Saro H. Armenian

PURPOSE: Dexrazoxane has been associated with preservation of left ventricular (LV) systolic function in relatively small studies of long-term childhood cancer survivors. What remains less clear is whether this association is also seen in larger populations over time and what effect dexrazoxane has on cardiomyopathy screening recommendations. METHODS: We analyzed echocardiographic data from participants who received doxorubicin treatment and were enrolled on Children's Oncology Group protocols P9404, P9425, P9426, P9754, and Dana Farber Cancer Institute protocol 95-01. Except for P9754, all protocols featured up-front 1:1 random assignment with dexrazoxane administered uniformly as an intravenous bolus before doxorubicin (10:1 mg/m ² dexrazoxane:doxorubicin dose). Blinded central echocardiogram remeasurements were used when possible; otherwise, data were abstracted from institutional reports. Differences and associations by ± dexrazoxane were estimated using generalized estimating equations and Cox proportional hazard models, adjusting for age, sex, doxorubicin dose, chest radiotherapy, and echocardiogram data type. RESULTS: Among 895 patients (mean follow-up, 5.9 years, 230 with ≥10-year follow-up; median doxorubicin dose, 360 mg/m ² ; 51% dexrazoxane-exposed) with evaluable echocardiograms (n = 2,279; 1,581 centrally remeasured; 698 report only), preserved LV systolic function was observed in patients treated with dexrazoxane (z-score difference 0.4 [95% CI, 0.2 to 0.5]) versus without. Dexrazoxane was also associated with decreased hazards of reduced LV function (fractional shortening P = .001). CONCLUSION: Dexrazoxane exerts a significant doxorubicin cardioprotective effect on LV systolic function long term and may reduce screening needs.

Survivors of childhood, adolescent, and young adult (CAYA) cancer and hematopoietic cell transplantation have an excess risk of prediabetes and cardiovascular disease. Though not well characterized among CAYA survivors, cancer‐directed therapies may alter body composition and metabolic health, potentially contributing to this risk. We evaluated body composition and physical activity among 100 long‐term CAYA survivors (40 with prediabetes; 60 controls without prediabetes/diabetes). Survivors with prediabetes reported lower physical activity and had greater central adiposity than controls. Higher body mass index, visceral adipose tissue index, waist circumference, and fat mass were associated with increased odds of prediabetes. These findings identify potentially modifiable targets of cardiometabolic vulnerability among CAYA survivors.

Background: Survivors of hematopoietic cell transplantation (HCT) have an increased risk of skin cancer, yet adherence to recommended skin self-examination (SSE) and annual physician skin examinations is low. Scalable strategies to improve screening in this high-risk population are needed. Patients and Methods: We conducted a randomized controlled trial of 720 adult survivors of HCT enrolled between October 30, 2020, and December 13, 2023. Participants received remotely delivered print materials and 12 educational text messages over 9 months (patient activation and education [PAE]). In the PAE plus physician activation group (PAE + Phys), providers also received educational materials and guidance on performing skin examinations. Primary outcomes were participant-reported SSE within the prior 2 months and physician skin examination within the prior 12 months, assessed at baseline and 12 months. Secondary outcomes included the number of body regions examined and skin cancer knowledge. Results: Median age at enrollment was 61 years (range, 18–81), and the median time from HCT until enrollment was 3.1 years (range, 1.7–5.3). The proportion of participants reporting both physician skin examination and SSE increased in both groups, from 15.8% to 47.5% in the PAE group (odds ratio [OR], 4.98; 95% CI, 3.54–7.02) and from 18.0% to 52.1% in the PAE + Phys group (OR, 5.49; 95% CI, 4.03–7.50), with no significant between-group difference. SSE increased significantly in both groups, from 34.7% to 81.5% in the PAE group and from 31.5% to 79.0% in the PAE + Phys group, without no significant between-group difference. Physician skin examinations increased from 32.1% to 55.3% in the PAE group and from 33.2% to 64.8% in the PAE + Phys group, with a significantly greater increase in the PAE + Phys group ( P =.01). The mean number of body regions examined more than doubled in both groups, and skin cancer knowledge and self-efficacy improved significantly. Conclusions: Remotely delivered interventions improved skin cancer screening among HCT survivors. Patient activation substantially increased SSE, whereas physician activation provided additional benefit for physician-performed skin examinations. These findings suggest that physician activation enhances clinician-performed screening and supports scalable survivorship care models for high-risk populations. ClinicalTrials.gov identifier: NCT04358276

