Neuroblastoma: A Tough Nut to Crack

2016 ◽  
pp. e548-e557 ◽  
Author(s):  
Frank Speleman ◽  
Julie R. Park ◽  
Tara O. Henderson
Keyword(s):  
Clinical Trials ◽  
Late Effects ◽  
Association Studies ◽  
Genomic Analysis ◽  
The United States ◽  
Malignant Neoplasms ◽  
Genome Wide Association Studies ◽  
Second Malignant Neoplasms ◽  
Tumor In Childhood

Neuroblastoma, an embryonal tumor arising from neural crest–derived progenitor cells, is the most common solid tumor in childhood, with more than 700 cases diagnosed per year in the United States. In the past several decades, significant advances have been made in the treatment of neuroblastoma. Treatment advances reflect improved understanding of the biology of neuroblastoma. Although amplification of MYCN was discovered in the early 1980s, our understanding of neuroblastoma oncogenesis has advanced in the last decade as a result of high-throughput genomic analysis, exome and whole-genome sequencing, genome-wide association studies, and synthetic lethal drug screens. Our refined understanding of neuroblastoma biology and genetics is reflected in improved prognostic stratification and appropriate tailoring of therapy in recent clinical trials. Moreover, for high-risk neuroblastoma, a disease that was uniformly fatal 3 decades ago, recent clinical trials incorporating autologous hematopoietic transplant and immunotherapy utilizing anti-GD2 antibody plus cytokines have shown improved event-free and overall survival. These advances have resulted in a growing population of long-term survivors of neuroblastoma. Examination of the late effects and second malignant neoplasms (SMNs) in both older generations of survivors and more recently treated survivors will inform both design of future trials and surveillance guidelines for long-term follow-up. As a consequence of advances in understanding of the biology of neuroblastoma, successful clinical trials, and refined understanding of the late effects and SMNs of survivors, the promise of precision medicine is becoming a reality for patients with neuroblastoma.

scholarly journals Balancing cure and long-term risks in acute lymphoblastic leukemia

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 190-197 ◽  
Author(s):  
Lewis B. Silverman
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Late Effects ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasms ◽  
Second Malignant Neoplasms ◽  
Current Therapies ◽  
Cure Rates ◽  
Long Term Survivors

Abstract Cure rates for children and adolescents with acute lymphoblastic leukemia (ALL) have improved dramatically over the last few decades. With this success has come increasing recognition of the adverse late effects of treatment. The significant long-term sequelae in the earliest cohort of long-term survivors treated in the 1970s and 1980s are well documented. To reduce the incidence of these late effects, the majority of pediatric patients treated on more contemporary regimens receive less intensive treatment than did those treated 30-40 years ago. However, current therapies are not risk free; children treated with contemporary regimens remain at risk for developing long-term toxicities, including cardiac dysfunction, osteonecrosis, neurocognitive impairment, and second malignant neoplasms. One of the great challenges facing clinical investigators today is to identify interventions that will reduce the frequency and severity of long-term toxicities without adversely affecting cure rates. The use of dexrazoxane as a cardioprotectant (to prevent anthracycline-associated cardiotoxicity) and alternate-week dosing of dexamethasone (to reduce the risk of osteonecrosis) are examples of 2 such successful strategies. This article provides an overview of the long-term toxicities associated with current therapies and reviews results of clinical trials designed to minimize the burden of cure in long-term survivors.

Approaches to Reduce the Long-Term Burden of Treatment-Related Complications in Survivors of Childhood Cancer

2015 ◽  
pp. 196-204 ◽  
Author(s):  
Saro H. Armenian ◽  
Leontien C. Kremer ◽  
Charles Sklar
Keyword(s):  
Cancer Survivors ◽  
Childhood Cancer ◽  
Late Effects ◽  
Childhood Cancer Survivors ◽  
The United States ◽  
Malignant Neoplasms ◽  
Hematopoietic Stem ◽  
Health Related ◽  
Survivors Of Childhood Cancer

Advances in diagnostics, treatment strategies, and supportive care have contributed to a marked improvement in outcomes for children with cancer. This has resulted in a growing number of long-term childhood cancer survivors. Currently there are over 360,000 individuals who are survivors of childhood cancer in the United States. However, treatment for patients with childhood cancer with chemotherapy, radiation, and/or hematopoietic stem cell transplantation can result in health-related complications that may not become evident until years after completion of treatment. As a result, several initiatives have been established to help standardize the surveillance for treatment-related late effects in childhood cancer survivors. This review highlights emerging concepts related to commonly reported late effects, such as subsequent malignant neoplasms, cardiovascular disease, and endocrinopathies. It also discusses relevant population-based screening strategies to mitigate the long-term health-related burden in vulnerable populations of survivors.

