Cardiovascular impact of near complete estrogen deprivation in premenopausal women with breast cancer: The CROWN study.

Survival with operable breast cancer has improved markedly in recent decades, however, treatment-related cardiovascular toxicities threaten to offset these gains. Ovarian function suppression paired with aromatase inhibition, for premenopausal women with hormone receptor (HR)-positive breast cancer, is a newer widely adopted therapy with the potential for significant long-term cardiovascular toxicity. Abrupt estrogen deprivation for non-cancer reasons is associated with accelerated coronary artery disease. Women with breast cancer treated with aromatase inhibition in addition to ovarian function suppression experience a dual hit with regards to estrogen exposure. The CaRdiac Outcomes With Near-complete estrogen deprivation (CROWN) study seeks to understand the early, subclinical natural history of cardiovascular compromise in young women undergoing near-complete estrogen deprivation (NCED) therapy. It is critical to understand the early subclinical development of cardiovascular disease to identify a window for therapeutic intervention before overt cardiovascular events occur. This three-site regional study (Atrium Health Wake Forest, Duke, and Virginia Commonwealth University) uses serial stress cardiac magnetic resonance (CMR) imaging and cardiac computed tomography angiography (CCTA) obtained during the initial two years of NCED therapy to study myocardial prefusion reserve (MPR), large cardiovascular vessel changes, left ventricular function, and other cardiovascular parameters. The CROWN cohort will consist of 90 premenopausal women with breast cancer, 67 with HR-positive disease receiving NCED and 23 comparators with HR-negative disease. Participants will undergo three annual CMR scans and 2 CCTA scans during the 2-year study period. After initial activation hurdles, accrual has been brisk, and the study is expected to complete accrual in December 2024. Efforts are in place to encourage participant retention with the study primary outcome, change in MPR between the two groups, to be reported in 2026 to 2027. The results of this study will enable premenopausal women with breast cancer to balance the health burdens of cancer at a young age and treatment-related cardiovascular morbidity. Finally, the tools developed here can be utilized to study cardiovascular risk across a range of cancer types and cancer therapies with the ultimate goals of both developing generalizable risk stratification tools as well as validating interventions which prevent overt cardiovascular compromise.

Duration of Simultaneous Exposure to High-Risk and Lower-Risk Nephrotoxic Antimicrobials in the Neonatal Intensive Care Unit (NICU) and Future Adolescent Kidney Health.

OBJECTIVE: To determine whether greater duration of simultaneous exposure to antimicrobials with high nephrotoxicity risk combined with lower-risk antimicrobials (simultaneous exposure) in the neonatal intensive care unit (NICU) is associated with worse later kidney health in adolescents born preterm with very low birth weight (VLBW). STUDY DESIGN: Prospective cohort study of participants born preterm with VLBW (<1500 g) as singletons between January 1, 1992, and June 30, 1996. We defined simultaneous exposure as a high-risk antimicrobial, such as vancomycin, administered with a lower-risk antimicrobial on the same date in the NICU. Outcomes were serum creatinine, estimated glomerular filtration rate (eGFR), and first-morning urine albumin-creatinine ratio (ACR) at age 14 years. We fit multivariable linear regression models with days of simultaneous exposure and days of nonsimultaneous exposure as main effects, adjusting for gestational age, birth weight, and birth weight z-score. RESULTS: Of the 147 out of 177 participants who had exposure data, 97% received simultaneous antimicrobials for mean duration 7.2 days (SD 5.6). No participant had eGFR <90 ml/min/1.73 m2. The mean ACR was 15.2 mg/g (SD 38.7) and 7% had albuminuria (ACR >30 mg/g). Each day of simultaneous exposure was associated only with a 1.04-mg/g higher ACR (95% CI 1.01 to 1.06). CONCLUSIONS: Despite frequent simultaneous exposure to high-risk combined with lower-risk nephrotoxic antimicrobials in the NICU, there were no clinically relevant associations with worse kidney health identified in adolescence. Although future studies are needed, these findings may provide reassurance in a population thought to be at increased risk of chronic kidney disease.

