Abstract
BACKGROUND
The introduction of intra-arterial chemotherapy (IAC) for treatment of retinoblastoma considerably changed the paradigm by which this disease is managed, with event-free survival ...rates being above 70%.
OBJECTIVE
To analyze efficacy of IAC treatment using alternative approaches to ophthalmic artery catheterization (OAC), such as external carotid artery approach or balloon-assisted drug delivery.
METHODS
This is a retrospective chart review for subjects receiving IAC for retinoblastoma. The primary approach was OAC. In cases in which selective OAC was not feasible, alternative routes including catheterization of the external carotid artery or use of a balloon-assisted drug infusion were used.
RESULTS
This study included 197 consecutive patients with 207 retinoblastomas who underwent 658 IAC procedures overall. The mean age at diagnosis was 24 mo, and 54.5% of the study population was male. Success rate with IAC was 97% (639). Alternative approaches to OAC were, in total, 42 cases (6.4%)—external carotid artery catheterization and use of ICA balloon were performed in 22 (3.3%) and 20 (3%) cases, respectively. A mean of 3.1 IAC cycles were performed for each patient. In total, there were 23 technical failures of the primary OAC technique (3.4%). Periprocedural adverse events occurred in 4 procedures (0.6%). Use of an alternative technique for chemotherapy delivery other than selective OAC in at least one IAC cycle was not a predictor of enucleation.
CONCLUSION
IAC is a safe and effective treatment option for retinoblastoma. Chemotherapy delivery using alternative techniques is as effective as selective OAC.
Graphical Abstract
Graphical Abstract
State-of-the-art genetic risk interpretation for a common complex disease such as coronary artery disease (CAD) requires assessment for both monogenic variants—such as those related to familial ...hypercholesterolemia—as well as the cumulative impact of many common variants, as quantified by a polygenic score.
The objective of the study was to describe a combined monogenic and polygenic CAD risk assessment program and examine its impact on patient understanding and changes to clinical management.
Study participants attended an initial visit in a preventive genomics clinic and a disclosure visit to discuss results and recommendations, primarily via telemedicine. Digital postdisclosure surveys and chart review evaluated the impact of disclosure.
There were 60 participants (mean age 51 years, 37% women, 72% with no known CAD), including 30 (50%) referred by their cardiologists and 30 (50%) self-referred. Two (3%) participants had a monogenic variant pathogenic for familial hypercholesterolemia, and 19 (32%) had a high polygenic score in the top quintile of the population distribution. In a postdisclosure survey, both the genetic test report (in 80% of participants) and the discussion with the clinician (in 89% of participants) were ranked as very or extremely helpful in understanding the result. Of the 42 participants without CAD, 17 or 40% had a change in management, including statin initiation, statin intensification, or coronary imaging.
Combined monogenic and polygenic assessments for CAD risk provided by preventive genomics clinics are beneficial for patients and result in changes in management in a significant portion of patients.
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Familial hypercholesterolemia variants impair clearance of cholesterol from the circulation and increase risk of coronary artery disease (CAD). The extent to which adherence to a healthy lifestyle is ...associated with a lower risk of CAD in carriers and noncarriers of variants warrants further study.
To assess the association of the interaction between familial hypercholesterolemia variants and adherence to a healthy lifestyle with risk of CAD.
This cross-sectional study used 2 independent data sets with gene sequencing and lifestyle data from the UK Biobank: a case-control study of 4896 cases and 5279 controls and a cohort study of 39 920 participants. Participants were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. The case-control study included participants with CAD and controls at enrollment. The cohort study used a convenience sample of individuals with available gene sequencing data. Statistical analysis was performed from April 2, 2019, to January 20, 2022.
Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist and adherence to a healthy lifestyle based on a 4-point scoring system (1 point for each of the following: healthy diet, regular exercise, not smoking, and absence of obesity).
Coronary artery disease, defined as myocardial infarction in the case-control study, and myocardial infarction, ischemic heart disease, or coronary revascularization procedure in the cohort study.
The case-control study included 10 175 participants (6828 men 67.1%; mean SD age, 58.6 7.2 years), and the cohort study included 39 920 participants (18 802 men 47.1%; mean SD age at the end of follow-up, 66.4 8.0 years). A variant was identified in 35 of 4896 cases (0.7%) and 12 of 5279 controls (0.2%), corresponding to an odds ratio of 3.0 (95% CI, 1.6-5.9), and a variant was identified in 108 individuals (0.3%) in the cohort study, in which the hazard ratio for CAD was 3.8 (95% CI, 2.5-5.8). However, this risk appeared to vary according to lifestyle categories in both carriers and noncarriers of familial hypercholesterolemia variants, without a significant interaction between carrier status and lifestyle (odds ratio, 1.2 95% CI, 0.6-2.5; P = .62). Among carriers, a favorable lifestyle conferred 86% lower risk of CAD compared with an unfavorable lifestyle (hazard ratio, 0.14 95% CI, 0.04-0.41). The estimated risk of CAD by the age of 75 years varied according to lifestyle, ranging from 10.2% among noncarriers with a favorable lifestyle to 24.0% among noncarriers with an unfavorable lifestyle and ranging from 34.5% among carriers with a favorable lifestyle to 66.2% among carriers with an unfavorable lifestyle.
This study suggests that, among carriers and noncarriers of a familial hypercholesterolemia variant, significant gradients in risk of CAD are noted according to adherence to a healthy lifestyle pattern. Similar to the general population, individuals who carry familial hypercholesterolemia variants are likely to benefit from lifestyle interventions to reduce their risk of CAD.
Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) ...cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.
To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.
This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.
PTVs in APOB and PCSK9.
Estimated untreated LDL cholesterol levels and CHD.
Among 19 073 NHLBI participants (10 598 55.6% female; mean SD age, 52 17 years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 55.0% female; mean SD age, 57 8 years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004).
Among 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.
Purpose of Review
Heart transplantation (HT) remains the optimal therapy for patients living with end-stage heart disease. Despite recent improvements in peri-transplant management, the median ...survival after HT has remained relatively static, and complications of HT, including infection, rejection, and allograft dysfunction, continue to impact quality of life and long-term survival.
Recent Findings
Omics technologies are becoming increasingly accessible and can identify novel biomarkers for, and reveal the underlying biology of, several disease states. While some technologies, such as gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA), are routinely used in the clinical care of HT recipients, a number of emerging platforms, including pharmacogenomics, proteomics, and metabolomics, hold great potential for identifying biomarkers to aid in the diagnosis and management of post-transplant complications. Omics-based assays can improve patient and allograft longevity by facilitating a personalized and precision approach to post-HT care.
Summary
The following article is a contemporary review of the current and future opportunities to leverage omics technologies, including genomics, transcriptomics, proteomics, and metabolomics in the field of HT.
Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants ...have recently been implicated in disease pathogenesis.
To assess the contributions of rare and common genetic variation to risk of HCM in the general population.
This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022.
Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors.
Risk of HCM.
The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics ACMG) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87).
Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.
