Prognostic and Added Value of Two-Dimensional Global Longitudinal Strain for Prediction of Survival in Patients with Light Chain Amyloidosis Undergoing Autologous Hematopoietic Cell Transplantation.

BACKGROUND: Autologous hematopoietic cell transplantation (HCT) is a first-line therapy for prolonging survival in patients with light-chain (AL) amyloidosis. Cardiac involvement is the most important determinant of survival. However, patients with advanced cardiac involvement have often been excluded from HCT because of high risk for transplantation-related mortality and poor overall survival. Whether baseline left ventricular global longitudinal strain (GLS) can provide additional risk stratification and predict survival after HCT in this high-risk population remains unclear. The aim of this study was to evaluate the prognostic implication of baseline GLS and the added value of GLS beyond circulating cardiac biomarkers for risk stratification in patients with AL amyloidosis undergoing HCT. METHODS: Eighty-two patients with newly diagnosed AL amyloidosis who underwent upfront HCT between January 2007 and April 2014 were included in the study. Clinical, echocardiographic, and serum cardiac biomarker data were collected at baseline and 12 months following HCT. GLS measurements were performed using a vendor-independent offline system. The median follow-up time for survivors was 58 months. RESULTS: Sixty-four percent of patients were in biomarker-based Mayo stage II or III. GLS, brain natriuretic peptide, troponin, and mitral E/A ratio were identified as the strongest predictors of survival (P < .0001). Other predictors included sex, creatinine, free AL, wall thickness, and ejection fraction. Mayo stage was significantly associated with outcome, with 5-year survival of 93%, 72% and 31% in stage I, II, and III patients, respectively. GLS of 17% was identified as the value that best discriminated survivors from nonsurvivors, and the application of this cutoff value provided further mortality risk stratification within each Mayo stage. CONCLUSIONS: GLS is a strong predictor of survival in patients with AL amyloidosis undergoing HCT, potentially providing incremental value over serum cardiac biomarkers for risk stratification. GLS should be considered as a standard parameter along with serum cardiac biomarkers when evaluating eligibility for HCT or other investigational therapies.

Prognostic utility of differential tissue characterization of cardiac neoplasm and thrombus via late gadolinium enhancement cardiovascular magnetic resonance among patients with advanced systemic cancer.

BACKGROUND: Late gadolinium enhancement (LGE-) cardiovascular magnetic resonance (CMR) is well-validated for cardiac mass (CMASS) tissue characterization to differentiate neoplasm (CNEO) from thrombus (CTHR): Prognostic implications of CMASS subtypes among systemic cancer patients are unknown. METHODS: CMASS + patients and controls (CMASS -) matched for cancer diagnosis and stage underwent a standardized CMR protocol, including LGE-CMR (IR-GRE) for tissue characterization and balanced steady state free precession cine-CMR (SSFP) for cardiac structure/function. CMASS subtypes (CNEO, CTHR) were respectively defined by presence or absence of enhancement on LGE-CMR; lesions were quantified for tissue properties (contrast-to-noise ratio (CNR); signal-to-noise ratio (SNR) and size. Clinical follow-up was performed to evaluate prognosis in relation to CMASS etiology. RESULTS: The study population comprised 126 patients with systemic neoplasms referred for CMR, of whom 50% (n = 63) had CMASS + (CNEO = 32%, CTHR = 18%). Cancer etiology differed between CNEO (sarcoma = 20%, lung = 18%) and CTHR (lymphoma = 30%, GI = 26%); cardiac function (left ventricular ejection fraction: 63 ± 9 vs. 62 ± 10%; p = 0.51∣ right ventricular ejection fraction: 53 ± 9 vs. 54 ± 8%; p = 0.47) and geometric indices were similar (all p = NS). LGE-CMR tissue properties assessed by CNR (13.1 ± 13.0 vs. 1.6 ± 1.0; p < 0.001) and SNR (29.7 ± 20.4 vs. 15.0 ± 11.4, p = 0.003) were higher for CNEO, consistent with visually-assigned diagnostic categories. CTHR were more likely to localize to the right atrium (78% vs. 25%, p < 0.001); nearly all (17/18) were associated with central catheters. Lesion size (17.3 ± 23.8 vs. 2.0 ± 1.5 cm2; p < 0.001) was greater with CNEO vs. CTHR, as was systemic disease burden (cancer-involved organs: 3.6 ± 2.0 vs. 2.3 ± 2.1; p = 0.02). Mortality during a median follow-up of 2.5 years was markedly higher among patients with CNEO compared to those with CTHR (HR = 3.13 [CI 1.54-6.39], p = 0.002); prognosis was similar when patients were stratified by lesion size assessed via area (HR = 0.99 per cm2 [CI 0.98-1.01], p = 0.40) or maximal diameter (HR = 0.98 per cm [CI 0.91-1.06], p = 0.61). CTHR conferred similar mortality risk compared to cancer-matched controls without cardiac involvement (p = 0.64) whereas mortality associated with CNEO was slightly higher albeit non-significant (p = 0.12). CONCLUSIONS: Among a broad cancer cohort with cardiac masses, CNEO defined by LGE-CMR tissue characterization conferred markedly poorer prognosis than CTHR, whereas anatomic assessment via cine-CMR did not stratify mortality risk. Both CNEO and CTHR are associated with similar prognosis compared to CMASS - controls matched for cancer type and disease extent.

