Ovarian function in female survivors of high-risk neuroblastoma.

INTRODUCTION: Data on ovarian function in neuroblastoma survivors are limited. We sought to determine the prevalence of ovarian dysfunction in a cohort of high-risk neuroblastoma survivors and compare outcomes among survivors treated with and without autologous stem cell rescue (ASCR) preceded by myeloablative chemotherapy. METHODS: Retrospective review of female survivors of high-risk neuroblastoma ≥5 years from diagnosis, diagnosed between 1982 and 2014, and followed in a tertiary cancer center. Participants were divided into two groups: individuals treated with conventional chemotherapy ± radiation ("non-ASCR") (n = 32) or with chemotherapy ± radiation followed by myeloablative chemotherapy with ASCR ("ASCR") (n = 51). Ovarian dysfunction was defined as follicle-stimulating hormone ≥15 mU/mL, while premature ovarian insufficiency (POI) was defined as persistent ovarian dysfunction requiring hormone replacement therapy. Poisson models were used to determine prevalence ratios of ovarian dysfunction and POI. RESULTS: Among 83 females (median attained age: 19 years [range, 10-36]; median follow-up: 15 years [range, 7-36]), 49 (59%) had ovarian dysfunction, and 34 (41%) developed POI. Survivors treated with ASCR were 3.2-fold more likely to develop ovarian dysfunction (95% CI: 1.8-6.0; p < 0.001) and 4.5-fold more likely to develop POI (95% CI: 1.7-11.7; p = 0.002) when compared with those treated with conventional chemotherapy, after adjusting for attained age. Two participants in the non-ASCR group and six in the ASCR group achieved at least one spontaneous pregnancy. DISCUSSION: Ovarian dysfunction is prevalent in female high-risk neuroblastoma survivors, especially after ASCR. Longitudinal follow-up of larger cohorts is needed to inform counseling about the risk of impaired ovarian function after neuroblastoma therapy.

Aetiology of pleural effusions in children living in a high TB endemic setting.

Confirming the aetiology of pleural effusion in children may be difficult in TB-endemic settings. We investigated the role of polymerase chain reaction (PCR) and routine biochemical tests in discriminating pleural effusion caused by bacteria from other aetiologies.This is a cross-sectional post-hoc analysis among children with pleural effusion in a tertiary hospital in South Africa, incorporating new data from PCR testing of stored pleural fluid. Aetiological classification was defined by microbiological confirmation.Ninety-one children were enrolled; the median age 31 months (IQR 12-102). The aetiology of pleural effusion was 40% (36/91) bacteria, 11% (10/91) TB, 3% (3/91) viruses, 11% (10/91) polymicrobial and 35% (32/91) had no pathogen identified. The most common pathogen was Staphylococcus aureus (27/91, 30%) with similar yields on culture and PCR, followed by Streptococcus pneumoniae (12/91, 13%), detected more commonly by PCR. PCR reduced the number of children with unconfirmed aetiologies from 48 to 32. Characteristics of children with no pathogen most resembled those with TB. Pleural fluid lactate dehydrogenase ≥1,716 U/L best discriminated bacterial pleural effusion from other aetiologies (sensitivity of 86%; specificity 95%).PCR improved detection of pathogens and reduced number of children with unconfirmed aetiologies in presumed exudative pleural effusion..

Risk of increased mortality in underweight survivors: A brief report from the Childhood Cancer Survivor Study.

