The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C)

The “delayed infection hypothesis” states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 10⁶ person-years of follow-up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77–0.99) and 0.85: (0.73–0.99), respectively. Being later-born was associated with similarly reduced hazards of CL and ALL compared to being first-born; HRs = 0.78: 95% CI: 0.58–1.05 and 0.73: 0.52–1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later-born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06–0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures.     

Prognostic factors of childhood acute lymphoblastic leukemia with TCF3::PBX1 in CCCG-ALL-2015: A multicenter study

Background

Contemporary risk-directed treatment has improved the outcome of patients with acute lymphoblastic leukemia (ALL) and TCF3::PBX1 fusion. In this study, the authors seek to identify prognostic factors that can be used to further improve outcome.

Methods

The authors studied 384 patients with this genotype treated on Chinese Children's Cancer Group ALL-2015 protocol between January 1, 2015 and December 31, 2019. All patients provisionally received intensified chemotherapy in the intermediate-risk arm without prophylactic cranial irradiation; those with high minimal residual disease (MRD) ≥1% at day 46 (end) of remission induction were candidates for hematopoietic cell transplantation.

Results

The overall 5-year event-free survival was 84.4% (95% confidence interval [CI], 80.6–88.3) and 5-year overall survival 88.9% (95% CI, 85.5–92.4). Independent factors associated with lower 5-year event-free survival were male sex (80.4%, [95% CI, 74.8–86.4] vs. 88.9%, [95% CI, 84.1–93.9] in female, p = .03) and positive day 46 MRD (≥0.01%) (62.1%, [95% CI, 44.2–87.4] vs. 87.1%, [95% CI, 83.4–90.9] in patients with negative MRD, p < .001). The presence of testicular leukemia at diagnosis (n = 10) was associated with particularly dismal 5-year event-free survival (33.3% [95% CI, 11.6–96.1] vs. 83.0% [95% CI, 77.5–88.9] in the other 192 male patients, p < .001) and was an independent risk factor (hazard ratio [HR], 5.7; [95% CI, 2.2–14.5], p < .001).

Conclusions

These data suggest that the presence of positive MRD after intensive remission induction and testicular leukemia at diagnosis are indicators for new molecular therapeutics or immunotherapy in patients with TCF3::PBX1 ALL.     

Parental occupational exposure to pesticides,animals and organic dust and risk of childhood leukemia and central nervous system tumors: Findings from the International Childhood Cancer Cohort Consortium (I4C)

Parental occupational exposures to pesticides, animals and organic dust have been associated with an increased risk of childhood cancer based mostly on case–control studies. We prospectively evaluated parental occupational exposures and risk of childhood leukemia and central nervous system (CNS) tumors in the International Childhood Cancer Cohort Consortium. We pooled data on 329,658 participants from birth cohorts in five countries (Australia, Denmark, Israel, Norway and United Kingdom). Parental occupational exposures during pregnancy were estimated by linking International Standard Classification of Occupations-1988 job codes to the ALOHA+ job exposure matrix. Risk of childhood (<15 years) acute lymphoblastic leukemia (ALL; n = 129), acute myeloid leukemia (AML; n = 31) and CNS tumors (n = 158) was estimated using Cox proportional hazards models to generate hazard ratios (HR) and 95% confidence intervals (CI). Paternal exposures to pesticides and animals were associated with increased risk of childhood AML (herbicides HR = 3.22, 95% CI = 0.97–10.68; insecticides HR = 2.86, 95% CI = 0.99–8.23; animals HR = 3.89, 95% CI = 1.18–12.90), but not ALL or CNS tumors. Paternal exposure to organic dust was positively associated with AML (HR = 2.38 95% CI = 1.12–5.07), inversely associated with ALL (HR = 0.55, 95% CI = 0.31–0.99) and not associated with CNS tumors. Low exposure prevalence precluded evaluation of maternal pesticide and animal exposures; we observed no significant associations with organic dust exposure. This first prospective analysis of pooled birth cohorts and parental occupational exposures provides evidence for paternal agricultural exposures as childhood AML risk factors. The different risks for childhood ALL associated with maternal and paternal organic dust exposures should be investigated further.     

Associations between early-life and in utero infections and cytomegalovirus-positive acute lymphoblastic leukemia in children

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.     