Patient Characteristics Associated with Telemedicine Use for Diabetes Mellitus Care: Experience of a University Health System.

OBJECTIVES: The objective was to understand the characteristics of patients who used telemedicine for diabetes management to inform future implementation of telemedicine. METHODS: We examined patient characteristics associated with telemedicine use for diabetes mellitus (DM) care between March 1, 2020 and April 1, 2021 (the coronavirus disease 2019 pandemic period) in a large university health system when telemedicine visits increased rapidly. Logistic regression models assessed patient characteristics associated with telemedicine visits and delays in DM process measures (hemoglobin A1c checks, nephropathy, and retinopathy evaluations) during the pandemic period after adjusting for potential confounders and corresponding values before the pandemic period (March 1, 2019-February 29, 2020). RESULTS: A total of 45,159 patients were seen from 987,791 visits during the pandemic period. The number of visits averaged one visit less during the pandemic period than before the pandemic period. Approximately 5.4% of patients used telemedicine during the pandemic period from 42,750 visits. The mean (standard deviation) telemedicine visit was 1.28 (0.91). Men, Asian, Black, and other race (vs White), having Medicare or uninsured (vs private insurance), were less likely to use telemedicine. Patients with more visits before the pandemic period were more likely to use telemedicine and less likely to experience a delay in DM process measures during the pandemic period. Telemedicine users were 18% less likely to experience a delay in nephropathy visits than nonusers, but without difference for other process measures. CONCLUSIONS: Race, sex, insurance, and prepandemic in-person visits were associated with telemedicine use for DM management in a large health system. Telemedicine use was not associated with delays in hemoglobin A1c testing, nephropathy, and retinopathy assessments. Understanding reasons for not using telemedicine is important to be able to deliver equitable DM care.

Mechanisms of mindfulness in patients with migraine: Results of a qualitative study.

OBJECTIVE: To understand the mechanisms of mindfulness' impact on migraine. BACKGROUND: Promising mindfulness research demonstrates potential benefit in migraine, but no data-driven model exists from the lived experiences of patients that explains the mechanisms of mindfulness in migraine. METHODS: Semi-structured qualitative interviews were conducted with adults with migraine who participated in two mindfulness-based stress reduction (MBSR) clinical trials (n = 43). Interviews were audio-recorded, transcribed, and summarized into a framework matrix with development of a master codebook. Constructivist grounded theory approach was used to identify themes/subthemes. RESULTS: Participants who learned mindfulness techniques through MBSR experienced altered pain perception, altered response to migraine attacks and disease, increased awareness of external and internal experiences, improved overall well-being, and group benefits. Mindfulness resulted in earlier stress-body awareness and increased interoceptive awareness resulting in earlier attack recognition, leading to earlier and more effective management. Interictal factors of self-blame, guilt, and stigma decreased while migraine acceptance, hope, empowerment, self-efficacy, and self-compassion increased. Improved emotion regulation resulted in decreased fear of migraine, pain catastrophizing, anticipatory anxiety, and pain reactivity. Although taught as prevention, mindfulness was used both acutely and prophylactically. We created a conceptual model hypothesizing that MBSR skills led to an infusion of mindfulness in daily life, resulting in altered pain perception and experience, ultimately leading to improvement in overall well-being, which may positively feed back to the infusion of mindfulness in daily life. The therapeutic benefit of learning mindfulness in a group setting may moderate these effects. CONCLUSIONS: This study identified several new potential mechanisms of mindfulness' effect on migraine. After learning MBSR skills, participants reported altered pain and migraine perception and experiences. Increased stress-body and interoceptive awareness resulted in earlier migraine awareness and treatment. Mindfulness may target important interictal factors that affect disease burden such as fear of migraine, pain catastrophizing, and anticipatory anxiety. This is the first data-driven study to help elucidate the mechanisms of mindfulness on migraine from patient voices and can help direct future research endeavors.

A single-center survey on physical activity barriers, behaviors and preferences in adults with epilepsy.

