Citations

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

AbstractThe purpose of this study was to develop and validate a population pharmacokinetic model for Z‐endoxifen in patients with advanced solid tumors and to identify clinical variables that influence pharmacokinetic parameters. Z‐endoxifen‐HCl was administered orally once a day on a 28‐day cycle (±3 days) over 11 dose levels ranging from 20 to 360 mg. A total of 1256 Z‐endoxifen plasma concentration samples from 80 patients were analyzed using nonlinear mixed‐effects modeling to develop a population pharmacokinetic model for Z‐endoxifen. A 2‐compartment model with oral depot and linear elimination adequately described the data. The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 4.89 L/h, 323 L, and 39.7 L, respectively, with weight‐effect exponents of 0.75, 1, and 1, respectively. This model was used to explore the effects of clinical and demographic variables on Z‐endoxifen pharmacokinetics. Weight, race on clearance, and aspartate aminotransferase on the absorption rate constant were identified as significant covariates in the final model. This novel population pharmacokinetic model provides insight regarding factors that may affect the pharmacokinetics of Z‐endoxifen and may assist in the design of future clinical trials.

Background: Careful selection of patients with expiratory central airway collapse (ECAC) that may benefit from tracheobronchoplasty (TBP) can be aided by a short-term airway stent evaluation. This can be performed with either silicone Y-stents (SYSs) or uncovered self-expanding metallic airway-stents (USEMAS). No direct comparison has been made between these 2 stent types. Methods: This was a small retrospective review of consecutive patients that underwent a stent evaluation. A propensity score was used to match patients in the USEMAS and SYS groups. Outcomes included complications, changes in the health-related quality-of-life (HR-QoL), and changes in exercise capacity. Baseline measurements were compared with those obtained during stent evaluation and after TBP. Results: Forty-two patients with severe ECAC underwent USEMAS placement, while 18 patients had an SYS placed. Propensity score matching resulted in 13 matched SYS and USEMAS pairs. The SYS group had an increased rate of mucus plugging (38.5% vs. 0%, P<0.047). Although not statically significant, a clinical improvement was observed in HR-QoL and exercise capacity in the USEMAS group during stent placement. In patients who underwent TBP, both USEMAS and SYS groups had a statistically significant change in the Modified Medical Research Council Dyspnea Scale during stent evaluation and after TBP. Conclusion: In patients with severe ECAC, short-term evaluation with airway stents appears to be safe and improves respiratory symptoms, HR-QoL, and exercise capacity. The use of USEMAS led to a lower complication rate, a greater improvement in HR-QoL and exercise capacity, and appeared to better predict how the patients would respond to TBP.

Introduction: Estrogens have been associated with risk of stroke in both men and women. Estradiol and estrone are synthesized from testosterone via the aromatase enzyme in both men and postmenopausal women. Genetic variation affecting function of the aromatase gene (CYP19A1) has been linked to elevated estradiol levels. We tested the hypothesis that these variants, as well as a modifying gene, are associated with ischemic stroke in three cohorts: the Vitamin Intervention for Stroke Prevention trial (VISP), Women’s Health Initiative (WHI), and Genetic Susceptibility to Early-Onset Stroke study (GEOS). Methods: Genomic data for individuals of European descent with ischemic stroke was compared against an equal number of controls: VISP (1723 cases - 65% men), WHI (436 cases - all postmenopausal women), GEOS (557 cases - all men age <55). Genotyping was funded through the Genomics and Randomized Trials Network (GARNET) and Gene Environment Association Studies (GENEVA) consortia. All cohorts used the Illumina Omni1-Quad chip for genotyping with imputation as needed. Eight candidate single nucleotide polymorphisms (SNPs) in CYP19A1 on chromosome 15 and an additional regulatory SNP in a modifier locus on chromosome 8 were chosen for analysis due to coding status or previous association with estradiol levels. Analyses were adjusted for age, hormone therapy use (women), and the top three principal components. Association results were determined as odds ratios for individual SNPs (effect allele = minor), with significance level of p<0.05. Results: GWAS results are tabulated. There were no significant differences in allele frequency for four SNPs in CYP19A1 among stroke patients and controls. The additional four SNPs were monomorphic in all three populations. The modifier gene SNP (rs1864729) was less common among young men with prior stroke in GEOS, but not men in VISP or in women. Conclusions: Aromatase genetic variation was not associated with risk of stroke in these three cohorts. One SNP that modifies aromatase function was less common among young, but not older men with stroke. Replication in other studies is necessary.