Use of medication during pregnancy and risk of childhood leukemia (Canada)

ObjectiveTo examine risk of childhood acute lymphoblastic leukemia (ALL) associated with maternal use of medications during pregnancy; in particular medications known or suspected to be teratogenic. Methods: Seven hundred and eighty nine children (<15years old) diagnosed with ALL in the province of Québec between 1980 and 2000 were recruited for study. A similar number of population based controls matched to cases (1:1) by sex and age were chosen from family allowance or health insurance files. Information was gathered via telephone interview with the subjects parents. Data were analyzed using conditional logistic regression. Results: Risk of childhood ALL was significantly increased in the offspring of mothers who reported using any medication (adjusted odds ratio (OR_adj)=1.3, 95 CI=1.0–1.6) or any teratogenic medication (OR_adj=1.4, 95 CI=1.1–1.9) during pregnancy. Among specific medication categories, only central nervous system depressants were associated with a significantly increased risk, although elevated odd ratios were found for anti-epileptics, immunosuppressants, oral contraceptives, and illicit drugs. Risk associated with use of teratogenic medications was higher with increased dose and in children diagnosed before two years of age. Conclusion: A modest increase in risk of ALL was found among children of mothers who used medication during pregnancy.     

Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes

Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI = 0.83–2.35), which increased to 2.96 (95% CI = 1.29–6.80) in the presence of a particular TFRC genotype for rs3817672 (Pinteraction = 0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR = 2.54, 95% CI = 1.05–6.12; Pinteraction with ethnicity = 0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR = 1.52–2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR = 2.0 per incremental change, 95% CI = 1.29–3.12; P = 0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.     

Autoimmune conditions and pancreatic cancer risk in older American adults

Pancreatic cancer (PC) is highly fatal, and its incidence is increasing in the United States. Population-based registry studies suggest associations between a few autoimmune conditions and PC risk, albeit based on a relatively small number of cases. We conducted a population-based, nested case-control study to examine the associations between autoimmune conditions and PC risk within the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare population. Incident primary malignant PC cases (n = 80 074) were adults ≥66 years and diagnosed between 1992 and 2015. Controls (n = 320 296) were alive at the time cases were diagnosed and frequency-matched to cases (4:1 ratio) by age, sex, and year of diagnosis. We used multivariable-adjusted, unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 45 autoimmune conditions identified from Medicare claims. Eight autoimmune conditions including ankylosing spondylitis (OR = 1.45; 95% CI: 1.14-1.84), Graves' disease (OR = 1.18; 95% CI: 1.03-1.34), localized scleroderma (OR = 1.27; 95% CI: 1.06-1.52), pernicious anemia (OR = 1.08; 95% CI: 1.02-1.14), primary sclerosing cholangitis (OR = 1.37; 95% CI: 1.18-1.59), pure red cell aplasia (OR = 1.31; 95% CI: 1.16-1.47), type 1 diabetes (OR = 1.11; 95% CI: 1.07-1.15), and ulcerative colitis (OR = 1.18; 95% CI: 1.07-1.31) were associated with increased PC risk (false discovery rate-adjusted P values <.10). In subtype analyses, these conditions were associated with pancreatic ductal adenocarcinoma, whereas only ulcerative colitis was associated with pancreatic neuroendocrine tumors. Our results support the hypothesis that autoimmune conditions may play a role in PC development.     

Maternal residential pesticide use and risk of childhood leukemia in Costa Rica

Evidence suggests that early‐life exposure to pesticides inside the home may be associated with childhood leukemia, however data from Latin American countries are limited. We examined whether self‐reported maternal residential pesticide use and nearby pesticide applications–before and after child's birth–were associated with acute lymphoblastic leukemia (ALL) in the Costa Rican Childhood Leukemia Study (CRCLS), a population‐based case‐control study (2001‐2003). Cases (n = 251 ALL) were diagnosed between 1995 and 2000 (age <15 years at diagnosis) and were identified through the Costa Rican Cancer Registry and National Children's Hospital. Population controls (n = 577) were drawn from the National Birth Registry. We fitted unconditional logistic regression models adjusted for child sex, birth year, and socioeconomic status to estimate the exposure‐outcome associations and also stratified by child sex. We observed that self‐reported maternal insecticide use inside the home in the year before pregnancy, during pregnancy, and while breastfeeding was associated with increased odds of ALL among boys [adjusted Odds Ratio (aOR) = 1.63 (95% confidence interval [95% CI]: 1.05–2.53), 1.75 (1.13–2.73), and 1.75 (1.12–2.73), respectively. We also found evidence of exposure‐response relationships between more frequent maternal insecticide use inside the home and increased odds of ALL among boys and girls combined. Maternal report of pesticide applications on farms or companies near the home during pregnancy and at any time period were also associated with ALL. Our study in Costa Rica highlights the need for education to minimize pesticide exposures inside and around the home, particularly during pregnancy and breastfeeding.     

