The Effect of Atorvastatin on Vascular Function and Structure in Young Adult Survivors of Childhood Cancer: A Randomized, Placebo-Controlled Pilot Clinical Trial.

Purpose: Many adult survivors of childhood cancer are at high-risk of developing cardiovascular disease. Cancer therapy may cause damage to the vascular endothelium, thereby initiating atherosclerosis. Atorvastatin has been shown to improve endothelial function independent of reducing cholesterol, as well as reduce/slow arterial stiffness and thickening, yet has never been studied in childhood cancer survivors (CCS). Methods: Twenty-seven young adult (age 26.8 ± 6.2 years) survivors of childhood acute lymphoblastic leukemia or Non-Hodgkin's lymphoma were randomly assigned (1:1) 40 mg/day of atorvastatin or placebo for 6 months. Brachial artery flow-mediated dilation (FMD), small artery reactive hyperemia index (RHI), arterial stiffness, and carotid artery elasticity/thickness were assessed. Results: Fifteen participants completed the trial. No significant treatment effect for any vascular outcomes was observed at 6 months; however, a significant decrease in peak FMD (-3.0 [95% confidence interval [CI]: -5.3, -0.7]) and a trending significant decrease in RHI (-0.3 [95% CI: -0.62, 0.01]) was observed in the placebo group, resulting in a trend toward a treatment effects (p < 0.10). No effect on arterial stiffness, carotid arterial elasticity, or thickness was observed. Conclusion: Six months of atorvastatin treatment did not improve endothelial function or arterial stiffness in young adult CCS. While a trend toward an improvement in endothelial function was present, findings should be interpreted with caution owing to the small number of evaluable participants and subsequent lack of sufficient power. Further research in a larger sample size is needed to fully elucidate the effects of atorvastatin on vascular function. Trial registered at clinicaltrials.gov as NCT01733953.

Association between mitochondrial DNA haplogroup and myelodysplastic syndromes.

Polymorphisms in mitochondrial DNA (mtDNA) are used to group individuals into haplogroups reflecting human global migration and are associated with multiple diseases, including cancer. Here, we evaluate the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non-Hispanic whites. We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation. We used SAS v.9.3 (SAS Institute, Cary, NC) to calculate odds ratios (OR) and 95% confidence intervals (CI) overall and stratified by MDS subtype and IPSS-R risk category. We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H + V), JT (J + T), IWX (I + W + X), UK (U + K), and Z for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR = 0.58, 95% CI 0.36, 0.92, P = 0.02). No statistically significant heterogeneity was observed in subgroup analyses. In this population-based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. While previously published studies provide biological plausibility for the observed association, further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. © 2016 Wiley Periodicals, Inc.

Obesity over the life course and risk of acute myeloid leukemia and myelodysplastic syndromes.

BACKGROUND: Overweight and obesity are known risk factors for a number of cancers, with recent evidence suggesting that risk of hematologic cancer is also increased in obese individuals. We evaluated associations between body mass index (BMI) at differing time points during the life course in population-based case control studies of acute myeloid leukemia (AML) and myelodysplatic syndromes (MDS). METHODS: Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. BMI was calculated using self-reported height and weight at ages 18, 35, and 50 years and two years prior to interview, and categorized as normal (18.5-25 kg/m(2)), overweight (25-29.9 kg/m(2)), obese class I (30-34.9 kg/m(2)), and obese class II/III (35+ kg/m(2)). All analyses were stratified by sex. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: We included 420 AML cases, 265 MDS cases and 1388 controls. Obesity two years prior to diagnosis was associated with AML in both males and females (OR=2.22, 95% CI 1.28, 3.85 and OR=1.85, 95% CI 1.08, 3.15 for BMI≥35 vs. BMI 18.5-24.9, respectively). In contrast, associations between obesity and MDS were observed only in females. Weight change in adulthood was not consistently associated with either outcome. CONCLUSION: Our results extend the emerging literature suggesting that obesity is a risk factor for hematologic malignancy and provide evidence that that the association remains regardless of timing of obesity. Obesity in adulthood is a modifiable risk factor for both MDS and AML.