BACKGROUND: Approximately 1 in 10 adult survivors of childhood cancer is underweight. Although the consequences of being overweight or obese have been well described, outcomes among childhood cancer survivors who are underweight are unknown. OBJECTIVE: To determine whether underweight status increases the risk of mortality. PROCEDURE: Cohort study: Marginal models with generalized estimating equations to evaluate the associations between body mass index (BMI), serious or life-threatening chronic conditions, and death in the setting of long-term follow-up questionnaires and National Death Index search. PARTICIPANTS: Childhood cancer five-year survivors diagnosed during 1970-1986 in the Childhood Cancer Survivor Study Exposure: Underweight status, defined as body mass index (BMI) < 18.5 kg/m2 compared with ideal body weight. Based on available literature on body weight and mortality from the general population, ideal body weight was defined as BMI 22.0-24.9 kg/m2. MAIN OUTCOMES: Overall mortality and cancer-specific mortality. RESULTS: Of 9454 survivors (median age 35 years old (range, 17-58), an average of 17.5 years from diagnosis), 627 (6.6%) participants were underweight at baseline or follow-up questionnaire. Of 184 deaths, 29 were among underweight survivors. Underweight status was more common among females (9.1% vs. 4.5%, p < .01) and participants with younger age at diagnosis (8.2% for < 5 years vs. 6.1% for ≥5 years, p < .01), lower household income (8.9% for < $20,000 vs. 6.0% for ≥ $20,000, p < .01), or a history of serious chronic condition (p = .05). After adjustment for these factors, in addition to prior smoking and a history of radiation therapy, the risk of all-cause mortality within two years of BMI report was increased (OR 2.85; 95% CI: 1.63-4.97; p < .01) for underweight survivors, compared with ideal-weight survivors. CONCLUSIONS: Childhood cancer survivors who are underweight are at increased risk for late mortality that appears unrelated to smoking status, recognized chronic disease, or subsequent malignancy. Whether targeted nutritional interventions would ameliorate this risk is unknown.

Use of Response Permutation to Measure an Imaging Dataset's Susceptibility to Overfitting by Selected Standard Analysis Pipelines.

RATIONALE AND OBJECTIVES: This study demonstrates a method for quantifying the impact of overfitting on the receiving operator characteristic curve (AUC) when using standard analysis pipelines to develop imaging biomarkers. We illustrate the approach using two publicly available repositories of radiology and pathology images for breast cancer diagnosis. MATERIALS AND METHODS: For each dataset, we permuted the outcome (cancer diagnosis) values to eliminate any true association between imaging features and outcome. Seven types of classification models (logistic regression, linear discriminant analysis, Naïve Bayes, linear support vector machines, nonlinear support vector machine, random forest, and multi-layer perceptron) were fitted to each scrambled dataset and evaluated by each of four techniques (all data, hold-out, 10-fold cross-validation, and bootstrapping). After repeating this process for a total of 50 outcome permutations, we averaged the resulting AUCs. Any increase over a null AUC of 0.5 can be attributed to overfitting. RESULTS: Applying this approach and varying sample size and the number of imaging features, we found that failing to control for overfitting could result in near-perfect prediction (AUC near 1.0). Cross-validation offered greater protection against overfitting than the other evaluation techniques, and for most classification algorithms a sample size of at least 200 was required to assess as few as 10 features with less than 0.05 AUC inflation attributable to overfitting. CONCLUSION: This approach could be applied to any curated dataset to suggest the number of features and analysis approaches to limit overfitting.

Association of breast cancer with quantitative mammographic density measures for women receiving contrast-enhanced mammography.

Women with high mammographic density have an increased risk of breast cancer. They may be offered contrast-enhanced mammography to improve breast cancer screening performance. Using a cohort of women receiving contrast-enhanced mammography, we evaluated whether conventional and modified mammographic density measures were associated with breast cancer. Sixty-six patients with newly diagnosed unilateral breast cancer were frequency matched on the basis of age to 133 cancer-free control individuals. On low-energy craniocaudal contrast-enhanced mammograms (equivalent to standard mammograms), we measured quantitative mammographic density using CUMULUS software at the conventional intensity threshold ("Cumulus") and higher-than-conventional thresholds ("Altocumulus," "Cirrocumulus"). The measures were standardized to enable estimation of odds ratio per adjusted standard deviation (OPERA). In multivariable logistic regression of case-control status, only the highest-intensity measure (Cirrocumulus) was statistically significantly associated with breast cancer (OPERA = 1.40, 95% confidence interval = 1.04 to 1.89). Conventional Cumulus did not contribute to model fit. For women receiving contrast-enhanced mammography, Cirrocumulus mammographic density may better predict breast cancer than conventional quantitative mammographic density.