Risk of childhood leukemia associated with parental smoking and alcohol consumption prior to conception and during pregnancy: the cross-Canada childhood leukemia study

Objective As part of a larger case–control study, the authors evaluated risk of childhood leukemia relative to parental self-reported smoking and alcohol consumption. Methods Children 0–14 years of age diagnosed with leukemia between 1990 and 1994 were ascertained through population-based sources at the time of diagnosis. For each participating case, an age, gender, and area-matched control was randomly selected from provincial government health insurance rolls. Risk factor information was obtained through personal interviews with each child’s parents. Conditional logistic regression models were used to examine risk of leukemia associated with parental smoking and drinking. Results Maternal alcohol consumption prior to conception (OR = 1.37, 95% CI, 0.99–1.90) and during pregnancy (OR = 1.39, 95% CI, 1.01–1.93) was associated with an excess risk of childhood leukemia, with a positive dose-response trend for increasing weekly consumption (p < 0.05). Similar results were observed for children diagnosed with acute lymphoblastic leukemia (ALL). Odds ratios for maternal cigarette smoking before and during pregnancy were consistently elevated above one, but not statistically significant. No relationship was observed with paternal drinking or smoking in the perinatal period. Conclusions Our study suggests that maternal alcohol drinking before or during pregnancy may contribute to an increased risk of childhood leukemia.     

Trends in childhood leukemia incidence over two decades from 1992 to 2013

Incidence rates of childhood leukemia in the United States have steadily increased over the last several decades, but only recently have disparities in the increase in incidence been recognized. In the current analysis, Surveillance, Epidemiology and End Results (SEER) data were used to evaluate recent trends in the incidence of childhood leukemia diagnosed at age 0–19 years from 1992 to 2013, overall and by age, race/ethnicity, gender and histologic subtype. Hispanic White children were more likely than non‐Hispanic White, non‐Hispanic Black or non‐Hispanic Asian children to be diagnosed with acute lymphocytic leukemia (ALL) from 2009 to 2013. From 1992 to 2013, a significant increase in ALL incidence was observed for Hispanic White children [annual percent change (APC)_Hispanic = 1.08, 95% CI: 0.59, 1.58]; no significant increase was observed for non‐Hispanic White, Black or Asian children. ALL incidence increased by about 3% per year from 1992 to 2013 for Hispanic White children diagnosed from 15 to 19 years (APC = 2.67; 95% CI: 0.88, 4.49) and by 2% for those 10–14 years (APC = 2.09; 95% CI: 0.57, 3.63), while no significant increases in incidence were observed in non‐Hispanic White, Black, or Asian children of the same age. Acute myeloid leukemia (AML) incidence increased among non‐Hispanic White children under 1 year at diagnosis, and among Hispanic White children diagnosed at age 1–4. The increase in incidence rates of childhood ALL appears to be driven by rising rates in older Hispanic children (10–14, and 15–19 years). Future studies are needed to evaluate reasons for the increase in ALL among older Hispanic children.     

Examination of gender effect in birth weight and miscarriage associations with childhood cancer (United Kingdom)

Background Higher birth weight and maternal history of miscarriage has been associated with an increased risk of childhood leukemia. The possibility that this association may be sex-specific has not been explored in detail in previous studies. Methods In a retrospective case-control study, 732 childhood (≤14 years) cancer cases from a population-based Registry in Northern England whose hospital birth records could be accessed and 3,723 controls matched for date and hospital of birth to the cases were compared. We examined birth weight for sex-specific associations with childhood cancer. Conditional logistic regression analysis was used for statistical evaluation of associations. Results In acute lymphoblastic leukemia (ALL) (225 cases and 1,163 matched controls), birth weight and sex showed a strong interaction (P = 0.003). In boys with ALL, but not in girls, there was a nonlinear association with birth weight (P for trend = 0.008; OR = 3.05 for the highest quintile compared to the second lowest quintile, 95% CI = 1.40–6.64; P = 0.005). When birth weights were adjusted using UK standards for gestational age and sex, the risk associations were similar in statistical significance and magnitude. Maternal history of miscarriage showed an association with all cancers and individually with ALL. The miscarriage association with ALL was statistically significant in boys only (OR = 1.91, 95% CI = 1.07–3.42; P = 0.03). A multivariable model for ALL containing other examined maternal and reproductive variables confirmed the independence of the birth weight and miscarriage associations. There was no birth weight or miscarriage associations in other cancers. Conclusions This study confirmed the risk associations with birth weight and miscarriages in childhood ALL. Statistically significant association of size at birth suggested marked differences in etiology between girls and boys.     