BACKGROUND: Improved understanding of physical activity barriersand preferences in people with epilepsyis needed to successfully design and perform larger, more robust effectivenesstrials. METHODS: Adult patients at a single tertiary epilepsy center between January and April 2020 were surveyed. The survey included a validated physical activity questionnaire (Physical Activity Scale for the Elderly) plus 15 items aimed to address 1) perceptions and beliefs regarding physical activity, 2) barriers to routine physical activity, and 3) willingness and ability to participate in a physical activity intervention and 4) current physical abilities, activities, and preferences. RESULTS: 95 participants with epilepsy (age 42 ± 16.2, 59 % female) completed the survey. Sixty-five participants (68.4 %) reported that they believe that physical activity could improve their seizure frequency. However, 40 % of those surveyed said their neurologist had never talked to them about physical activity. The most commonly reported barriers to physical activity were lack of time (24.7 %) and fear of having a seizure (19.7 %), while barriers to intervention participation included being unable to come to in-person sessions (53 % of those willing to participate),living far away (39.3 %), time constraints (28.6 %), and lack of transportation (21.4 %). CONCLUSION: Future physical activity studies in people with epilepsy should focus on using tailored interventions that accommodate their unique beliefs and barriers.

Intermediate-risk pulmonary embolism: echocardiography predictors of clinical deterioration.

BACKGROUND: We determine the predictive value of transthoracic echocardiographic (TTE) metrics for clinical deterioration within 5 days in adults with intermediate-risk pulmonary embolism (PE). METHODS: This was a prospective observational study of intermediate-risk PE patients. To determine associations of TTE and clinical predictors with clinical deterioration, we used univariable analysis, Youden's index for optimal thresholds, and multivariable analyses to report odds ratios (ORs) or area under the curve (AUC). RESULTS: Of 306 intermediate-risk PE patients, 115 (37.6%) experienced clinical deterioration. PE patients who had clinical deterioration within 5 days had greater baseline right ventricle (RV) dilatation and worse systolic function than the group without clinical deterioration as indicated by the following: RV basal diameter 4.46 ± 0.77 versus 4.20 ± 0.77 cm; RV/LV basal width ratio 1.14 ± 0.29 versus 1.02 ± 0.24; tricuspid annular plane systolic excursion (TAPSE) 1.56 ± 0.55 versus 1.80 ± 0.52 cm; and RV systolic excursion velocity 10.40 ± 3.58 versus 12.1 ± 12.5 cm/s, respectively. Optimal thresholds for predicting clinical deterioration were: RV basal width 3.9 cm (OR 2.85 [1.64, 4.97]), RV-to-left ventricle (RV/LV) ratio 1.08 (OR 3.32 [2.07, 5.33]), TAPSE 1.98 cm (OR 3.3 [2.06, 5.3]), systolic excursion velocity 10.10 cm/s (OR 2.85 [1.75, 4.63]), and natriuretic peptide 190 pg/mL (OR 2.89 [1.81, 4.62]). Significant independent predictors were: transient hypotension 6.1 (2.2, 18.9), highest heart rate 1.02 (1.00, 1.03), highest respiratory rate 1.02 (1.00, 1.04), and RV/LV ratio 1.29 (1.14, 1.47). By logistic regression and random forest analyses, AUCs were 0.80 (0.73, 0.87) and 0.78 (0.70, 0.85), respectively. CONCLUSIONS: Basal RV, RV/LV ratio, and RV systolic function measurements were significantly different between intermediate-risk PE patients grouped by subsequent clinical deterioration.

Tolerability of bevacizumab and chemotherapy in a phase 3 clinical trial with human epidermal growth factor receptor 2-negative breast cancer: A trajectory analysis of adverse events.

