: Randomized clinical trials of definitive RT for patients with localized prostate cancer comprising a substantial number of Black men (self-identified race) enrolled that reported on treatment-specific and overall outcomes.

Data Extraction And Synthesis: Individual patient data were obtained from 7 NRG Oncology/Radiation Therapy Oncology Group randomized clinical trials evaluating definitive RT with or without short- or long-term androgen deprivation therapy. Unadjusted Fine-Gray competing risk models, with death as a competing risk, were developed to evaluate the cumulative incidences of end points. Cox proportional hazards models were used to evaluate differences in all-cause mortality and the composite outcome of distant metastasis (DM) or death. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed.

Main Outcomes And Measures: Subdistribution hazard ratios (sHRs) of biochemical recurrence (BCR), DM, and prostate cancer-specific mortality (PCSM).

Results: A total of 8814 patients (1630 [18.5%] Black and 7184 [81.5%] White) were included; mean (SD) age was 69.1 (6.8) years. Median follow-up was 10.6 (IQR, 8.0-17.8) years for surviving patients. At enrollment, Black men were more likely to have high-risk disease features. However, even without adjustment, Black men were less likely to experience BCR (sHR, 0.88; 95% CI, 0.58-0.91), DM (sHR, 0.72; 95% CI, 0.58-0.91), or PCSM (sHR, 0.72; 95% CI, 0.54-0.97). No significant differences in all-cause mortality were identified (HR, 0.99; 95% CI, 0.92-1.07). Upon adjustment, Black race remained significantly associated with improved BCR (adjusted sHR, 0.79; 95% CI, 0.72-0.88; P < .001), DM (adjusted sHR, 0.69; 95% CI, 0.55-0.87; P = .002), and PCSM (adjusted sHR, 0.68; 95% CI, 0.50-0.93; P = .01).

Conclusions And Relevance: The findings of this meta-analysis suggest that Black men enrolled in randomized clinical trials present with more aggressive disease but have better BCR, DM, and PCSM with definitive RT compared with White men, suggesting that other determinants of outcome, such as access to care, are important factors of achieving racial equity.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.39769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717118PMC
December 2021

Performance of a Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Derived Risk-Stratification Tool for High-risk and Very High-risk Prostate Cancer.

JAMA Netw Open 2021 12 1;4(12):e2138550. Epub 2021 Dec 1.

Department of Radiation Oncology, University of Michigan, Ann Arbor.

Importance: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear.

Objectives: To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools.

Design, Setting, And Participants: This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021.

Exposures: Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy.

Main Outcomes And Measures: PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index.

Results: Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database.

Conclusions And Relevance: These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.38550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669522PMC
December 2021

An Integrated, Scalable, Electronic Video Consent Process to Power Precision Health Research: Large, Population-Based, Cohort Implementation and Scalability Study.

J Med Internet Res 2021 12 8;23(12):e31121. Epub 2021 Dec 8.

Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.

Background: Obtaining explicit consent from patients to use their remnant biological samples and deidentified clinical data for research is essential for advancing precision medicine.

Objective: We aimed to describe the operational implementation and scalability of an electronic universal consent process that was used to power an institutional precision health biobank across a large academic health system.

Methods: The University of California, Los Angeles, implemented the use of innovative electronic consent videos as the primary recruitment tool for precision health research. The consent videos targeted patients aged ≥18 years across ambulatory clinical laboratories, perioperative settings, and hospital settings. Each of these major areas had slightly different workflows and patient populations. Sociodemographic information, comorbidity data, health utilization data (ambulatory visits, emergency room visits, and hospital admissions), and consent decision data were collected.

Results: The consenting approach proved scalable across 22 clinical sites (hospital and ambulatory settings). Over 40,000 participants completed the consent process at a rate of 800 to 1000 patients per week over a 2-year time period. Participants were representative of the adult University of California, Los Angeles, Health population. The opt-in rates in the perioperative (16,500/22,519, 73.3%) and ambulatory clinics (2308/3390, 68.1%) were higher than those in clinical laboratories (7506/14,235, 52.7%; P<.001). Patients with higher medical acuity were more likely to opt in. The multivariate analyses showed that African American (odds ratio [OR] 0.53, 95% CI 0.49-0.58; P<.001), Asian (OR 0.72, 95% CI 0.68-0.77; P<.001), and multiple-race populations (OR 0.73, 95% CI 0.69-0.77; P<.001) were less likely to participate than White individuals.

