Case Report: Blinatumomab as upfront consolidation and maintenance therapy in a pediatric patient with high-risk B-cell acute lymphoblastic leukemia

IntroductionB-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children. The current conventional chemotherapy regimens have high overall survival but with significant short- and long-term toxicities, sometimes requiring delay and termination of chemotherapy. Bispecific T-cell engager antibody blinatumomab has been successful in achieving bone marrow remission and acting as bridging therapy in minimal residual disease (MRD)-positive relapsed adult and pediatric B-ALL patients. Its role as upfront therapy is being explored. Here, we report the first case to our knowledge showing the feasibility, tolerability, and sustained remission using blinatumomab upfront as consolidation and maintenance therapy for 2 years in a pediatric patient with high-risk B-ALL who had significant toxicities with conventional chemotherapy.'Case presentationAn 11-year-old Hispanic girl presented with complaints of fever, abdominal pain, and fatigue. On further evaluation, she had tachycardia, pallor, cervical lymphadenopathy, and pancytopenia. Bone marrow studies confirmed high-risk B-ALL. The patient was started on induction chemotherapy per AALL1131. Her induction course was complicated by syncope, febrile neutropenia, and invasive cryptococcal fungal infection. End-of-induction bone marrow results were MRD negative. Further chemotherapy was withheld due to cardiopulmonary and renal failure, along with ventricular arrhythmias requiring intensive care. The patient received two cycles of blinatumomab as consolidation therapy and then transitioned back to conventional consolidation therapy; however, it was terminated mid-consolidation due to Pseudomonas and Aspergillus sepsis. She was then given blinatumomab maintenance therapy for 2 years and tolerated it well without any irreversible toxicity. She had an episode of Staphylococcus epidermidis sepsis and pneumonia treated by antibiotics and a single episode of a seizure while on blinatumomab therapy. At the time of publication, she is 25 months off treatment and in sustained remission without any further transplant or chemotherapy. She received monthly intravenous immunoglobulin G during the blinatumomab maintenance.ConclusionBlinatumomab given upfront as consolidation and maintenance therapy for 2 years in a pediatric high-risk B-ALL patient with significant toxicities to conventional chemotherapy was feasible and very well tolerated without any irreversible toxicity and led to sustained remission without any bridging transplant or further chemotherapy

Differential DNA methylation marks and gene comethylation of COPD in African-Americans with COPD exacerbations

Supplementary data and methods are provided in Additional file 1. This file includes additional methodological details related to study design, Tables S1 and S2, and Figures S1-S3. (DOCX 3650 kb

Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma

Background: Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20). Methods: 10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association. Results: Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51–2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01–0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids. Conclusion: IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids

Workshop report - Interdisciplinary metabolomic epidemiology: The pathway to clinical translation

Metabolomic epidemiology studies are complex and require a broad array of domain expertise. Although many metabolite-phenotype associations have been identified; to date, few findings have been translated to the clinic. Bridging this gap requires understanding of both the underlying biology of these associations and their potential clinical implications, necessitating an interdisciplinary team approach. To address this need in metabolomic epidemiology, a workshop was held at Metabolomics 2023 in Niagara Falls, Ontario, Canada that highlighted the domain expertise needed to effectively conduct these studies -- biochemistry, clinical science, epidemiology, and assay development for biomarker validation -- and emphasized the role of interdisciplinary teams to move findings towards clinical translation

A gap analysis of UK biobank publications reveals SNPs associated with intrinsic subtypes of breast cancer

Breast cancer is a multifaceted disease and a leading cause of cancer morbidity and mortality in females across the globe. In 2020 alone, 2.3 million women were diagnosed and 685,000 died of breast cancer worldwide. With the number of diagnoses projected to increase to 3 million per year by 2040 it is essential that new methods of detection and disease stratification are sought to decrease this global cancer burden. Although significant improvements have been made in breast cancer diagnosis and treatment, the prognosis of breast cancer remains poor in some patient groups (i.e. triple negative breast cancer), necessitating research into better patient stratification, diagnosis and drug discovery. The UK Biobank, a comprehensive biomedical and epidemiological database with a wide variety of multiomics data (genomics, proteomics, metabolomics) offers huge potential to uncover groundbreaking discoveries in breast cancer research leading to improved patient stratification. Combining genomic, proteomic, and metabolic profiles of breast cancer in combination with histological classification, can aid treatment decisions through accurate diagnosis and prognosis prediction of tumor behaviour. Here, we systematically reviewed PubMed publications reporting the analysis of UK Biobank data in breast cancer research. Our analysis of UK Biobank studies in the past five years identified 125 publications, of which 76 focussed on genomic data analysis. Interestingly, only two studies reported the analysis of metabolomics and proteomics data, with none performing multiomics analysis of breast cancer. A meta-analysis of the 76 publications identified 2870 genetic variants associated with breast cancer across 445 genes. Subtype analysis revealed differential genetic alteration in 13 of the 445 genes and the identification of 59 well-established breast cancer genes. in differential pathways. Pathway interaction analyses illuminated their involvement in general cancer biomolecular pathways (e.g. DNA damage repair, Gene expression). While our meta-analysis only measured genetic differences in breast cancer due to current usage of UK Biobank data, minimal multi-omics analyses have been performed and the potential for harnessing multi-omics strategies within the UK Biobank cohort holds promise for unravelling the biological signatures of distinct breast cancer subtypes further in the future.</p

