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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder that occurs as a consequence of immune dysregulation. HLH can be primary (familial or non-familial) or secondary to infection, autoimmune disease or malignancy. Malignancy-associated HLH is often accompanied by hematologic and lymphoid neoplasms. This report describes the case of a 3-year-old girl with an initial diagnosis of acute lymphoblastic leukemia who subsequently developed HLH during primary chemotherapy. She was admitted with a pulmonary infection, and initial blood tests showed thrombocytopenia and anemia. Whole-exome sequencing of gene and whole transcriptome RNA sequencing data indicated mutations of UNC13D. The hospital course was complicated by multiple infections, altered mental status and acute respiratory distress syndrome. HLH secondary to multiple infections that achieved remission following targeted therapy with ruxolitinib, in conjunction with corticosteroids and other complementary treatments. This report provides a synopsis of the diagnostic and treatment procedures implemented in this case. [ABSTRACT FROM AUTHOR]

Background: PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. The authors identified 28 pediatric PDGFRB‐positive ALL. They analyzed the features, outcomes, and prognostic factors of this disease. Methods: This multicenter, retrospective study included 6457 pediatric patients with newly diagnosed PDGFRB fusion ALL according to the CCCG‐ALL‐2015 and CCCG‐ALL‐2020 protocols from April 2015 to April 2022 in 20 hospitals in China. Of these patients, 3451 were screened for PDGFRB fusions. Results: Pediatric PDGFRB‐positive ALL accounted for only 0.8% of the 3451 cases tested for PDGFRB. These patients included 21 males and seven females and 24 B‐ALL and 4 T‐ALL; the median age was 10 years; and the median leukocyte count was 29.8 × 109/L at baseline. Only one patient had eosinophilia. Three patients had an IKZF1 deletion, three had chromosome 5q31‐33 abnormalities, and one suffered from a complex karyotype. The 3‐year event‐free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) were 33.1%, 65.5%, and 32.1%, respectively, with a median follow‐up of 25.5 months. Twenty patients were treated with chemotherapy plus tyrosine‐kinase inhibitors (TKIs) and eight were treated without TKI. Complete remission (CR) rates of them were 90.0% and 63.6%, respectively, but no differences in EFS, OS, or CIR. Univariate analyses showed patients with IKZF1 deletion or measurable residual disease (MRD) ≥0.01% after induction had inferior outcomes (p <.05). Conclusions: Pediatric PDGFRB‐positive ALL has a poor outcome associated with high‐risk features. Chemotherapy plus TKIs can improve the CR rate, providing an opportunity for lower MRD levels and transplantation. MRD ≥0.01% was a powerful adverse prognostic factor, and stratified treatment based on MRD may improve survival for these patients. Plain Language Summary: Pediatric acute lymphoblastic leukemia patients with PDGFRB fusions are associated with high‐risk clinical features such as older age, high white blood cell count at diagnosis, high measurable residual disease after induction therapy, and increased risk of leukemia relapse.Chemotherapy plus tyrosine‐kinase inhibitors can improve the complete remission rate and provide an opportunity for lower measurable residual disease (MRD) levels and transplantation for pediatric PDGFRB‐positive acute lymphoblastic leukemia (ALL) patients.The MRD level was also a powerful prognostic factor for pediatric PDGFRB‐positive ALL patients. Pediatric acute lymphoblastic leukemia (ALL) patients with PDGFRB fusions are associated with high‐risk clinical features. Chemotherapy plus tyrosine‐kinase inhibitors can improve the complete remission rate and provide an opportunity for lower measurable residual disease (MRD) levels and transplantation for pediatric PDGFRB‐positive ALL patients. The MRD level was also a powerful prognostic factor for pediatric PDGFRB‐positive ALL patients. [ABSTRACT FROM AUTHOR]

The clinical outcome for children diagnosed with acute lymphoblastic leukemia is a testimony to the success of modern medicine. Over the past few decades, survival has climbed from ∼10% to >90% for certain subgroups. Yet, the outcome for those with relapsed disease is often poor, and survivors struggle with a multitude of healthcare issues, some of which are lifelong. In recent years, the advent of the widespread sequencing of tumors has made available patients with previously unrecognized subtypes of leukemia, who have the potential to benefit from the addition of targeted therapies. Indeed, the promise of precision medicine, encompassing a person's environment, genetics and lifestyle, is likely to have profound impact on further tailoring therapies that are likely to improve outcomes, diminish toxicity and ultimately pave the pathway for a healthier population. [ABSTRACT FROM AUTHOR]

Background: Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although cure rates exceed 85%, current chemotherapy regimens have high toxicity rates, and the prognosis for patients who relapse remains poor. Immunotherapy has allowed for a reduction in adverse effects and toxicities, and created more treatment options for children with relapsed or refractory disease. Blinatumomab, a bispecific T-cell engager antibody that targets CD19 and CD3, has successfully treated pediatric patients with ALL, yet poses unique challenges with administration and management. The role of the pediatric oncology nurse is essential in ensuring blinatumomab therapy is safe and efficacious. As a result of the complicated administration process and specific management, different institutions have implemented specific protocols, but no guideline exists specifically for nurses. Nurses are at the forefront of care and require nursing- based guidelines when delivering blinatumomab therapy. Objective: To provide a clinical overview for nurses administering and managing blinatumomab in the pediatric oncology population. Methods: A literature review was performed using CINAHL and PubMed. Findings: Two-hundred fifteen articles were searched using the terms blinatumomab and pediatric acute lymphoblastic leukemia. A secondary search was performed, adding in terms nurse and nursing management. Eighteen articles were identified as relevant to this review and are synthesized in this article. A standardized approach specific to nursing is necessary to care for pediatric patients receiving blinatumomab to ensure patient safety and optimize maximum efficacy of the immunotherapy. [ABSTRACT FROM AUTHOR]

Variations in pharmacokinetic responses to high-dose methotrexate are essential for the prognosis and management of toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL) patients. This systematic review aimed to identify and evaluate genetic polymorphisms that are significantly associated with the pharmacokinetic parameters of methotrexate during the consolidation phase of pediatric ALL treatment. Using the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, we systematically reviewed the literature from 2013 to 2023. The databases used were PubMed and Scopus. The outcomes of interest are the study design, patient characteristics, sample size, chemotherapy protocol utilized, pharmacokinetic parameters identified, and genetic polymorphisms implicated. We included 31 articles in the qualitative synthesis and found that the SLCO1B1, ABCB1, ABCC2, and MTHFR genes appear to play significant roles in MTX metabolism and clearance. Among these, variations in SLCO1B1 have the most significant and consistent impact on methotrexate clearance. These implicated variants may contribute to the precision and tailoring of HD-MTX treatment in pediatric ALL patients. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder that occurs as a consequence of immune dysregulation. HLH can be primary (familial or non-familial) or secondary to infection, autoimmune disease or malignancy. Malignancy-associated HLH is often accompanied by hematologic and lymphoid neoplasms. This report describes the case of a 3-year-old girl with an initial diagnosis of acute lymphoblastic leukemia who subsequently developed HLH during primary chemotherapy. She was admitted with a pulmonary infection, and initial blood tests showed thrombocytopenia and anemia. Whole-exome sequencing of gene and whole transcriptome RNA sequencing data indicated mutations of UNC13D. The hospital course was complicated by multiple infections, altered mental status and acute respiratory distress syndrome. HLH secondary to multiple infections that achieved remission following targeted therapy with ruxolitinib, in conjunction with corticosteroids and other complementary treatments. This report provides a synopsis of the diagnostic and treatment procedures implemented in this case.