Maternal Pregnancy Loss,Birth Characteristics,and Childhood Leukemia (United States)

Objective: The authors evaluated the relation between maternal pregnancy loss, birth characteristics, and childhood leukemia in the Northern California Childhood Leukemia Study. Methods: Incident cases of childhood leukemia (age 0–14 years) were rapidly ascertained, and controls were randomly selected from birth records and individually matched to cases. A total of 366 cases [313 acute lymphoblastic leukemia (ALL) and 53 acute myeloid leukemia (AML)] and 460 controls were included in this analysis. The biological mothers of all subjects provided detailed reproductive history and birth characteristics of the index children during a personal interview. Odds ratio (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Data on maternal pregnancy loss and birth characteristics were also available from the birth certificates of 96.3% of all subjects. Results: History of miscarriage was associated with a significantly increased risk of AML (OR = 2.94, 95% CI: 1.03, 8.34), but not ALL. Neither birth weight, birth order, or parental ages appeared to be an important predictor of the risk of ALL or AML. A comparison between data from two different sources (interview versus birth certificate) indicated good reproducibility and offered some evidence against recall bias. Conclusion: Maternal history of miscarriage is associated with an increased risk of childhood AML.     

Lack of association between the hOGG1 Ser326Cys polymorphism and breast cancer risk: evidence from 11 case–control studies

The functional Ser326Cys polymorphism in the human 8-oxogunaine DNA glycosylase (hOGG1) gene has been implicated in breast cancer risk. However, the published findings are inconsistent. We therefore performed a meta-analysis to investigate this relationship. Eleven published case–control studies, including 6,804 breast cancer cases and 6,725 controls were identified. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. Overall, no significant associations between the hOGG1 Ser326Cys polymorphism and breast cancer risk were found for Cys/Cys versus Ser/Ser (OR = 1.07, 95% CI: 0.94–1.20), Ser/Cys versus Ser/Ser (OR = 0.99, 95% CI: 0.91–1.07), Cys/Cys + Ser/Cys versus Ser/Ser (OR = 1.00, 95% CI = 0.93–1.08), and Cys/Cys versus Ser/Cys + Ser/Ser (OR = 1.07, 95% CI: 0.97–1.18). In the stratified analysis by ethnicity, source of controls, and menopausal status, significant associations were still not observed in all genetic models. Taken together, the results suggest that the hOGG1 Ser326Cys polymorphism is not associated with breast cancer risk.     

Birth weight and childhood leukemia: A meta‐analysis and review of the current evidence

A growing body of evidence suggests that childhood leukemia may be initiated in utero when lymphoid and myeloid cells are not fully differentiated and are particularly susceptible to malignant transformation. A fixed effects meta‐analysis examining the association between birth weight and childhood leukemia was conducted including 32 studies and 16,501 cases of all types of leukemia (OL), 10,974 cases of acute lymphoblastic leukemia (ALL), and 1,832 cases of acute myeloid leukemia (AML). The odd ratios (OR) for the association of high birth weight with OL, ALL and AML were 1.35 (95% CI: 1.24, 1.48), 1.23 (95% CI: 1.15, 1.32), and 1.40 (95% CI: 1.11, 1.76), respectively, compared with normal birth weight. Low birth weight was not associated with overall and ALL leukemia, but with AML (OR = 1.50; 95% CI: 1.05, 2.13). Per 1000 g increase in birth weight, the OR for OL was 1.18 (95% CI: 1.13, 1.23) and ALL 1.18 (95% CI: 1.12, 1.23). The combined available evidence from observational studies suggests that high birth weight is associated with an increased risk of overall leukemia and ALL. For AML the risk may be elevated at both high and low extremes of birth weight, suggesting a U‐shaped association. © 2008 Wiley‐Liss, Inc.     