Morbidity and mortality after treatment of Ewing sarcoma: A single-institution experience.

BACKGROUND: Children, adolescents, and young adults treated for Ewing sarcoma (ES) are at risk for disease-related and treatment-related complications. We aimed to describe early and late overall mortality, cause-specific mortality, and key adverse health outcomes in a large, single-institutional cohort of patients with ES. METHODS: Patients with ES diagnosed at age less than 40 years and treated at Memorial Sloan Kettering between 1974 and 2012 were included. Overall survival was estimated using Kaplan-Meier methods. Cox proportional hazards were used to examine the association of clinical and pathologic variables with overall survival. Cause-specific mortality was evaluated with the cumulative incidence function accounting for competing risks. RESULTS: Three hundred patients with ES (60.3% male; median age at diagnosis: 16.8 years [range: 0.3-39]; 30.0% with metastatic disease at diagnosis) were followed for a median of 7.8 years (range: 0.2-37). Five-year overall survival was 65.2% (95% confidence interval [95% CI], 59.8-71.1%) for the entire cohort; 78.6% for those with localized disease; 40.1% for those with isolated pulmonary metastases; and 28.1% for those with extrapulmonary metastases. In multivariable analysis, older age at diagnosis, minority race/ethnicity, and metastatic disease at diagnosis were associated with inferior survival. Ten-year cumulative incidence of relapse/progression was 40.1%, with eight late relapses occurring at a median of 6.3 years after diagnosis (range: 5-14). Seventeen patients developed subsequent neoplasms (treatment-related myelodysplastic syndrome/acute myelogenous leukemia = 9; solid tumors = 6; nonmelanoma skin cancer [NMSC] = 4). Excluding NMSC and melanoma in situ, the cumulative incidence of subsequent malignant neoplasms at 25 years was 15% (95% CI, 4.8-25.1%). CONCLUSION: Patients with ES are at high risk for relapse/progression and second cancers.

"Second" Primary Cardiac Sarcoma in a Patient With Ewing Sarcoma. Always Expect The Unexpected.

A high suspicion for relapsed metastatic disease must arise when an intracardiac mass is detected in a patient with a recent history of Ewing sarcoma. Nevertheless, the scenario may eventually turn out to be much more complex than expected, and the possibility that the intracardiac tumor may instead be a "second" primary sarcoma, although extremely rare, should also be considered. We describe the first case of concomitant diagnosis of Ewing sarcoma and low-grade myxoid spindle cell sarcoma in the same young patient.

Pattern and Prognostic Implications of Cardiac Metastases Among Patients With Advanced Systemic Cancer Assessed With Cardiac Magnetic Resonance Imaging.

