Publications

BACKGROUND: Hypertension is documented in dogs with cancer receiving toceranib, but no studies have evaluated left ventricular (LV) systolic function and biomarkers of endothelial function.

OBJECTIVES: To characterize changes in echocardiographic variables and biomarkers of endothelial function in dogs treated with toceranib.

ANIMALS: Twenty-six client-owned dogs with no evidence of pre-existing cardiac disease or systemic hypertension are receiving a single agent toceranib for cancer treatment.

METHODS: Dogs were enrolled in this prospective observational study with study visits at baseline, 1, 3, and 5 months after starting toceranib for echocardiographic exams, blood and urine collection, and blood pressure measurements, with an additional blood pressure obtained 2 weeks after starting toceranib. Serum markers of vascular endothelial function (VEGF, endothelin-1, platelet derived growth factor [PDGF], prostacyclin, cyclic guanosine monophosphate [cGMP]) and urinary nitrate were evaluated with ELISA.

RESULTS: Dogs were enrolled between 2019 and 2023. Systolic blood pressure increased 2 weeks after initiating toceranib treatment (p = 0.009). Serum prostacyclin concentration was lower after 1 month of treatment (mean 98.8 pg/mL vs. 140.0 pg/mL at baseline, p = 0.03), and serum VEGF concentration was higher after 3 months of treatment (mean of 247.8 pg/mL vs. 135.4 pg/mL at baseline, p = 0.01). Global longitudinal strain (GLS) decreased at the five-month time point (mean -14.5% vs. -15.7% at baseline, p = 0.048) with no significant change in LV fractional shortening by M-mode or ejection fraction by Simpson's method of discs.

CONCLUSIONS: Dogs treated with toceranib might have higher systemic blood pressure associated with changes in VEGF and prostacyclin and decreased systolic function.

Anthracyclines are an effective treatment for hematologic malignancies but have significant risk of cardiotoxicity that increases with lifetime dose, best characterized for doxorubicin. However, patients may receive different anthracycline formulations, and cardiotoxic dose equivalency for nondoxorubicin anthracyclines is uncertain, making it challenging to calculate a patient's lifetime dose to make decisions about safety of additional anthracycline treatment and risk stratification for monitoring and cardioprotective strategies. In addition, dexrazoxane reduces the risk of cardiovascular toxicity with anthracyclines but how to incorporate previous dexrazoxane treatment into risk stratification is unclear. Here, a young woman previously treated with anthracyclines as induction therapy for acute myeloid leukemia and concern for previous anthracycline cardiotoxicity presented with disease relapse. Because optimal therapy included retreatment with anthracyclines, this case demonstrates the multidisciplinary discussion for her case, reviewing the risks and benefits of repeat anthracycline exposure and detailing the evidence for strategies to monitor and prevent worsening cardiotoxicity.

The optimal treatment of patients with diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) with preexisting cardiomyopathy is uncertain. An anonymous, electronic survey was distributed by e-mail to three US lymphoma cooperative groups, two community hospitals, and twelve academic medical systems, and distributed at one international lymphoma meeting. Fifty hematology-oncology providers caring for patients with lymphoma were included. In response to a vignette of a 67-yo with Stage III DLBCL with LVEF of 40-45%, 15 (30%) would use non-anthracycline regimens, 13 (26%) R-CHOP with liposomal doxorubicin instead of doxorubicin, 11 (22%) R-CHOP without modification and 6 (12%) R-CHOP with a continuous doxorubicin infusion. In a second vignette of a patient with HL in remission after frontline treatment with doxorubicin cumulative dose 300 mg/m2, 16 (32%) would order an echocardiogram after treatment. There was substantial variability in preferred treatment regimens with preexisting cardiomyopathy and in cardiac monitoring after anthracycline.