Abstract Background A compromised nutritional status jeopardizes a positive prognosis in acute lymphoblastic leukemia (ALL) patients. In low- and middle-income countries, ~ 50% of children with ALL are malnourished at diagnosis time, and undergoing antineoplastic treatment increases the risk of depleting their nutrient stores. Nutrition interventions are implemented in patients with cancer related malnutrition. We aimed to evaluate the effect of nutrition interventions in children diagnosed with ALL under treatment. Methods Using a predefined protocol, we searched for published or unpublished randomized controlled trials in: Cochrane CENTRAL, MEDLINE, EMBASE, LILACS, and SciELO, and conducted complementary searches. Studies where at least 50% of participants had an ALL diagnosis in children ≤ 18 years, active antineoplastic treatment, and a nutrition intervention were included. Study selection and data extraction were conducted independently by three reviewers, and assessment of the risk of bias by two reviewers. Results were synthesized in both tabular format and narratively. Results Twenty-five studies (out of 4097 records) satisfied the inclusion requirements. There was a high risk of bias in eighteen studies. Interventions analyzed were classified by compound/food (n = 14), micronutrient (n = 8), and nutritional support (n = 3). Within each group the interventions and components (dose and time) tested were heterogeneous. In relation to our primary outcomes, none of the studies reported fat-free mass as an outcome. Inflammatory and metabolic markers related to nutritional status and anthropometric measurements were reported in many studies but varied greatly across the studies. For our secondary outcomes, fat mass or total body water were not reported as an outcome in any of the studies. However, some different adverse events were reported in some studies. Conclusions This review highlights the need to conduct high-quality randomized controlled trials for nutrition interventions in children with ALL, based on their limited number and heterogeneous outcomes. Registration of the review protocol Guzmán-León AE, Lopez-Teros V, Avila-Prado J, Bracamontes-Picos L, Haby MM, Stein K. Protocol for a Systematic Review: Nutritional interventions in children with acute lymphoblastic leukemia undergoing an tineoplastic treatment. International prospective register of systematic reviews. 2021; PROSPERO CRD:42,021,266,761 ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=266761 ).

Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre-leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV-positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995-2015) for the presence of CMV DNA identifying CMV-positive and CMV-negative cases. We performed a case-only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV-positive and CMV-negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01-1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV-positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06-4.37 and OR: 2.06, 95% CI: 1.17-3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV-positive (OR: 2.12, 95% CI: 1.24-3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV-positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.

Background: A compromised nutritional status jeopardizes a positive prognosis in acute lymphoblastic leukemia (ALL) patients. In low- and middle-income countries, ~ 50% of children with ALL are malnourished at diagnosis time, and undergoing antineoplastic treatment increases the risk of depleting their nutrient stores. Nutrition interventions are implemented in patients with cancer related malnutrition. We aimed to evaluate the effect of nutrition interventions in children diagnosed with ALL under treatment. Methods: Using a predefined protocol, we searched for published or unpublished randomized controlled trials in: Cochrane CENTRAL, MEDLINE, EMBASE, LILACS, and SciELO, and conducted complementary searches. Studies where at least 50% of participants had an ALL diagnosis in children ≤ 18 years, active antineoplastic treatment, and a nutrition intervention were included. Study selection and data extraction were conducted independently by three reviewers, and assessment of the risk of bias by two reviewers. Results were synthesized in both tabular format and narratively. Results: Twenty-five studies (out of 4097 records) satisfied the inclusion requirements. There was a high risk of bias in eighteen studies. Interventions analyzed were classified by compound/food (n = 14), micronutrient (n = 8), and nutritional support (n = 3). Within each group the interventions and components (dose and time) tested were heterogeneous. In relation to our primary outcomes, none of the studies reported fat-free mass as an outcome. Inflammatory and metabolic markers related to nutritional status and anthropometric measurements were reported in many studies but varied greatly across the studies. For our secondary outcomes, fat mass or total body water were not reported as an outcome in any of the studies. However, some different adverse events were reported in some studies. Conclusions: This review highlights the need to conduct high-quality randomized controlled trials for nutrition interventions in children with ALL, based on their limited number and heterogeneous outcomes. Registration of the review protocol: Guzmán-León AE, Lopez-Teros V, Avila-Prado J, Bracamontes-Picos L, Haby MM, Stein K. Protocol for a Systematic Review: Nutritional interventions in children with acute lymphoblastic leukemia undergoing an tineoplastic treatment. International prospective register of systematic reviews. 2021; PROSPERO CRD:42,021,266,761 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=266761). [ABSTRACT FROM AUTHOR]

The genomic analyses of pediatric acute lymphoblastic leukemia (ALL) subtypes, particularly T-cell and B-cell lineages, have been pivotal in identifying potential therapeutic targets. Typical genomic analyses have directed attention toward the most commonly mutated genes. However, assessing the contribution of mutations to cancer phenotypes is crucial. Therefore, we estimated the cancer effects (scaled selection coefficients) for somatic substitutions in T-cell and B-cell cohorts, revealing key insights into mutation contributions. Cancer effects for well-known, frequently mutated genes like NRAS and KRAS in B-ALL were high, which underscores their importance as therapeutic targets. However, less frequently mutated genes IL7R, XBP1, and TOX also demonstrated high cancer effects, suggesting pivotal roles in the development of leukemia when present. In T-ALL, KRAS and NRAS are less frequently mutated than in B-ALL. However, their cancer effects when present are high in both subtypes. Mutations in PIK3R1 and RPL10 were not at high prevalence, yet exhibited some of the highest cancer effects in individual T-cell ALL patients. Even CDKN2A, with a low prevalence and relatively modest cancer effect, is potentially highly relevant for the epistatic effects that its mutated form exerts on other mutations. Prioritizing investigation into these moderately frequent but potentially high-impact targets not only presents novel personalized therapeutic opportunities but also enhances the understanding of disease mechanisms and advances precision therapeutics for pediatric ALL. [ABSTRACT FROM AUTHOR]

Background: Methotrexate-induced toxicities often occur in pediatric ALL undergoing chemotherapy. Methotrexate is inhibiting folate metabolism so no DNA synthesis occurs. Folate deficiency can occur before and after administration of methotrexate high dose (MTX-HD). This also may affect the outcome of chemotherapy. However, there has been limited research on folate levels in blood during MTX-HD therapy and its correlation to toxicity. Objective: To analyze the correlation between folate levels and toxicity following high-dose methotrexate (MTX-HD) administration in pediatric patients with acute lymphoblastic leukemia (ALL). Methods: This prospective observational study included 31 pediatric ALL patients aged 1-18 years undergoing consolidation phase chemotherapy. Serum folate levels were measured before and after MTX-HD using CalSet Folate, and MTX-induced toxicities were observed within 48 hours postadministration. Data were analyzed using the Wilcoxon Signed Rank test and Spearman Correlation Test, with p<0.05 considered significant. Results: Thirty-one subjects were included, with a median age of 4 years. Median folate levels increased significantly from 23.5 ng/mL before to 40 ng/mL after MTX-HD (p<0.05). Common toxicities included mucositis (100%), neutropenia (45.2%), DILI (35.5%), and AKI (6.4%). No significant correlation was found between folate levels and these toxicities (p>0.05). Conclusion: Significant differences in folate levels were observed before and after MTX-HD. Despite high folate levels, MTX-induced toxicities still occurred, suggesting other factors may contribute to toxicity. [ABSTRACT FROM AUTHOR]