Exercise and QUality diet After Leukemia (EQUAL): A randomized weight loss trial among adult survivors of childhood leukemia in the Childhood Cancer Survivor Study.

BACKGROUND: Obesity is prevalent in childhood cancer survivors and interacts with cancer treatments to potentiate risk for cardiovascular (CV) death. We tested a remote weight-loss intervention that was effective among adults with CV risk factors in a cohort of adult survivors of childhood acute lymphoblastic leukemia (ALL) with overweight/obesity. METHODS: In this phase 3 efficacy trial, survivors of ALL enrolled in the Childhood Cancer Survivor Study with body mass index (BMI)≥25 kg/m2 were randomized to a remotely-delivered weight-loss intervention versus self-directed weight loss, stratified by history of cranial radiotherapy (CRT). The primary endpoint was the difference in weight loss at 24-months in an intent-to-treat analysis. Analyses were performed using linear mixed effects models. RESULTS: Among 358 survivors (59% female, median attained age: 37 years, IQR: 33-43), baseline mean (SD) weight was 98.6 kg (24.0) for the intervention group (n=181) and 94.9 kg (20.3) for controls (n=177). Adherence to the intervention was poor; 15% of individuals in the intervention completed 24/30 planned coaching calls. Weight at 24-months was available for 274 (77%) participants. After controlling for CRT, sex, race/ethnicity, and age, the mean (SE) change in weight from baseline to 24-months was -0.4 kg (0.8) for intervention and 0.2 kg (0.6) for control participants (p=0.59). CONCLUSIONS: A remote weight-loss intervention that was successful among adults with CV conditions did not result in significant weight loss among adult survivors of childhood ALL. IMPACT: Future interventions in this population must be tailored to the unique needs of survivors to encourage engagement and adherence.

Mechanisms of Exercise Intolerance Across the Breast Cancer Continuum: A Pooled Analysis of Individual Patient Data.

PURPOSE: The purpose of this study is to evaluate the prevalence of abnormal cardiopulmonary responses to exercise and pathophysiological mechanism(s) underpinning exercise intolerance across the continuum of breast cancer (BC) care from diagnosis to metastatic disease. METHODS: Individual participant data from four randomized trials spanning the BC continuum ([1] prechemotherapy [n = 146], [2] immediately postchemotherapy [n = 48], [3] survivorship [n = 138], and [4] metastatic [n = 47]) were pooled and compared with women at high-risk of BC (BC risk; n = 64). Identical treadmill-based peak cardiopulmonary exercise testing protocols evaluated exercise intolerance (peak oxygen consumption; V̇O2peak) and other resting, submaximal, and peak cardiopulmonary responses. The prevalence of 12 abnormal exercise responses was evaluated. Graphical plots of exercise responses were used to identify oxygen delivery and/or uptake mechanisms contributing to exercise intolerance. Unsupervised, hierarchical cluster analysis was conducted to explore exercise response phenogroups. RESULTS: Mean V̇O2peak was 2.78 ml O2.kg-1·min-1 (95% confidence interval [CI], -3.94, -1.62 mL O2.kg-1·min-1; P < 0.001) lower in the pooled BC cohort (52 ± 11 yr) than BC risk (55 ± 10 yr). Compared with BC risk, the pooled BC cohort had a 2.5-fold increased risk of any abnormal cardiopulmonary response (odds ratio, 2.5; 95% confidence interval, 1.2, 5.3; P = 0.014). Distinct exercise responses in BC reflected impaired oxygen delivery and uptake relative to control, although considerable inter-individual heterogeneity within cohorts was observed. In unsupervised, hierarchical cluster analysis, six phenogroups were identified with marked differences in cardiopulmonary response patterns and unique clinical characteristics. CONCLUSIONS: Abnormal cardiopulmonary response to exercise is common in BC and is related to impairments in oxygen delivery and uptake. The identification of exercise response phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions.

Association of exercise with pan-cancer incidence and overall survival.

Lavery et al. show that the association between exercise and risk of cancer varied as a function of organ site and amount of exercise. Exercise was also associated with a longevity benefit regardless of a cancer diagnosis or not. This study further highlights the importance of exercise as an effective cancer preventive strategy.

