Haptoglobin Gene Expression and Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A COG-ALTE03N1 Report

Article describes how anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms

Tele-ophthalmology for age-related macular degeneration and diabetic retinopathy screening: A systematic review and meta-analysis

Background: To synthesize high-quality evidence to compare traditional in-person screening and tele-ophthalmology screening.Methods: Only randomized controlled trials (RCTs) were included in this systematic review and meta-analysis. The intervention of interest was any type of tele-ophthalmology, including screening of diseases using remote devices. Studies involved patients receiving care from any trained provider via tele-ophthalmology, compared with those receiving equivalent face-to-face care. A search was executed on the following databases: Medline, EMBASE, EBM Reviews, Global Health, EBSCO-CINAHL, SCOPUS, ProQuest Dissertations and Theses Global, OCLC Papers First, and Web of Science Core Collection. Six outcomes of care for age-related macular degeneration (AMD), diabetic retinopathy (DR), or glaucoma were measured and analyzed.Results: Two hundred thirty-seven records were assessed at the full-text level; six RCTs fulfilled inclusion criteria and were included in this review. Four studies involved participants with diabetes mellitus, and two studies examined choroidal neovascularization in AMD. Only data of detection of disease and participation in the screening program were used for the meta-analysis. Tele-ophthalmology had a 14% higher odds to detect disease than traditional examination; however, the result was not statistically significant (n = 2,012, odds ratio: 1.14, 95% confidence interval (CI): 0.52-2.53, p = 0.74). Meta-analysis results show that odds of having DR screening in the tele-ophthalmology group was 13.15 (95% CI: 8.01-21.61; p \u3c 0.001) compared to the traditional screening program.Conclusions: The current evidence suggests that tele-ophthalmology for DR and age-related macular degeneration is as effective as in-person examination and potentially increases patient participation in screening

Multiple Gene-Environment Interactions on the Angiogenesis Gene-Pathway Impact Rectal Cancer Risk and Survival

Characterization of gene-environment interactions (GEIs) in cancer is limited. We aimed at identifying GEIs in rectal cancer focusing on a relevant biologic process involving the angiogenesis pathway and relevant environmental exposures: cigarette smoking, alcohol consumption, and animal protein intake. We analyzed data from 747 rectal cancer cases and 956 controls from the Diet, Activity and Lifestyle as a Risk Factor for Rectal Cancer study. We applied a 3-step analysis approach: first, we searched for interactions among single nucleotide polymorphisms on the pathway genes; second, we searched for interactions among the genes, both steps using Logic regression; third, we examined the GEIs significant at the 5% level using logistic regression for cancer risk and Cox proportional hazards models for survival. Permutation-based test was used for multiple testing adjustment. We identified 8 significant GEIs associated with risk among 6 genes adjusting for multiple testing: TNF (OR = 1.85, 95% CI: 1.10, 3.11), TLR4 (OR = 2.34, 95% CI: 1.38, 3.98), and EGR2 (OR = 2.23, 95% CI: 1.04, 4.78) with smoking; IGF1R (OR = 1.69, 95% CI: 1.04, 2.72), TLR4 (OR = 2.10, 95% CI: 1.22, 3.60) and EGR2 (OR = 2.12, 95% CI: 1.01, 4.46) with alcohol; and PDGFB (OR = 1.75, 95% CI: 1.04, 2.92) and MMP1 (OR = 2.44, 95% CI: 1.24, 4.81) with protein. Five GEIs were associated with survival at the 5% significance level but not after multiple testing adjustment: CXCR1 (HR = 2.06, 95% CI: 1.13, 3.75) with smoking; and KDR (HR = 4.36, 95% CI: 1.62, 11.73), TLR2 (HR = 9.06, 95% CI: 1.14, 72.11), EGR2 (HR = 2.45, 95% CI: 1.42, 4.22), and EGFR (HR = 6.33, 95% CI: 1.95, 20.54) with protein. GEIs between angiogenesis genes and smoking, alcohol, and animal protein impact rectal cancer risk. Our results support the importance of considering the biologic hypothesis to characterize GEIs associated with cancer outcomes