Background: Medications used to treat acute lymphoblastic leukemia (ALL), such as l-asparaginase, can cause blood lipid disturbances. These can also be associated with polymorphisms of the lipoprotein lipase (LpL) and apolipoprotein E (APOE) genes. Procedure: We aimed to investigate the association between lipid profile, certain LpL and APOE gene polymorphisms (rs268, rs328, rs1801177 and rs7412, rs429358 respectively) as well as the risk subgroup in 30 pediatric patients being treated for ALL, compared with 30 pediatric ALL survivors and 30 healthy controls. Results: The only APOE gene polymorphism with significant allelic and genotypic heterogeneity was rs429358. Further analysis of this polymorphism showed that genotype (CC, CT, or TT) was significantly associated with (1) changes in the lipid profile at the end of consolidation (total cholesterol, LDL, apo-B100, and lipoprotein a) and during re-induction (total cholesterol and apo-B100), and (2) classification in the high risk-ALL subgroup (for CC genotype/C allele presence). Conclusions: Lipid abnormalities in children being treated for ALL may be associated with the APOE genotype, which is also possibly associated with risk stratification. Further research is needed to confirm the potential prognostic value of these findings. [ABSTRACT FROM AUTHOR]

Yoona Choi,1,2,&ast; Bo Kyung Kim,3,4,&ast; Jung-Hyun Won,2,5 Jae Won Yoo,6 Wona Choi,7 Surin Jung,7 Jae Yoon Kim,7,8 In Young Choi,7 Nack-Gyun Chung,6 Jae Wook Lee,6 Jung Yoon Choi,3,4 Hyoung Jin Kang,3,4,9 Howard Lee1,2,5,10,11 1Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; 2Center for Convergence Approaches in Drug Development, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; 3Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea; 4Seoul National University Cancer Research Institute, Seoul, Republic of Korea; 5Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; 6Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 7Department of Medical Informatics, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 8Department of Biomedicine & Health Sciences, the Catholic University of Korea, Seoul, Republic of Korea; 9Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea; 10Advanced Institutes of Convergence Technology, Suwon, Republic of Korea; 11Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Howard Lee, Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea, Email howardlee@snu.ac.kr Hyoung Jin Kang, Department of Pediatrics, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea, Email kanghj@snu.ac.krBackground: Rapid reduction of leukemic cells in the bone marrow during remission induction chemotherapy (RIC) can lead to significant complications such as tumor lysis syndrome (TLS). We investigated whether prephase steroid treatment before RIC could decrease TLS incidence and improve overall survival in pediatric patients with acute lymphoblastic leukemia (ALL).Methods: Data were extracted from the Common Data Model databases in two tertiary-care hospitals in Seoul, South Korea. Patients were classified into the treated or untreated group if they had received RIC with prephase steroid treatment ≥ 7 days before RIC in 2012– 2021 or not, respectively. Stabilized Inverse Probability of Treatment Weighting (sIPTW) was applied to ensure compatibility between the treated and untreated groups. The incidence of TLS within 14 days of starting RIC, overall survival (OS), and the incidence of adverse events of special interest were the primary endpoints. Multiple sensitivity analyses were performed.Results: Baseline characteristics were effectively balanced between the treated (n=308.4) and untreated (n=246.6) groups after sIPTW. Prephase steroid treatment was associated with a significant 88% reduction in the risk of TLS (OR 0.12, 95% CI: 0.03– 0.41). OS was numerically greater in the treated group than in the untreated group although the difference was not statistically significant (HR 0.64, 95% CI 0.25– 1.64). The treated group experienced significantly elevated risks for hyperbilirubinemia and hyperglycemia. The reduction in TLS risk by prephase steroid treatment was maintained in all of the sensitivity analyses.Conclusion: Prephase steroid treatment for ≥ 7 days before RIC in pediatric patients with ALL reduces the risk of TLS, while careful monitoring for toxicities is necessary. If adequately analyzed, real-world data can provide crucial effectiveness and safety information for proper management of pediatric patients with ALL, for whom prospective randomized studies may be difficult to perform for ethical and practical reasons.Keywords: pediatric acute lymphoblastic leukemia, tumor lysis syndrome, remission induction chemotherapy, prephase steroid treatment, common data model

Abstract Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, and despite considerable progress in treatment outcomes, relapses still pose significant risks of mortality and long-term complications. To address this challenge, we employed a supervised machine learning technique, specifically random survival forests, to predict the risk of relapse and mortality using array-based DNA methylation data from a cohort of 763 pediatric ALL patients treated in Nordic countries. The relapse risk predictor (RRP) was constructed based on 16 CpG sites, demonstrating c-indexes of 0.667 and 0.677 in the training and test sets, respectively. The mortality risk predictor (MRP), comprising 53 CpG sites, exhibited c-indexes of 0.751 and 0.754 in the training and test sets, respectively. To validate the prognostic value of the predictors, we further analyzed two independent cohorts of Canadian (n = 42) and Nordic (n = 384) ALL patients. The external validation confirmed our findings, with the RRP achieving a c-index of 0.667 in the Canadian cohort, and the RRP and MRP achieving c-indexes of 0.529 and 0.621, respectively, in an independent Nordic cohort. The precision of the RRP and MRP models improved when incorporating traditional risk group data, underscoring the potential for synergistic integration of clinical prognostic factors. The MRP model also enabled the definition of a risk group with high rates of relapse and mortality. Our results demonstrate the potential of DNA methylation as a prognostic factor and a tool to refine risk stratification in pediatric ALL. This may lead to personalized treatment strategies based on epigenetic profiling.

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, and despite considerable progress in treatment outcomes, relapses still pose significant risks of mortality and long-term complications. To address this challenge, we employed a supervised machine learning technique, specifically random survival forests, to predict the risk of relapse and mortality using array-based DNA methylation data from a cohort of 763 pediatric ALL patients treated in Nordic countries. The relapse risk predictor (RRP) was constructed based on 16 CpG sites, demonstrating c-indexes of 0.667 and 0.677 in the training and test sets, respectively. The mortality risk predictor (MRP), comprising 53 CpG sites, exhibited c-indexes of 0.751 and 0.754 in the training and test sets, respectively. To validate the prognostic value of the predictors, we further analyzed two independent cohorts of Canadian (n = 42) and Nordic (n = 384) ALL patients. The external validation confirmed our findings, with the RRP achieving a c-index of 0.667 in the Canadian cohort, and the RRP and MRP achieving c-indexes of 0.529 and 0.621, respectively, in an independent Nordic cohort. The precision of the RRP and MRP models improved when incorporating traditional risk group data, underscoring the potential for synergistic integration of clinical prognostic factors. The MRP model also enabled the definition of a risk group with high rates of relapse and mortality. Our results demonstrate the potential of DNA methylation as a prognostic factor and a tool to refine risk stratification in pediatric ALL. This may lead to personalized treatment strategies based on epigenetic profiling. [ABSTRACT FROM AUTHOR]

Aeromonas caviae infection of the bloodstream and intestine is a rare and severe opportunistic infection in immunocompromised people. In Southwest China, we first reported a case of bloodstream and intestinal infection with multidrug-resistant (MDR) Aeromonas caviae in a 4-year-old child with T-cell acute lymphoblastic leukemia. Blood and stool cultures were used to identify the infection. The selection of antibiotics was based on clinical expertise and medication sensitivity tests. We used linezolid, levofloxacin, and polymyxin B to treat the patient aggressively. Aeromonas caviae infection is uncommon in juvenile acute lymphoblastic leukemia. Doctors should be aware of the likelihood of opportunistic infection during the post-chemotherapy bone marrow suppression period. We further conducted a review of the literature and performed a detailed analysis of Aeromonas infection in pediatric leukemia. It is becoming increasingly apparent that antibiotic is abused domestically and abroad, resulting in the sharp increase of MDR bacteria. In general, most of the Aeromonas isolates are susceptible to third- or fourth-generation cephalosporins, aminoglycosides, quinolones, and carbapenem, but drug-resistant strains are being reported increasingly. We summarized the drug resistance rate of Aeromonas caviae and Aeromonas hydrophila in China in the last 10 years. Early recognition and effective treatment will improve prognosis and reduce mortality.