scholarly journals Risk of developing second malignant neoplasms in patients with neuroblastoma: a population study of the US SEER database

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Hongnan Zhen ◽  
Hui Guan ◽  
Jiabin Ma ◽  
Wenhui Wang ◽  
Shen Jing ◽  
...  
Keyword(s):  
Risk Factor ◽  
Digestive System ◽  
Survival Rates ◽  
Endocrine System ◽  
Malignant Neoplasms ◽  
Seer Database ◽  
The Us ◽  
Second Malignant Neoplasms ◽  
Risk Patients

Abstract Background Neuroblastoma is a common extracranial malignant tumor in children. Its main treatment modality is a combination of chemotherapy, radiotherapy, and surgery. Given the advances in chemotherapy regimens and the widespread use of bone marrow transplantation over the decades, there has been improvement in treatment efficacy, which has led to prolonged patient survival. Accordingly, long-term complications have become a growing concern among physicians and patients. This study aimed to analyze the survival rate of patients with neuroblastoma and the risk factors for developing second malignant neoplasms (SMNs). Methods The SEER 18 Regs (1973–2015) and SEER 9 Regs (1973–2015) data of the surveillance, epidemiology, and end results (SEER) database of the US National Cancer Institute were adopted for survival and SMN analysis. Results The 5-, 10-, and 20-year overall survival rates of patients with neuroblastoma were 67%, 65%, and 62%, respectively. Among 38 patients with neuroblastoma who presented with SMNs, those with abdomen as the primary site accounted for the majority (63.2%), followed by those with thorax (26.3%) and other sites (10.5%). SMNs occurred more commonly in non-specific neuroblastoma (incidence: 0.87%) than ganglioneuroblastoma (incidence: 0.3%). Compared with the general population, the risk of SMN is significantly higher (SIR = 4.36). The risk of developing SMNs was significantly higher in the digestive system (SIR = 7.29), bones and joints (SIR = 12.91), urinary system (SIR = 23.48), brain and other nervous systems (SIR = 5.70), and endocrine system (SIR = 5.84). Multivariate analysis revealed that the year of diagnosis (OR = 2.138, 95% CI = 1.634–2.797, p < 0.001) was the only independent risk factor for developing SMNs. Conclusion This study identifies the risk factor for developing SMNs in patients with neuroblastoma, which could facilitate individualized screening for high-risk patients, to allow early diagnosis and treatment of SMNs.

scholarly journals Underrepresentation of Adults and Older Adults With Disabilities in Behavioral Clinical Trials: A Scoping Review

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 644-644
Author(s):  
Susan Stark ◽  
Marian Keglovits ◽  
Sandra Espín Tello
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Scoping Review ◽  
People With Disabilities ◽  
The United States ◽  
Health Condition ◽  
Research Strategies ◽  
Behavioral Studies ◽  
Behavioral Trials

Abstract A lack of evidence-based interventions for people aging with long-term physical disabilities exists. To examine the exclusion of people with disabilities in behavioral clinical trials, a scoping review was conducted. ClinicalTrials.gov was searched for interventional behavioral studies from the United States completed from 2008–2018, with results focused on adults (18–64) and older adults (65+). In total, 158 clinical trials were included. In 129 articles, health conditions were excluded 697 times. Seventy-one clinical trials excluded at least one health condition with strong justification, 11 with poor justification, and 115 without justification. There is strong evidence that people with disabilities are excluded from behavioral clinical trials, often without justification. To help close this gap, our presentation will discuss how translational research strategies, focused on adapting existing EB behavioral trials, can be used to increase the availability of interventions that address the needs of individuals aging with and into long-term disabilities. Part of a symposium sponsored by the Lifelong Disabilities Interest Group.

Primary Sjögren Syndrome

2015 ◽  
Author(s):  
E. William St. Clair ◽  
Melissa A. Wells
Keyword(s):  
Keratoconjunctivitis Sicca ◽  
Association Studies ◽  
Connective Tissue Diseases ◽  
Lymphocyte Activation ◽  
Genome Wide Association Studies ◽  
Dry Eyes ◽  
Rheumatologic Diseases ◽  
Genome Wide ◽  
Chronic Inflammatory Condition

This review focuses on the primary category of Sjögren syndrome (SS), a chronic inflammatory condition that is defined by the presence of dry eyes (keratoconjunctivitis sicca) or dry mouth (xerostomia) in the absence of other rheumatologic diseases. SS may also have extraglandular manifestations in the form of pulmonary, renal, gastrointestinal, and neurologic diseases that can cause significant morbidity and increased mortality and is distinct from other connective tissue diseases. Although the etiology of primary SS is unknown, genome-wide association studies are continuing to reveal that susceptibility to the disease is based on genetic predisposition; patients with primary SS have been identified with several non–major histocompatibility complex genetic polymorphisms that are statistically associated with increased disease susceptibility. In a recent study, blood CD4+ T cells from patients with primary SS were shown to differ in their patterns of DNA methylation compared with healthy controls and demonstrated that many genes involved in lymphocyte activation and the immune response were poised for transcription. Treatment of primary SS mainly involves relief of symptoms and prevention of long-term disease complications. Although biologic therapies have been studied, the results so far have been either negative or inconclusive. This review contains 5 highly rendered figures, 5 tables, and 89 references.