Spine MRI Identifies Clinically Relevant Findings in Patients With Cancer Presenting With Back Pain.

STUDY DESIGN: This is a retrospective, cross-sectional study. OBJECTIVE: The primary aim was to identify the diagnostic yield of spine magnetic resonance imaging (MRI) in detecting malignant pathology in cancer patients with back pain. We also sought to evaluate the role of MRI extent ( i.e. regional vs. total) in identifying malignant pathology. SUMMARY OF BACKGROUND DATA: No prior study has systematically investigated the yield of spine MRI in a large cohort of cancer patients. METHODS: Spine MRI reports from 2017 to 2021 for back pain (acute and nonspecified chronicity) in cancer patients were reviewed to identify clinically relevant findings: malignant (1) epidural, (2) leptomeningeal, (3) intramedullary, (4) osseous disease, and (5) fracture. Logistic regression was used to evaluate the association between MRI extent and the presence of cancer-related findings. For patients with multiple MRIs, short-interval scans (≤4 mo) were evaluated to assess the yield of repeat imaging. RESULTS: At least one cancer-related finding was identified on 52% of 5989 spine MRIs ordered for back pain and 57% of 1130 spine MRIs ordered specifically for acute back pain. The most common pathology was malignant osseous disease (2545; 43%). Across all five categories, most findings (77%-89%) were new/progressive. Odds of identifying a finding were significantly higher with total versus regional spine MRIs ( P <0.001). Although only 14 patients had a positive regional MRI followed shortly by a positive total spine MRI, most of these repeat total spine MRIs (78%) identified findings outside the scope of the initial regional scan. Twenty-one patients had both computed tomography and MRI within 30 days of each other; eight (38%) had compression fractures appreciated on MRI but not on computed tomography. CONCLUSIONS: Our findings suggest imaging the total spine in cancer patients with back pain given higher odds of identifying malignant pathology and instances of capturing otherwise not visualized disease. Further work is warranted to confirm these findings.

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer.

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m-2, HR: 2.33 for 300-399 mg m-2 and HR: 2.78 for ≥400 mg m-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

Modeling Tumor Growth Using Partly Conditional Survival Models: A Case Study in Colorectal Cancer.

PURPOSE: There are multiple approaches to modeling the relationship between longitudinal tumor measurements obtained from serial imaging and overall survival. Many require strong assumptions that are untestable and debatable. We illustrate how to apply a novel, more flexible approach, the partly conditional (PC) survival model, using images acquired during a phase III, randomized clinical trial in colorectal cancer as an example. METHODS: PC survival approaches were used to model longitudinal volumetric computed tomography data of 1,025 patients in the completed VELOUR trial, which evaluated adding aflibercept to infusional fluorouracil, leucovorin, and irinotecan for treating metastatic colorectal cancer. PC survival modeling is a semiparametric approach to estimating associations of longitudinal measurements with time-to-event outcomes. Overall survival was our outcome. Covariates included baseline tumor burden, change in tumor burden from baseline to each follow-up time, and treatment. Both unstratified and time-stratified models were investigated. RESULTS: Without making assumptions about the distribution of the tumor growth process, we characterized associations between the change in tumor burden and survival. This change was significantly associated with survival (hazard ratio [HR], 1.04; 95% CI, 1.02 to 1.05; P < .001), suggesting that aflibercept works at least in part by altering the tumor growth trajectory. We also found baseline tumor size prognostic for survival even when accounting for the change in tumor burden over time (HR, 1.02; 95% CI, 1.01 to 1.02; P < .001). CONCLUSION: The PC modeling approach offers flexible characterization of associations between longitudinal covariates, such as serially assessed tumor burden, and survival time. It can be applied to a variety of data of this nature and used as clinical trials are ongoing to incorporate new disease assessment information as it is accumulated, as indicated by an example from colorectal cancer.

Peripheral Arterial Disease is Associated With Higher Rates of Hospital Encounters and Mortality in Cancer Patients: A Retrospective Study Conducted at a Tertiary Cancer Center.

