Genome-wide study identifies novel genes associated with bone toxicities in children with acute lymphoblastic leukaemia.

Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.

Principles in the Development of Contemporary Treatment of Childhood Malignancies: The First 75 Years.

Over the last 75 years, pediatric cancer has gone from nearly universally fatal, to having a >80% chance of long-term survival. Below we share highlights in this 75-year history, beginning with the "birth" of chemotherapy in treating childhood leukemia, through the development of multiagent chemotherapy, risk-stratified therapy, the use of molecular strategies in diagnosis and treatment, and adapting treatment to the needs of particularly vulnerable patient groups such as adolescents and young adults (AYAs). While pediatric leukemia treatment demonstrates the ever-improving cures achieved through iterative incorporation of novel discoveries, this experience is contrasted with that of osteosarcoma, where scientific advances made over recent decades have yet to be translated into meaningful improvements in long-term survival.

Impairment of health-related quality of life for children with acute lymphoblastic leukemia over the first year of therapy: A report from the DFCI ALL Consortium.

Background: Children treated for acute lymphoblastic leukemia (ALL) receive prolonged treatment, resulting in toxicities that affect health-related quality of life (HR-QoL). Longitudinal assessment of HR-QoL allows improved understanding of experiences with ALL.

Procedure: Parent-proxy and child self-report HR-QoL over the first year of chemotherapy were evaluated in the context of DFCI Protocol 05-001, a phase 3 therapeutic trial for childhood ALL.

Effect of BMI on toxicities and survival among adolescents and young adults treated on DFCI Consortium ALL trials.

Adolescent and young adults (AYAs) with acute lymphoblastic leukemia (ALL) treated with asparaginase-containing pediatric regimens are commonly overweight or obese. We studied the association of body mass index (BMI) on outcomes of 388 AYAs aged 15 to 50 years treated on Dana-Farber Cancer Institute (DFCI) consortium regimens (2008-2021). BMI was normal in 207 (53.

Effect of Black Garlic on Microbiological Properties, Lipid Oxidation, Residual Nitrite, Nitrosamine Formation and Sensory Characteristics in a Semi-Dry Fermented Sausage.

This study was conducted with the aim of determining the effects of different black garlic (BG) levels (1%, 2% and 3%) on quality characteristics of a semi-dry fermented sausage (heat-treated sucuk). In addition, the effect of cooking time (0, 1 or 3 min at 180 °C on a hot plate) on nitrosamine formation was investigated. Fresh garlic (FG, 1%) was evaluated as the control group.

A Review on the Role of Lactic Acid Bacteria in the Formation and Reduction of Volatile Nitrosamines in Fermented Sausages.

Nitrosamines are -nitroso compounds with carcinogenic, mutagenic and teratogenic properties. These compounds could be found at certain levels in fermented sausages. Fermented sausages are considered to be a suitable environment for nitrosamine formation due to acid formation and reactions such as proteolysis and lipolysis during ripening.

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer.

Purpose: Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of alterations () in pediatric cancers to inform future clinical trial design.

Methods: Tumors with alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571).

The occurrence of volatile N-nitrosamines in heat-treated sucuk in relation to pH, a and residual nitrite.

In this study, the occurrence of volatile nitrosamines were investigated in heat-treated sucuk, a kind of semi-dry fermented sausage. The pH, a and residual nitrite of the samples were also determined. In addition, a principal component analysis (PCA) was also performed in order to elucidate the relationship between nitrosamine and these variables.

Predictors of thrombosis in children receiving therapy for acute lymphoblastic leukemia: Results from Dana-Farber Cancer Institute ALL Consortium trial 05-001.

Background/objectives: Although thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1-18 years) treated on the Dana-Farber Cancer Institute ALL 05-001 trial.

Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001.

Purpose: Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase.

Methods: Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m/dose. Patients received one induction dose.

Genetic ancestry and skeletal toxicities among childhood acute lymphoblastic leukemia patients in the DFCI 05-001 cohort.

