BACKGROUND: Acute leukemia is the most common pediatric cancer, with an incidence peak at 2-5 years of age. Despite the medical advances improving survival rates, children suffer from significant side effects of treatments as well as its high social and economic impact. The frequent prenatal origin of this developmental disease follows the two-hit carcinogenesis model established in the 70s: a first hit in prenatal life with the creation of genetic fusion lesions or aneuploidy in hematopoietic progenitor/stem cells, and usually a second hit in the pediatric age that converts the preleukemic clone into clinical leukemia. Previous research has mostly focused on postnatal environmental factors triggering the second hit.
CONCLUSIONS: There is scarce evidence on prenatal risk factors associated with the first hit. Mainly retrospective case-control studies suggested several environmental and lifestyle determinants as risk factors. If these associations could be confirmed, interventions focused on modifying prenatal factors might influence the subsequent risk of leukemia during childhood and reveal unexplored research avenues for the future. In this review, we aim to comprehensively summarize the currently available evidence on prenatal risk factors for the development of childhood leukemia. According to the findings of this review, parental age, ethnicity, maternal diet, folate intake, alcohol consumption, X-ray exposure, pesticides, perinatal infections, and fetal growth may have a significant role in the appearance of preleukemic lesions during fetal life. Other factors such as socioeconomic status, consumption of caffeinated beverages, and smoking consumption have been suggested with inconclusive evidence. Additionally, investigating the association between prenatal factors and genetic lesions associated with childhood leukemia at birth is crucial. Prospective studies evaluating the link between lifestyle factors and genetic alterations could provide indirect evidence supporting new research avenues for leukemia prevention. Maternal diet and lifestyle factors are modifiable determinants associated with adverse perinatal outcomes that could be also related to preleukemic lesions.
CONCLUSIONS: Parental age, ethnicity, maternal diet, folate intake, alcohol consumption, X-ray exposure, pesticides, perinatal infections, and fetal growth may have a significant role in the appearance of preleukemic lesions during fetal life. Dedicating efforts to studying maternal lifestyle during pregnancy and its association with genetic lesions leading to childhood leukemia could lead to novel prevention strategies.

The long-term effects of environmental pollution have been of concern as several pollutants are carcinogenic, potentially inducing a variety of cancers, including childhood cancer, which is a leading cause of death around the world and, thus, is a public health issue. The present scoping review aimed to update and summarize the available literature to detect specific environmental pollutants and their association with certain types of childhood cancer. Studies published from 2013 to 2023 regarding environmental pollution and childhood cancer were retrieved from the PubMed database. A total of 174 studies were eligible for this review and were analyzed. Our search strategy brought up most of the articles that evaluated air pollution (29%) and pesticides (28%). Indoor exposure to chemicals (11%), alcohol and tobacco use during pregnancy (16%), electromagnetic fields (12%), and radon (4%) were the subjects of less research. We found a particularly high percentage of positive associations between prenatal and postnatal exposure to indoor (84%) and outdoor (79%) air pollution, as well as to pesticides (82%), and childhood cancer. Positive associations were found between leukemia and pesticides and air pollution (33% and 27%); CNS tumors and neuroblastoma and pesticides (53% and 43%); and Wilms tumor and other rare cancers were found in association with air pollution (50%). Indoor air pollution was mostly reported in studies assessing several types of cancer (26%). Further studies are needed to investigate the mechanisms underlying the potential associations between indoor/outdoor air pollution and pesticide exposure with childhood cancer risk as more preventable measures could be taken.

This study investigated the impact of residential radon exposure on human cancers (i.e., lung cancer and childhood leukemia) through a systematic review and meta-analysis of case−control studies. A total of 9724 articles obtained from electronic databases were assessed; however, only 55 case−control studies were eligible after manually screening and eliminating unnecessary studies. The causal associations were addressed by determining the meta-analysis’s estimated size effects (i.e., ORs/RRs) of the meta-analysis. Residential radon was revealed to significantly increase the incidence of lung cancer and childhood leukemia with pooled ORs of 1.38 [1.19; 1.60] (I2 = 90%; p < 0.00001) and 1.43 [1.19; 1.72] (I2 = 0% and p = 0.51), respectively. In addition, subgroup analyses were performed to reduce the heterogeneity of the initial meta-analyses. The results provided strong evidence that inhaling radon in the indoor environments is closely associated with the development of lung cancer and childhood leukemia in patients living in Europe and areas with high radon levels (≥100 Bq/m3).

