Historically, patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission at the end of induction (EOI) have had poor long-term survival. The goal of this study was to ...examine the efficacy of contemporary therapy, including allogeneic hematopoietic stem cell transplantation (HSCT) in first remission (CR1).
Induction failure (IF) was defined as the persistence of at least 5% bone marrow (BM) lymphoblasts and/or extramedullary disease after 4-6 weeks of induction chemotherapy. Disease features and clinical outcomes were reported in 325 of 6,167 (5%) patients age 21 years and younger treated in 14 cooperative study groups between 2000 and 2018.
With a median follow-up period of 6.4 years (range, 0.3-17.9 years), the 10-year overall survival (OS) was 54.7% (SE = 2.9), which is significantly higher than the 27.6% (SE = 2.9) observed in the historical cohort from 1985 to 2000. There was no significant impact of sex, age, white blood cell count, central nervous system disease status, T-cell maturity, or BM disease burden at EOI on OS. Postinduction complete remission (CR) was achieved in 93% of patients with 10-year OS of 59.6% (SE = 3.1%) and disease-free survival (DFS) of 56.3% (SE = 3.1%). Among the patients who achieved CR, 72% underwent HSCT and their 10-year DFS (with a 190-day landmark) was significantly better than nontransplanted patients (63.8% SE = 3.6
45.5% SE = 7.1;
= .005), with OS of 66.2% (SE = 3.6) versus 50.8% (SE = 6.8);
= .10, respectively.
Outcomes for patients age 21 years and younger with T-ALL and IF have improved in the contemporary treatment era with a DFS benefit among those undergoing HSCT in CR1. However, outcomes still lag considerably behind those who achieve remission at EOI, warranting investigation of new treatment approaches.
Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously ...identified.
To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors.
Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10(-9)). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation.
Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.
The underlying pathways that lead to relapse in childhood acute lymphoblastic leukemia (ALL) are unknown. To comprehensively characterize the molecular evolution of relapsed childhood B-precursor ...ALL, we used human 500K single-nucleotide polymorphism arrays to identify somatic copy number alterations (CNAs) in 20 diagnosis/relapse pairs relative to germ line. We identified 758 CNAs, 66.4% of which were less than 1 Mb, and deletions outnumbered amplifications by approximately 2.5:1. Although CNAs persisting from diagnosis to relapse were observed in all 20 cases, 17 patients exhibited differential CNA patterns from diagnosis to relapse. Of the 396 CNAs observed in 20 relapse samples, only 69 (17.4%) were novel (absent in the matched diagnosis samples). EBF1 and IKZF1 deletions were particularly frequent in this relapsed ALL cohort (25.0% and 35.0%, respectively), suggesting their role in disease recurrence. In addition, we noted concordance in global gene expression and DNA copy number changes (P = 2.2 × 10−16). Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse.
•Heterozygous carriers of deleterious germ line NBN variants are at risk of B-ALL development.•Protein instability is the main mechanism for loss-of-function variants in the NBN gene.
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...Biallelic mutation in the DNA-damage repair gene NBN is the genetic cause of Nijmegen breakage syndrome, which is associated with predisposition to lymphoid malignancies. Heterozygous carriers of germ line NBN variants may also be at risk for leukemia development, although this is much less characterized. By sequencing 4325 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), we systematically examined the frequency of germ line NBN variants and identified 25 unique, putatively damaging NBN coding variants in 50 patients. Compared with the frequency of NBN variants in gnomAD noncancer controls (189 unique, putatively damaging NBN coding variants in 472 of 118 479 individuals), we found significant overrepresentation in pediatric B-ALL (P = .004; odds ratio, 1.8). Most B-ALL–risk variants were missense and cluster within the NBN N-terminal domains. Using 2 functional assays, we verified 14 of 25 variants with severe loss-of-function phenotypes and thus classified these as nonfunctional or partially functional. Finally, we found that germ line NBN variant carriers, all of whom were identified as heterozygous genotypes, showed similar survival outcomes relative to those with wild type status. Taken together, our findings provide novel insights into the genetic predisposition to B-ALL, and the impact of NBN variants on protein function and suggest that heterozygous NBN variant carriers may safely receive B-ALL therapy. These trials were registered at www.clinicaltrials.gov as #NCT01225874, NCT00075725, NCT00103285, NCI-T93-0101D, and NCT00137111.
Biallelic loss-of-function germ line variants in the DNA damage repair gene nibrin (NBN) cause Nijmegen breakage syndrome, which carries an increased risk of childhood acute lymphoblastic leukemia (ALL). By studying a cohort of >4000 patients with ALL, Escherich et al reveal that deleterious heterozygous germ line variants in NBN result in a loss of protein stability and are associated with an increased risk of pediatric B-cell ALL. The authors’ findings further our knowledge of germ line predisposition for sporadic cases of childhood ALL and will prompt the search for more predisposition genes.
Despite four decades of resilience research, resilience remains a poor fit for practice as a scientific construct. Using the literature, we explored the concepts attributed to the development of ...resilience, identifying those that mitigate symptoms of distress caused by adversity and facilitate coping in seven classes of illness: transplants, cancer, mental illness, episodic illness, chronic and painful illness, unexpected events, and illness within a dyadic relationship. We identified protective, compensatory, and challenge-related coping-concept strategies that healthcare workers and patients use during the adversity experience. Healthcare-worker assessment and selection of appropriate coping concepts enable the individual to control their distress, resulting in attainment of equanimity and the state of resilience, permitting the resilient individual to work toward recovery, recalibration, and readjustment. We inductively developed and linked these conceptual components into a dynamic framework, The Resilience Framework for Nursing and Healthcare, making it widely applicable for healthcare across a variety of patients.