Hormonal and Reproductive Factors and Risk of Myeloproliferative Neoplasms in Postmenopausal Women.

BACKGROUND: Hormonal and reproductive history has been associated with risk of some hematologic malignancies, but their role in myeloproliferative neoplasms (MPN) is largely unknown. METHODS: Using a population-based cohort study, we evaluated the association of these factors with risk of MPN overall, and for essential thrombocythemia (ET) and polycythemia vera (PV) specifically. Incident MPN cases from 1993 to 2004 were identified via linkage to Medicare. RR and 95% confidence intervals (CI) were estimated utilizing Cox proportional hazard regression. RESULTS: After >250,000 person-years of follow-up, 257 cases of MPN were identified (172 ET, 64 PV). Ever use of hormone therapy (HT) was associated with an increased risk of ET (RR = 1.63; 95% CI, 1.19-2.23) but a decreased risk of PV (RR = 0.58; 95% CI, 0.34-0.98). There were no statistically significant associations of oral contraceptives or reproductive factors with MPN risk overall, or by MPN subtype. Bilateral oophorectomy was associated with increased risk of ET (RR = 1.58; 95% CI, 1.11-2.25) and decreased risk of PV (RR = 0.32; 95% CI, 0.12-0.88). There was no association of ovulatory years with ET risk; however, there was increased risk of PV (RR = 1.68 for >36.8 compared with ≤27.6 years; P trend = 0.045). Adjustment for potential confounding factors did not alter these associations. CONCLUSIONS: HT use and bilateral oophorectomy had opposite associations for ET and PV. Except for ovulatory years and PV risk, reproductive history did not appear to play a role in the etiology of MPN. IMPACT: This study suggests different mechanistic impacts of estrogen, and perhaps distinct etiologies, for the two major MPN subtypes.

Active transportation in adult survivors of childhood cancer and neighborhood controls.

PURPOSE: Childhood cancer survivors (CCS) are at high risk of treatment-related late effects, including cardiovascular disease and diabetes, which can be exacerbated by inadequate physical activity (PA). Previous PA interventions targeting CCS have focused on the domain of leisure-time/recreational PA. Active transportation, another domain of PA, has not been described in CCS. Therefore, this study aimed to identify active transportation behaviors, barriers, and correlates in adult CCS. METHODS: We recruited 158 adult CCS and 153 controls matched on age, sex, and neighborhood for a survey regarding active transportation behaviors and perceptions. Linear and logistic regression models accounting for correlation among matched participants were used. RESULTS: Adult CCS engaged in similar levels of active transportation as controls (2.72 vs. 2.32 h/week, P = 0.40) despite perceiving greater health-related barriers (1.88 vs. 1.65 (measured on four-point Likert scale), P = 0.01). Marital/relationship status (odds ratio (OR) = 0.30, 95 % confidence interval (CI) = 0.11-0.81), planning/psychosocial barriers (OR = 0.15, 95 % CI = 0.04-0.53), and perceived neighborhood walkability (OR = 2.55, 95 % CI = 1.14-5.66) were correlates of active transportation among adult CCS, while objective neighborhood walkability (OR = 1.03, 95 % CI = 1.01-1.05) was a correlate among controls. CONCLUSIONS: Results suggest adult CCS and controls utilize active transportation at approximately equal levels. Factors other than health, including perceived neighborhood walkability, are related to active transportation behaviors to a greater degree in adult CCS. IMPLICATIONS FOR CANCER SURVIVORS: Interventions might consider promoting active transportation as a way to incorporate more PA into the daily lives of adult CCS. Such interventions will not be likely successful, however, without existing or improved neighborhood walkability/bikeability.

Cross platform analysis of methylation, miRNA and stem cell gene expression data in germ cell tumors highlights characteristic differences by tumor histology.