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) and inferior treatment outcomes relative to non-Hispanic White children. We previously reported that Hispanic children with ALL had lower risk of fracture and osteonecrosis. To unravel the genetic root of such ethnic differences, we genotyped 449 patients from the DFCI 05-001 cohort and analyzed their ancestry.

Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001.

Background/objectives: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy.

Design/methods: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm.

HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

To evaluate the association between human leukocyte antigen (HLA) alleles and native asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. , and alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts.

Protective Effects of Dietary Intake of Antioxidants and Treatment-Related Toxicity in Childhood Leukemia: A Report From the DALLT Cohort.

Purpose: The benefits and risks of supplementation with antioxidants during cancer therapy have been a controversial area. Few studies have systematically evaluated dietary intake of antioxidants with toxicity and survival in childhood cancer. We sought to determine the role of dietary intake of antioxidants on rates of infections, mucositis, relapse, and disease-free survival during induction and postinduction phases of therapy among children and adolescents with acute lymphoblastic leukemia (ALL).

An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients.

Background: NUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis.

Genes identified through genome-wide association studies of osteonecrosis in childhood acute lymphoblastic leukemia patients.

To evaluate top-ranking genes identified through genome-wide association studies for an association with corticosteroid-related osteonecrosis in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Lead SNPs from these studies, as well as other variants in the same genes, pooled from whole exome sequencing data, were analyzed for an association with osteonecrosis in childhood ALL patients from Quebec cohort. Top-ranking variants were verified in the replication patient group.

Nitrosamine formation in a semi-dry fermented sausage: Effects of nitrite, ascorbate and starter culture and role of cooking.

In this study, effects of ingoing nitrite level (0, 50, 100 and 150 mg/kg), use of sodium ascorbate, addition of starter culture (Lactobacillus plantarum GM77 + Staphylococcus xylosus GM92) and cooking level (control, medium, medium well, well done and very well done) on nitrosamine formation in heat-treated sucuk, a type of semi-dry fermented sausage, were investigated. The use of ascorbate had no significant effect on NDMA (N-Nitrosodimethylamine) and NPIP (N-Nitrosopiperidine) contents in the presence of starter culture. A higher NPYR (N- Nitrosopyrrolidine) content was detected in the group with starter culture at 150 mg/kg nitrite level in comparison to the group without starter culture.

Nitrosamines in sucuk: Effects of black pepper, sodium ascorbate and cooking level.

This study determined effects of different black pepper levels (5, 10 or 15 g kg), sodium ascorbate usage and cooking level (raw, medium, medium well and well done) on nitrosamine formation in sucuk (a kind of dry fermented sausage). Sodium ascorbate decreased residual nitrite considerably. Cooking level had a very significant effect on nitrosodimethylamine (NDMA), nitrosopyrrolidine (NPYR) and nitrosopiperidine (NPIP) contents.

Fluctuations in dietary intake during treatment for childhood leukemia: A report from the DALLT cohort.

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Nutritional morbidities are a persistent problem facing pediatric patients during and after treatment and age-gender groups that are at risk for nutritional conditions have not been clearly identified. Therapy is a contributing factor; however, the role of dietary intake remains largely unknown.

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia.

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2).

Genomic and clinical characterization of B/T mixed phenotype acute leukemia reveals recurrent features and T-ALL like mutations.

The B/T subtype of mixed phenotype acute leukemia (B/T MPAL) is defined by co-expression of antigens of both B- and T-cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics and driver mutations that underlie the pathogenesis of this rare subtype of acute leukemia are scarcely known. We identified nine cases of B/T MPAL from multiple institutions and correlated clinical and immunophenotypic findings with next-generation sequencing data.

Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001.

Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001 tested a new risk stratification system in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). At study entry, B-ALL patients were classified as standard risk (SR) or high risk (HR) based on age, white blood cell (WBC) count, and central nervous system status. After achieving complete remission (CR), patients with high end-induction minimal residual disease (MRD) (≥10 by polymerase chain reaction analysis of patient-specific antigen receptor rearrangements) and/or adverse cytogenetics ( rearrangement or hypodiploidy) were reclassified as very high risk (VHR) and received intensified therapy.