Glucocorticoids are important therapy for acute lymphoblastic leukemia (ALL) and their major adverse effect is osteonecrosis. Our goal was to identify genetic and nongenetic risk factors for ...osteonecrosis. We performed a genome-wide association study of single nucleotide polymorphisms (SNPs) in a discovery cohort comprising 2285 children with ALL, treated on the Children's Oncology Group AALL0232 protocol (NCT00075725), adjusting for covariates. The minor allele at SNP rs10989692 (near the glutamate receptor GRIN3A locus) was associated with osteonecrosis (hazard ratio = 2.03; P = 3.59 × 10−7). The association was supported by 2 replication cohorts, including 361 children with ALL on St. Jude's Total XV protocol (NCT00137111) and 309 non-ALL patients from Vanderbilt University's BioVU repository treated with glucocorticoids (odds ratio OR = 1.87 and 2.26; P = .063 and .0074, respectively). In a meta-analysis, rs10989692 was also highest ranked (P = 2.68 × 10−8), and the glutamate pathway was the top ranked pathway (P = 9.8 × 10−4). Osteonecrosis-associated glutamate receptor variants were also associated with other vascular phenotypes including cerebral ischemia (OR = 1.64; P = 2.5 × 10−3), and arterial embolism and thrombosis (OR = 1.88; P = 4.2 × 10−3). In conclusion, osteonecrosis was associated with inherited variations near glutamate receptor genes. Further understanding this association may allow interventions to decrease osteonecrosis. These trials are registered at www.clinicaltrials.gov as #NCT00075725 and #NCT00137111.
•Comprehensive study of glucocorticoid-induced osteonecrosis identifies glutamate receptor gene variants as risk factors.
We conducted the first human leukocyte antigen (HLA) allele and genome‐wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of ...asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St Jude Children’s Research Hospital’s Total XVI (TXVI, n = 598) and Children’s Oncology Group AALL0232 (n = 2,472) and AALL0434 (n = 1,189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort‐specific covariates and then combined using meta‐analyses. Nongenetic risk factors included fewer intrathecal injections (P = 2.7 × 10−5 in TXVI) and male sex (P = 0.025 in AALL0232). HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity (P < 5.0 × 10−5) in patients with primarily European ancestry (EA), with the three alleles associating in a single haplotype. The top allele HLA‐DQB1*02:02 was tagged by HLA‐DQB1 rs1694129 in EAs (r2 = 0.96) and less so in non‐EAs. All single nucleotide polymorphisms associated with pegaspargase hypersensitivity reaching genome‐wide significance in EAs were in class II HLA loci, and were partially replicated in non‐EAs, as is true for other HLA associations. The rs9958628 variant, in ARHGAP28 (previously linked to immune response in children) had the strongest genetic association (P = 8.9 × 10−9) in non‐EAs. The HLA‐DQB1*02:02‐DRB1*07:01‐DQA1*02:01 associated with hypersensitivity reactions to pegaspargase is the same haplotype associated with reactions to non‐PEGylated asparaginase, even though the antigens differ between the two preparations.
Atrial septal defect is one of the most common forms of congenital heart malformation. We identified a new locus linked with atrial septal defect on chromosome 14q12 in a large family with dominantly ...inherited atrial septal defect. The underlying mutation is a missense substitution, I820N, in α-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain. The cardiac transcription factor TBX5 strongly regulates expression of MYH6, but mutant forms of TBX5, which cause Holt-Oram syndrome, do not. Morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of the atrial septum without overtly affecting atrial chamber formation. These data provide evidence for a link between a transcription factor, a structural protein and congenital heart disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Although traditional Chinese medicine (TCM) is widely used, its effect on health outcomes is not well understood. This study employed a cohort sequential design to investigate levels and rates of ...change in health from midlife to older adulthood in TCM users and nonusers. A sample of 1,302 community‐dwelling adults aged 53 to 80 was selected from individuals interviewed in the 1999 Taiwan Longitudinal Study on Aging (TLSA) and reinterviewed in 2003 and 2007. TCM users were identified as participants who reported visiting a Chinese medicine clinic in the year before each of the three interviews. Health outcomes included physical function, self‐rated health, cognitive function, and depressive symptoms. Approximately one in five adults reported that they used TCM in at least one wave of the 3 interview years, but less than one in twenty across all waves. Controlling for time‐varying sociodemographic and health conditions, levels and rates of change in physical and cognitive function did not differ according to TCM use. Although adults who reported using TCM had higher depressive symptoms (βTCM = 0.979, 95% confidence interval (CI) = 0.200–1.758) and poorer self‐rated health (βTCM = −0.267, 95% CI = −0.267 to −0.081) at baseline, their rates of change in these outcomes did not differ from those who did not use TCM. Subgroup analyses revealed that TCM use benefited adults with higher depressive symptoms by attenuating worsening depressive symptoms (βTCM×Age = −0.221, 95% CI = −0.434 to −0.007). Further research aimed at understanding the specific mechanisms by which TCM affects health outcomes is warranted.
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