Abstract 439: Trajectory Analysis of Left Ventricular Dimensions From Biobank Data Uncovers Novel Genetic Associations

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Tess Pottinger ◽  
Megan J Puckelwartz ◽  
Lorenzo L Pesce ◽  
Anthony Gacita ◽  
Isabella Salamone ◽  
...  
Keyword(s):  
Heart Failure ◽  
Longitudinal Data ◽  
Association Studies ◽  
The United States ◽  
Left Ventricular ◽  
Genome Wide Association Studies ◽  
Qtc Interval ◽  
Regulatory Regions ◽  
Genome Wide ◽  
Over Time

Background: Approximately 6 million adults in the United States have heart failure. The progression of heart failure is variable arising from differences in sex, age, genetic background including ancestry, and medication response. Many population-based genetic studies of heart failure have been cross-sectional in nature, failing to gain additional power from longitudinal analyses. As heart failure is known to change over time, using longitudinal data trajectories as a quantitative trait will increase power in genome wide association studies (GWAS). Methods: We used the electronic health record in a racially and ethnically diverse medical biobank from a single, metropolitan US center. We used whole genome data from 896 unrelated participants analyzed, including 494 who had at least 1 electrocardiogram and 324 who had more than 1 echocardiogram (average of 3 observations per person). A mixture model based semiparametric latent growth curve model was used to cluster outcome measures used for genome-wide analyses. Results: GWAS on the trajectory probability of QTc interval identified significant associations with variants in regulatory regions proximal to the WLS gene, which encodes Wntless, a Wnt ligand secretion mediator. WLS was previously associated with QTc and myocardial infarction, thus confirming the power of the method. GWAS on the trajectory probability of left ventricular diameter (LVIDd) identified significant associations with variants in regulatory regions near MYO10 , which encodes unconventional Myosin-10. MYO10 was previously associated with obesity and metabolic syndrome. Conclusions: This is the first study to show an association with variants in or near MYO10 and left ventricular dimension changes over time. Further, we found that using trajectory probabilities can provide increased power to find novel associations with longitudinal data. This reduces the need for larger cohorts, and increases yield from smaller, well-phenotyped cohorts, such as those found in biobanks. This approach should be useful in the study of rare diseases and underrepresented populations.

Aftercare

2020 ◽  
pp. 78-104
Author(s):  
Tom Boterberg ◽  
Yen-Ch’ing Chang ◽  
Karin Dieckmann ◽  
Mark Gaze ◽  
Helen Woodman
Keyword(s):  
Young People ◽  
Adult Life ◽  
Response Assessment ◽  
Malignant Neoplasms ◽  
Children And Young People ◽  
Long Term Follow Up ◽  
Second Malignant Neoplasms ◽  
Ongoing Surveillance ◽  
Treatment Summary

Chapter 5 discusses care during and after radiotherapy for children and young people. During and immediately after treatment, children and young people receiving radiotherapy need monitoring for acute complications of treatment and may require supportive care. Following completion of treatment, a response assessment is needed, followed by ongoing surveillance for recurrence. If relapse occurs, consideration can be given to further treatment, which may be radical or palliative in intent. With the passing of time, the risks of relapse recede and monitoring for the late effects of treatment becomes more important. As the majority of patients will have some long-term sequelae, some of which can be ameliorated by timely intervention, patients should be followed in a multidisciplinary clinic. A detailed treatment summary will help predict the risk of complications and guide long-term follow-up. Patients, when they reach adult life, should be aware of possible problems, including fertility issues and second malignant neoplasms.

scholarly journals Association of Established Blood Pressure Loci With 10‐Year Change in Blood Pressure and Their Ability to Predict Incident Hypertension

2020 ◽  
Vol 9 (16) ◽  
Author(s):  
Alaitz Poveda ◽  
Naeimeh Atabaki‐Pasdar ◽  
Shafqat Ahmad ◽  
Göran Hallmans ◽  
Frida Renström ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Genetic Variants ◽  
Association Studies ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Swedish Population ◽  
Long Term Changes ◽  
Traditional Risk Factors