BACKGROUND: E5103 was a study designed to evaluate the efficacy and safety of bevacizumab. It was a negative trial for the end points of invasive disease-free survival and overall survival. The current work examines the tolerability of bevacizumab and other medication exposures with respect to clinical outcomes and patient-reported outcomes (PROs). METHODS: Adverse events (AEs) collected from the Common Terminology Criteria for Adverse Events were summarized to form an AE profile at each treatment cycle. All-grade and high-grade events were separately analyzed. The change in the AE profile over the treatment cycle was delineated as distinct AE trajectory clusters. AE-related and any-reason early treatment discontinuations were treated as clinical outcome measures. PROs were measured with the Functional Assessment of Cancer Therapy-Breast + Lymphedema. The relationships between the AE trajectory and early treatment discontinuation as well as PROs were analyzed. RESULTS: More than half of all AEs (57.5%) were low-grade. A cluster of patients with broad and mixed AE (all-grade) trajectory grades was significantly associated with any-reason early treatment discontinuation (odds ratio [OR], 2.87; P = .01) as well as AE-related discontinuation (OR, 4.14; P = .001). This cluster had the highest count of all-grade AEs per cycle in comparison with other clusters. Another cluster of patients with primary neuropathic AEs in their trajectories had poorer physical well-being in comparison with a trajectory of no or few AEs (P < .01). A high-grade AE trajectory did not predict discontinuations. CONCLUSIONS: A sustained and cumulative burden of across-the-board toxicities, which were not necessarily all recognized as high-grade AEs, contributed to early treatment discontinuation. Patients with neuropathic all-grade AEs may require additional attention for preventing deterioration in their physical well-being.

Learning the full impact of migraine through patient voices: A qualitative study.

OBJECTIVE: To better characterize the ways that migraine affects multiple domains of life. BACKGROUND: Further understanding of migraine burden is needed. METHODS: Adults with migraine randomized to mindfulness-based stress reduction or headache education arms (n = 81) in two separate randomized clinical trials participated in semistructured in-person qualitative interviews conducted after the interventions. Interviews queried participants on migraine impact on life and were audio-recorded, transcribed, and summarized into a framework matrix. A master codebook was created until meaning saturation was reached and magnitude coding established code frequency. Themes and subthemes were identified using a constructivist grounded theory approach. RESULTS: Despite most participants being treated with acute and/or prophylactic medications, 90% (73/81) reported migraine had a negative impact on overall life, with 68% (55/81) endorsing specific domains of life impacted and 52% (42/81) describing impact on emotional health. Six main themes of migraine impact emerged: (1) global negative impact on overall life; (2) impact on emotional health; (3) impact on cognitive function; (4) impact on specific domains of life (work/career, family, social); (5) fear and avoidance (pain catastrophizing and anticipatory anxiety); and (6) internalized and externalized stigma. Participants reported how migraine (a) controls life, (b) makes life difficult, and (c) causes disability during attacks, with participants (d) experiencing a lack of control and/or (e) attempting to push through despite migraine. Emotional health was affected through (a) isolation, (b) anxiety, (c) frustration/anger, (d) guilt, (e) mood changes/irritability, and (f) depression/hopelessness. Cognitive function was affected through concentration and communication difficulties. CONCLUSIONS: Migraine has a global negative impact on overall life, cognitive and emotional health, work, family, and social life. Migraine contributes to isolation, frustration, guilt, fear, avoidance behavior, and stigma. A greater understanding of the deep burden of this chronic neurological disease is needed to effectively target and treat what is most important to those living with migraine.

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis.

Adoptive cellular therapy (ACT) with the Th17 subset of CD4+ T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets, including conventionally activated CD8+ T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.

Patient preferences for direct-to-consumer telemedicine services: a nationwide survey.

BACKGROUND: Direct-to-consumer (DTC) telemedicine providers has the potential to change the traditional patient-physician relationship. Professional medical organizations recommend that telemedicine exist within the medical home. This study aims to understand patients' preferences and desires for DTC telemedicine. METHODS: We conducted a nationwide survey of 4345 survey respondents demographically balanced to represent the United States adult population. The survey consisted of questions assessing the respondents' attributes and their willingness and comfortability using telemedicine as well as the importance and desired attributes of a provider providing care via telemedicine. RESULTS: Relatively few respondents (3.5%) had ever had an online video visit with their care provider. Respondents were more willing to see their own provider via telemedicine than unwilling (52% vs. 25%). Additionally, respondents were less willing to use telemedicine to see a different provider from the same healthcare organization (35%) and were least willing to see a different provider from a different organization (19%). Forty-one percent of respondents felt it was unimportant that their current provider offer telemedicine, and only 15% would consider leaving their current provider to a new provider who offers telemedicine as an option. More than half (56%) of respondents felt it was important to have an established relationship with a provider they're having a telemedicine visit with. Nearly two-thirds of respondents (60%) felt it was important for a telemedicine provider to have access to their health records. CONCLUSIONS: Patients prefer to use telemedicine with their own doctor with whom they have an established relationship.