Childcare attendance and risk of childhood acute lymphoblastic leukaemia: A register study based on the Danish childcare database

Childhood acute lymphoblastic leukaemia (ALL) is suggested to result from a dysregulated immune response to infections in children with a preleukaemic state. Childcare in early life supposedly may protect against childhood ALL by facilitating sufficient exposure to infections to stimulate and ensure normal maturation of the immune system. We assessed the association between childcare attendance before age 2 years and risk of childhood ALL in a register-based cohort study, including all children aged 2 to 14 years born in Denmark during 1991 to 2014 with available childcare information recorded in the Danish Childcare Database (n = 1 116 185). Cox regression was used to estimate hazard ratios (HRs) comparing children enrolled in childcare and children not enrolled before age 2 years. Further, we assessed the association according to age at enrolment, type of childcare facility and specific ALL subtypes. During 10 460 811 person-years of follow-up, 460 children developed ALL at ages 2 to 14 years. Of these, 57 (12.4%) never attended childcare before age 2 years compared with 10.6% in the total cohort. Compared with homecare, childcare attendance before age 2 years was associated with a statistically non-significantly, marginally decreased risk of childhood ALL with adjusted HR = 0.87 (95% confidence interval [CI]: 0.65-1.16). Risk estimates did neither vary statistically significantly by age at enrolment nor by type of childcare facility and also not between childhood ALL subtypes, including frequently prenatally initiated ALL subtypes. Results from this large, nationwide register-based study provided no evidence that childcare attendance in the first years of life protects against childhood ALL.     

The prevalence of signs and symptoms of childhood leukemia and lymphoma in Fars Province, Southern Iran

Background: Leukemia and lymphomas are still the common childhood cancers in Iran. This study was undertaken to determine the prevalence of signs and symptoms of these malignancies in children of Fars Province, Southern Iran. Methods: A total of 368 cases of children who were less than 15 years old and diagnosed as acute lymphocytic leukemia (ALL, n = 211), acute myeloid leukemia (AML, n = 64), Burkitt lymphoma (BL, n = 40), chronic myeloid leukemia (CML, n = 5), Hodgkin's disease (HD, n = 33) or non-Burkitt-type, non-Hodgkin's lymphoma (NBNHL, n = 15) referring to the hospitals of Shiraz University of Medical Sciences from April 1997 to March 2002 were enrolled. A questionnaire was provided to record the age, median age at the onset of the disease, sex, type of malignancy and the signs and symptoms at the time of presentation. Results: The common sign or symptoms were fever (74%), in ALL, AML, NHL, and BL patients, hepatosplenomegaly (100%) in CML patients, and lymphadenopathy (54%) and fever (54%) in Hodgkin's disease. Conclusion: Knowledge of signs and symptoms and types of presentations of childhood leukemia and lymphoma may help a physician to improve the patient's outcome. This study revealed that attention to uncommon signs and symptoms in history taking and physical examination together with laboratory tests may increase the physicians’ awareness and better diagnosis of pediatric malignancies and would also be beneficial for the patient.     

TRAIL-R1 polymorphisms and cancer susceptibility: An evidence-based meta-analysis

Published data on the association between tumour necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1 or DR4) polymorphisms rs20575 (C626G), rs2230229 (A1322G) and rs20576 (A683C) and cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of nine studies, among which eight articles including 2941 cases and 3358 controls described C626G genotypes, three articles including 736 cases and 668 controls described A1322G genotypes and three studies totalling 1550 cases and 2257 controls described A683C genotypes were involved in this meta-analysis. Overall, all three polymorphisms were associated with cancer susceptibility. For C626G polymorphism, there was no association between C626G polymorphism and the risk of cancer in all genetic models when all the eligible studies were pooled into the meta-analysis. In the subgroup analysis by source of controls, statistically significantly reduced cancer risks were found among groups with population-based controls for CG versus CC (OR = 0.77, 95% CI:0.65–0.91, P_{heterogeneity} = 0.007) and dominant model (OR = 0.84, 95% CI:0.72–0.99, P_{heterogeneity} = 0.409). For A1322G polymorphism, we found it was associated with a significantly elevated cancer risk of all cancer types in different genetic models (homozygote comparison: OR = 2.80, 95% CI:1.16–6.76, P_{heterogeneity} = 0.905; dominant model comparison: OR = 1.57, 95% CI:1.02–2.41, P_{heterogeneity} = 0.167; and recessive model comparison: OR = 1.22, 95% CI:0.94–1.60, P_{heterogeneity} = 0.535). Similar results were obtained from A683C polymorphism (homozygote comparison: OR = 3.21, 95% CI:1.26–8.20, P_{heterogeneity} = 0.012; dominant model comparison: OR = 1.61, 95% CI: 1.09–2.36, P_{heterogeneity} = 0.000; and recessive model comparison: OR = 2.79, 95% CI: 1.17–6.68, P_{heterogeneity} = 0.025). In summary, this meta-analysis suggests that TRAIL-R1 C626G polymorphism is marginally associated with cancer susceptibility, and both TRAIL-R1 A1322G G allele and A683C C allele are associated with increased risk for cancer.     