BACKGROUND: Alterations in methylation patterns, miRNA expression, and stem cell protein expression occur in germ cell tumors (GCTs). Our goal is to integrate molecular data across platforms to identify molecular signatures in the three main histologic subtypes of Type I and Type II GCTs (yolk sac tumor (YST), germinoma, and teratoma). METHODS: We included 39 GCTs and 7 paired adjacent tissue samples in the current analysis. Molecular data available for analysis include DNA methylation data (Illumina GoldenGate Cancer Methylation Panel I), miRNA expression (NanoString nCounter miRNA platform), and stem cell factor expression (SABiosciences Human Embryonic Stem Cell Array). We evaluated the cross platform correlations of the data features using the Maximum Information Coefficient (MIC). RESULTS: In analyses of individual datasets, differences were observed by tumor histology. Germinomas had higher expression of transcription factors maintaining stemness, while YSTs had higher expression of cytokines, endoderm and endothelial markers. We also observed differences in miRNA expression, with miR-371-5p, miR-122, miR-302a, miR-302d, and miR-373 showing elevated expression in one or more histologic subtypes. Using the MIC, we identified correlations across the data features, including six major hubs with higher expression in YST (LEFTY1, LEFTY2, miR302b, miR302a, miR 126, and miR 122) compared with other GCT. CONCLUSIONS: While prognosis for GCTs is overall favorable, many patients experience resistance to chemotherapy, relapse and/or long term adverse health effects following treatment. Targeted therapies, based on integrated analyses of molecular tumor data such as that presented here, may provide a way to secure high cure rates while reducing unintended health consequences.

Factors associated with hematopoietic cell transplantation (HCT) among patients in a population-based study of myelodysplastic syndrome (MDS) in Minnesota.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective erythropoiesis, and an increased risk of developing acute myeloid leukemia. Treatment planning for patients with MDS is a complex process, and we sought to better characterize hematopoietic cell transplantation (HCT) outcomes and the factors that play into decision-making regarding referral of adults with MDS for definitive therapy with HCT. Patients enrolled in a population-based study of MDS between April 2010 and January 2013 who underwent HCT within the first year after enrollment were included in this analysis. Age- and risk-matched MDS patient controls also enrolled during that time period were used as a comparison. Survival was significantly better in the HCT group (48 vs. 21 %, log-rank p value 0.009). Non-HCT patients were more likely to have comorbidities, and HCT patients were more likely to have a college degree and an income >$80,000. All three of these variables were independently associated with HCT, but none impacted survival. Patients with MDS in our study who underwent HCT had better survival than a comparable group of patients who did not undergo HCT. With refined treatment techniques, more patients may be able to be considered for this therapy. More work needs to be done to determine why education and income appear to impact the decision to pursue HCT, but these factors may impact referral to an academic center where aggressive therapy like HCT is more likely to be considered.

Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children's Oncology Group study.

Family history of lymphoid neoplasm (LN) is a strong and consistently observed Hodgkin lymphoma (HL) risk factor, although it has been only marginally examined in pediatric/adolescent patients. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL cases diagnosed at 0-14 years at Children's Oncology Group institutions in 1989-2003. Detailed histories were captured by structured telephone interviews with parents of 517 cases and 783 controls. Epstein-Barr virus (EBV) RNA detection was performed for 355 available case tumors. Two analytic strategies were applied to estimate associations between family cancer history and pediatric/adolescent HL. In a standard case-control approach, multivariate conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). In a reconstructed cohort approach, each relative was included as a separate observation, and multivariate proportional hazards regression was used to produce hazard ratios (HRs) and 95% CIs. Using the latter, pediatric/adolescent HL was associated with a positive family history (HR = 1.20, 95% CI: 1.06-1.36), particularly early-onset cancers (HR = 1.30, 95% CI: 1.06-1.59) and those in the paternal lineage (HR = 1.38, 95% CI: 1.16-1.65), with a suggested association for LN in first-degree relatives (HR = 3.61, 95% CI: 0.87-15.01). There were no discernable patterns for EBV+ versus EBV- HL. The clustering of LN within pedigrees may signal shared genetic susceptibility or common environmental exposures. Heritable genetic risk variants have only recently begun to be discovered, however. These results are consistent with other studies and provide a compelling rationale for family-based studies to garner information about genetic susceptibility to HL.