BACKGROUND: Recent genome-wide association studies (GWAS) have identified a number of novel SNPs associated with blood pressure and hypertension-related traits although studies were very large (approaching 80K participants) and effect sizes were modest with per allele effect sizes as small variants as a single millimeter of mercury difference in blood pressure. However, because hypertension is the most potent modifiable risk factor for ischemic stroke, lowering blood pressure by a few mm Hg can translate into measurable decrease in stroke risk. METHODS: We investigated 22 hypertension (HTN) associated SNPs in a case-control analysis of ischemic stroke in multiple stroke studies including the Siblings With Ischemic Stroke Study (SWISS), the Ischemic Stroke Genetics Study (ISGS), the Bio-Repository of DNA in Stroke (BRAINS), the Vitamin Intervention for Stroke Prevention (VISP) trial, and the Women's Health Initiative (WHI). SWISS/ISGS/BRAINS were analyzed together and included subtype information. Genotyping was funded through the individual studies, the Genomics and Randomized Trials Network (GARNET) consortium, and the SHARe (SNP Health Association Resource). All studies had both raw and imputed GWAS data. Analyses included the following phenotypes: all ischemic stroke, stroke subtypes, and age-at-stroke-onset and were stratified by race. Analyses were minimally adjusted for age, sex and principal components 1 & 2. Alpha was set at 0.05. RESULTS: Eleven of the SNPs from the HTN GWAS were associated with ischemic stroke in European ancestry from one or more of the study populations. Two SNPs on chromosome 12 and one on chromosome 21 were associated in multiple European ancestry cohorts. No SNP was associated in all studies. A SNP previously associated with HTN in African ancestry populations was associated with stroke in African-Americans. Analysis of subtypes found associations with small vessel disease and cardioembolic stroke but not large artery disease. The case-only age-at-stroke-onset analysis also found associations for the two SNPs on chromosome 12. CONCLUSION: These data suggest that candidate SNPs from a HTN GWAS may be associated with ischemic stroke and warrant further investigation. Racial differences were observed. Replication in populations from the other SiGN (Stroke Genetics Network), GENEVA (Gene Environment Association Studies) consortium, and the ISGC (International Stroke Genetics Consortium) studies are underway.

Abstract Background: As the development and use of oral anticancer agents increases, it is critical to understand patient adherence to both standard and investigational agents. The open label, phase 3 multicenter PALLAS trial investigates whether adding 2 years of the CDK4/6 inhibitor palbociclib (P) to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) over adjuvant ET alone in patients (pts) with HR- positive, HR2-negative, stage II-III breast cancer. Pts were randomly assigned to either Palbociclib (125 mg/day, 3 weeks on, 1 week off, in a 28-day cycle) plus ongoing provider/patient-choice adjuvant ET (P+ET) versus ET alone. We examined patient-reported adherence to ET +/- P during the first two years of study treatment. Methods: Adherence outcomes were measured in English-speaking pts in the U.S., UK, Ireland and Australia, Spanish-speaking pts in Spain and Mexico, and German-speaking pts in Germany and Austria. Adherence measures included drug diaries completed at each cycle, pill counts (for P only) collected at each study visit, and the Morisky Medication Adherence Scale-4 item and the McHorney Adherence Estimator questionnaires completed at cycles 2, 3, 6, 12, 18, and 24 (22 months). Mean adherence for each cycle was defined as the average proportion of prescribed pills taken (via drug diary) across all patients who initiated that cycle. Persistence was defined as the duration of drug initiation to treatment cessation (via drug diary). Generalized estimating equations were used to model the “most adherent” pts on the Morisky (score = 