The association between childhood leukemia and extremely low frequency magnetic fields (ELF-MF) generated by power lines and various electric appliances has been studied extensively during the past 40 years. However, the conditions under which ELF-MF represent a risk factor for leukemia are still unclear. Therefore, we have performed a systematic review and meta-analysis to clarify the relation between ELF-MF from several sources and childhood leukemia. We have systematically searched Medline, Scopus, Cochrane Database of Systematic Review and DARE to identify each article that has examined the relationship between ELF-MF and childhood leukemia. We have performed a global meta-analysis that takes into account the different measures used to assess magnetic field exposure: magnetic flux density measurements (<0.2 µT vs. >0.2 µT), distances between the child\'s home and power lines (>200 m vs. <200 m) and wire codings (low current configuration vs. high current configuration). Moreover, meta-analyses either based on magnetic flux densities, on proximity to power lines or on wire codings have been performed. The association between electric appliances and childhood leukemia has also been examined. Of the 863 references identified, 38 studies have been included in our systematic review. Our global meta-analysis indicated an association between childhood leukemia and ELF-MF (21 studies, pooled OR=1.26; 95% CI 1.06-1.49), an association mainly explained by the studies conducted before 2000 (earlier studies: pooled OR=1.51; 95% CI 1.26-1.80 vs. later studies: pooled OR=1.04; 95% CI 0.84-1.29). Our meta-analyses based only on magnetic field measurements indicated that the magnetic flux density threshold associated with childhood leukemia is higher than 0.4 µT (12 studies, >0.4 µT: pooled OR=1.37; 95% CI 1.05-1.80; acute lymphoblastic leukemia alone: seven studies, >0.4 µT: pooled OR=1.88; 95% CI 1.31-2.70). Lower magnetic fields were not associated with leukemia (12 studies, 0.1-0.2 µT: pooled OR=1.04; 95% CI 0.88-1.24; 0.2-0.4 µT: pooled OR=1.07; 95% CI 0.87-1.30). Our meta-analyses based only on distances (five studies) showed that the pooled ORs for living within 50 m and 200 m of power lines were 1.11 (95% CI 0.81-1.52) and 0.98 (95% CI 0.85-1.12), respectively. The pooled OR for living within 50 m of power lines and acute lymphoblastic leukemia analyzed separately was 1.44 (95% CI 0.72-2.88). Our meta-analyses based only on wire codings (five studies) indicated that the pooled OR for the very high current configuration (VHCC) was 1.23 (95% CI 0.72-2.10). Finally, the risk of childhood leukemia was increased after exposure to electric blankets (four studies, pooled OR=2.75; 95% CI 1.71-4.42) and, to a lesser extent, electric clocks (four studies, pooled OR=1.27; 95% CI 1.01-1.60). Our results suggest that ELF-MF higher than 0.4 µT can increase the risk of developing leukemia in children, probably acute lymphoblastic leukemia. Prolonged exposure to electric appliances that generate magnetic fields higher than 0.4 µT like electric blankets is associated with a greater risk of childhood leukemia.

Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15-3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39-4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00-1.99) and insecticide (OR: 1.60, 95%CI: 1.11-2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12-0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44-3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98-5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (ORparental: 1.75, 95%CI: 1.08-2.85; ORpaternal: 1.20, 95%CI: 1.07-1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure.

Introduction: A systematic review was performed to assess the prognostic value of Measurable Residual Disease (MRD) during treatment, for relapse and overall survival in pediatric acute myeloid leukemia (AML).Areas covered: A systematic search of available literature was performed to identify original full-text articles concerning MRD as prognostic for relapse and survival in pediatric AML. Thirteen studies were included, and in all studies, MRD positivity during treatment was associated with worse clinical outcome. MRD positivity was significantly associated with a higher probability of relapse in eleven studies. However, MRD negativity does not exclude the possibility of relapse in pediatric AML, while positivity early during therapy does not exclude cure.Expert opinion: MRD positivity during treatment has emerged as the most powerful prognostic factor in pediatric AML concerning relapse and overall survival and is useful for risk-group adapted treatment. Future studies should identify the optimal time-point(s) for MRD measurements and the optimal technique, to further improve its prognostic significance.