Physical Activity, Fitness, and Cardiometabolic Risk Factors in Adult Survivors of Childhood Cancer with a History of Hematopoietic Cell Transplantation.

Along with other childhood cancer survivors (CCS), hematopoietic cell transplantation (HCT) survivors are at high risk of treatment-related late effects, including cardiovascular disease and diabetes. Cardiometabolic risk factor abnormalities may be exacerbated by inadequate physical activity (PA). Relationships between PA and cardiometabolic risk factors have not been well described in CCS with HCT. PA (self reported), mobility (timed up and go test), endurance (6-minute walk test), handgrip strength, and cardiometabolic risk factors were measured in 119 HCT survivors and 66 sibling controls ages ≥18 years. Adjusted comparisons between HCT survivors and controls and between categories of low and high PA, mobility, endurance, and strength were performed with linear regression. Among HCT survivors, the high PA group had lower waist circumference (WC) (81.9 ± 2.5 versus 88.6 ± 3.1 cm ± standard error (SE), P = .009) than the low PA group, whereas the high endurance group had lower WC (77.8 ± 2.6 versus 87.8 ± 2.5 cm ± SE, P = .0001) and percent fat mass (33.6 ± 1.8 versus 39.4 ± 1.7% ± SE, P = .0008) and greater insulin sensitivity (IS) (10.9 ± 1.0 versus 7.42 ± 1.14 mg/kg/min ± SE via euglycemic insulin clamp, P = .001) than the low endurance group. Differences were greater in HCT survivors than in controls for WC between low and high PA groups, triglycerides between low and high mobility groups, and WC, systolic blood pressure, and IS between low and high endurance groups (all Pinteraction <.05). Higher endurance was associated with a more favorable cardiometabolic profile in HCT survivors, suggesting that interventions directed to increase endurance in survivors may reduce the risk of future cardiovascular disease.

Differences in community and academic practice patterns for newly diagnosed myelodysplastic syndromes (MDS) patients.

PURPOSE: The heterogeneous nature of myelodysplastic syndromes (MDS) complicates therapeutic decision making, particularly for newly diagnosed disease. Factors impacting the treatment plan in this early period of disease course are poorly defined. This study determines whether therapeutic choices for newly diagnosed MDS are associated with location of treatment (community or academic), prognostic risk category, and patient age. METHODS: The adults in Minnesota with myelodysplastic syndromes (AIMMS) database was utilized in this statewide, prospective population-based study conducted by the University of Minnesota (UMN), Mayo Clinic, and Minnesota Department of Health. Adult (age 20+ years) cases of MDS newly diagnosed starting in April 2010 were invited to participate. This analysis includes patients enrolled during the first study year with 1-year follow-up data. Treatment choices (supportive, active, and transplant) were stratified by the international prognostic scoring system (IPSS) and the revised-IPSS (IPSS-R), then separated into groups by location of care and age (<65 or 65+ years). Academic-based care was any contact with the UMN and Mayo Clinic; community-based care was all other clinical sites. RESULTS: Stratification by IPSS and IPSS-R showed supportive care decreased and active care increased with advancing risk categories (p<0.0001). Comparing treatment setting, community-based care had 77% supportive and 23% active treatment; academic-based care was 36% supportive, 41% active, and 23% transplant (p<0.0001). By age groups, patients <65 years with intermediate, high, or very high risk disease by IPSS-R received 97% active care/transplant, compared to only 52% of patients age 65+. CONCLUSIONS: Younger patients and those treated at academic centers had a more aggressive treatment approach. Whether these treatment differences convey improved disease control and mortality, and therefore should be extended more frequently to older and community-based patients, is the subject of ongoing prospective study.