10 years later: assessing the impact of public health efforts on the collection of family health history.

In 2004, a nationwide survey found that the majority (96.3%) of Americans believed their family health history (FHx) was important for their own health; however, only a third (29.8%) of respondents had ever actively collected this information. Over the past decade, government agencies, advocacy groups, professional societies, and healthcare provider organizations have aimed to improve the collection rates and utilization of FHx. This study assesses the current attitudes, knowledge, and practices of Americans regarding their FHx and whether the interventions over the past 10 years have led to any FHx-related changes. We conducted a nationwide survey of 5,258 respondents using the same measures used in the 2004 survey. Overall, there was little change in Americans knowledge and use of FHx information. While there was a statistically significant increase in respondents who have actively collected their FHx (36.9%), respondents know roughly the same or less about his or her FHx today. Furthermore, only a small fraction (2.6%) had ever collected their FHx using a web-based FHx tool. Several factors were identified which influence whether an individual actively collects his or her FHx. New FHx tools and approaches may be necessary to promote clinically meaningful improvement in FHx collection among patients.

A 'crying wolf' game of interspecific kleptoparasitic mutualism.

We model a potentially mutualistic interaction between a species making antipredator alarm calls and a species which eavesdrops on those calls. Callers may or may not make deceptive alarm calls in order to kleptoparasitize food from eavesdroppers, which in turn may either heed or ignore all alarm calls. The two most likely outcomes in our model are either maximally deceptive callers and maximally trusting eavesdroppers, or persistently cycling strategy frequencies. The latter is favoured by low predator density, low density of any alternative honest alarm-calling species, ability of eavesdroppers to preferentially heed calls when costs of doing so are low and, in some cases, low food availability.

Computational Pathology for Accurate Prediction of Breast Cancer Recurrence: Development and Validation of a Deep Learning-based Tool.

Accurate recurrence risk stratification is crucial for optimizing treatment plans for breast cancer patients. Current prognostic tools like Oncotype DX (ODX) offer valuable genomic insights for HR+/HER2- patients but are limited by cost and accessibility, particularly in underserved populations. In this study, we present Deep-BCR-Auto, a deep learning-based computational pathology approach that predicts breast cancer recurrence risk from routine H&E-stained whole slide images (WSIs). Our methodology was validated on two independent cohorts: the TCGA-BRCA dataset and an in-house dataset from The Ohio State University (OSU). Deep-BCR-Auto demonstrated robust performance in stratifying patients into low- and high-recurrence risk categories. On the TCGA-BRCA dataset, the model achieved an area under the receiver operating characteristic curve (AUROC) of 0.827, significantly outperforming existing weakly supervised models (p=0.041). In the independent OSU dataset, Deep-BCR-Auto maintained strong generalizability, achieving an AUROC of 0.832, along with 82.0% accuracy, 85.0% specificity, and 67.7% sensitivity. These findings highlight the potential of computational pathology as a cost-effective alternative for recurrence risk assessment, broadening access to personalized treatment strategies. This study underscores the clinical utility of integrating deep learning-based computational pathology into routine pathological assessment for breast cancer prognosis across diverse clinical settings.

Risk of Obesity and Unhealthy Central Adiposity in Adolescents Born Preterm With Very Low Birthweight Compared to Term-Born Peers.