The clinical outcome for children diagnosed with acute lymphoblastic leukemia is a testimony to the success of modern medicine. Over the past few decades, survival has climbed from ∼10% to >90% for certain subgroups. Yet, the outcome for those with relapsed disease is often poor, and survivors struggle with a multitude of healthcare issues, some of which are lifelong. In recent years, the advent of the widespread sequencing of tumors has made available patients with previously unrecognized subtypes of leukemia, who have the potential to benefit from the addition of targeted therapies. Indeed, the promise of precision medicine, encompassing a person’s environment, genetics and lifestyle, is likely to have profound impact on further tailoring therapies that are likely to improve outcomes, diminish toxicity and ultimately pave the pathway for a healthier population.

Immune milieus play an important role in various types of cancer. The present study focuses on the effect of Th1 cytokines on pediatric acute lymphoblastic leukemia (ALL). The reaction of ALL cell lines and patient-derived xenografts (PDX) to the most important Th1 cytokines TNF-α (tumor necrosis factor alpha) and IFN-γ (interferon gamma) is analyzed and correlated with the respective cytokine receptors and the intracellular signaling molecules. ALL cell lines and ALL PDX display a great heterogeneity in cell death after incubation with TNF-α and IFN-γ. Several samples show a dose-dependent and additive induction of cell death by both cytokines; others do not react at all or even display an increased viability. Apoptosis is the main type of cell death induced by Th1 cytokines in ALL cells. Over all leukemia cells analyzed, IFN-γ receptor (IFNGR) shows a higher expression than both TNF-receptors, resulting in higher phosphorylation of STAT1 (signal transducer and activator of transcription) compared to phosphorylation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells) in the TNF pathway. The activation of STAT1 correlates with the amount of cell death after stimulation with Th1 cytokines. TNF-α and IFN-γ lead to heterogeneous reactions in ALL cell lines and ALL PDX but are able to induce cell death by apoptosis in the majority of ALL blasts. The correlation of a high expression of IFNGR and following activation of STAT1 with cell death indicates an important role for IFN-γ signaling in this setting. [ABSTRACT FROM AUTHOR]

Abstract Background To evaluate the treatment cost and cost effectiveness of a risk‐stratified therapy to treat pediatric acute lymphoblastic leukemia (ALL) in India. Methods The cost of total treatment duration was calculated for a retrospective cohort of ALL children treated at a tertiary care facility. Children were risk stratified into standard (SR), intermediate (IR) and high (HR) for B‐cell precursor ALL, and T‐ALL. Cost of therapy was obtained from the hospital electronic billing systems and details of outpatient (OP) and inpatient (IP) from electronic medical records. Cost effectiveness was calculated in disability‐adjusted life years. Results One hundred and forty five patients, SR (50), IR (36), HR (39), and T‐ALL (20) were analyzed. Median cost of the entire treatment for SR, IR, HR, and T‐ALL was found to be $3900, $5500, $7400, and $8700, respectively, with chemotherapy contributing to 25%–35% of total cost. Out‐patient costs were significantly lower for SR (p

Background: To evaluate the treatment cost and cost effectiveness of a risk‐stratified therapy to treat pediatric acute lymphoblastic leukemia (ALL) in India. Methods: The cost of total treatment duration was calculated for a retrospective cohort of ALL children treated at a tertiary care facility. Children were risk stratified into standard (SR), intermediate (IR) and high (HR) for B‐cell precursor ALL, and T‐ALL. Cost of therapy was obtained from the hospital electronic billing systems and details of outpatient (OP) and inpatient (IP) from electronic medical records. Cost effectiveness was calculated in disability‐adjusted life years. Results: One hundred and forty five patients, SR (50), IR (36), HR (39), and T‐ALL (20) were analyzed. Median cost of the entire treatment for SR, IR, HR, and T‐ALL was found to be $3900, $5500, $7400, and $8700, respectively, with chemotherapy contributing to 25%–35% of total cost. Out‐patient costs were significantly lower for SR (p < 0.0001). OP costs were higher than in‐patient costs for SR and IR, while in‐patient costs were higher in T‐ALL. Costs for non‐therapy admissions were significantly higher in HR and T‐ALL (p < 0.0001), representing over 50% of costs of in‐patient therapy. HR and T‐ALL also had longer durations of non‐therapy admissions. Based on WHO‐CHOICE guidelines, the risk‐stratified approach was very cost effective for all categories of patients. Conclusions: Risk‐stratified approach to treat childhood ALL is very cost‐effective for all categories in our setting. The cost for SR and IR patients is significantly reduced through decreased IP admissions for both, chemotherapy and non‐chemotherapy reasons. [ABSTRACT FROM AUTHOR]

Extramedullary relapse in acute lymphoblastic leukemia (ALL) usually occurs in the central nervous system and testes those are known as sanctuary sites. Only a few cases of isolated breast relapse after allogeneic hematopoietic stem cell transplantation (HSCT) have been reported in pediatric ALL, with little known about the optimal treatment and prognosis of such cases. Herein, we report a pediatric case of isolated breast relapse with early T-cell precursor ALL after HSCT. We also describe a literature review of six pediatric cases, including our case.

Duloxetine is indicated for the treatment of chemotherapy-induced neuropathic pain in adults. It is also indicated for anxiety, depression, and fibromyalgia in children. A rare side effect of syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported in adults, but not in pediatrics or pediatric oncology patients. We present the case of a 10-year-old child with acute lymphoblastic leukemia, who developed SIADH after duloxetine was given for chemotherapy-induced neuropathic pain and comorbid anxiety. The SIADH resolved after duloxetine was stopped. This case highlights a rare side effect of duloxetine and caution should be taken when prescribing duloxetine to children. [ABSTRACT FROM AUTHOR]

Abstract Background Children with acute lymphoblastic leukemia (ALL) undergoing chemotherapy experience a relatively high risk of infection. And the disturbance of gut microbiota is generally believed to impair intestinal barrier function and may induce bacterial infections and inflammation. The study aimed to investigate the alterations in the gut microbiota and assess its relationship with chemotherapy-induced pneumonia in pediatric ALL patients. Methods We conducted a case–control study with 14 cases affected by pneumonia and 44 unaffected subjects and characterized the physiological parameters and gut microbiota by microarray-based technique. Results There were significant differences in α- and β-diversity in the affected group compared with the control group. At species level, the LEfSe analysis revealed that Enterococcus malodoratus, Ochrobactrum anthropi and Actinomyces cardiffensis were significantly abundant in the affected subjects. A receiver operating characteristic (ROC) curve yielded the area under the curve (AUC) of 0.773 for classification between the two groups. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in the bacterial secretion system were more enriched in the affected group than in the control group. Conclusions Gut microbiota alteration was associated with chemotherapy-induced pneumonia in pediatric ALL patients, which provided a new perspective on the personalized clinical care of pediatric ALL.