An exploratory analysis of mitochondrial haplotypes and allogeneic hematopoietic cell transplantation outcomes.

Certain mitochondrial haplotypes (mthaps) are associated with disease, possibly through differences in oxidative phosphorylation and/or immunosurveillance. We explored whether mthaps are associated with allogeneic hematopoietic cell transplantation (HCT) outcomes. Recipient (n = 437) and donor (n = 327) DNA were genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, and K2). HCT outcomes for mthap matched siblings (n = 198), all recipients, and all donors were modeled using relative risks (RR) and 95% confidence intervals and compared with mthap H, the most common mitochondrial haplotypes. Siblings with I and V were significantly more likely to die within 5 years (RR = 3.0; 95% confidence interval [CI], 1.2 to 7.9; and RR = 4.6; 95% CI, 1.8 to 12.3, respectively). W siblings experienced higher acute graft-versus-host disease (GVHD) grades II to IV events (RR = 2.1; 95% CI, 1.1 to 2.4) with no events for those with K or K2. Similar results were observed for all recipients combined, although J recipients experienced lower GVHD and higher relapse. Patients with I donors had a 2.7-fold (1.2 to 6.2) increased risk of death in 5 years, whereas few patients with K2 or W donors died. No patients with K2 donors and few patients with U donors relapsed. Mthap may be an important consideration in HCT outcomes, although validation and functional studies are needed. If confirmed, it may be feasible to select donors based on mthap to increase positive or decrease negative outcomes.

Physical activity and cardiovascular risk factors in childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCS) are at high risk of developing treatment-related late effects, including cardiovascular disease and diabetes. Late effects can be exacerbated by low physical activity (PA) levels. Relationships between PA and cardiovascular risk factors during childhood have not been well described in CCS. PROCEDURE: PA and cardiovascular risk factors were measured cross-sectionally in 319 CCS and 208 sibling controls aged 9-18 years. Comparisons between CCS and controls and associations of outcomes with PA (dichotomized at 60 min/day or treated as continuous) were performed with linear regression. RESULTS: Among CCS, the high PA group had lower percent fat mass (24.4% vs. 29.8%, P < 0.0001), abdominal subcutaneous fat (67.9 vs. 97.3 cm3 , P = 0.0004), and abdominal visceral fat (20.0 vs. 24.9 cm3 , P = 0.007) and greater lean body mass (41.3 vs. 39.5 kg, P = 0.009) than the low PA group. Comparing CCS to controls, differences in waist circumference (Pinteraction = 0.04), percent fat mass (Pinteraction = 0.04), and abdominal subcutaneous (Pinteraction = 0.02) and visceral (Pinteraction = 0.004) fat between low and high PA groups were greater in CCS than controls, possibly due to greater overall adiposity in CCS. CONCLUSIONS: High PA in CCS resulted in an improved cardiovascular profile, consisting primarily of lower fat mass and greater lean mass, similar to that observed in controls. This suggests interventions directed to increase PA in CCS may reduce the risk of future cardiovascular disease. Pediatr Blood Cancer 2015;62:305-310. © 2014 Wiley Periodicals, Inc.

Immune-related conditions and acute leukemia in children with Down syndrome: a Children's Oncology Group report.

BACKGROUND: Children with Down syndrome have unique immune profiles and increased leukemia susceptibility. METHODS: Mothers of 158 children with Down syndrome diagnosed with acute leukemia at 0 to 19 years in 1997 to 2002 and 173 children with Down syndrome but no leukemia were interviewed. Associations were evaluated via multivariable unconditional logistic regression. RESULTS: No associations were detected for asthma, eczema, allergies, or hypothyroidism. Diabetes mellitus associated with leukemia (OR = 9.23; 95% confidence interval 2.33-36.59); however, most instances occurred concurrent with or after the leukemia diagnosis. CONCLUSIONS AND IMPACT: Children with Down syndrome who develop leukemia have increased diabetes risk, likely due to treatment and underlying susceptibility factors.