Conclusions: This is one of the few large-scale, electronic video-based consent implementation programs that reports a 65.5% (26,314/40,144) average overall opt-in rate across a large academic health system. This rate is higher than those previously reported for email (3.6%) and electronic biobank (50%) informed consent rates. This study demonstrates a scalable recruitment approach for population health research.
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http://dx.doi.org/10.2196/31121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8701720PMC
December 2021

Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers.

Cancers (Basel) 2021 Nov 24;13(23). Epub 2021 Nov 24.

Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs.
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http://dx.doi.org/10.3390/cancers13235908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657291PMC
November 2021

Duodenal Microbiome and Serum Metabolites Predict Hepatocellular Carcinoma in a Multicenter Cohort of Patients with Cirrhosis.

Dig Dis Sci 2021 Nov 20. Epub 2021 Nov 20.

Department of Public Health Sciences, School of Medicine and Comprehensive Cancer Center, University of California, Davis, Medical Sciences 1C, One Shields Avenue, Davis, CA, 95616, USA.

Background: Hepatocellular carcinoma (HCC) is rapidly increasing in the U.S. and is a leading cause of mortality for patients with cirrhosis. Discovering novel biomarkers for risk stratification of HCC is paramount. We examined biomarkers of the gut-liver axis in a prospective multicenter cohort.

Methods: Patients with cirrhosis without a history of HCC were recruited between May 2015 and March 2020 and prospectively followed at 3 tertiary care hospitals in Los Angeles. Microbiome analysis was performed on duodenal biopsies and metabolomic analysis was performed on serum samples, collected at the time of enrollment. Optimal microbiome-based survival analysis and Cox proportional hazards regression analysis were used to determine microbiota and metabolite associations with HCC development, respectively.

Results: A total of 227 participants with liver cirrhosis contributed a total of 459.58 person-years of follow-up, with 14 incident HCC diagnoses. Male sex (HR = 7.06, 95% CI = 1.02-54.86) and baseline hepatic encephalopathy (HE, HR = 4.65, 95% CI = 1.60-13.52) were associated with developing HCC over follow-up. Adjusting for age, sex, baseline HE, and alkaline phosphatase, an increased risk of HCC were observed for participants with the highest versus lowest three quartiles for duodenal Alloprevotella (HR = 3.22, 95% CI = 1.06-9.73) and serum taurocholic acid (HR = 6.87, 95% CI = 2.32-20.27), methionine (HR = 9.97, 95% CI = 3.02-32.94), and methioninesulfoxide (HR = 5.60, 95% CI = 1.84-17.10). Being in the highest quartile for Alloprevotella or methionine had a sensitivity and specificity for developing HCC of 85.71% and 60.56%, respectively, with an odds ratio of 10.92 (95% CI = 2.23-53.48).

Conclusion: Alloprevotella and methionine, methioninesulfoxide, and taurocholic acid predicted future HCC development in a high-risk population of participants with liver cirrhosis.
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http://dx.doi.org/10.1007/s10620-021-07299-2DOI Listing
November 2021

Protocol for pragmatic randomised trial: integrating electronic health record-based behavioural economic 'nudges' into the electronic health record to reduce preoperative testing for patients undergoing cataract surgery.

BMJ Open 2021 11 3;11(11):e049568. Epub 2021 Nov 3.

Division of General Internal Medicine and Health Services Research, Department of Medicine, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA

Introduction: Robust randomised trial data have shown that routine preoperative (pre-op) testing for cataract surgery patients is inappropriate. While guidelines have discouraged testing since 2002, cataract pre-op testing rates have remained unchanged since the 1990s. Given the challenges of reducing low-value care despite strong consensus around the evidence, innovative approaches are needed to promote high-value care. This trial evaluates the impact of an interdisciplinary electronic health record (EHR) intervention that is informed by behavioural economic theory.