5 vs score &lt;5) and “low risk” for adherence problems on the McHorney (score=0 vs score &gt;0) to compare the average difference between arms over time for ET, adjusting for baseline demographic and clinical variables. Results: 81% (N=4688) of PALLAS pts were included in this analysis. Median persistence to ET was 23.6 months in P + ET (n=2169), 23.7 months in ET alone (2136) and 20.4 months for P (n=2194). The number of pts who initiated each cycle for ET declined over time and was similar between arms; the decline was more marked for P (Table 1). Mean adherence range as measured by drug diary was 98.2-99.3% for ET in P+ET and 98.0 - 99.4% in ET alone; and for P, ranged from 93.4 - 98.8%. The adherence and persistence results were nearly identical whether measured by drug diary or pill count for P. The observed percent “most adherent” for P measured by the Morisky scale ranged from 71.9% - 79.6% and the percent “low risk” for adherence problems measured by the McHorney scale, 64.0% - 73.4%. The percent of pts “most adherent” and “low risk” for adherence problems to ET was higher, on average over time, in the P+ET group compared to ET alone (75% vs 68%, p&lt;0.01; 75% vs 72%, p=.05, respectively). Conclusions: Self-reported mean adherence for both P + ET and ET alone was strikingly high for pts who remained on therapy; persistence was also high with ET during the 2-year treatment period. Current analyses suggest that nonadherence to either P or ET was likely not a major contributor to the iDFS results seen in the overall PALLAS trial. These results illustrate the importance of measuring and monitoring patient adherence to oral study agents. Support: AFT, Pfizer; ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). https://acknowledgments.alliancefound.org Table 1.Adherence and persistence in PALLAS over the 24 month treatment periodPalbocicilb + ETETPalbociclibETETTreatment cycleMean Adherence (SD)N*Mean Adherence (SD)NMean Adherence (SD)N193.4 (13.8)229098.7 (6.1)230999.0 (5.2)2343294.7 (13.3)218198.8 (6.4)220398.4 (7.1)2206397.4 (10.1)211298.7 (7.3)214298.8 (6.3)2168497.6 (10.2)203598.6 (7.8)211099.0 (5.7)2154597.6 (11.1)197598.3 (7.9)209398.1 (8.3)2148698.1 (8.7)189998.7 (6.6)203798.5 (8.2)2116798.1 (9.3)185599.0 (6.3)201298.6 (7.3)2102898.0 (9.1)181098.2 (8.2)199798.1 (8.2)2092998.4 (7.4)173399.0 (6.4)196298.8 (6.8)20511098.3 (8.6)171499.2 (4.9)194699.0 (5.5)20381198.3 (8.0)169198.5 (7.3)193798.2 (8.2)20311298.7 (6.2)161299.1 (5.3)191098.7 (7.5)19861398.5 (7.7)159698.9 (6.4)189398.8 (7.1)19691497.9 (9.3)157698.4 (7.3)188298.0 (9.1)19611598.5 (6.9)151499.2 (4.6)185499.0 (6.0)19281698.2 (8.7)148699.1 (4.6)183599.1 (5.7)19131798.1 (9.8)147998.3 (7.8)182698.5 (6.4)19031898.7 (6.8)141699.3 (4.1)176899.2 (5.3)18601998.7 (7.3)140899.3 (3.8)175699.4 (3.1)18482098.4 (8.9)139798.9 (5.3)174298.7 (5.8)18382198.5 (7.5)130199.0 (6.1)167698.8 (7.1)17842297.8 (9.7)124698.8 (6.2)164799.2 (5.7)17692398.1 (8.8)118098.2 (8.5)161998.4 (8.0)17552498.8 (7.2)108699.0 (6.3)146898.9 (7.1)16192598.8 (6.7)99699.2 (5.2)143298.8 (7.1)15892697.9 (11.2)84599.1 (5.7)140998.6 (8.8)1578ET=Endocrine therapy * Number of pts who initiated the treatment cycle. Citation Format: Eileen Shinn, David Zahrieh, Angela DeMichele, Nick Zdenkowski, Julie Lemieux, Jun Mao, Vesna Bjelic-Radisic, Michelle Naughton, Georg Pfeiler, Karen Gelmon, Ingrid Mayer, Daniel Egle, Gabriele Zoppoli, Tiffany Traina, Miguel Martin Jiménez, Silvia Antolin Novoa, Tufia Haddad, Arlene Chan, Alistair Edward Ring, Antonio Wolff, Jose JuanPonce Lorenzo, Dhanusha Sabanathan, Hal Burstein, Zbigniew Ireneusz Nowecki, Gunda Pristauz-Telsnigg, Adam Brufsky, Meritxell Bellet-Ezquerra, Theodoros Foukakis, Yelena Novik, Gabor Rubovszky, Karoline Muehlbacher, Otto Metzger, Theodora Goulioti, Ernest Law, Ann Partridge, Lisa Carey, Alex Zoroufy, Dominik Hlauschek, Christian Fesl, Erica Mayer, Michael Gnant. Adherence with adjuvant endocrine therapy with or without Palbociclib in the PALLAS trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-12-01.