Feasibility and preliminary efficacy of the effects of flavanoid-rich purple grape juice on the vascular health of childhood cancer survivors: a randomized, controlled crossover trial.

BACKGROUND: Childhood cancer survivors have an increased risk of developing cardiovascular disease following treatment, yet few interventions have been evaluated to reduce this risk. Purple grape juice (pGJ), a rich source of flavonoids with antioxidant properties, has been shown in adults to reduce oxidative stress and improve endothelial function. We examined the effects of supplementing meals with pGJ on microvascular endothelial function and markers of oxidative stress and inflammation in 24 cancer survivors (ages 10-21 years). PROCEDURE: In a randomized controlled crossover trial consisting of two, 4 week intervention periods, each preceded by a 4 week washout period, subjects received in random order 6 ounces twice daily of pGJ and clear apple juice (cAJ; similar in calories but lower in flavonoids). Measurements were obtained before and after each supplementation period; change was evaluated using mixed effects ANOVA. RESULTS: pGJ did not improve endothelial function, measured using digital reactive hyperemia, compared with cAJ (mean change: pGJ 0.06, cAJ 0.22; difference of mean change [95% CI]: -0.16 [-0.42 - 0.11], P = 0.25). No significant changes in plasma concentrations of oxidized-LDL, myeloperoxidase, or high sensitivity C-reactive protein were observed. CONCLUSION: After 4 weeks of daily consumption of flavonoid-rich pGJ, no measurable change in vascular function was observed in these childhood cancer survivors.

Incidence of intracranial germ cell tumors by race in the United States, 1992-2010.

Little is known about the etiology of intracranial germ cell tumors (iGCTs), although international incidence data suggest that the highest incidence rates occur in Asian countries. In this analysis, we used 1992-2010 data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program to determine whether rates of iGCT were also high in Asian/Pacific Islanders living in the United States. Frequencies, incidence rates and survival rates were evaluated for the entire cohort and for demographic subgroups based on sex, age category (0-9 and 10-29 years), race (white, black, and Asian/Pacific Islander), and tumor location (pineal gland vs. other) as sample size permitted. Analyses were conducted using SEER*Stat 8.1.2. We observed a significantly higher incidence rate of iGCT in Asian/Pacific Islanders compared with whites (RR = 2.05, 95 % CI 1.57-2.64, RR = 3.04, 95 % CI 1.75-5.12 for males and females, respectively) in the 10-29 year age group. This difference was observed for tumors located both in the pineal gland and for tumors in other locations. Five-year relative survival differed by demographic and tumor characteristics, although these differences were not observed in comparisons limited to cases treated with radiation. Increased incidence rates of iGCT in individuals of Asian descent in the SEER registry are in agreement with data from the International Agency for Research on Cancer, where Japan and Singapore were among the countries with highest incidence. The increased incidence in individuals of Asian ancestry in the United States suggests that underlying genetic susceptibility may play a role in the etiology of iGCT.

Neonatal medical exposures and characteristics of low birth weight hepatoblastoma cases: a report from the Children's Oncology Group.

BACKGROUND: Hepatoblastoma is a malignancy of young children. Low birth weight is associated with significantly increased risk of hepatoblastoma and neonatal medical exposures are hypothesized as contributors. This study represents the largest case-control study of hepatoblastoma to date and aimed to define the role of neonatal exposures in hepatoblastoma risk among low birth weight children. PROCEDURE: Incident hepatoblastoma cases who were born <2,500 g (N = 60), diagnosed between 2000 and 2008, were identified through the Children's Oncology Group. Controls were recruited through state birth registries (N = 51). Neonatal medical exposures were abstracted from medical records. Subjects from the Vermont Oxford Network were used for further comparisons, as were existing reports on neonatal medical exposures. RESULTS: Case-control comparisons were hindered by poor matching within birth weight strata. Cases were smaller and received more aggressive neonatal treatment compared to controls, and reflected high correlation levels between birth weight and treatments. Similar difficulty was encountered when comparing cases to Vermont Oxford Network subjects; cases were smaller and required more aggressive neonatal therapy. Furthermore, it appears hepatoblastoma cases were exposed to a greater number of diagnostic X-rays than in case series previously reported in the neonatal literature. CONCLUSIONS: This study presents the largest case series of hepatoblastoma in <2,500 g birth weight infants with accompanying neonatal medical exposure data. Findings confirm that birth weight is highly correlated with exposure intensity, and neonatal exposures are themselves highly correlated, which hampers the identification of a causal exposure among hepatoblastoma cases. Experimental models or genetic susceptibility testing may be more revealing of etiology.