Methods And Analysis: This pragmatic randomised trial is being conducted at UCLA Health between June 2021 and June 2022 with a 12-month follow-up period. We are randomising all UCLA Health physicians who perform pre-op visits during the study period to one of the three nudge arms or usual care. These three nudge alerts address (1) patient harm, (2) increased out-of-pocket costs for patients and (3) psychological harm to the patients related to pre-op testing. The nudges are triggered when a physician starts to order a pre-op test. We hypothesise that receipt of a nudge will be associated with reduced pre-op testing. The primary outcome will be the change in the percentage of patients undergoing pre-op testing at 12 months. Secondary outcomes will include the percentage of patients undergoing specific categories of pre-op tests (labs, EKGs, chest X-rays (CXRs)), the efficacy of each nudge, same-day surgery cancellations and cost savings.

Ethics And Dissemination: The study protocol was approved by the institutional review board of the University of California, Los Angeles as well as a nominated Data Safety Monitoring Board. If successful, we will have created a tool that can be disseminated rapidly to EHR vendors across the nation to reduce inappropriate testing for the most common low-risk surgical procedures in the country.

Trial Registration Number: ClinicalTrials.gov identifier: NCT04104256.
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http://dx.doi.org/10.1136/bmjopen-2021-049568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572383PMC
November 2021

Abnormal paraoxonase-1 (PON1) enzyme activity in idiopathic inflammatory myopathies.

Rheumatology (Oxford) 2022 05;61(6):2512-2523

Division of Rheumatology.

Objectives: Patients with idiopathic inflammatory myopathies (IIM) have severe vascular involvement, which contributes to disease morbidity and mortality. Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL) associated protein that protects the vascular endothelium from oxidative injury and damage. The current work assessed the functional and genetic determinants of PON1 activity in IIM patients.

Methods: A total of 184 IIM patients and 112 healthy controls (HC) were included. PON1 enzyme activity was assessed by paraoxonase, arylesterase and lactonase assays, and the Q192R PON1 single nucleotide polymorphism (SNP) was analysed. Multivariate regression models examined associations of PON1 activity with IIM diagnosis and myositis disease outcomes.

Results: The arylesterase and lactonase activities of PON1 were significantly lower in IIM patients compared with HC. Higher myositis disease activity, the presence of severe IIM-associated interstitial lung disease (ILD), and the presence of MDA5 or anti-synthetase antibodies were significantly associated with lower PON1 activity. The PON1 Q192R polymorphism was strongly linked to the paraoxonase activity of PON1 in IIM, and patients with the PON1 QQ genotype had better IIM disease outcomes compared with patients with the QR or RR genotypes.

Conclusions: The arylesterase and lactonase activities of PON1 are significantly impaired in IIM patients compared with HC, and inversely associate with IIM disease activity and the presence of severe ILD. The PON1 QQ genotype associates with more favourable disease outcomes in IIM patients. Large prospective studies are needed to further evaluate the role of PON1 and PON1 genetic polymorphisms in the development and propagation of IIM and IIM-ILD.
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http://dx.doi.org/10.1093/rheumatology/keab795DOI Listing
May 2022

Correction: Electronic Video Consent to Power Precision Health Research: A Pilot Cohort Study.

JMIR Form Res 2021 Oct 21;5(10):e33891. Epub 2021 Oct 21.

David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.

[This corrects the article DOI: 10.2196/29123.].
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http://dx.doi.org/10.2196/33891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8569543PMC
October 2021

Head-to-Head Comparison of Ga-PSMA-11 PET/CT and mpMRI with a Histopathology Gold Standard in the Detection, Intraprostatic Localization, and Determination of Local Extension of Primary Prostate Cancer: Results from a Prospective Single-Center Imaging Trial.

J Nucl Med 2022 Jun 14;63(6):847-854. Epub 2021 Oct 14.

Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California.