Introduction: Mercaptopurine (6-MP) is the backbone of the consolidation and maintenance therapy for paediatric acute lymphoblastic leukaemia (ALL). Nevertheless, it can cause critical myelosuppression. Predicting adverse reactions to 6-MP often involves the investigation of pharmacogenetic variants; in particular thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15). Lately, NUDT15 variants have been shown to play a significant pharmacogenetic role in predicting 6-MP intolerance in children of Asian descent. Case Report: We present a six-year-old male child of Indian origin with persistent cytopenia after treatment. This prompted targeted sequencing of the genes TPMT and NUD15. The results revealed two copies of the variant of NUD15 rs116855232, that is, NUDT15 *2 genotype. Management and Outcome: Since the NUDT15 *2 allele classified the patient as a poor metabolizer, he was restarted on a low dose of 6-MP, which he tolerated. Discussion: Individuals with the NUDT15 *2allele (*2/*2 genotype) are poor metabolizers of thiopurines which results in an adverse reaction to 6-MP. About 3.5% of Indians show variations in the TPMT gene as compared to 19.4% variations observed in NUDT15, which makes the latter a more reliable disease marker. [ABSTRACT FROM AUTHOR]

To further emphasize the clinical–genetic features and prognosis of CDKN2A/B deletions in childhood acute lymphoblastic leukemia (ALL), we retrospectively analyzed 819 consecutive B-ALL patients treated with the Chinese Children's Cancer Group ALL-2015 (CCCG-ALL-2015) protocol, and fluorescence in situ hybridization (FISH) analysis on CDKN2A/B deletion was available for 599 patients. The prevalence of CDKN2A/B gene deletions was 20.2% (121/599) of B-ALL. CDKN2A/B deletions were significantly associated with older age, higher leukocyte counts, a higher percentage of hepatosplenomegaly, and a higher frequency of BCR-ABL (p < 0.05). Those patients achieved similar minimal residual disease (MRD) clearance and complete remission compared to patients without CDKN2A/B deletion. The CDKN2A/B deletions were correlated with inferior outcomes, including a 3-year event-free survival (EFS) rate (69.8 ± 4.6 vs. 89.2 ± 1.6%, p = 0.000) and a 3-year overall survival (OS) rate (89.4% ± 2.9% vs. 94.7% ± 1.1%, p = 0.037). In multivariable analysis, CDKN2A/B deletion was still an independent prognostic factor for EFS in total cohorts (p < 0.05). We also detected a multiplicative interaction between CDKN2A/B deletions and TP53 deletion on dismal prognosis (p -interaction < 0.05). In conclusion, CDKN2A/B deletion is associated with distinct characteristics and serves as a poor prognostic factor in pediatric ALL, especially in TP53 deletion carriers. [ABSTRACT FROM AUTHOR]

To further emphasize the clinical–genetic features and prognosis of CDKN2A/B deletions in childhood acute lymphoblastic leukemia (ALL), we retrospectively analyzed 819 consecutive B-ALL patients treated with the Chinese Children’s Cancer Group ALL-2015 (CCCG-ALL-2015) protocol, and fluorescence in situ hybridization (FISH) analysis on CDKN2A/B deletion was available for 599 patients. The prevalence of CDKN2A/B gene deletions was 20.2% (121/599) of B-ALL. CDKN2A/B deletions were significantly associated with older age, higher leukocyte counts, a higher percentage of hepatosplenomegaly, and a higher frequency of BCR-ABL (p < 0.05). Those patients achieved similar minimal residual disease (MRD) clearance and complete remission compared to patients without CDKN2A/B deletion. The CDKN2A/B deletions were correlated with inferior outcomes, including a 3-year event-free survival (EFS) rate (69.8 ± 4.6 vs. 89.2 ± 1.6%, p = 0.000) and a 3-year overall survival (OS) rate (89.4% ± 2.9% vs. 94.7% ± 1.1%, p = 0.037). In multivariable analysis, CDKN2A/B deletion was still an independent prognostic factor for EFS in total cohorts (p < 0.05). We also detected a multiplicative interaction between CDKN2A/B deletions and TP53 deletion on dismal prognosis (p-interaction < 0.05). In conclusion, CDKN2A/B deletion is associated with distinct characteristics and serves as a poor prognostic factor in pediatric ALL, especially in TP53 deletion carriers.

Purpose of Review: The treatment of acute lymphoblastic leukemia (ALL) is one of the success stories of pediatric oncology, but challenges and questions remain, including the optimal approach to the treatment of central nervous system (CNS) leukemia. It is unclear why some children with ALL develop CNS leukemia and others do not, and there remains debate regarding optimal regimens for prophylaxis, upfront treatment, and the treatment of CNS relapses. These topics are especially important since both cranial radiation therapy (CRT) and intensive intrathecal therapy carry risks of both short- and long-term adverse effects. In this review, we aim to identify areas of ongoing debate on this topic, review the biology of CNS leukemia, and summarize clinical trial data that address some of these questions. Recent Findings: Both retrospective and meta-analyses have demonstrated that few patients with ALL benefit from CRT as a component of CNS-directed treatment for de novo disease, allowing cooperative groups to greatly limit the number of patients undergoing CRT as part of their initial ALL regimens. More recent efforts are focusing on how best to assay for low levels of CNS disease at the time of diagnosis, as well as the biological drivers that may result in CNS leukemia in certain patients. Summary: Progress remains to be made in the identification and treatment of CNS leukemia in pediatric ALL. Advancements have occurred to limit the number of children undergoing CRT, but much has yet to be learned to better understand the biology of and risk factors for CNS leukemia, and novel approaches are required to approach CNS relapse of ALL. [ABSTRACT FROM AUTHOR]

Pediatric acute lymphoblastic leukemia (pALL), a malignancy of the lymphoid line of blood cells, accounts for a large percentage of all childhood leukemia cases. Although the 5-year survival rate for children with ALL has greatly improved over years, using chemotherapeutics as its first-line treatment still causes short- and long-term side effects. Furthermore, induction of toxicity and resistance, as well as the high cost, limit their application. Phytochemicals, with remarkable cancer preventive and chemotherapeutic characteristics, may serve as old solutions to new challenges. Bioactive plant secondary metabolites have exhibited promising antileukemic and adjunctive effects by targeting various molecular processes, including autophagy, cell cycle, angiogenesis, and extrinsic/intrinsic apoptotic pathways. Although numerous reports have shown that various plant secondary metabolites can interfere with the progression of malignancies, including leukemia, there was no comprehensive review article on the effect of phytochemicals on pALL. This systematic review aims to provide critical and cohesive analysis of the potential of various naturally-occurring plant secondary metabolites in the management of pALL with the understanding of underlying molecular and cellular mechanisms of action.

Acute lymphoblastic leukemia is the most frequent cancer in children: it represents 80% of leukemias and about 24% of all neoplasms diagnosed between 0 and 14 years. Acute lymphoblastic leukemia mainly affects children between 2 and 5 years old and in this age group the incidence is about 80–90 cases per million per year. In acute lymphoblastic leukemia, cancer cells multiply rapidly and accumulate in the bone marrow and subsequently invade the blood. However, at the time of diagnosis, leukemia rarely occurs outside the bone marrow or blood vessels and the extramedullary involvement happens mostly in patients with refractory or relapsing disease. In this article, we report an unusual clinical presentation of acute B cell lymphoblastic leukemia with intestinal and ovarian localizations in a 5-year-old girl. [ABSTRACT FROM AUTHOR]