Background: Early-life factors such as preterm birth or very low birthweight (VLBW) are associated with increased cardiovascular disease risk. However, it remains unknown whether this is due to an increased risk of obesity (unhealthy central adiposity) because studies have predominantly defined obesity based on BMI, an imprecise adiposity measure. Objective: Investigate if adolescents born preterm with VLBW have a higher risk of unhealthy central adiposity compared to term-born peers. Study Design: Cross-sectional analysis of data from a prospective cohort study of 177 individuals born preterm with VLBW (<1500 g) and 51 term-born peers (birthweight ≥2500 g). Individuals with congenital anomalies, genetic syndromes, or major health conditions were excluded. Height, weight, waist circumference, skin fold thickness, and dual energy X-ray absorptiometry body composition were measured at age 14 years. We calculated BMI percentiles and defined overweight/obesity as BMI ≥85th percentile for age and sex. We estimated the preterm-term differences in overweight/obesity prevalence and adiposity distribution with multivariable generalized linear models. Results: There was no difference in small for gestational age status or overweight/obesity prevalence. Compared to term, youth born preterm with VLBW had lower BMI z-score [ß -0.38, 95% confidence limits (CL) -0.75 to -0.02] but no differences in adiposity apart from subscapular-to-triceps ratio (STR; ß 0.18, 95% CL 0.08 to 0.28). Conclusions: Adolescents born preterm with VLBW had smaller body size than their term-born peers and had no differences in central adiposity except greater STR.

Low Stroke Volume Predicts Deterioration in Intermediate-Risk Pulmonary Embolism: Prospective Study.

Introduction: Prognosis and management of patients with intermediate-risk pulmonary embolism (PE) is challenging. We investigated whether stroke volume may be used to identify the subset of this population at increased risk of clinical deterioration or PE-related death. Our secondary objective was to compare echocardiographic measurements of patients who received escalated interventions vs anticoagulation monotherapy. Methods: We selected patients with intermediate-risk PE, who had comprehensive echocardiography within 18 hours of PE diagnosis and before any escalated interventions, from a PE registry populated by 11 emergency departments. Echocardiographers measured right ventricle (RV) size, tricuspid annular plane systolic excursion (TAPSE), and stroke volume (SV) using velocity time integral (VTI) by left ventricular (LV) outflow tract Doppler or two-dimensional method of discs (MOD). The primary outcome was a composite of PE-related death, cardiac arrest, catecholamine administration for sustained hypotension, or emergency respiratory intervention during the index hospitalization. Secondary outcome was escalated intervention with reperfusion or extracorporeal membrane oxygenation therapy. Results: Of 370 intermediate-risk PE patients (mean age 64.0 ± 15.5 years, 38.1% male), 39 (10.5%) had the primary outcome. These 39 patients had lower mean SV regardless of measurement method than those without the primary outcome: SV MOD 36.2 vs 49.9 milliliters (mL), P < 0.001; SV Doppler 41.7 vs 57.2 mL, P = 0.003; VTI 13.6 vs 17.9 centimeters [cm], P = 0.003. Patients with primary outcome also had lower mean TAPSE than those without (1.54 vs 1.81 cm, P = 0.003). Multivariable models, selecting SV as predictor, had area under the receiver operating curve of 0.8 and Brier score 0.08. The best echocardiographic predictor of our primary outcome was SV MOD (odds ratio 0.72 [0.53, 0.94], P = 0.02). Patients who received escalated interventions had significantly lower SV or surrogate measurements, greater RV dilatation, and lower RV systolic function than patients who received anticoagulation monotherapy. Conclusion: Low stroke volume was a predictor of clinical deterioration and PE-related death. Low SV may be used to identify a subset of intermediate-risk PE patients, who are higher risk (intermediate-high risk), and for whom escalated interventions should be considered.

Comparison of Treatment Approaches and Subsequent Outcomes within a Pulmonary Embolism Response Team Registry.