The role of prostate-specific membrane antigen (PSMA)-targeted PET in comparison to multiparametric MRI (mpMRI) in the evaluation of intraprostatic cancer foci is not well defined. The aim of our study was to compare the diagnostic performance of Ga-PSMA-11 PET/CT (PSMA PET/CT), mpMRI, and PSMA PET/CT + mpMRI using 3 independent masked readers for each modality and with histopathology as the gold standard in the detection, intraprostatic localization, and determination of local extension of primary prostate cancer. Patients with intermediate- or high-risk prostate cancer who underwent PSMA PET/CT as part of a prospective trial (NCT03368547) and mpMRI before radical prostatectomy were included. Each imaging modality was interpreted by 3 independent readers who were unaware of the other modality result. A central majority rule was applied (2:1). Pathologic examination of whole-mount slices was used as the gold standard. Imaging scans and whole-mount slices were interpreted using the same standardized approach on a segment level and a lesion level. A "neighboring" approach was used to define imaging-pathology correlation for the detection of individual prostate cancer foci. Accuracy in determining the location, extraprostatic extension (EPE), and seminal vesicle invasion (SVI) of prostate cancer foci was assessed using receiver-operating-characteristic curve analysis. Interreader agreement was calculated using intraclass correlation coefficient analysis. The final analysis included 74 patients (14 [19%] with intermediate risk and 60 [81%] with high risk). The cancer detection rate (lesion-based analysis) was 85%, 83%, and 87% for PSMA PET/CT, mpMRI, and PSMA PET/CT + mpMRI, respectively. The change in AUC was statistically significant between PSMA PET/CT + mpMRI and the 2 imaging modalities alone for delineation of tumor localization (segment-based analysis) ( < 0.001) but not between PSMA PET/CT and mpMRI ( = 0.093). mpMRI outperformed PSMA PET/CT in detecting EPE ( = 0.002) and SVI ( = 0.001). In the segment-level analysis, intraclass correlation coefficient analysis showed moderate reliability among PSMA PET/CT and mpMRI readers using a 5-point Likert scale (range, 0.53-0.64). In the evaluation of T staging, poor reliability was found among PSMA PET/CT readers and poor to moderate reliability was found for mpMRI readers. PSMA PET/CT and mpMRI have similar accuracy in the detection and intraprostatic localization of prostate cancer foci. mpMRI performs better in identifying EPE and SVI. For the T-staging evaluation of intermediate to high-risk prostate cancer, mpMRI should still be considered the imaging modality of reference. Whenever available, PSMA PET/MRI or the coregistration or fusion of PSMA PET/CT and mpMRI (PSMA PET/CT + mpMRI) should be used as it improves tumor extent delineation.
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http://dx.doi.org/10.2967/jnumed.121.262398DOI Listing
June 2022

Evaluation of the University of California Diabetes Prevention Program (UC DPP) Initiative.

BMC Public Health 2021 09 30;21(1):1775. Epub 2021 Sep 30.

David Geffen School of Medicine at the University of California, Los Angeles, 1100 Glendon Ave, Suite 850, Los Angeles, CA, 90024, USA.

Background: Type 2 diabetes can negatively impact long term health outcomes, healthcare costs and quality of life. However, intensive lifestyle interventions, including the Diabetes Prevention Program (DPP), can significantly lower risk of incident type 2 diabetes among overweight adults with prediabetes. Unfortunately, the majority of adults in the US who are at risk of developing diabetes do not engage in DPP-based lifestyle change programs. Increased adoption of evidence-based obesity and diabetes prevention interventions, such as the DPP, may help large employers reduce health risks and improve health outcomes among employees. In 2018, the University of California Office of thePresident (UCOP) implemented the UC DPP Initiative, a novel, multi-component program to address diabetes and obesity prevention across the UC system.

Methods: The goal of our study is to conduct a multifaceted evaluation of the UC DPP Initiative using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Our evaluation will integrate unique and diverse UC data sources, including electronic health record (EHR) data, administrative claims, campus-based DPP cohort data, qualitative interviews and site visits. Our primary outcome of interest is the mean percent weight change among three groups of overweight/obese UC beneficiaries at risk for diabetes at 12-month follow-up. Secondary outcomes include mean percent weight change at 24-month follow-up, barriers and facilitators associated with implementatio, as well as  the degree of program adoption and maintenance.

Discussion: Our study will help inform diabetes and obesity prevention efforts across the UC system. Findings from this evaluation will also be highly applicable to universities and large employers, as well as community organizers, healthcare organizations and insurers implementing the DPP and/or other health promotion interventions.
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http://dx.doi.org/10.1186/s12889-021-11731-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482560PMC
September 2021

Investigation of Combination Treatment With an Aromatase Inhibitor Exemestane and Carboplatin-Based Therapy for Postmenopausal Women With Advanced NSCLC.

JTO Clin Res Rep 2021 Apr 3;2(4):100150. Epub 2021 Feb 3.

Division of Hematology-Oncology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, California.