Background: At the population level, Black patients with multiple myeloma (MM) may experience worse survival than White patients. The authors examined how autologous stem cell transplantation (ASCT), insurance, and Medicaid expansion relate to racial differences in real‐world overall survival (rwOS). Methods: Data from 4932 patients with MM (24% Black) in the Flatiron Health Research Database were analyzed using Cox regression (rwOS), Fine and Gray competing‐risk models (ASCT), and polytomous regression (insurance). Results: Adjusted for demographic and clinical factors, Black patients had worse rwOS than White patients (adjusted hazard ratio [aHR], 1.11; 95% confidence interval [CI], 1.00–1.23), which became nonsignificant when adjusted for ASCT and/or health insurance. Lack of ASCT was associated with inferior rwOS (aHR, 0.59; 95% CI, 0.51–0.67). Black patients were less likely to receive ASCT (younger than 65 years: adjusted subdistribution HR [asHR], 0.64; 95% CI, 0.57–0.72; 65 years and older: asHR, 0.54; 95% CI, 0.42–0.69) and experienced a longer time to transplantation. Medicaid was associated with a lower likelihood of ASCT in patients younger than 65 years (aHR, 0.50; 95% CI, 0.38–0.67) and was three times more common among Black than White patients. Among patients who received oncology care, Medicaid expansion was not associated with changes in Medicaid coverage, ASCT receipt, or rwOS. Conclusions: Medicaid was associated with a lower likelihood of ASCT and was more prevalent among Black patients. Reduced receipt of ASCT was linked to inferior survival, contributing to survival disparities. Within this treated cohort, Medicaid expansion did not improve coverage, ASCT receipt, or survival, suggesting that structural barriers beyond insurance persist. Targeted efforts to improve ASCT access among Medicaid‐insured patients are needed.

Background: Children's Oncology Group (COG) study ALTE11C1 prospectively evaluated ovarian reserve in female adolescents/young adults (AYAs) with lymphoma from diagnosis to 1 year post‐end of treatment (EOT). Healthy peers provided normative comparisons. Procedure: From 2013 to 2018, female participants ≥6 months post‐menarche with newly diagnosed lymphoma were enrolled at COG institutions, along with healthy peers. All completed study entry questionnaires and menstrual cycle‐independent blood draws for anti‐Müllerian hormone (AMH), follicle‐stimulating hormone (FSH), and estradiol; lymphoma participants had four additional draws during and after treatment. Associations between biomarkers, disease and treatment characteristics were evaluated. Logistic regression and recursive partitioning analyses identified predictors of diminished ovarian reserve (DOR: AMH p < 0.01) and 1 year post‐EOT (1.7 vs. 4.1 ng/mL; p < 0.01). AMH declined during treatment, with partial recovery post‐EOT to below study entry levels ( p < 0.01). Those with advanced stage Hodgkin lymphoma and/or B symptoms had the lowest AMH. By 1 year post‐EOT, 34% had DOR; study entry AMH less than 1 ng/mL ( p = 0.003) and higher alkylator exposure ( p = 0.01) were independent predictors. Most participants with study entry AMH less than 1 ng/mL (76%) or CED ≥6.6 g/m ² (75%) demonstrated DOR at 1 year post‐EOT. No participant had acute ovarian failure at 1 year post‐EOT. Conclusions: Lymphoma and its treatments affect ovarian reserve in female AYA patients. Low AMH at diagnosis and high alkylator exposure predict post‐therapy DOR and can guide fertility preservation counseling.

BACKGROUND: The objective of this cluster randomized controlled trial was to determine the feasibility and safety of an intensive (systolic blood pressure [SBP] <120 mm Hg) versus usual care (SBP <140 mm Hg) approach to SBP control in patients with renal cell or thyroid cancer initiating VEGFR (vascular endothelial growth factor)-tyrosine kinase inhibitors. METHODS: A phase II site–based cluster randomized controlled trial compared intensive SBP control to usual care, incorporating a centralized BP advisory core to guide BP management. Patients underwent home BP monitoring and study visits at baseline, 1, 2, 3, and 6 months. SBP was compared between the 2 study arms using bootstrapped CIs. Common Terminology Criteria for Adverse Events and patient-reported outcomes were summarized. RESULTS: Overall, 61 patients with renal cell (n=58) or thyroid cancer (n=3) from 10 sites were enrolled; 30 at 5 sites were randomized to intensive SBP control and 31 at 5 sites to usual care. A lower SBP was observed in the intensive SBP control arm compared with usual care, with mean differences of −12.2 (95% CI, −18.1 to −7.0) mm Hg at 1 month, −7.6 (95% CI, −15.3 to −0.4) mm Hg at 3 months, and −6.9 (95% CI, −19.3 to 6.0) mm Hg at 6 months. In the usual care arm, Grade 3 Common Terminology Criteria for Adverse Events for kidney injury (n=4), hypotension (n=3), and dyspnea (n=2) were numerically greater compared with the intensive SBP control (n=1, 2, and 0, respectively). Patient-reported outcomes were largely similar between the 2 groups. CONCLUSIONS: This first-ever randomized controlled trial of SBP control in an active cancer population demonstrates the feasibility, safety, and tolerability of intensive SBP control with VEGFR tyrosine kinase inhibitors. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04467021.