Abstract Background: Quality of life (QOL) in breast cancer patients (pts) can be greatly impacted by initial treatment and ongoing therapy, particularly if side effects and symptoms are not well tolerated. The PALLAS trial investigated whether the addition of 2 years of palbociclib (palbo) to adjuvant endocrine therapy (ET) improved invasive disease-free survival (iDFS) over adjuvant ET alone. We report on the main patient-reported outcome (PRO) quality of life (QOL) and symptom severity results of this trial by treatment arm. Methods: PALLAS is an ongoing multicenter, open label phase 3 trial that enrolled hormone receptor positive, HER2-negative, stage II-III breast cancer patients at 406 cancer centers across 21 countries. Patients were randomly assigned (1:1) to either 2 years of palbo (125mg/day, 3 weeks on 1 week off) plus ongoing provider or patient-choice adjuvant ET (palbo+ET) versus ongoing ET alone. The primary study endpoint was iDFS. Treatment with palbo in all pts stopped at the time of the second interim analysis (5/2020) due to futility; all pts then moved to follow up. The PRO analyses were triggered for completion after awareness of the pre-specified 469 iDFS cases in November 2020. Eight PRO endpoints were measured serially (i.e., day 1 of each monthly cycle for the first 3 months, then every 3 months for the first 2 years, and once at year 3). The endpoints were the EORTC QLQ-C30 global health status/QOL score, the Brief Fatigue Inventory score, the modified Brief Pain Inventory severity and pain interference scores, the EORTC QLQ-BR23 alopecia score, and the Breast Cancer Prevention Trial hot flash symptoms, vaginal problems, and musculoskeletal pain scores. Linear mixed models compared the average difference between arms across time points during the initial 2-year treatment period adjusting for cycle 1 day 1 (C1D1) PRO scores, demographic and clinical variables. The average differences between arms (palbo+ET vs ET alone) and the two-sided (1-[0.05/8]) x 100% confidence intervals, adjusted for multiple comparisons, were calculated. Analysis of covariance compared the average between-arm differences by endpoint at 3 years. Results: The PRO intention to collect population included 4688 (81%) of the overall trial pts, and was clinically and demographically representative of the remaining 1073 pts. Each analysis population, with measures at C1D1 and at least 1 post-C1D1 assessment for each PRO endpoint, comprised ≥ 89% of the 4688 pts and the proportions were similar between arms. After adjustment for baseline covariates, on average, no clinically important differences between arms were observed for any of the eight endpoints over the 2 year treatment period (Table 1). All effect sizes were below the pre-specified 0.2 threshold. These PRO results were similar at the 3 year time point. Conclusions: No clinically significant differences in either patient-reported QOL or symptom severity were found, on average, between participants in the two PALLAS treatment arms while either taking palbo+ET or ET alone, or after study-wide termination of palbo. In general, the addition of palbociclib in the adjuvant breast cancer setting did not contribute to increased symptom burden within this survivorship population. Further analyses will examine the relationship between PROs and treatment discontinuation by arm and study time point. Support: AFT, Pfizer, https://acknowledgments.alliancefound.org Table 1.Results of the Patient-Reported QOL and Symptom Severity Analyses Between the Two Treatment Arms During the First 2 Years of PALLASPRO Endpoint *Palbo + ET Adjusted average score (95% CI)ET alone Adjusted average score (95% CI)Average Difference + (Palbo + ET vs ET alone)[99.38% CI] Clinically ++ Important DifferenceEORTC QLQ-C30 Global