Introduction: Estrogen receptors (ER) (ERα, ERβ) and aromatase (key enzyme for estrogen synthesis) are expressed in most human NSCLCs. High intratumoral estrogen levels and elevated aromatase expression in NSCLC predict poor outcome. This open-label, phase 1b, single-center study evaluated the safety and tolerability of escalating doses of the aromatase inhibitor, exemestane, in combination with carboplatin and pemetrexed in postmenopausal women with stage IV nonsquamous NSCLC.

Methods: Patients received exemestane (starting 1-wk before chemotherapy) at 25 mg orally (PO) daily (cohort 1) or 50 mg PO daily (cohort 2) combined with carboplatin (area under the curve 6 mg × min/mL) and pemetrexed (500 mg/m) intravenously every 3 weeks for four cycles. Thereafter, patients were eligible for continued therapy with exemestane and pemetrexed or pemetrexed alone.

Results: A total of 10 patients consented for therapy, and two patients failed in the screening. Four patients completed the therapy in cohort 1 and four patients in cohort 2. The median number of cycles administered was 15 (range: 1-54). Maximum tolerated dose was exemestane 50 mg PO daily with combination chemotherapy. Intention-to-treat analysis revealed an objective response rate (ORR) of 62.5% (five of eight patients with partial response) and a clinical benefit rate of 87.5% (seven of eight patients with either stable disease or partial response). ORR was associated with aromatase expression ( = 0.02). Circulating estrogen levels decreased with exemestane use, and quality of life measurements did not significantly change during the treatment. There were no adverse events.

Conclusions: The combination of carboplatin, pemetrexed, and exemestane in postmenopausal women with metastatic NSCLC is safe and well tolerated. Biomarker studies revealed that ORR correlates with tumor aromatase expression. These findings support future clinical trials to confirm the antitumor efficacy with this combination therapy.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474426PMC
April 2021

Head & neck melanoma: A 22-year experience of recurrence following sentinel lymph node biopsy.

Laryngoscope Investig Otolaryngol 2021 Aug 21;6(4):738-746. Epub 2021 Jun 21.

Department of Otolaryngology-Head and Neck Surgery University of California Los Angeles Los Angeles, California USA.

Objective: To examine the clinicopathologic factors that contribute to regional and distant recurrence in intermediate to high risk head and neck melanoma patients after sentinel lymph node biopsy (SLNB).

Methods: This study is a retrospective review from an academic tertiary care center. Patients treated with SLNB for head and neck melanoma from 1997 to 2019 were reviewed and characterized by sentinel lymph node (SLN) status. Clinical variables were examined for the impact on regional and distant recurrence in SLNB-negative patients using univariable and multivariable Cox regression analysis.

Results: One hundred and fifty four patients were included. Of note, 127 (82.5 %) were men, and the average age was 61.3 years. Median follow-up was 68.6 weeks. Pathologic review of SLNs found 3.9% positive for metastatic melanoma; 96.1% were negative. Regional recurrence was significantly associated with tumor stage and age on multivariate analysis. A total of 4.5% of patients recurred in a previously labeled negative basin. Scalp subsite accounted for 30.5% of primary tumors and was more likely to yield a positive SLN on univariate analysis ( = .023). Tumor stage and age were significantly associated with distant metastasis on multivariable analysis ( = .026,  < .001 respectively).

Conclusion: We report a number of prognostic trends in head and neck melanoma. SLN positivity was found more often in patients with a primary tumor of the scalp. Regional recurrence was significantly associated with age and tumor stage, whereas distant recurrence was significantly associated with tumor staging and scalp subsite. Scalp subsite was associated with an increased risk for nodal metastasis and distant recurrence.

Level Of Evidence: 3.
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http://dx.doi.org/10.1002/lio2.605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356881PMC
August 2021

Radiation therapy dose and androgen deprivation therapy in localized prostate cancer: a meta-regression of 5-year outcomes in phase III randomized controlled trials.

Prostate Cancer Prostatic Dis 2022 03 16;25(1):126-128. Epub 2021 Aug 16.

Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Background: While multiple randomized trials have evaluated the benefit of radiation therapy (RT) dose escalation and the use and prolongation of androgen deprivation therapy (ADT) in the treatment of prostate cancer, few studies have evaluated the relative benefit of either form of treatment intensification with each other. Many trials have included treatment strategies that incorporate either high or low dose RT, or short-term or long-term ADT (STADT or LTADT), in one or more trial arms. We sought to compare different forms of treatment intensification of RT in the context of localized prostate cancer.