Although bone fragility may already be present at diagnosis of pediatric acute lymphoblastic leukemia (ALL), routine performance of dual‐energy X‐ray absorptiometry (DXA) in every child is not universally feasible. The aim of this study was to develop and validate a risk prediction model for low lumbar spine bone mineral density (LS BMD Z‐score ≤ −2.0) at diagnosis, as an important indicator for fracture risk and further treatment‐related BMD aggravation. Children with ALL (4–18 years), treated according to the Dutch Childhood Oncology Group protocol (DCOG‐ALL9; model development; n = 249) and children from the Canadian Steroid‐Associated Osteoporosis in the Pediatric Population cohort (STOPP; validation; n = 99) were included in this study. Multivariable logistic regression analyses were used to develop the prediction model and to confirm the association of low LS BMD at diagnosis with symptomatic fractures during and shortly after cessation of ALL treatment. The area under the receiver operating characteristic curve (AUC) was used to assess model performance. The prediction model for low LS BMD at diagnosis using weight (β = −0.70) and age (β = −0.10) at diagnosis revealed an AUC of 0.71 (95% CI, 0.63–0.78) in DCOG‐ALL9 and 0.74 (95% CI, 0.63–0.84) in STOPP, and resulted in correct identification of 71% of the patients with low LS BMD. We confirmed that low LS BMD at diagnosis is associated with LS BMD at treatment cessation (OR 5.9; 95% CI, 3.2–10.9) and with symptomatic fractures (OR 1.7; 95% CI, 1.3–2.4) that occurred between diagnosis and 12 months following treatment cessation. In meta‐analysis, LS BMD at diagnosis (OR 1.6; 95% CI, 1.1–2.4) and the 6‐month cumulative glucocorticoid dose (OR 1.9; 95% CI, 1.1–3.2) were associated with fractures that occurred in the first year of treatment. In summary, a prediction model for identifying pediatric ALL patients with low LS BMD at diagnosis, as an important indicator for bone fragility, was successfully developed and validated. This can facilitate identification of future bone fragility in individual pediatric ALL patients. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Background: Children with acute lymphoblastic leukemia (ALL) undergoing chemotherapy experience a relatively high risk of infection. And the disturbance of gut microbiota is generally believed to impair intestinal barrier function and may induce bacterial infections and inflammation. The study aimed to investigate the alterations in the gut microbiota and assess its relationship with chemotherapy-induced pneumonia in pediatric ALL patients.Methods: We conducted a case-control study with 14 cases affected by pneumonia and 44 unaffected subjects and characterized the physiological parameters and gut microbiota by microarray-based technique.Results: There were significant differences in α- and β-diversity in the affected group compared with the control group. At species level, the LEfSe analysis revealed that Enterococcus malodoratus, Ochrobactrum anthropi and Actinomyces cardiffensis were significantly abundant in the affected subjects. A receiver operating characteristic (ROC) curve yielded the area under the curve (AUC) of 0.773 for classification between the two groups. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in the bacterial secretion system were more enriched in the affected group than in the control group.Conclusions: Gut microbiota alteration was associated with chemotherapy-induced pneumonia in pediatric ALL patients, which provided a new perspective on the personalized clinical care of pediatric ALL. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to evaluate the cytogenetic and fluorescent in situ hybridization (FISH) profile in children with acute lymphoblastic leukemia (ALL), referred to a university hospital in a 5-year 6-month period.Subjects and Methods: Cytogenetic analysis of the bone marrow aspirate specimens of 91 patients was performed by standard Giemsa (G)-banding and interphase FISH (iFISH).Results: The frequency of chromosomal abnormalities detected by G-banding was 29.5%, and the frequency of nonrandom abnormalities with independent prognostic significance identified by iFISH was 46.4%. The abnormality with the highest frequency was gain of RUNX1 (n = 18, 21.4%), followed by ETV6/RUNX1 fusion (n = 7, 8.3%), and gain of KMT2A (n = 6, 7.1%). Additionally, rarely reported gains of ETV6, PBX1, and ABL1 were observed at a frequency of 6% (n = 5), and the deletion of ETV6 and TCF3 was seen at a frequency of 3.6% (n = 3) and 2.3% (n = 2), respectively. A 10-year old with intrachromosomal amplification of chromosome 21 was also observed.Conclusions: This study strengthens and widens the current knowledge of the cytogenetic landscape of pediatric ALL. [ABSTRACT FROM AUTHOR]

During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors’ late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy’s long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines’ possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect’s vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.

During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors' late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy's long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines' possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect's vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors. [ABSTRACT FROM AUTHOR]

Personalized medicine is focused on research disciplines that contribute to the individualization of therapy, such as pharmacogenomics and pharmacotranscriptomics. Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. It is one of the pediatric malignancies with the highest cure rate, but still a lethal outcome due to therapy accounts for 1–3% of deaths. Further improvement of treatment protocols is needed through the implementation of pharmacogenomics and pharmacotranscriptomics. The research study was aimed at discovering pharmacogenetic and pharmacotranscriptomic markers of response to therapy with thiopurine and glucocorticoid drugs, methotrexate and vincristine in children with ALL in Serbia. Blood and bone marrow samples from children with ALL were collected at the University Children's Hospital in Belgrade. Variants in the studied genes were detected by PCR and Sanger sequencing. The expression level of NUDT15 in mononuclear cells was determined by real-time PCR. Next-generation sequencing using cancer panel TruSeq Amplicon, Illumina was also performed to assess drug resistance. Correlation of pharmacomarkers with clinical parameters was performed using statistical tests. A polygenic risk score based prediction model for the development of methotrexate-induced hepatotoxicity was developed. A number of molecular markers responsible for the efficacy, side effects and toxicity of drugs used to treat ALL, ie. glucocorticoids, vincristine, asparaginase, anthracyclines, thiopurines and methotrexate. Their application in clinical practice is still insufficient. Research efforts should be focused on analyzing data and designing predictive models that use machine learning algorithms. Bioinformatics tools and the implementation of artificial intelligence will help personalized medicine come to life in clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Background Treatment stratification based on bone marrow minimal residual disease (MRD) at set time points has resulted in considerably improved survival in pediatric acute lymphoblastic leukemia (ALL). Treatment response is assessed using bone marrow samples. MicroRNAs (miRs) easily traffic among fluid spaces and are more stable than most other RNA classes. We examined the role of circulating miRs as putative less invasive MRD biomarkers. Methods In an exploratory experiment, expression of 46 preselected miRs was studied in platelet-free blood plasma samples of 15 de novo, 5 relapsed ALL patients and 10 controls by Custom TaqMan Array Advanced MicroRNA Card. Based on their high expression in ALL compared to controls, and on the reduction observed along the induction therapy, four miRs were selected for further analyses: miR-128-3p, -181a-5p, -181b-5p and 222-3p. Their expression was measured by qPCR at 4 time points in 27 de novo ALL patients treated in the ALL IC-BFM 2009 study. Results The expression of all 4 miRs significantly decreased over the first week of therapy (miR-128-3p: log2 fold change − 2.86; adjusted p 3.6 × 10−7; miR-181b-5p: log2 fold change − 1.75; adjusted p 1.48 × 10−2; miR-181a-5p: log2 fold change -1.33; adjusted p 3.12 × 10−2; miR-222-3p: log2 fold change − 1.25; adjusted p 1.66 × 10−2). However, no significant further reduction in miR expression was found after the 8th day of therapy. Measured drop in expression of 2 miRs at day 8 strongly correlated with day 15 bone marrow flow cytometry MRD results (miR-128-3p: Pearson’s r = 0.88, adjusted p = 2.71 × 10−4; miR-222-3p: r = 0.81, adjusted p = 2.99 × 10−3). Conclusion In conclusion, these circulating miRs might act as biomarkers of residual leukemia. MiR-128-3p and miR-222-3p in blood predict day 15 flow cytometry MRD results 7 days earlier. Although, their sensitivity falls behind that of bone marrow flow cytometry MRD at day 15.