Review of economic evaluations of teleophthalmology as a screening strategy for chronic eye disease in adults

Background/aims: Teleophthalmology is well positioned to play a key role in screening of major chronic eye diseases. Economic evaluation of cost-effectiveness of teleophthalmology, however, is lacking. This study provides a systematic review of economic studies of teleophthalmology screening for diabetic retinopathy (DR), glaucoma and macular degeneration.Methods: Structured search of electronic databases and full article review yielded 20 cost-related articles. Sixteen articles fulfilled the inclusion criteria and were retained for a narrative review: 12 on DR, 2 on glaucoma and 2 on chronic eye disease.Results: Teleophthalmology for DR yielded the most cost savings when compared with traditional clinic examination. The study settings varied among urban, rural and remote settings, community, hospital and health mobile units. The most important determinant of cost-effectiveness of teleophthalmology was the prevalence of DR among patients screened, indicating an increase of cost savings with the increase of screening rates. The required patient pool size to be screened varied from 110 to 3500 patients. Other factors potentially influencing cost-effectiveness of teleophthalmology were older patient age, regular screening and full utilisation of the equipment. Teleophthalmology for glaucoma was more cost-effective compared with in-person examination. Similarly, increasing number of glaucoma patients targeted for screening yielded more cost savings.Conclusions: This economic review provides supportive evidence of cost-effectiveness of teleophthalmology for DR and glaucoma screening potentially increasing screening accessibility especially for rural and remote populations. Special selection of the targeted screening population will optimise the cost-effectiveness of teleophthalmology

Outcomes of COVID-19 in Patients With Cancer: Report From the National COVID Cohort Collaborative (N3C)

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.PURPOSE Variation in risk of adverse clinical outcomes in patients with cancer and COVID-19 has been reported from relatively small cohorts. The NCATS’ National COVID Cohort Collaborative (N3C) is a centralized data resource representing the largest multicenter cohort of COVID-19 cases and controls nationwide. We aimed to construct and characterize the cancer cohort within N3C and identify risk factors for all-cause mortality from COVID-19. METHODS We used 4,382,085 patients from 50 US medical centers to construct a cohort of patients with cancer. We restricted analyses to adults ≥ 18 years old with a COVID-19–positive or COVID-19–negative diagnosis between January 1, 2020, and March 25, 2021. We followed N3C selection of an index encounter per patient for analyses. All analyses were performed in the N3C Data Enclave Palantir platform. RESULTS A total of 398,579 adult patients with cancer were identified from the N3C cohort; 63,413 (15.9%) were COVID-19–positive. Most common represented cancers were skin (13.8%), breast (13.7%), prostate (10.6%), hematologic (10.5%), and GI cancers (10%). COVID-19 positivity was significantly associated with increased risk of all-cause mortality (hazard ratio, 1.20; 95% CI, 1.15 to 1.24). Among COVID-19–positive patients, age ≥ 65 years, male gender, Southern or Western US residence, an adjusted Charlson Comorbidity Index score ≥ 4, hematologic malignancy, multitumor sites, and recent cytotoxic therapy were associated with increased risk of all-cause mortality. Patients who received recent immunotherapies or targeted therapies did not have higher risk of overall mortality. CONCLUSION Using N3C, we assembled the largest nationally representative cohort of patients with cancer and COVID-19 to date. We identified demographic and clinical factors associated with increased all-cause mortality in patients with cancer. Full characterization of the cohort will provide further insights into the effects of COVID-19 on cancer outcomes and the ability to continue specific cancer treatments

Sample average treatment effect on the treated (SATT) analysis using counterfactual explanation identifies BMT and SARS-CoV-2 vaccination as protective risk factors associated with COVID-19 severity and survival in patients with multiple myeloma