BACKGROUND: Cardiac magnetic resonance (CMR) imaging is well validated for tissue characterization of cardiac masses but has not been applied to study pattern and prognostic implications of cardiac metastases (CMETs) among patients with systemic cancer. METHODS AND RESULTS: The population consisted of 60 patients with stage IV cancer (32 patients with CMETs, 28 diagnosis-matched controls) undergoing CMR. CMET was defined as a discrete mass with vascular tissue properties on delayed enhancement CMR. CMET-positive patients and controls had similar clinical characteristics, cardiac geometry, and function (P=NS). Leading cancer types associated with CMET were sarcoma, melanoma, and gastrointestinal. Patients with CMETs had similar distribution of extracardiac metastatic disease compared with controls (organs involved: 3.4±2.0 versus 2.7±1.9, P=0.17). In 94% of patients with CMETs, there were metastases involving ≥1 extracardiac organ (66% lung involvement). CMET location varied (right ventricle 44%, right atrium 19%, left ventricle 28%, left atrium 9%, pericardial 25%); 22% of cases had multichamber involvement. Right-sided chamber involvement was common in hematologic/lymphatic spread (67%); pericardial involvement was common with direct spread (64%). Regarding tissue properties on delayed enhancement CMR, CMETs commonly (59%) demonstrated heterogeneous enhancement (41% diffuse enhancement). Heterogeneous lesions were larger and had increased border irregularity (P<0.05). Survival 6 months post-CMR was numerically lower among patients with CMETs (56% [95% CI 39-74%]) versus stage IV cancer-matched controls (68% [95% CI 50-86%]), although differences between groups were nonsignificant (P=0.42). CONCLUSIONS: CMETs vary regarding etiology, location, and tissue properties on CMR, highlighting need for comprehensive surveillance of cardiac involvement regardless of cancer origin. Prognosis remains poor with for patients with CMETs, albeit similar to that for stage IV cancer controls matched for cancer etiology.

Cardiac Safety of Paclitaxel Plus Trastuzumab and Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer.

INTRODUCTION: Myocardial strain imaging and blood biomarkers have been proposed as adjuncts to left ventricular ejection fraction (LVEF) monitoring for the early detection of cardiotoxicity during cancer therapy. We report the results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer. PATIENTS AND METHODS: Patients with 0-1 lines of prior therapy were treated with weekly paclitaxel (80 mg/m(2)) plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks. Exploratory endpoints were GLS measured with speckle-tracking echocardiography every 3 months and TnI and BNP levels measured every 6 weeks (immediately pre- and postchemotherapy infusion) at 6 time points. RESULTS: Sixty-seven of 69 enrolled patients were treated with THP: 19 (28%) had hypertension, 8 (12%) had diabetes, 11 (16%) had hyperlipidemia, and 26 (38%) had smoking history. After a median follow-up of 21 months (range: 3-38 months), no patients developed symptomatic heart failure. Two patients (3.0%) experienced asymptomatic LVEF decline (grade 2). The mean GLS (±SD) was 19% ± 2% (baseline), 19% ± 2% (month 6), and 19% ± 3% (month 12). Detectable TnI (>0.06 ng/mL) and elevated BNP (>100 pg/mL) levels were observed in 3 (4.3%) and 2 (3.0%) patients, respectively, but were not associated with LVEF decline. CONCLUSION: The absence of any significant changes in GLS and cardiac biomarkers (TnI and BNP) further support the cardiac safety of THP in patients with metastatic HER2-positive breast cancer. IMPLICATIONS FOR PRACTICE: Dual anti-HER2 therapy with trastuzumab and pertuzumab in combination with taxane-based chemotherapy improves overall survival in patients with metastatic HER2-positive breast cancer. There is a critical need to investigate the potential cardiotoxicity of dual anti-HER2 blockade, given the importance of HER2 signaling in cardiac homeostasis and stress response. Global longitudinal strain and cardiac biomarkers have been proposed as adjuncts to left ventricular ejection fraction for the early detection of cardiotoxicity. In this phase II study of combination trastuzumab and pertuzumab with paclitaxel, no clinically significant change was observed in global longitudinal strain or cardiac biomarkers. These results further support the cardiac safety of dual anti-HER2 blockade previously reported in the CLEOPATRA study. The findings in the current study also call into question the role of intensive cardiac monitoring among patients treated with anti-HER2 therapy in the absence of anthracyclines. Less frequent cardiac assessments could lead to a reduction in unnecessary treatment interruption and is an important consideration given the rise in medical expenditures, but this requires further investigation.

The changes in cardiac physiology with aging and the implications for the treating oncologist.

The link between cancer, cardiovascular disease, and aging is well documented. In this review, we highlight the physiologic and pathologic changes associated with the cardiovascular aging process, the role they play when interfaced with various cancer therapies and the implications for the treating oncologist.