Joint GWAS Analysis: Comparing similar GWAS at different genomic resolutions identifies novel pathway associations with six complex diseases

We show here that combining two existing genome wide association studies (GWAS) yields additional biologically relevant information, beyond that obtained by either GWAS separately. We propose Joint GWAS Analysis, a method that compares a pair of GWAS for similarity among the top SNP associations, top genes identified, gene functional clusters, and top biological pathways. We show that Joint GWAS Analysis identifies additional enriched biological pathways that would be missed by traditional Single-GWAS analysis. Furthermore, we examine the similarities of six complex genetic disorders at the SNP-level, gene-level, gene-cluster-level, and pathway-level. We make concrete hypotheses regarding novel pathway associations for several complex disorders considered, based on the results of Joint GWAS Analysis. Together, these results demonstrate that common complex disorders share substantially more genomic architecture than has been previously realized and that the meta-analysis of GWAS needs not be limited to GWAS of the same phenotype to be informative

Mean Time to Extinction of Source-Sink Metapopulation for Different Spatial Considerations

This issue was undated. The date given is an estimate.18 pages, 1 article*Mean Time to Extinction of Source-Sink Metapopulation for Different Spatial Considerations* (Izquierdo-Sabido, Agustin; Lasky, Jessica; Muktoyuk, Mark; Sabillon, Selim A.) 18 page

Polymorphisms in IL12A and cockroach allergy in children with asthma

<p>Abstract</p> <p>Background</p> <p>IL12A has been implicated in T-cell development and may thus influence the development of atopy and allergic diseases.</p> <p>Methods</p> <p>We tested for association between four linkage disequilibrium (LD)-tagging SNPs (rs2243123, rs2243151, rs668998, and rs17826053) in <it>IL12A </it>and asthma and allergy-related (serum total and allergen-specific IgE, and skin test reactivity [STR] to two common allergens) phenotypes in two samples: 417 Costa Rican children with asthma and their parents, and 470 families of 503 white children in the Childhood Asthma Management Program (CAMP). The analysis was conducted using the family-based association test (FBAT) statistic implemented in the PBAT program.</p> <p>Results</p> <p>Among Costa Rican children with asthma, homozygosity for the minor allele of each of two SNPs in <it>IL12A </it>(rs2243123 and rs2243151) was associated with increased risks of STR to American cockroach (P ≤ 0.03 for both SNPs), STR to German cockroach (P ≤ 0.01 for both SNPs), and having a positive IgE to German cockroach (P < 0.05 for both SNPs). Among children in CAMP, homozygosity for the minor allele of SNP rs2243151 in <it>IL12A </it>was inversely associated with STR to German cockroach (P = 0.03) and homozygosity for the minor allele of SNP rs17826053 in <it>IL12A </it>was associated with increased risks of STR to American cockroach (P = 0.01) and STR to German cockroach (P = 0.007). There was no significant association between any SNP in <it>IL12A </it>and asthma, STR to dust mite, or total IgE in Costa Rica or CAMP.</p> <p>Conclusion</p> <p>Our findings suggest that variants in <it>IL12A </it>influence cockroach allergy among children with asthma.</p

Metabolomic-derived endotypes of age-related macular degeneration (AMD): A step towards identification of disease subgroups

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a complex pathophysiology and phenotypic diversity. Here, we apply Similarity Network Fusion (SNF) to cluster AMD patients into putative metabolomics-derived endotypes. Using a discovery cohort of 163 AMD patients from Boston, US, and a validation cohort of 214 patients from Coimbra, Portugal, we identified four distinct metabolomics-derived endotypes with varying retinal structural and functional characteristics, confirmed across both cohorts. Patients clustered into Endotype 1 exhibited a milder form of AMD and were characterized by low levels of amino acids in specific metabolic pathways. Meanwhile, patients clustered into both Endotype 3 and 4 were associated with more severe AMD and exhibited low levels of fatty acid metabolites and elevated levels of sphingomyelins and fatty acid metabolites, respectively. These preliminary findings indicate that metabolomics-derived endotyping may offer a refined strategy for categorizing AMD patients based on their specific pathophysiological underpinnings, rather than relying solely on traditional observational clinical indicators