Objectives: To characterize the association between pulmonary embolism (PE) severity and bleeding risk with treatment approaches, outcomes, and complications. Methods: Secondary analysis of an 11-hospital registry of adult ED patients treated by a PE response team (August 2016-November 2022). Predictors were PE severity and bleeding risk. The primary outcome was treatment approach: anticoagulation monotherapy vs. advanced intervention (categorized as "immediate" or "delayed" based on whether the intervention was received within 12 hours of PE diagnosis or not). Secondary outcomes were death, clinical deterioration, and major bleeding. Results: Of the 1832 patients, 139 (7.6%), 977 (53.3%), and 9 (0.5%) were classified as high-risk, intermediate-high, intermediate-low, and low-risk severity, respectively. There were 94 deaths (5.1%) and 218 patients (11.9%) had one or more clinical deterioration events. Advanced interventions were administered to 86 (61.9%), 195 (27.6%), and 109 (11.2%) patients with high-risk, intermediate-high, and intermediate-low severity, respectively.Major bleeding occurred in 61/1440 (4.2%) on ACm versus 169/392 (7.6%) with advanced interventions (p <0.001): bleeding withcatheter-directed thrombolysiswas 19/145 (13.1%) versus 33/154(21.4%) with systemic thrombolysis,p= 0.07. High risk was twice as strong as intermediate-high risk for association with advanced intervention (OR: 5.3 (4.2 and 6.9) vs. 1.9 (1.6 and 2.2)). High risk (OR: 56.3 (32.0 and 99.2) and intermediate-high risk (OR: 2.6 (1.7 and 4.0)) were strong predictors of clinical deterioration. Major bleeding was significantly associated with advanced interventions (OR: 5.2 (3.5 and 7.8) for immediate, 3.3 (1.8 and 6.2)) for delayed, and high-risk PE severity (OR: 3.4 (1.9 and 5.8)). Conclusions: Advanced intervention use was associated with high-acuity patients experiencing death, clinical deterioration, and major bleeding with a trend towards less bleeding with catheter-directed interventions versus systemic thrombolysis.

Importance of Low- and Moderate-Grade Adverse Events in Patients' Treatment Experience and Treatment Discontinuation: An Analysis of the E1912 Trial.

PURPOSE: Despite defined grades of 1 to 5 for adverse events (AEs) on the basis of Common Terminology Criteria for Adverse Events criteria, mild (G1) and moderate (G2) AEs are often not reported in phase III trials. This under-reporting may inhibit our ability to understand patient toxicity burden. We analyze the relationship between the grades of AEs experienced with patient side-effect bother and treatment discontinuation. METHODS: We analyzed a phase III Eastern Cooperative Oncology Group-American College of Radiology Imaging Network trial with comprehensive AE data. The Likert response Functional Assessment of Cancer Therapy-GP5 item, "I am bothered by side effects of treatment" was used to define side-effect bother. Bayesian mixed models were used to assess the impact of G1 and G2 AE counts on patient side-effect bother and treatment discontinuation. AEs were further analyzed on the basis of symptomatology (symptomatic or asymptomatic). The results are given as odds ratios (ORs) and 95% credible interval (CrI). RESULTS: Each additional G1 and G2 AEs experienced during a treatment cycle increased the odds of increased self-reported patient side-effect bother by 13% (95% CrI, 1.06 to 1.21) and 35% (95% CrI, 1.19 to 1.54), respectively. Furthermore, only AEs defined as symptomatic were associated with increased side-effect bother, with asymptomatic AEs showing no association regardless of grade. Count of G2 AEs increased the odds of treatment discontinuation by 59% (95% CrI, 1.32 to 1.95), with symptomatic G2 AEs showing a stronger association (OR, 1.75; 95% CrI, 1.28 to 2.39) relative to asymptomatic G2 AEs (OR, 1.45; 95% CrI, 1.12 to 1.89). CONCLUSION: Low- and moderate-grade AEs are related to increased odds of increased patient side-effect bother and treatment discontinuation, with symptomatic AEs demonstrating greater magnitude of association than asymptomatic. Our findings suggest that limiting AE capture to grade 3+ misses important contributors to treatment side-effect bother and discontinuation.

Patient-Reported Adverse Events and Early Treatment Discontinuation Among Patients With Multiple Myeloma.