Elevated pulmonary vascular resistance (PVR) is a risk factor for mortality after heart transplantation (HT), but whether this association differs for patients with and without left ventricular assist device (LVAD) support before HT is unknown. We analyzed adult first-time HT recipients from the United Network for Organ Sharing (UNOS) registry transplanted between 2010 and 2021. We quantified the association between PVR and the outcomes of 30 day graft failure and 1 year mortality using multivariable logistic regression, stratified by LVAD support status at the time of HT. Pulmonary vascular resistance was modeled using restricted cubic splines to identify clinically relevant risk thresholds. We also examined the association with 10 year survival using multivariable Cox proportional hazards regression. For PVR values less than approximately 2 WU, higher PVR was independently associated with a higher risk of early graft failure (odds ratio [OR] = 1.58, 95% CI: 1.06-2.36) and a higher risk of 1 year mortality (OR = 1.32, 95% CI: 1.10-1.59) among LVAD patients only (interaction p = 0.023 and 0.03, respectively). However, for patients surviving at least 1 year, PVR was not associated with long-term mortality among either subgroup. Whether more aggressive reduction of PVR among HT candidates supported with LVADs can mitigate these risks requires further study.

BACKGROUND AND OBJECTIVES: Despite the significant impact of heart failure on both members of the care dyad, few interventions focus on optimizing the health of the dyad. The current study examined the feasibility and acceptability of the novel Taking Care of Us (TCU) program with mid-late-life couples living with heart failure and explored preliminary efficacy.

RESEARCH DESIGN AND METHODS: This NIH Stage I study used a 2-arm randomized controlled trial with pretest-post-test design and an additional 5-month follow-up to compare TCU with an educational counseling attention-control condition. 37 couples were randomized to TCU (18 couples) or an educational control group (19 couples). Both programs were delivered virtually over 2 months.

RESULTS: Adults with heart failure were primarily male (mean age = 66.32, standard deviation [SD] = 13.72); partners were primarily female (mean age = 63.00, SD = 12.73). Feasibility findings were mixed with over half of the eligible couples randomized, but only 67% of TCU couples completed the post-test. Acceptability of the TCU program was strong for both adults with heart failure and their partners. Recommendations for change focused on shortening session length, offering fewer sessions, and providing alternative modes of delivery. Exploratory between-group analyses found medium effect sizes for physical and mental health and dyadic management for both members of the couple, with many effects remaining 3 months later.

DISCUSSION AND IMPLICATIONS: Findings suggest the TCU program is acceptable to couples with heart failure and shows promise for optimizing outcomes. Recommendations and strategies for improving retention and a more diverse sample are discussed.

CLINICAL TRIAL REGISTRATION: NCT04737759.

BACKGROUND: A predictive model for early-stage classic Hodgkin's lymphoma (cHL) does not exist. Leveraging patient-level data from large clinical trials and registries, we developed and validated a model that we term the Early-Stage cHL International Prognostication Index (E-HIPI) to predict 2-year progression-free survival (PFS).

METHODS: We developed the model using the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines in 3000 adults with newly diagnosed early-stage cHL from four international phase III clinical trials conducted from 1994 to 2011. External validation was performed in two cohorts, totaling 2360 treated patients from five international cHL registries (1996 to 2019). Two-year PFS was estimated using a Cox model with pretreatment variables selected using backward elimination. Internal validation corrected for overfitting. External validation assessed discrimination and calibration. The final model was also compared against European Organisation for Research and Treatment of Cancer (EORTC) favorable or unfavorable status.

RESULTS: The median age in the development cohort was 31.2 years; 77.4% had stage II disease. The estimated 2-year PFS was 93.7%. Final variables retained in the model were sex and continuous values of maximum tumor diameter (MTD), and levels of hemoglobin and albumin. The optimism-corrected C statistic in the development cohort was 0.63 (95% confidence interval, 0.60 to 0.69). Two-year PFS was lower in the validation cohorts 1 (90.3%) and 2 (91.6%). In validation cohort 1, the C statistic was 0.63 and the calibration slope was near 1, but overall calibration indicated underprediction, which improved on updating the intercept. The performance was similar in validation cohort 2. In addition, higher-risk E-HIPI scores were associated with worse outcomes in both the EORTC unfavorable and favorable subgroups. When included altogether in one Cox model, the E-HIPI was associated with PFS, whereas EORTC favorable or unfavorable status was not. Online risk calculators were developed (https://rtools.mayo.edu/holistic_ehipi/).