Farm residence and lymphohematopoietic cancers in the Iowa Women's Health Study.

BACKGROUND: Cancer incidence in male farmers has been studied extensively; however, less is known about risk among women residing on farms or in agricultural areas, who may be exposed to pesticides by their proximity to crop fields. We extended a previous follow-up of the Iowa Women's Health Study cohort to examine farm residence and the incidence of lymphohematopoietic cancers. Further, we investigated crop acreage within 750 m of residences, which has been associated with higher herbicide levels in Iowa homes. METHODS: We analyzed data for a cohort of 37,099 Iowa women aged 55-69 years who reported their residence location (farm, rural (not a farm), town size based on population) at enrollment in 1986. We identified incident lymphohematopoietic cancers (1986-2009) by linkage with the Iowa Cancer Registry. Using a geographic information system, we geocoded addresses and calculated acreage of pasture and row crops within 750 m of homes using the 1992 National Land Cover Database. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariate analyses of cancer risk in relation to both residence location and crop acreage. RESULTS: As found in an earlier analysis of residence location, risk of acute myeloid leukemia (AML) was higher among women living on farms (HR=2.23, 95%CI: 1.25-3.99) or rural areas (but not on a farm) (HR=1.95, 95%CI: 0.89-4.29) compared with women living in towns of >10,000 population. We observed no association between farm or rural residence and non-Hodgkin lymphoma (NHL; overall or for major subtypes) or multiple myeloma. In analyses of crop acreage, we observed no association between pasture or row crop acreage within 750 m of homes and risk of leukemia overall or for the AML subtype. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) risk was nonsignificantly elevated among women with pasture acreage within 750 m of their home (HRs for increasing tertiles=1.8, 1.8 and 1.5) and with row crop acreage within 750 m (HRs for increasing tertiles of acreage=1.4, 1.5 and 1.6) compared to women with no pasture or row crop acreage, respectively. CONCLUSIONS: Iowa women living on a farm or in a rural area were at increased risk of developing AML, which was not related to crop acreage near the home. Living near pasture or row crops may confer an increased risk of CLL/SLL regardless of residence location. Further investigation of specific farm-related exposures and these cancers among women living on farms and in agricultural areas is warranted.

The Children's Oncology Group Childhood Cancer Research Network (CCRN): case catchment in the United States.

BACKGROUND: The Childhood Cancer Research Network (CCRN) was established within the Children's Oncology Group (COG) in July 2008 to provide a centralized pediatric cancer research registry for investigators conducting approved etiologic and survivorship studies. The authors conducted an ecological analysis to characterize CCRN catchment at >200 COG institutions by demographic characteristics, diagnosis, and geographic location to determine whether the CCRN can serve as a population-based registry for childhood cancer. METHODS: During 2009 to 2011, 18,580 US children newly diagnosed with cancer were registered in the CCRN. These observed cases were compared with age-specific, sex-specific, and race/ethnicity-specific expected numbers calculated from Surveillance, Epidemiology, and End Results (SEER) Program cancer incidence rates and 2010 US Census data. RESULTS: Overall, 42% of children (18,580 observed/44,267 expected) who were diagnosed with cancer at age <20 years were registered in the CCRN, including 45%, 57%, 51%, 44%, and 24% of those diagnosed at birth, ages 1 to 4 years, ages 5 to 9 years, ages 10 to 14 years, and ages 15 to 19 years, respectively. Some malignancies were better represented in the CCRN (leukemia, 59%; renal tumors, 67%) than others (retinoblastoma, 34%). There was little evidence of differences by sex or race/ethnicity, although rates in nonwhites were somewhat lower than rates in whites. CONCLUSIONS: Given the low observed-to-expected ratio, it will be important to identify challenges and barriers to registration to improve case ascertainment, especially for rarer diagnoses and older age groups; however, it is encouraging that some diagnoses in younger children are fairly representative of the population. Overall, the CCRN is providing centralized, real-time access to cases for research and could be used as a model for other national cooperative groups.