Cancer and peripheral arterial disease (PAD) have overlapping risk factors and common genetic predispositions. The concomitant effects of PAD and cancer on patients have not been well studied. The objective of this retrospective study is to evaluate outcomes of cancer patients with PAD. A query was made into Memorial Sloan Kettering Cancer Center's database to assess outcome of patients with and without the diagnosis of PAD (using ICD 9 and 10 codes). Inclusion criteria were patients diagnosed with lung, colon, prostate, bladder, or breast cancer between January 1, 2013 and December 12, 2018. A total of 77,014 patients were included in this cohort. 1,426 patients (1.8%, 95% CI 1.8-1.9) carried a diagnosis of PAD. PAD diagnosis was most prevalent in bladder cancer (4.7%, 95% CI 4.1-5.2) and lung cancer patients (4.6%, 95% CI 4.2-4.9). In regression models adjusted for cancer diagnosis, age at cancer diagnosis, stage, diabetes, hyperlipidemia, hypertension, coronary artery disease, cerebrovascular disease, smoking, and BMI > 30, patients with PAD had significantly higher odds of UCC admissions (OR 1.50, 95%CI 1.32-1.70, P < 0.001), inpatient admissions (OR 1.32, 95%CI 1.16-1.50, P < 0.001), and ICU admissions (OR 1.64, 95%CI 1.31-2.03, P < 0.001). After adjusting for all these same factors, patients with PAD had a 13% higher risk of dying relative to patients without PAD (HR 1.13, 95% CI 1.04-1.22, P = 0.003). Cancer patients with PAD had higher risks of ICU stays, UCC visits, inpatient admissions, and mortality compared to cancer patients without PAD even when adjusting for CAD, stroke, other comorbidities, cancer diagnosis, and cancer stage.

Pan-Cancer Analysis of Postdiagnosis Exercise and Mortality.

PURPOSE: The impact of postdiagnosis exercise on cause-specific mortality in cancer survivors and whether this differs on the basis of cancer site is unclear. METHODS: We performed an analysis of 11,480 patients with cancer enrolled in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. Patients with a confirmed diagnosis of cancer completing a standardized survey quantifying exercise after diagnosis were included. The primary outcome was all-cause mortality (ACM); secondary end points were cancer mortality and mortality from other causes. Cox models were used to estimate the cause-specific hazard ratios (HRs) for ACM, cancer, and noncancer mortality as a function of meeting exercise guidelines versus not meeting guidelines with adjustment for important clinical covariates. RESULTS: After a median follow-up of 16 years from diagnosis, 4,665 deaths were documented (1,940 due to cancer and 2,725 due to other causes). In multivariable analyses, exercise consistent with guidelines was associated with a 25% reduced risk of ACM compared with nonexercise (HR, 0.75; 95% CI, 0.70 to 0.80). Compared with nonexercise, exercise consistent with guidelines was associated with a significant reduction in cancer mortality (HR, 0.79; 95% CI, 0.72 to 0.88) and mortality from other causes (HR, 0.72; 95% CI, 0.66 to 0.78). The inverse relationship between exercise and cause-specific mortality varied by exercise dose. Exercise consistent with guidelines was associated with a reduced hazard of ACM for multiple cancer sites. Reduction in cancer mortality for exercisers was only observed in head and neck and renal cancer. CONCLUSION: In this pan-cancer sample of long-term cancer survivors, exercise consistent with guidelines was associated with substantial ACM benefit driven by both reductions in cancer and noncancer mortality. The cause-specific impact of exercise differed as a function of cancer site.

The impact of antenatal and postnatal indoor air pollution or tobacco smoke exposure on lung function at 3 years in an African birth cohort.