Abstract Background Many cases of acute lymphoblastic leukemia (ALL) carry visible acquired chromosomal changes of pathogenetic, diagnostic, and prognostic importance. Nevertheless, from one-fourth to half of newly diagnosed ALL patients have no visible chromosomal changes detectable by G-banding analysis at diagnosis. The introduction of powerful molecular methodologies has shown that many karyotypically normal ALLs carry clinically important submicroscopic aberrations. Case presentation We used fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), RNA sequencing, reverse transcription (RT) and genomic polymerase chain reaction (PCR), as well as Sanger sequencing to investigate a case of pediatric ALL with a normal karyotype. FISH with a commercial PDGFRB breakapart probe showed loss of the distal part of the probe suggesting a breakpoint within the PDGFRB locus. aCGH revealed submicroscopic deletions in chromosome bands 5q32q35.3 (about 30 Mb long, starting within PDGFRB and finishing in the CANX locus), 7q34 (within TCRB), 9p13 (PAX5), 10q26.13 (DMBT1), 14q11.2 (TRAC), and 14q32.33 (within the IGH locus). RNA sequencing detected an in-frame GTF2I–PDGFRB and an out-of-frame IKZF1–TYW1 fusion transcript. Both fusion transcripts were verified by RT-PCR together with Sanger sequencing and interphase FISH. The GTF2I–PDGFRB fusion was also verified by genomic PCR and FISH. The corresponding GTF2I–PDGFRB fusion protein would consist of almost the entire GTF2I and that part of PDGFRB which harbors the catalytic domain of the tyrosine kinase. It would therefore seem to lead to abnormal tyrosine kinase activity in a manner similar to what has been seen for other PDGFRB fusion proteins. Conclusions The examined pediatric leukemia is a Ph-like ALL which carries novel GTF2I–PDGFRB and IKZF1–TYW1 fusion genes together with additional submicroscopic deletions. Because hematologic neoplasms with PDGFRB-fusion genes can be treated with tyrosine kinase inhibitors, the detection of such novel fusions may be clinically important. Since the GTF2I–PDGFRB could be detected only after molecular studies of the leukemic cells, further investigations of ALL-cases, perhaps especially but not exclusively with a normal karyotype, are needed in order to determine the frequency of GTF2I–PDGFRB in leukemia, and also to find out which clinical impact the fusion may have.

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, representing 25% of all new cancer diagnoses. Advances in genomic sequencing have demonstrated that inherited genetic risk factors play a larger role in leukemia development than previously appreciated. Aim We identified a father–daughter dyad with childhood B‐cell ALL and aimed to investigate whether the pair shared a gene associated with leukemia predisposition. Methods We performed whole exome sequencing on their leukemia and germline samples and RNA‐seq on their leukemia samples. Results We discovered a novel germline chromosomal structural variant in chromosome 1q32.2 within the TRAF3IP3 gene. TRAF3IP3 regulates B‐cell lymphopoiesis, and this mutation likely resulted in a predisposition to leukemia by causing expansion of immature B‐cell precursors which are highly vulnerable to secondary somatic mutations. Based on the lack of concordance in the somatic mutational profiles between this dyad's leukemia samples, we suspect that the acquired somatic mutations rather than this germline mutation are what dictated their leukemia phenotypes, which we confirmed through RNA‐seq by comparing to sporadic cases of B‐cell ALL. Conclusion This research may have identified a novel gene involved in leukemogenesis which may also be involved in de novo cases of ALL. Additional studies are needed to further characterize this TRAF3IP3 structural variant, the co‐occurring somatic mutations within these leukemia samples and their combined role in leukemogenesis.

Purpose: Despite improvements in frontline pediatric acute lymphoblastic leukemia (ALL) treatment, relapse remains a concern. Research in adult cancer patients suggests that patient-reported symptoms may predict survival, but the relationship between symptoms and relapse for pediatric ALL has received little attention. Methods: Pediatric patients with ALL (age 2–18 years) and/or their primary caregivers completed symptom surveys at the end of induction, start of delayed intensification (DI), start of maintenance cycle 1 (MC1), and start of maintenance cycle 2 (MC2). Symptom clusters for co-occurring fatigue, pain, sleep disruptions, and nausea were defined using latent profile analysis. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between symptom clusters, individual symptoms, and subsequent relapse were calculated using multivariable Cox proportional hazards models, adjusting for clinical and demographic factors. Results: Eligible patients (n = 208) were followed an average of 2.6 years for the incidence of relapse (n = 22). Associations between relapse and symptoms were identified for fatigue at DI (HR = 1.83, 95%CI 1.23–2.73) and MC1 (HR = 2.14, 95%CI 1.62–2.84), pain at DI (HR = 1.80, 95%CI 1.19–2.72), nausea at the end of induction (HR = 1.19, 95%CI 1.01–1.39), and sleep disturbances at the end of induction (HR = 2.00, 95%CI 1.11–3.62), DI (HR = 1.73, 95%CI 1.01–2.96), and MC1 (HR = 2.19, 95%CI 1.10–4.35). Symptom clusters comprised of individuals with a higher average symptom burden at DI were significantly (p < 0.05) associated with relapse. Conclusion: Patient-reported symptoms may provide prognostic information to aid in the identification of pediatric ALL patients at increased risk of relapse. [ABSTRACT FROM AUTHOR]

Context: Cancer-related fatigue (CRF) is one of the most distressing and persistent symptoms reported during pediatric acute lymphoblastic leukemia (ALL) therapy; however, information on the pathways underlying CRF severity is limited.Objectives: We conducted global metabolomics profiling of cerebrospinal fluid (CSF) samples to provide insight into the underlying mechanisms of CRF.Methods: Fatigue in pediatric ALL patients (2012-2017) was assessed during postinduction therapy approximately six months after diagnosis. Postinduction CSF was collected from 171 participants, comprising discovery (n = 86) and replication (n = 85) cohorts. We also conducted secondary validation using diagnostic CSF from 48 replication cohort participants. CSF metabolomic profiling was performed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS/MS. Kendall's rank correlation was used to evaluate associations between metabolite abundance and CRF. False discovery rate was used to account for multiple comparisons.Results: Participants were 56% males and 59% Hispanic with a mean age at diagnosis of 8.5 years. A total of 274 CSF-derived metabolites were common to the discovery and replication cohorts. Eight metabolites were significantly associated with fatigue in the discovery cohort (P < 0.05), of which three were significant in the replication cohort, including false discovery rate-corrected associations with gamma-glutamylglutamine (Pcombined = 6.2E-6) and asparagine (Pcombined = 3.5E-4). Notably, the abundance of gamma-glutamylglutamine in diagnostic CSF samples was also significantly associated with fatigue (P = 0.0062).Conclusion: The metabolites identified in our assessment have been implicated in neurotransmitter transportation and glutathione recycling, suggesting that glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF. This information could inform targeted therapies for reducing CRF in at-risk individuals. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) and their role in competitive endogenous RNA (ceRNA) networks have emerged as fundamental debates in the biological processes of initiation and progression of cancer. This study aimed to identify and measure the expression levels of relevant ceRNA regulatory genes contributing to acute lymphoblastic leukemia (ALL). lncRNA H19 and BCL-2 mRNA were chosen based on in silico studies and their interactions with miR-326. Subsequently, the aforementioned coding/non-coding gene expression profiles were measured using qRT-PCR in 50 bone marrow samples, including 33 cases with pediatric ALL and 17 controls with no evidence of malignancy. lncRNA H19 was identified as an oncogenic factor which was noticeably increased in the newly diagnosed patients (P = 0.0019, AUC = 0.84) and negatively associated with miR-326 (r = −0.6, P = 0.02). Furthermore, a negative correlation was introduced between the transcriptional levels of miR-326 and the anti-apoptotic BCL-2 gene (r = −0.6, P = 0.028). The novel experimental and bioinformatic results achieved in this study may provide new insights into the molecular leukemogenesis of pediatric ALL. [ABSTRACT FROM AUTHOR]