Abstract Patients with multiple myeloma (MM), an age-dependent neoplasm of antibody-producing plasma cells, have compromised immune systems and might be at increased risk for severe COVID-19 outcomes. This study characterizes risk factors associated with clinical indicators of COVID-19 severity and all-cause mortality in myeloma patients utilizing NCATS’ National COVID Cohort Collaborative (N3C) database. The N3C consortium is a large, centralized data resource representing the largest multi-center cohort of COVID-19 cases and controls nationwide (>16 million total patients, and >6 million confirmed COVID-19+ cases to date). Our cohort included myeloma patients (both inpatients and outpatients) within the N3C consortium who have been diagnosed with COVID-19 based on positive PCR or antigen tests or ICD-10-CM diagnosis code. The outcomes of interest include all-cause mortality (including discharge to hospice) during the index encounter and clinical indicators of severity (i.e., hospitalization/emergency department/ED visit, use of mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)). Finally, causal inference analysis was performed using the Coarsened Exact Matching (CEM) and Propensity Score Matching (PSM) methods. As of 05/16/2022, the N3C consortium included 1,061,748 cancer patients, out of which 26,064 were MM patients (8,588 were COVID-19 positive). The mean age at COVID-19 diagnosis was 65.89 years, 46.8% were females, and 20.2% were of black race. 4.47% of patients died within 30 days of COVID-19 hospitalization. Overall, the survival probability was 90.7% across the course of the study. Multivariate logistic regression analysis showed histories of pulmonary and renal disease, dexamethasone, proteasome inhibitor/PI, immunomodulatory/IMiD therapies, and severe Charlson Comorbidity Index/CCI were significantly associated with higher risks of severe COVID-19 outcomes. Protective associations were observed with blood-or-marrow transplant/BMT and COVID-19 vaccination. Further, multivariate Cox proportional hazard analysis showed that high and moderate CCI levels, International Staging System (ISS) moderate or severe stage, and PI therapy were associated with worse survival, while BMT and COVID-19 vaccination were associated with lower risk of death. Finally, matched sample average treatment effect on the treated (SATT) confirmed the causal effect of BMT and vaccination status as top protective factors associated with COVID-19 risk among US patients suffering from multiple myeloma. To the best of our knowledge, this is the largest nationwide study on myeloma patients with COVID-19

Identification of novel hypermethylated or hypomethylated CpG sites and genes associated with anthracycline-induced cardiomyopathy

Abstract Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at ‘CpG’ sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case–control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe ‘cg15939386’ in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy

Nonelective coronary artery bypass graft outcomes are adversely impacted by Coronavirus disease 2019 infection, but not altered processes of care: A National COVID Cohort Collaborative and National Surgery Quality Improvement Program analysisCentral MessagePerspective

Objective: The effects of Coronavirus disease 2019 (COVID-19) infection and altered processes of care on nonelective coronary artery bypass grafting (CABG) outcomes remain unknown. We hypothesized that patients with COVID-19 infection would have longer hospital lengths of stay and greater mortality compared with COVID-negative patients, but that these outcomes would not differ between COVID-negative and pre-COVID controls. Methods: The National COVID Cohort Collaborative 2020-2022 was queried for adult patients undergoing CABG. Patients were divided into COVID-negative, COVID-active, and COVID-convalescent groups. Pre-COVID control patients were drawn from the National Surgical Quality Improvement Program database. Adjusted analysis of the 3 COVID groups was performed via generalized linear models. Results: A total of 17,293 patients underwent nonelective CABG, including 16,252 COVID-negative, 127 COVID-active, 367 COVID-convalescent, and 2254 pre-COVID patients. Compared to pre-COVID patients, COVID-negative patients had no difference in mortality, whereas COVID-active patients experienced increased mortality. Mortality and pneumonia were higher in COVID-active patients compared to COVID-negative and COVID-convalescent patients. Adjusted analysis demonstrated that COVID-active patients had higher in-hospital mortality, 30- and 90-day mortality, and pneumonia compared to COVID-negative patients. COVID-convalescent patients had a shorter length of stay but a higher rate of renal impairment. Conclusions: Traditional care processes were altered during the COVID-19 pandemic. Our data show that nonelective CABG in patients with active COVID-19 is associated with significantly increased rates of mortality and pneumonia. The equivalent mortality in COVID-negative and pre-COVID patients suggests that pandemic-associated changes in processes of care did not impact CABG outcomes. Additional research into optimal timing of CABG after COVID infection is warranted