Background and Aims: The objective of this study was to define the relationships between the circulating proteome and metabolome with cardiac structure and function in patients with breast cancer receiving cardiotoxic therapies. Methods: Proteomics and metabolomics profiling was performed in a longitudinal, prospective cohort study of breast cancer patients receiving anthracyclines and/or trastuzumab, using the Olink Explore 3072 platform and rapid liquid chromatography-mass spectrometry, respectively. Multivariable linear mixed-effect models evaluated the contemporaneous (same visit) and lagged (subsequent visit) associations between repeated measures of individual proteins or metabolites with quantitative echocardiographic measures of cardiac structure [left ventricular (LV) mass and left atrial volume index] and function [LV ejection fraction (LVEF), longitudinal and circumferential strain, E/e′, and ventricular-arterial coupling]. Cox regression and pathway enrichment analyses were conducted for biomarkers demonstrating significant associations with cardiac function. Results: Across 547 breast cancer participants (median age 50 years), 203 unique proteins and 16 unique metabolites were significantly associated with measures of cardiac structure and function in contemporaneous and lagged analyses. Notably, cathepsin C was associated with LVEF [false discovery rate (FDR), P = .017], longitudinal strain (FDR, P = .046), left atrial volume index (FDR, P = .035), and incident cardiac dysfunction, defined by an LVEF decline ≥10% to <50% (hazard ratio .61, 95% confidence interval .41, .90). The 147 proteins associated with cardiac function were enriched in biological processes reflective of protein deubiquitination, protein modification by small protein removal, macromolecule catabolic processes, and global metabolic pathways. Individual metabolites significantly associated with cardiac function (LVEF, longitudinal strain) included n-acetylglutamine, aspartic acid, acetylasparagine, alanyl-alanine, and prolyl-glycine (FDR, P-value < .001), and belonged to amino acids and derivatives and peptides. Conclusions: These findings provide translational insights into cancer therapy-related cardiac dysfunction and remodelling and identify potential new biomarkers of cardiotoxicity. There is an important need for validation of these findings and a deeper understanding of the biology of these biomarkers.

Background: Frailty is highly prevalent in survivors of multiple myeloma (MM) after autologous hematopoietic cell transplantation and is associated with poor functional recovery and adverse clinical outcomes. Although exercise is known to improve physical function, traditional center-based rehabilitation models are often inaccessible to this population during early posttransplant recovery. Mobile health (mHealth)–supported exercise may offer a scalable alternative; however, evidence in hematologic malignancies remains limited. Objective: This study aimed to evaluate the effects of a 16-week mHealth-supported exercise rehabilitation program on frailty phenotype and physical function in survivors of MM within 180 days after autologous hematopoietic cell transplantation. Methods: In this single-center randomized controlled trial, participants who self-reported as prefrail or frail were randomized 1:1 to an mHealth-supported exercise group (n=16) or usual care control (n=16). Remote assessments were conducted at baseline (week 0), midpoint (week 9), and follow-up (week 17). The intervention consisted of 8 weeks of supervised tele-exercise (3 sessions/week, 50 minutes/session), followed by 8 weeks of independent home-based exercise using the same mHealth platform. Exercise intensity was prescribed using a repetitions-in-reserve–based rating of perceived exertion approach with symptom-guided progression. The primary outcome was change in the 5-component Fried frailty phenotype score (0-5). Secondary outcomes included Short Physical Performance Battery components, chair stand time, gait speed, and handgrip strength. Intention-to-treat analyses were conducted using generalized estimating equations to evaluate between-group differences over time. Results: Participants had a mean age of 64.6 (SD 7.1) years and were enrolled a mean of 136 (SD 36.3) days posttransplant. At baseline, 94% (30/32) of participants were classified as frail. Adherence to the supervised sessions was 85% (326/384 sessions), and adherence during the unsupervised phase was 78% (298/384 sessions). The exercise group demonstrated a significantly greater reduction in frailty score compared with control from baseline to week 17 (P<.001). Between-group difference estimates showed a clinically meaningful improvement favoring exercise at both week 9 and week 17 (P<.001). Chair stand time improved significantly in the exercise group compared with control, with faster completion times observed at week 9 and sustained through week 17 (P=.002). Improvements in other Short Physical Performance Battery components and handgrip strength favored the exercise group but did not reach statistical significance. No serious adverse events occurred. Conclusions: A 16-week mHealth-supported, progressively prescribed exercise rehabilitation program was feasible, safe, and effective in reversing frailty phenotype and improving functional mobility in survivors of MM early after autologous transplantation. This approach provides a scalable model for delivering structured rehabilitation during a high-risk recovery window. Larger trials incorporating attention-matched controls and longer follow-up are warranted. Trial Registration: ClinicalTrials.gov NCT05142371; https://clinicaltrials.gov/study/NCT05142371