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatrics, and immune‐related genes (IRGs) play crucial role in its development. Our study aimed to identify prognostic immune biomarkers of pediatric ALL and construct a risk assessment model. Methods Pediatric ALL patients’ gene expression data were downloaded from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. We screened differentially expressed IRGs (DEIRGs) between the relapse and non‐relapse groups. Cox regression analysis was used to identify optimal prognostic genes, then, a risk model was constructed, and its accuracy was verified in different cohorts. Results We screened 130 DEIRGs from 251 pediatric ALL samples. The top three pathways that DEIRGs may influence tumor progression are NABA matrisome‐associated, chemotaxis, and antimicrobial humoral response. A set of 84 prognostic DEIRGs was identified by using univariate Cox analysis. Then, Lasso regression and multivariate Cox regression analysis screened four optimal genes (PRDX2, S100A10, RORB, and SDC1), which were used to construct the prognostic risk model. The risk score was calculated and the survival analysis results showed that high‐risk score was associated with poor overall survival (OS) (p = 3.195 × 10−7). The time‐dependent survival receiver operating characteristic curves showed good prediction accuracy (Area Under Curves for 3‐year, 5‐year OS were 0.892 and 0.89, respectively). And the predictive performance of our risk model was successfully verified in testing cohort and entire cohort. Conclusions Our prognostic risk model can effectively divide pediatric ALL patients into high‐risk and low‐risk groups, which may help predict clinical prognosis and optimize individualized treatment.

Background: Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatrics, and immune‐related genes (IRGs) play crucial role in its development. Our study aimed to identify prognostic immune biomarkers of pediatric ALL and construct a risk assessment model. Methods: Pediatric ALL patients' gene expression data were downloaded from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. We screened differentially expressed IRGs (DEIRGs) between the relapse and non‐relapse groups. Cox regression analysis was used to identify optimal prognostic genes, then, a risk model was constructed, and its accuracy was verified in different cohorts. Results: We screened 130 DEIRGs from 251 pediatric ALL samples. The top three pathways that DEIRGs may influence tumor progression are NABA matrisome‐associated, chemotaxis, and antimicrobial humoral response. A set of 84 prognostic DEIRGs was identified by using univariate Cox analysis. Then, Lasso regression and multivariate Cox regression analysis screened four optimal genes (PRDX2, S100A10, RORB, and SDC1), which were used to construct the prognostic risk model. The risk score was calculated and the survival analysis results showed that high‐risk score was associated with poor overall survival (OS) (p = 3.195 × 10−7). The time‐dependent survival receiver operating characteristic curves showed good prediction accuracy (Area Under Curves for 3‐year, 5‐year OS were 0.892 and 0.89, respectively). And the predictive performance of our risk model was successfully verified in testing cohort and entire cohort. Conclusions: Our prognostic risk model can effectively divide pediatric ALL patients into high‐risk and low‐risk groups, which may help predict clinical prognosis and optimize individualized treatment. [ABSTRACT FROM AUTHOR]

Most children are surviving acute lymphoblastic leukemia (ALL) today. Yet, the emergence of cardiometabolic comorbidities in this population may impact long-term outcomes including the quality of life and lifespan. Obesity is a major driver of cardiometabolic disorders in the general population, and in ALL patients it is associated with increased risk of hypertension, dysglycemia, and febrile neutropenia when compared with lean ALL patients undergoing therapy. This systematic review aims to assess the current evidence for bariatric interventions to manage obesity in children with ALL. The primary outcome for this systematic review was the change in BMI z-score with implementation of the interventions studied. Literature searches were conducted in several databases. Ten publications addressing the study question were included in this review, and five studies were used in the meta-analysis to assess the impact of the bariatric interventions on obesity. The BMI z-score did not change significantly with the interventions. However, the quality of evidence was low, which precluded the recommendation of their use. In conclusion, prospective, rigorous, adequately powered, and high-quality longitudinal studies are urgently needed to deliver effective lifestyle interventions to children with ALL to treat and prevent obesity. These interventions, if successful, may improves cardiometabolic health outcomes and enhance the quality of life and life expectancy in children with ALL. [ABSTRACT FROM AUTHOR]

Background: The T-cell engager antibody blinatumomab (BlincytoT⁢M) represents a promising rescue therapy for relapsed/refractory CD19+ acute lymphoblastic leukemia (B-ALL), although ~20–30% of patients still do not respond to treatment. Blinatumomab creates a tight synapsis between CD3+ T-lymphocytes and leukemic CD19+ B-cells, resulting in a granzyme B (GzB)-mediated specific lysis of leukemic cells. Methods: Aim of the study was to provide evidence that variability in blinatumomab response could have a genetic basis in PAX5, one of the most often mutated genes in B-ALL, affecting the CD19 surface expression on lymphoblasts, and could be explored in vitro by means of a cytofluorimetric assay, staining both surface antigens (CD45, CD19 and CD3) and intracytoplasmic markers (7AAD, Syto16). Two human immortalized B-ALL cell lines (NALM6 and REH) were chosen for their different PAX5 and CD19 protein levels, as verified by western blot and flow cytometry, respectively. Results: In contrast to NALM6, REH cells do not express the full-length PAX5 protein and show less CD19 on the cell surface (fluorescence peak median intensity: 9155 versus 28895). Co-cultures of CD3+ T-lymphocytes from healthy donors and B-ALL cell lines were seeded at an effector-to-target cell ratio of 1:10 for simulating the condition existing in the bone marrow due to the malignant invasion of blast cells. Co-cultures were exposed in vitro to blinatumomab and the simultaneous increase in blast mortality and T-lymphocytes activation induced by the drug was observed at day +7 (both effects: p < 0.0001 versus untreated, two-way ANOVA, Bonferroni post-test), and was particularly pronounced in REH compared to NALM6 co-cultures (p < 0.05). Surprisingly, daily release of GzB in supernatants, measured by an ELISA assay, was significantly lower in drug-exposed REH co-cultures compared to NALM6 at early time-points (days +3 and +4, p-value < 0.0001, three-way ANOVA), reaching a comparable plateau only towards the end of the incubation period (at day +5). Only 2 out of 5 primary co-cultures of leukemic and mononuclear cells isolated from bone marrow aspirates of B-ALL patients (age: median 10.7 years, interquartile range (IQR) 3.4; males: 60%) responded to the drug in vitro (simultaneous blast mortality and T-lymphocyte activation: both effects: p < 0.0001 versus untreated) and at different drug concentrations. Results were unrelated to the percentages of immature CD19+ B-cells in the diagnostic samples. Conclusions: In conclusion, cytofluorimetric analysis can highlight the different response induced by blinatumomab among co-cultures. Whether and how this difference is affected by PAX5-regulated CD19 expression is unclear and whether it is predictive of in vivo response to therapy remains to be established. Further dedicated studies are required to investigate these issues in detail.

Acute lymphoblastic leukemia is the most common malignancy in children and is characterized by numerous genetic and epigenetic abnormalities. Epigenetic mechanisms, including DNA methylations and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. Emerging studies are increasing our understanding of the epigenetic role of leukemogenesis and have demonstrated the potential of DNA methylations and histone modifications as a biomarker for lineage and subtypes classification, predicting relapse, and disease progression in acute lymphoblastic leukemia. Epigenetic abnormalities are relatively reversible when treated with some small molecule-based agents compared to genetic alterations. In this review, we conclude the genetic and epigenetic characteristics in ALL and discuss the future role of DNA methylation and histone modifications in predicting relapse, finally focus on the individual and precision therapy targeting epigenetic alterations.