Methods: Using preferred reporting items for systemic reviews and meta-analyses (PRISMA) guidelines, we collected over 40 phases III clinical trials comparing different forms of RT for localized prostate cancer. We performed a meta-regression of 40 individual trials with 21,429 total patients to allow a comparison of the rates and cumulative proportions of 5-year overall survival (OS), prostate cancer-specific mortality (PCSM), and distant metastasis (DM) for each treatment arm of every trial.

Results: Dose-escalation either in the absence or presence of STADT failed to significantly improve any 5-year outcome. In contrast, adding LTADT to low dose RT significantly improved 5-year PCSM (Odds ratio [OR] 0.34, 95% confidence interval [CI] 0.22-0.54, p < 0.001) and DM (OR 0.35, 95% CI 0.20-0.63. p < 0.001) over low dose RT alone. Adding STADT also significantly improved 5-year PCSM over low dose RT alone (OR 0.55, 95% CI 0.41-0.75, p < 0.001).

Conclusion: While limited by between-study heterogeneity and a lack of individual patient data, this meta-analysis suggests that adding ADT, versus increasing RT dose alone, offers a more consistent improvement in clinical endpoints.
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http://dx.doi.org/10.1038/s41391-021-00432-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018418PMC
March 2022

Knowledge and Needs of Resident Physicians Regarding Osteoporosis: A Nationwide Survey of Residents.

JBMR Plus 2021 Aug 1;5(8):e10524. Epub 2021 Jul 1.

Department of Internal Medicine University of California, San Francisco San Francisco CA USA.

Large-scale studies have not addressed the knowledge level of US resident physicians regarding osteoporosis management. We gauged the knowledge level of family medicine, internal medicine, and obstetrics and gynecology resident physicians regarding osteoporosis management. In 2019, we sent an anonymous survey via e-mail to all program directors of Accreditation Council for Graduate Medical Education-accredited residency programs in family medicine, internal medicine, and obstetrics and gynecology for distribution to resident physicians. Knowledge items assessed osteoporosis screening, diagnosis, and treatment. We received responses from 182 family medicine, 275 internal medicine, and 122 obstetrics and gynecology programs. Of 582 resident physician respondents, 31% were family medicine residents, 47% were internal medicine residents, and 21% were obstetrics and gynecology residents. Although 77% of respondents correctly selected the -score threshold for the diagnosis of osteoporosis among persons aged 50 years and older (-2.5), only 20% of respondents correctly identified minimal-trauma hip fracture as being diagnostic of osteoporosis. One-third of respondents correctly identified which medications were demonstrated in clinical trials to decrease hip fracture risk. Fifteen percent of respondents correctly identified that denosumab and alendronate are associated with osteonecrosis of the jaw; and 40% of respondents correctly identified that decline in bone density is more rapid after discontinuation of denosumab than after discontinuation of bisphosphonates. Less than half of resident physicians knew that bisphosphonate-associated atypical femoral fractures are duration-dependent. One-quarter of respondents felt not at all prepared to manage osteoporosis. In this nationwide survey of resident physicians, knowledge regarding osteoporosis diagnosis and treatment was poor, with a striking lack of knowledge regarding the two most serious adverse effects of osteoporosis pharmacotherapy (osteonecrosis of the jaw and atypical femoral fractures). The undertreatment of osteoporosis is unlikely to improve without increased education of resident physicians. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328797PMC
August 2021

Baseline pro-inflammatory gene expression in whole blood is related to adverse long-term outcomes after transcatheter aortic valve replacement: a case control study.

BMC Cardiovasc Disord 2021 08 2;21(1):368. Epub 2021 Aug 2.

Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.

Background: Age-associated inflammation and immune system dysfunction have been implicated as mechanisms that increase risk for adverse long-term procedural outcomes in older adults. The purpose of this study was to investigate relationships between baseline inflammatory and innate antiviral gene expression and outcomes after transcatheter aortic valve replacement (TAVR) in older adults with severe aortic stenosis.