Background Genome‐wide association studies have identified >1000 genetic variants cross‐sectionally associated with blood pressure variation and prevalent hypertension. These discoveries might aid the early identification of subpopulations at risk of developing hypertension or provide targets for drug development, amongst other applications. The aim of the present study was to analyze the association of blood pressure‐associated variants with long‐term changes (10 years) in blood pressure and also to assess their ability to predict hypertension incidence compared with traditional risk variables in a Swedish population. Methods and Results We constructed 6 genetic risk scores (GRSs) by summing the dosage of the effect allele at each locus of genetic variants previously associated with blood pressure traits (systolic blood pressure GRS (GRS SBP ): 554 variants; diastolic blood pressure GRS (GRS DBP ): 481 variants; mean arterial pressure GRS (GRS MAP ): 20 variants; pulse pressure GRS (GRS PP ): 478 variants; hypertension GRS (GRS HTN ): 22 variants; combined GRS (GRS com b ): 1152 variants). Each GRS was longitudinally associated with its corresponding blood pressure trait, with estimated effects per GRS SD unit of 0.50 to 1.21 mm Hg for quantitative traits and odds ratios (ORs) of 1.10 to 1.35 for hypertension incidence traits. The GRS comb was also significantly associated with hypertension incidence defined according to European guidelines (OR, 1.22 per SD; 95% CI, 1.10‒1.35) but not US guidelines (OR, 1.11 per SD; 95% CI, 0.99‒1.25) while controlling for traditional risk factors. The addition of GRS comb to a model containing traditional risk factors only marginally improved discrimination (Δarea under the ROC curve = 0.001–0.002). Conclusions GRSs based on discovered blood pressure‐associated variants are associated with long‐term changes in blood pressure traits and hypertension incidence, but the inclusion of genetic factors in a model composed of conventional hypertension risk factors did not yield a material increase in predictive ability.

Current Challenges in the Genetics of Psoriatic Arthritis: A Report from the GRAPPA 2009 Annual Meeting

2011 ◽  
Vol 38 (3) ◽  
pp. 564-566 ◽  
Author(s):  
PROTON RAHMAN
Keyword(s):  
Psoriatic Arthritis ◽  
Annual Meeting ◽  
Association Studies ◽  
Environment Interaction ◽  
Genome Wide Association Studies ◽  
Novel Genes ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Genome Wide

Psoriasis and psoriatic arthritis (PsA) are heterogeneous diseases. While both have a strong genetic basis, it is strongest for PsA, where fewer investigators are studying its genetics. Over the last year the number of independent genetic loci associated with psoriasis has substantially increased, mostly due to completion of multiple genome-wide association studies (GWAS) in psoriasis. At least 2 GWAS efforts are now under way in PsA to identify novel genes in this disease; a metaanalysis of genome-wide scans and further studies must follow to examine the genetics of disease expression, epistatic interaction, and gene-environment interaction. In the long term, it is anticipated that genome-wide sequencing is likely to generate another wave of novel genes in PsA. At the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) in Stockholm, Sweden, in 2009, members discussed issues and challenges regarding the advancement of the genetics of PsA; results of those discussions are summarized here.

Results of the BRD CAP project: progress toward identifying genetic markers associated with BRD susceptibility

2014 ◽  
Vol 15 (2) ◽  
pp. 157-160 ◽  
Author(s):  
Alison Van Eenennaam ◽  
Holly Neibergs ◽  
Christopher Seabury ◽  
Jeremy Taylor ◽  
Zeping Wang ◽  
...  
Keyword(s):  
Association Studies ◽  
Clinical Signs ◽  
The United States ◽  
Feedlot Cattle ◽  
United States Department ◽  
Genome Wide Association Studies ◽  
Dairy Calf ◽  
Definition Of ◽  
Genetic Evaluations ◽  
Quantitative Definition

AbstractThe Bovine Respiratory Disease Coordinated Agricultural Project (BRD CAP) is a 5-year project funded by the United States Department of Agriculture (USDA), with an overriding objective to use the tools of modern genomics to identify cattle that are less susceptible to BRD. To do this, two large genome wide association studies (GWAS) were conducted using a case:control design on preweaned Holstein dairy heifers and beef feedlot cattle. A health scoring system was used to identify BRD cases and controls. Heritability estimates for BRD susceptibility ranged from 19 to 21% in dairy calves to 29.2% in beef cattle when using numerical scores as a semi-quantitative definition of BRD. A GWAS analysis conducted on the dairy calf data showed that single nucleotide polymorphism (SNP) effects explained 20% of the variation in BRD incidence and 17–20% of the variation in clinical signs. These results represent a preliminary analysis of ongoing work to identify loci associated with BRD. Future work includes validation of the chromosomal regions and SNPs that have been identified as important for BRD susceptibility, fine mapping of chromosomes to identify causal SNPs, and integration of predictive markers for BRD susceptibility into genetic tests and national cattle genetic evaluations.

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