BACKGROUND AND OBJECTIVE: Indoor air pollution (IAP) and tobacco smoke exposure (ETS) are global health concerns contributing to the burden of childhood respiratory disease. Studies assessing the effects of IAP and ETS in preschool children are limited. We assessed the impact of antenatal and postnatal IAP and ETS exposure on lung function in a South African birth cohort, the Drakenstein Child Health Study. METHODS: Antenatally enrolled mother-child pairs were followed from birth. Lung function measurements (oscillometry, multiple breath washout and tidal breathing) were performed at 6 weeks and 3 years. Quantitative antenatal and postnatal IAP (particulate matter [PM10 ], volatile organic compounds [VOC]) and ETS exposures were measured. Linear regression models explored the effects of antenatal and postnatal exposures on lung function at 3 years. RESULTS: Five hundred eighty-four children had successful lung function testing, mean (SD) age of 37.3 (0.7) months. Exposure to antenatal PM10 was associated with a decreased lung clearance index (p < 0.01) and postnatally an increase in the difference between resistance at end expiration (ReE) and inspiration (p = 0.05) and decrease in tidal volume (p = 0.06). Exposure to antenatal VOC was associated with an increase in functional residual capacity (p = 0.04) and a decrease in time of expiration over total breath time (tE /tTOT ) (p = 0.03) and postnatally an increase in respiratory rate (p = 0.05). High ETS exposure postnatally was associated with an increase in ReE (p = 0.03). CONCLUSION: Antenatal and postnatal IAP and ETS exposures were associated with impairment in lung function at 3 years. Strengthened efforts to reduce IAP and ETS exposure are needed.

Ethnic diversity in treatment response for colorectal cancer: proof of concept for radiomics-driven enrichment trials.

BACKGROUND: Several barriers hamper recruitment of diverse patient populations in multicenter clinical trials which determine efficacy of new systemic cancer therapies. PURPOSE: We assessed if quantitative analysis of computed tomography (CT) scans of metastatic colorectal cancer (mCRC) patients using imaging features that predict overall survival (OS) can unravel the association between ethnicity and efficacy. METHODS: We retrospectively analyzed CT images from 1584 mCRC patients in two phase III trials evaluating FOLFOX ± panitumumab (n = 331, 350) and FOLFIRI ± aflibercept (n = 437, 466) collected from August 2006 to March 2013. Primary and secondary endpoints compared RECIST1.1 response at month-2 and delta tumor volume at month-2, respectively. An ancillary study compared imaging phenotype using a peer-reviewed radiomics-signature combining 3 imaging features to predict OS landmarked from month-2. Analysis was stratified by ethnicity. RESULTS: In total, 1584 patients were included (mean age, 60.25 ± 10.57 years; 969 men). Ethnicity was as follows: African (n = 50, 3.2%), Asian (n = 66, 4.2%), Caucasian (n = 1413, 89.2%), Latino (n = 27, 1.7%), Other (n = 28, 1.8%). Overall baseline tumor volume demonstrated Africans and Caucasians had more advanced disease (p < 0.001). Ethnicity was associated with treatment response. Response per RECIST1.1 at month-2 was distinct between ethnicities (p = 0.048) with higher response rate (55.6%) in Latinos. Overall delta tumor volume at month-2 demonstrated that Latino patients more likely experienced response to treatment (p = 0.021). Radiomics phenotype was also distinct in terms of tumor radiomics heterogeneity (p = 0.023). CONCLUSION: This study highlights how clinical trials that inadequately represent minority groups may impact associated translational work. In appropriately powered studies, radiomics features may allow us to unravel associations between ethnicity and treatment efficacy, better elucidate mechanisms of resistance, and promote diversity in trials through predictive enrichment. CLINICAL RELEVANCE STATEMENT: Radiomics could promote clinical trial diversity through predictive enrichment, hence benefit to historically underrepresented racial/ethnic groups that may respond variably to treatment due to socioeconomic factors and built environment, collectively referred to as social determinants of health. KEY POINTS: •Findings indicate ethnicity was associated with treatment response across all 3 endpoints. First, response per RECIST1.1 at month-2 was distinct between ethnicities (p = 0.048) with higher response rate (55.6%) in Latinos. •Second, the overall delta tumor volume at month-2 demonstrated that Latino patients were more likely to experience response to treatment (p = 0.021). Radiomics phenotype was also distinct in terms of tumor radiomics heterogeneity (p = 0.023).

Association of Circulating Cardiomyocyte Cell-Free DNA With Cancer Therapy-Related Cardiac Dysfunction in Patients Undergoing Treatment for ERBB2-Positive Breast Cancer.