Health Status/QOL71.7 (71.2, 72.2)74.0 (73.5, 74.5)-2.3 (-3.3, -1.4)**NoBrief Fatigue Inventory Score2.3 (2.2, 2.3)2.1 (2.0, 2.1)0.2 (0.1, 0.3)NoModified Brief Pain Inventory - Severity Score2.3 (2.2, 2.3)2.4 (2.4, 2.5)-0.2 (-0.3, -0.1)NoModified Brief Pain Inventory - Interference Score1.7 (1.6, 1.7)1.7 (1.6, 1.7)0.0 (-0.1, 0.1)NoEORTC QLQ-BR23 Alopecia1.4 (1.4, 1.4)1.3 (1.3, 1.3)0.1 (0.1, 0.1)NoBreast Cancer Prevention Trial - Hot Flash Symptoms1.2 (1.2, 1.3)1.2 (1.2, 1.3)0.0 (-0.1, 0.1)NoBreast Cancer Prevention Trial - Vaginal Problems0.8 (0.8, 0.8)0.8 (0.7, 0.8)0.0 (0.0, 0.1)NoBreast Cancer Prevention Trial - Musculoskeletal Pain1.2 (1.2, 1.2)1.3 (1.3, 1.3)-0.1 (-0.2, 0.0)No* For the EORTC QLQ-C30 Global Health Status/QOL subscale, higher scores indicate better QOL. For all other PRO endpoints, higher scores indicate worse symptom levels. ** The lower bound of the one-sided CI (adjusted for multiple comparisons) was -3.3. Because the lower limit is greater than the pre-specified non-inferiority margin of -3.44, non-inferiority of palbo+ET relative to ET-alone was concluded. The non-inferiority margin corresponds to a 0.2 SD in the EORTC QLQ-C30 global health/QOL score. +The average difference was adjusted for the following baseline covariates: Cycle 1 day 1 score, region (if applicable), age category, first adjuvant ET, race, ethnicity, N-stage, T-stage, histological grade, PgR, prior chemotherapy, ECOG Performance Status. ++Based on each instrument’s published clinically relevant cut-offs, if available. After calculating Cohen’s d treatment effect sizes, (i.e. by dividing the average difference by the ET-alone arm standard deviation from cycle 1 day 1), all effect sizes were below the pre-specified 0.2 threshold, and would not be considered clinically important. Citation Format: Michelle Joy Naughton, David Zahrieh, Michael Gnant, Nicholas Zdenkowski, Julie Lemieux, Jun J Mao, Vesna Bjelic-Radisic, Eileen Shinn, Marija Balic, Christoph Thomssen, Jane Neisel, Manuel Ruiz-Echarri, Sibylle Loibl, Claudine Isaacs, David Cameron, Fernando Manuel Henao Carrasco, Matthew Goetz, Viktor Wette, Gustavo Werutsky, Hope Rugo, Marcus Vetter, Ling-Ming Tseng, Kathy Miller, Florian Fitzal, Juan Miguel Gil Gil, Haeseong Park, Barbro Linderholm, Emilio Bajetta, Zoneddy Dayao, Aleix Prat, Karin Ehrhardt, Otto Metzger, Amal Arahmani, Ernest Law, Ann Partridge, Lisa Carey, Alex Zoroufy, Amylou Dueck, Dominik Hlauschek, Angela DeMichele, Erica Mayer. Quality of life and symptom severity in the PALLAS randomized trial of palbociclib with adjuvant endocrine therapy in early breast cancer (AFT-05) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-01.

AbstractAmidst the COVID‐19 pandemic and social uprisings demanding social and racial equity worldwide, there is an increasing demand for health justice training for health workers. However, there are scant evidence‐based assessments of the impact of such courses. Between 2010 and 2020, SocMed—a 501(c)3 non‐profit social justice organization—offered two distinct courses about health equity, the social determinants of health, and social medicine to health workers through the University of Minnesota in Minneapolis, Minnesota and Saint Mary Hospital Lacor in Gulu, Uganda. This study assesses the immediate impact of the SocMed curriculum on participants measured by a pre‐course and post‐course survey. In Minnesota, paired pre‐course and post‐course survey responses (mean n = 69; SD = 23) spanned years 2016–2019, while Uganda paired pre‐course and post‐course survey responses (mean n = 64; SD = 21) spanned years 2012–2013 and 2017–2019. Findings indicate that the course improved participants’ knowledge in all 24 of the topics in the Minnesota course and 42 of 44 topics in the Uganda course (significant at p < 0.05).