SARS-CoV-2 infection in patients with chronic lymphocytic leukemia: The Italian Hematology Alliance on COVID-19 cohort

COVID-19, the disease caused by SARS-CoV-2, is still afflicting thousands of people across the globe. Few studies on COVID-19 in chronic lymphocytic leukemia (CLL) are available. Here, we analyzed data from the CLL cohort of the Italian Hematology Alliance on COVID-19 (NCT04352556), which included 256 CLL patients enrolled between 25 February 2020 and 1 February 2021. Median age was 70 years (range 38–94) with male preponderance (60.1%). Approximately half of patients (n = 127) had received at least one line of therapy for CLL, including 108 (83.7%) who were on active treatment at the time of COVID-19 or received their last therapy within 12 months. Most patients (230/256, 89.9%) were symptomatic at COVID-19 diagnosis and the majority required hospitalization (n = 176). Overall, after a median follow-up of 42 days (IQR 24–96), case fatality rate was 30.1%, and it was 37.5% and 24.4% in the first (25 February 2020–22 June 2020) and second wave (23 June 2020–1 February 2021), respectively (p = 0.03). At multivariate analysis, male sex (HR 1.82, 95% CI 1.03–3.24, p = 0.04), age over than 70 years (HR 2.23, 95% CI 1.23–4.05, p = 0.01), any treatment for CLL given in the last 12 months (HR 1.72, 95% CI 1.04–2.84, p = 0.04) and COVID-19 severity (severe: HR 5.66, 95% CI 2.62–12.33, p < 0.0001; critical: HR 15.99, 95% CI 6.93–36.90, p < 0.0001) were independently associated with poor survival. In summary, we report a dismal COVID-related outcome in a significant fraction of CLL patients, that can be nicely predicted by clinical parameters.     

Extremely low-frequency magnetic fields and survival from childhood acute lymphoblastic leukemia: an international follow-up study

A previous US study reported poorer survival in children with acute lymphoblastic leukemia (ALL) exposed to extremely low-frequency magnetic fields (ELF–MF) above 0.3 μT, but based on small numbers. Data from 3073 cases of childhood ALL were pooled from prospective studies conducted in Canada, Denmark, Germany, Japan, UK and US to determine death or relapse up to 10 years from diagnosis. Adjusting for known prognostic factors, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival and event-free survival for ELF–MF exposure categories and by 0.1 μT increases. The HRs by 0.1 μT increases were 1.00 (CI, 0.93–1.07) for event-free survival analysis and 1.04 (CI, 0.97–1.11) for overall survival. ALL cases exposed to >0.3 μT did not have a poorer event-free survival (HR=0.76; CI, 0.44–1.33) or overall survival (HR=0.96; CI, 0.49–1.89). HRs varied little by subtype of ALL. In conclusion, ELF–MF exposure has no impact on the survival probability or risk of relapse in children with ALL.     

Allergic Disorders and the Risk of Childhood Acute Lymphoblastic Leukemia (United States)

Objectives: To test the hypothesis that childhood acute lymphoblastic leukemia (ALL) is associated with allergic disorders. Methods: We compared the histories of selected allergic disorders (asthma, hay fever, food or drug allergies, eczema, and hives) of 1842 cases of ALL with those of 1986 individually matched controls. The histories of the allergic disorders among siblings of cases and controls were also compared. Results: The combined history of any one or more of the five allergic disorders evaluated was associated with a significant reduced risk of ALL (adjusted OR = 0.7, 95% CI 0.6–0.8), as were hhistories of four specific allergic disorders (asthma, hay fever, food or drug allergies, and eczema). The combined history of any one or more of the five allergic disorders among any of the siblings of the study subjects also revealed a significantly inverse association (adjusted OR = 0.9, 95% CI 0.8–1.0). Conclusion: The results from this study, in agreement with most previous studies on adult cancer, suggest that allergic disorders may be associated with a reduced risk of childhood ALL.