Importance: Cancer therapy-related cardiac dysfunction (CTRCD) is a potentially serious cardiotoxicity of treatments for ERBB2-positive breast cancer (formerly HER2). Identifying early biomarkers of cardiotoxicity could facilitate an individualized approach to cardiac surveillance and early pharmacologic intervention. Circulating cell-free DNA (cfDNA) of cardiomyocyte origin is present during acute cardiac injury but has not been established as a biomarker of CTRCD. Objective: To determine whether circulating cardiomyocyte cfDNA is associated with CTRCD in patients with ERBB2-positive breast cancer treated with anthracyclines and ERBB2-targeted therapy. Design, Setting, and Participants: A prospective cohort of 80 patients with ERBB2-positive breast cancer enrolled at an academic cancer center between July 2014 and April 2016 underwent echocardiography and blood collection at baseline, after receiving anthracyclines, and at 3 months and 6 months of ERBB2-targeted therapy. Participants were treated with doxorubicin-based chemotherapy followed by trastuzumab (+/- pertuzumab). The current biomarker study includes participants with sufficient biospecimen available for analysis after anthracycline therapy. Circulating cardiomyocyte-specific cfDNA was quantified by a methylation-specific droplet digital polymerase chain reaction assay. Data for this biomarker study were collected and analyzed from June 2021 through April 2022. Main Outcomes and Measures: The outcome of interest was 1-year CTRCD, defined by symptomatic heart failure or an asymptomatic decline in left ventricular ejection fraction (≥10% from baseline to less than lower limit of normal or ≥16%). Values for cardiomyocyte cfDNA and high-sensitivity cardiac troponin I (hs-cTnI) measured after patients completed treatment with anthracyclines were compared between patients who later developed CTRCD vs patients who did not using the Wilcoxon rank sum test, and the association of post-anthracycline cardiomyocyte cfDNA level with CTRCD was estimated using logistic regression. Results: Of 71 patients included in this study, median (IQR) age was 50 (44-58) years, all were treated with dose-dense doxorubicin, and 48 patients underwent breast radiotherapy. Ten of 71 patients (14%) in this analysis developed CTRCD. The level of cardiomyocyte cfDNA at the post-anthracycline time point was higher in patients who subsequently developed CTRCD (median, 30.5 copies/mL; IQR, 24-46) than those who did not (median, 7 copies/mL; IQR, 2-22; P = .004). Higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD (hazard ratio, 1.02 per 1-copy/mL increase; 95% CI, 1.00-1.03; P = .046). Conclusions and Relevance: This study found that higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD. Cardiomyocyte cfDNA quantification shows promise as a predictive biomarker to refine risk stratification for CTRCD among patients with breast cancer receiving cardiotoxic cancer therapy, and its use warrants further validation. Trial Registration: ClinicalTrials.gov Identifier: NCT02177175.

Benign and malignant pulmonary parenchymal findings on chest CT among adult survivors of childhood and young adult cancer with a history of chest radiotherapy.

PURPOSE: Childhood and young adult cancer survivors exposed to chest radiotherapy are at increased risk of lung cancer. In other high-risk populations, lung cancer screening has been recommended. Data is lacking on prevalence of benign and malignant pulmonary parenchymal abnormalities in this population. METHODS: We conducted a retrospective review of pulmonary parenchymal abnormalities in chest CTs performed more than 5 years post-cancer diagnosis in survivors of childhood, adolescent, and young adult cancer. We included survivors exposed to radiotherapy involving the lung field and followed at a high-risk survivorship clinic between November 2005 and May 2016. Treatment exposures and clinical outcomes were abstracted from medical records. Risk factors for chest CT-detected pulmonary nodule were assessed. RESULTS: Five hundred and ninety survivors were included in this analysis: median age at diagnosis, 17.1 years (range, 0.4-39.8); and median time since diagnosis, 22.3 years (range, 1-58.6). At least one chest CT more than 5 years post-diagnosis was performed in 338 survivors (57%). Among these, 193 (57.1%) survivors had at least one pulmonary nodule detected on a total of 1057 chest CTs, resulting in 305 CTs with 448 unique nodules. Follow-up was available for 435 of these nodules; 19 (4.3%) were malignant. Risk factors for first pulmonary nodule were older age at time of CT, CT performed more recently, and splenectomy. CONCLUSIONS: Benign pulmonary nodules are very common among long-term survivors of childhood and young adult cancer. IMPLICATIONS FOR CANCER SURVIVORS: High prevalence of benign pulmonary nodules in cancer survivors exposed to radiotherapy could inform future guidelines on lung cancer screening in this population.