CONCLUSIONS: Utilizing objective, continuous, and readily available variables, we developed and validated a new prediction model for early-stage cHL. Male sex, lower hemoglobin or albumin levels, and higher MTDs were associated with worse PFS. (Funded by the National Cancer Institute; grant number, NCI R01 CA 262265-04.).

PURPOSE: Breast cancer treatment results in increased cardiotoxicity risk; a risk-guided approach to cardioprotection has not been fully tested.

METHODS: This single-center, randomized Phase I trial enrolled patients with Stage I-III breast cancer who planned to receive anthracycline and/or trastuzumab therapy. An internally validated cardiotoxicity risk score classified participants as low or elevated risk. Elevated risk participants were randomized to receive open-label carvedilol or usual care for 12 months, beginning at cancer therapy initiation. Study visits occurred at baseline, 3, 6, 9, 12, and 24 months. Primary outcomes included feasibility, safety, and tolerability. Exploratory outcomes included echocardiography, biologic, and patient-reported measures.

RESULTS: Of the 166 eligible patients approached, 68 (41%) agreed to participate and ultimately enrolled. Among these participants (median age 52, 35% Black), 49 were classified as low and 19 elevated risk. Within the elevated risk group, 13 were randomized to carvedilol and 6 usual care. For those randomized to carvedilol, the median maximum dose was 6.25 mg twice daily, with 93% adherence. Adverse events of interest (grade 3 + bradycardia, hypotension, or fatigue) occurred in 9% with carvedilol, 13% in usual care, and 4% in low risk groups. One (1.5%) low risk participant experienced cardiac dysfunction. There were no substantial differences in secondary outcomes across groups. The participant withdrawal rate was 7%.

CONCLUSIONS: This Phase 1 trial demonstrates that a risk-guided strategy can be applied to patients with active cancer. However, additional strategies are necessary to optimize the design and execution of non-treatment intervention trials in patients with active cancer.

TRIAL REGISTRATION: NCT04023110.

BACKGROUND: Radiation therapy (RT) improves breast cancer outcomes, but cardiac morbidity remains a concern.

OBJECTIVES: This study sought to evaluate changes in cardiac function after RT and the relationship between cardiac dose metrics and echocardiography-derived measures of function.

METHODS: In a longitudinal cohort study of women with breast cancer, radiation cardiac dose metrics and core lab quantitated echocardiographic measures of cardiac function were evaluated. Dose metrics included the whole heart, left ventricle, right ventricle, and left anterior descending artery (LAD). Echocardiographic measures included left ventricular ejection fraction (LVEF), longitudinal strain, circumferential strain, E/e' (ratio of early diastolic mitral inflow velocity to early diastolic mitral annular tissue velocity), Ea/Es (ventricular arterial coupling; ratio of effective arterial elastance to end systolic elastance), and right ventricular fractional area change. The mean change in echocardiographic measures over time and the association between cardiac dose metrics and echocardiographic measures were estimated by repeated-measures multivariable linear regression via generalized estimating equations.

RESULTS: The cohort included 303 participants (median age 52 years, 33.3% African American) who received adjuvant RT (2010-2019) with a median mean heart dose of 1.19 Gy (Q1-Q3: 0.75-2.61 Gy), were followed over a median of 5.1 years (Q1-Q3: 3.2-7.1 years). Across all participants, there was a modest increase in LVEF (52.1% pre-RT to 54.3% at 5 years; P < 0.001) but a worsening in sensitive measures of function, such as circumferential strain (-23.7% pre-RT to -21.0% at 5 years; P = 0.003). Among left-sided/bilateral breast cancer participants, changes in cardiac function were observed across all parameters (P < 0.05). The maximum LAD dose was associated with a modest worsening in LVEF, longitudinal strain, circumferential strain, and E/e'.

CONCLUSIONS: Over a median of 5.1 years, modest changes in cardiac function were observed with RT. Maximum LAD dose was associated with a worsening in systolic and diastolic function parameters.