Methods: We performed a retrospective case-control study comparing pre-procedural pro-inflammatory and Type 1 interferon (IFN) gene expression in 48 controls with favorable outcomes (alive 1 year after TAVR with improved quality of life [QoL]) versus 48 individuals with unfavorable outcomes (dead by 1 year or alive at 1 year but with reduced QoL). Gene expression was evaluated in whole blood via (1) pre-defined composite scores of 19 inflammation-associated genes and 34 Type I IFN response genes, and (2) pro-inflammatory and antiviral transcription factor activity inferred from promotor based bioinformatics analyses of genes showing > 25% difference in average expression levels across groups. All analyses were adjusted for age, gender, body mass index, diabetes, immunosuppression, cardiovascular disease (CVD), and frailty.

Results: Relative to controls, those with unfavorable outcomes demonstrated higher expression of the pro-inflammatory gene composite prior to TAVR (p < 0.01) and bioinformatic indicators of elevated Nuclear Factor kB (p < 0.001) and Activator Protein 1 (p < 0.001) transcription factor activity, but no significant differences in Type I IFN-related gene expression.

Conclusions: These results demonstrate that a pro-inflammatory state prior to TAVR, independent of CVD severity and frailty status, is associated with worse long-term procedural outcomes.
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http://dx.doi.org/10.1186/s12872-021-02186-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327421PMC
August 2021

Electronic Video Consent to Power Precision Health Research: A Pilot Cohort Study.

JMIR Form Res 2021 09 8;5(9):e29123. Epub 2021 Sep 8.

David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.

Background: Developing innovative, efficient, and institutionally scalable biospecimen consent for remnant tissue that meets the National Institutes of Health consent guidelines for genomic and molecular analysis is essential for precision medicine efforts in cancer.

Objective: This study aims to pilot-test an electronic video consent that individuals could complete largely on their own.

Methods: The University of California, Los Angeles developed a video consenting approach designed to be comprehensive yet fast (around 5 minutes) for providing universal consent for remnant biospecimen collection for research. The approach was piloted in 175 patients who were coming in for routine services in laboratory medicine, radiology, oncology, and hospital admissions. The pilot yielded 164 completed postconsent surveys. The pilot assessed the usefulness, ease, and trustworthiness of the video consent. In addition, we explored drivers for opting in or opting out.

Results: The pilot demonstrated that the electronic video consent was well received by patients, with high scores for usefulness, ease, and trustworthiness even among patients that opted out of participation. The revised more animated video pilot test in phase 2 was better received in terms of ease of use (P=.005) and the ability to understand the information (P<.001). There were significant differences between those who opted in and opted out in their beliefs concerning the usefulness of tissue, trusting researchers, the importance of contributing to science, and privacy risk (P<.001). The results showed that "I trust researchers to use leftover biological specimens to promote the public's health" and "Sharing a biological sample for research is safe because of the privacy protections in place" discriminated opt-in statuses were the strongest predictors (both areas under the curve were 0.88). Privacy concerns seemed universal in individuals who opted out.

Conclusions: Efforts to better educate the community may be needed to help overcome some of the barriers in engaging individuals to participate in precision health initiatives.
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http://dx.doi.org/10.2196/29123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459215PMC
September 2021

Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer.

Cancers (Basel) 2021 Jul 18;13(14). Epub 2021 Jul 18.

Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

Recent advances in immunotherapy have reshaped the clinical management of lung cancer, and immune checkpoint inhibitors (ICIs) are now first-line treatment for advanced lung cancer. However, the majority of patients do not respond to ICIs as single agents, and many develop resistance after initial responses. Therefore, there is urgent need to improve the current ICI strategies. Murine models currently available for pre-clinical studies have serious limitations for evaluating novel immunotherapies. GEMMs are reliable and predictable models driven by oncogenic mutations mirroring those found in cancer patients. However, they lack the mutational burden of human cancers and thus do not elicit proper immune surveillance. Carcinogen-induced models are characterized by mutational burden that more closely resembles human cancer, but they often require extremely long experimental times with inconsistent results. Here, we present a hybrid model in which genetically engineered mice are exposed to the carcinogen -Methyl--Nitrosourea (MNU) to increase tumor mutational burden (TMB), induce early-stage immune responses, and enhance susceptibility to ICIs. We anticipate that this model will be useful for pre-clinical evaluation of novel immunotherapies.
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http://dx.doi.org/10.3390/cancers13143595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307650PMC
July 2021
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