Allergic diseases and risk of hematopoietic malignancies in a cohort of postmenopausal women: a report from the Iowa Women's Health Study.

BACKGROUND: Allergic diseases signify immune dysregulation attributable to underlying genetics and environmental exposures. Associations between various allergies and hematopoietic cancers have been observed, albeit inconsistently; however, few prospective studies have examined the risk, and even fewer among older adults. METHODS: We examined risk of incident hematopoietic cancers in those reporting allergic diseases in a population-based cohort of 22,601 older women (Iowa Women's Health Study). Self-reported allergic status, including asthma, hay fever, eczema, and/or other allergies, was determined via questionnaire in 1997 (mean age, 72 years; range, 63-81 years). Incident cancers were ascertained by linkage with the Iowa Cancer Registry from 1997 to 2011. Cox proportional hazards regression was performed to estimate multivariate-adjusted HR and 95% confidence intervals (CI) for myeloid (N = 177) and lymphoid (N = 437) malignancies, respectively. RESULTS: Allergic diseases were not associated with risk of myeloid (HR, 1.00; 95% CI, 0.72-1.37) or lymphoid (HR, 0.99; 95% CI, 0.81-1.22) malignancies overall, or for most allergic and malignant subtypes examined. Self-reported asthma was positively associated with development of myelodysplastic syndrome (MDS; HR, 2.00; 95% CI, 0.93-4.32). In addition, there was a 30% to 40% decrease in risk of both lymphoid and myeloid cancers in those reporting rural residences but no association in those reporting urban residences; the interaction between residence and allergy was statistically significant for lymphoid malignancies (Pinteraction = 0.05). CONCLUSIONS AND IMPACT: These results suggest that asthma may contribute to the pathogenesis of MDS, a finding consistent with the chronic antigen stimulation hypothesis. Susceptibility differences by location of residence are concordant with the hygiene hypothesis and merit additional exploration.

CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets.

Myelodysplastic syndromes (MDS) are stem cell disorders that can progress to acute myeloid leukemia. Although hematopoietic cell transplantation can be curative, additional therapies are needed for a disease that disproportionally afflicts the elderly. We tested the ability of a CD16xCD33 BiKE to induce natural killer (NK) cell function in 67 MDS patients. Compared with age-matched normal controls, CD7(+) lymphocytes, NK cells, and CD16 expression were markedly decreased in MDS patients. Despite this, reverse antibody-dependent cell-mediated cytotoxicity assays showed potent degranulation and cytokine production when resting MDS-NK cells were triggered with an agonistic CD16 monoclonal antibody. Blood and marrow MDS-NK cells treated with bispecific killer cell engager (BiKE) significantly enhanced degranulation and tumor necrosis factor-α and interferon-γ production against HL-60 and endogenous CD33(+) MDS targets. MDS patients had a significantly increased proportion of immunosuppressive CD33(+) myeloid-derived suppressor cells (MDSCs) that negatively correlated with MDS lymphocyte populations and CD16 loss on NK cells. Treatment with the CD16xCD33 BiKE successfully reversed MDSC immunosuppression of NK cells and induced MDSC target cell lysis. Lastly, the BiKE induced optimal MDS-NK cell function irrespective of disease stage. Our data suggest that the CD16xCD33 BiKE functions against both CD33(+) MDS and MDSC targets and may be therapeutically beneficial for MDS patients.