BACKGROUND: Infections may play a role in the etiology of childhood cancer and immunizations may be protective because vaccinations stimulate the immune system. Observational studies reported inconsistent associations between vaccination and risk of childhood cancer. Since a synthesis of the evidence is lacking, we conducted a meta-analysis stratified by histological and site-specific cancer.
METHODS: We performed a systematic review (CRD42020148579) following PRISMA guidelines and searched for literature in MEDLINE, Embase, and the Science Citation Index databases. We identified in three literature databases 7,594 different articles of which 35 met the inclusion criteria allowing for 27 analyses of 11 cancer outcomes after exposure to nine different types of vaccinations. We calculated summary odds ratios (ORs) and 95% confidence intervals (CIs) using random effects models.
RESULTS: We observed four inverse associations between childhood leukemia and certain vaccines as well as the number of vaccinations: OR 0.49 (95% CI = 0.32 to 0.74) for leukemia death after bacillus Calmette-Guérin vaccination; OR 0.76 (95% CI = 0.65 to 0.90) for acute lymphoblastic leukemia after Haemophilus influenzae type b vaccination; OR 0.57 (95% CI = 0.36 to 0.88) for leukemia; and OR 0.62 (95% CI = 0.46 to 0.85) for acute lymphoblastic leukemia after three or more vaccinations of any type. All other conducted analyses did not show any associations.
CONCLUSIONS: The results are consistent with the hypothesis that vaccinations reduce the risk of childhood leukemia. However, the robustness and validity of these results is limited due to the small number, substantial heterogeneity, and methodological limitations of available studies.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) may present with signs and symptoms related to extramedullary involvement, therefore, leads to delayed diagnosis of ALL in children. This study aims to consider the extramedullary manifestations of ALL in children and their proper treatment.
METHODS: The databases were searched for all relevant subjects including \"acute lymphoblastic leukemia\", \"clinical presentation\", \"unusual presentation\", \"childhood acute lymphoblastic leukemia\", \"presenting features of ALL\", \"extramedullary presentation\", and \"atypical presentation\" from April 1968 to June 2020. The Inclusion criteria for this review study were all cases reported, case series, and studies about extramedullary presentations of ALL in pediatrics. Eighty-seven studies had inclusion criteria. All reported studies were analyzed given their extramedullary presentations, age, sex, treatment option, and prognostic factors. A two-sided P-value less than 0.05 was considered statistically significant.
RESULTS: In this review study, the extramedullary initial signs and symptoms of ALL were related to musculoskeletal system 17 (19.5%) especially bony symptoms and hypercalcemia. The additional extramedullary presentations of ALL in order of frequency include; renal involvement, 17 (19.5%), hepatic symptom 12 (13.8%), orbital presentation 10 (11.5%), neurologic signs 8 (9%), dermatological manifestations 5 (5.8%), oral presentations 5 (5.8%), hypereosinophilia 5 (5.8%), abdominal manifestation 3 (3.5%), pericardial involvement 2 (2.3%), and the other miscellaneous presentations 3 (3.5%).
CONCLUSIONS: The clinicians must become familiar with these extramedullary presentations of ALL in pediatrics to avoid the delayed diagnosis of this disease and increase the probable chance of survival by early detection.

OBJECTIVE: Diabetes mellitus (DM) is widely recognized as a risk factor for diverse cancers in adults. However, the association between maternal diabetes and risk of childhood cancer in the offspring has so far not been well studied. We thus conducted a meta-analysis to evaluate the role of maternal diabetes on the risk of childhood cancer.
METHODS: We performed a comprehensive literature search to identify eligible studies published up to June 20, 2020, including the PubMed, Web of science and Embase databases. Summary odds ratios (OR) and 95% confidence intervals (CI) were computed using a random-effects model (I2 ≥ 25%) or a fixed-effect model (I2 < 25%).
RESULTS: Totally, sixteen case-control and six cohort studies on the risk of childhood cancer associated with maternal diabetes were included. Overall, children of diabetic women had a significantly increased risk in childhood malignancy (OR, 1.30; 95% CI, 1.10-1.53). Notably, a significantly elevated risk of childhood cancer in the offspring was found for women with pre-existing diabetes (OR, 1.41; 95% CI, 1.17-1.70), but not for women with gestational diabetes mellitus (GDM) (OR, 1.10; 95% CI, 0.94-1.28). For site-specific cancers, maternal diabetes was associated with a higher risk of leukemia in offspring (OR, 1.30; 95% CI, 1.15-1.48), especially for acute lymphoblastic leukemia (OR, 1.44; 95% CI, 1.27-1.64). However, no significant associations were observed between maternal diabetes and the risk of lymphomas and retinoblastoma.
CONCLUSIONS: Our meta-analysis indicates that maternal diabetes is associated with an increased risk of childhood cancer in the offspring, particularly for acute lymphoblastic leukemia. Future study should investigate the underlying biological mechanisms behind the association.

Chimerism analysis following hematopoietic stem cell transplantation (HSCT) for leukemia is routinely applied in parallel with quantification of minimal residual disease (MRD) to identify imminent relapse. In the past decades, new methods with a lower limit of detection compared to standard methods have been developed, so-called microchimerism analysis. Microchimerism analysis is fast, simple, applicable across pre-HSCT disease-type and can be applied on peripheral blood allowing frequent testing during follow-up. Monitoring of microchimerism in blood could replace repeated bone marrow analysis for MRD and allow earlier detection of imminent relapse or graft failure. Clinical studies in single center cohorts have shown conflicting but promising results. There is currently no consensus on the interpretation of microchimerism analysis and heterogeneity of studies remains a major obstacle for inter-study comparisons and meta-analysis in this field. We have conducted a systematic review of studies investigating associations between microchimerism and relapse of leukemia post-HSCT. We summarize current evidence and provide suggestions for future research.