Benign and Malignant Findings on Chest CT Among Adult Survivors of Childhood and Young Adult Cancer with a History of Chest Radiotherapy.

Purpose : Childhood and young adult cancer survivors exposed to chest radiotherapy are at increased risk of lung cancer. In other high-risk populations, lung cancer screening has been recommended. Data is lacking on prevalence of benign and malignant imaging abnormalities in this population. Methods : We conducted a retrospective review of imaging abnormalities in chest CTs performed more than 5 years post-cancer diagnosis in survivors of childhood, adolescent, and young adult cancer. We included survivors exposed to radiotherapy involving the lung field and followed at a high-risk survivorship clinic between November 2005 and May 2016. Treatment exposures and clinical outcomes were abstracted from medical records. Risk factors for chest CT-detected pulmonary nodule were assessed. Results : Five hundred and ninety survivors were included in this analysis; median age at diagnosis, 17.1 years (range, 0.4-39.8) and median time since diagnosis, 21.1 years (range, 0.4-58.6). At least one chest CT more than 5 years post-diagnosis was performed in 338 survivors (57%). Among these, 193 (57.1%) survivors had at least one pulmonary nodule detected on a total of 1057 chest CTs, resulting in 305 CTs with 448 unique nodules. Follow-up was available for 435 of these nodules; 19 (4.3%) were malignant. Risk factors for first pulmonary nodule were older age at time of CT, CT performed more recently and splenectomy. Conclusions : Benign pulmonary nodules are very common among long-term survivors of childhood and young adult cancer. Implications for Cancer Survivors: High prevalence of benign pulmonary nodules in cancer survivors exposed to radiotherapy could inform future guidelines on lung cancer screening in this population.

Rationale and design of a cardiac safety study for reduced cardiotoxicity surveillance during HER2-targeted therapy.

BACKGROUND: Echocardiograms are recommended every 3 months in patients receiving human epidermal growth factor 2 (HER2)-targeted therapy for surveillance of left ventricular ejection fraction (LVEF). Efforts to tailor treatment for HER2-positive breast cancer have led to greater use of non-anthracycline regimens that are associated with lower cardiotoxicity risk, raising into question the need for frequent cardiotoxicity surveillance for these patients. This study seeks to evaluate whether less frequent cardiotoxicity surveillance (every 6 months) is safe for patients receiving a non-anthracycline HER2-targeted treatment regimen. METHODS/DESIGN: We will enroll 190 women with histologically confirmed HER2-positive breast cancer scheduled to receive a non-anthracycline HER2-targeted treatment regimen for a minimum of 12 months. All participants will undergo echocardiograms before and 6-, 12-, and 18-months after initiation of HER2-targeted treatment. The primary composite outcome is symptomatic heart failure (New York Heart Association class III or IV) or death from cardiovascular causes. Secondary outcomes include: 1) echocardiographic indices of left ventricular systolic function; 2) incidence of cardiotoxicity, defined by a ≥ 10% absolute reduction in left ventricular ejection fraction (LVEF) from baseline to < 53%; and 3) incidence of early interruption of HER2-targeted therapy. CONCLUSIONS: To our knowledge, this will be the first prospective study of a risk-based approach to cardiotoxicity surveillance. We expect findings from this study will inform the development of updated clinical practice guidelines to improve cardiotoxicity surveillance practices during HER2-positive breast cancer treatment. TRIAL REGISTRATION: The trial was registered in the ClinicalTrials.gov registry (identifier NCT03983382) on June 12, 2019.