Importance: There is substantial interest in capturing cancer treatment tolerability from the patient's perspective using patient-reported outcomes (PROs). Objective: To examine whether a PRO question, item 5 from the Functional Assessment of Cancer Therapy-General General Physical Wellbeing Scale (GP5), was associated with early treatment discontinuation (ETD) due to adverse events. Design, Setting, and Participants: This prospective survey study was conducted from February to April 2023. Among participants in the ECOG-ACRIN E1A11 trial (a phase 3, parallel design trial conducted between 2013 and 2019), patients with newly diagnosed multiple myeloma were randomized to receive bortezomib (VRd) or carfilzomib (KRd) plus lenalidomide and dexamethasone as induction therapy. The GP5 item was administered at baseline (pretreatment) and at 1 month, 2.8 months, and 5.5 months postbaseline. Eligible participants included patients with newly diagnosed multiple myeloma treated at community oncology practices or academic medical centers in the US. Exposures: GP5 response options were "very much," "quite a bit," "somewhat," "a little bit," and "not at all." Responses at each assessment while undergoing treatment (1 month, 2.8 months, and 5.5 months) were categorized as high adverse event bother (ie, "very much," and "quite a bit") and low adverse event bother (ie, "somewhat," "a little bit," or "not at all"). In addition, change from baseline to each assessment while undergoing treatment was calculated and categorized as worsening by 1 response category and 2 or more response categories. Main Outcome and Measure: ETD due to adverse events (yes vs no) was analyzed using logistic regression adjusting for treatment group, performance status, gender, race, and disease stage. Results: Of the 1087 participants in the original trial, 1058 (mean [SD] age 64 [9] years; 531 receiving VrD [50.2%]; 527 receiving KRd [49.8%]) responded to item GP5 and were included in the secondary analysis. A small proportion (142 patients [13.4%]) discontinued treatment early due to AEs. For those with high adverse-effect bother, GP5 while undergoing treatment was associated with ETD at 1 month (adjusted odds ratio [aOR], 2.20; 95% CI, 1.25-3.89), 2.8 months (aOR, 3.41; 95% CI, 2.01-5.80), and 5.5 months (aOR, 4.66; 95% CI, 1.69-12.83). Worsening by 2 or more response categories on the GP5 was associated with ETD at 2.8 months (aOR, 3.02; 95% CI, 1.64-5.54) and 5.5 months (aOR, 5.49; 95% CI, 1.45-20.76). Conclusions and Relevance: In this survey study of the E1A11 trial, worse GP5 response was associated with ETD. These findings suggest that simple assessment of adverse-effect bother while receiving treatment is an efficient way to indicate treatment tolerability and ETD risk.

Statins Do Not Significantly Affect Oxidative Nitrosative Stress Biomarkers in the PREVENT Randomized Clinical Trial.

PURPOSE: Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT; NCT01988571) randomized patients with breast cancer or lymphoma receiving anthracyclines to atorvastatin 40 mg daily or placebo. We evaluated the effects of atorvastatin on oxidative and nitrosative stress biomarkers, and explored whether these biomarkers could explain the lack of effect of atorvastatin on LVEF (left ventricular ejection fraction) in PREVENT. PATIENTS AND METHODS: Blood samples were collected and cardiac MRI was performed before doxorubicin initiation and at 6 and 24 months. Thirteen biomarkers [arginine-nitric oxide metabolites, paraoxonase-1 (PON-1) activity, and myeloperoxidase] were measured. Dimensionality reduction using principal component analysis was used to define biomarker clusters. Linear mixed-effects models determined the changes in biomarkers over time according to treatment group. Mediation analysis determined whether biomarker clusters explained the lack of effect of atorvastatin on LVEF. RESULTS: Among 202 participants with available biomarkers, median age was 53 years; 86.6% had breast cancer; median LVEF was 62%. Cluster 1 levels, reflecting arginine methylation metabolites, were lower over time with atorvastatin, although this was not statistically significant (P = 0.081); Cluster 2 levels, reflecting PON-1 activity, were significantly lower with atorvastatin (P = 0.024). There were no significant changes in other biomarker clusters (P > 0.05). Biomarker clusters did not mediate an effect of atorvastatin on LVEF (P > 0.05). CONCLUSIONS: Atorvastatin demonstrated very modest effects on oxidative/nitrosative stress biomarkers in this low cardiovascular risk population. Our findings provide potential mechanistic insight into the lack of effect of atorvastatin on LVEF in the PREVENT trial.