Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal.

BACKGROUND: Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. METHODS: In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. RESULTS: A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. CONCLUSIONS: As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

Investigation of a Common Clinical Approach to Poor Growth in Preterm Infants.

OBJECTIVE: This study aimed to determine the effect of elevated energy intake with medium-chain triglyceride (MCT) oil or formula powder on growth velocity and weight z-score in very low birth weight infants receiving human milk and human milk fortifier. STUDY DESIGN: This was a cohort study of infants exposed to MCT oil or formula powder for at least 7 days. Mean 7-day change in growth velocity and weight z-scores were compared pre- and postintervention. RESULTS: Forty-three infants received increased energy with either MCT oil or formula powder. Infants receiving MCT oil were more preterm and had a lower birth weight. When evaluating 7-day changes pre- and postintervention, growth velocity increased from 10.0 g/kg/day to 19.8 g/kg/day, and change in weight Z-score increased from -0.24 to 0.05. CONCLUSION: This clinical approach using MCT oil or formula powder for additional energy was associated with improved, at least short-term, growth velocity and weight z-score trajectory.

Acute Kidney Injury Guidelines Are Associated With Improved Recognition and Follow-up for Neonatal Patients.

BACKGROUND: Studies demonstrate that neonatal acute kidney injury (AKI) is associated with increased morbidity and mortality. Acute kidney injury survivors are at risk for renal dysfunction and chronic kidney disease and require long-term follow-up. PURPOSE: To maximize identification of AKI and ensure referral, we created guidelines for diagnosis, evaluation, and management of AKI. METHODS/SEARCH STRATEGY: Retrospective cohort study of neonatal intensive care unit patients treated before guideline implementation (cohort 1; n = 175) and after (cohort 2; n = 52). Outcome measures included AKI incidence, documented diagnosis, and pediatric nephrology consultation. Statistical methods included t tests, Fisher exact tests, and Wilcoxon rank sum tests. FINDINGS/RESULTS: We found 68 AKI episodes in 52 patients in cohort 1 and 15 episodes in 12 patients in cohort 2. Diagnosis and documentation of AKI improved after guideline implementation (C1:24/68 [35%], C2: 12/15 [80%]; P = .003) as did pediatric nephrology consultation (C1:12/68 [18%]; C2: 12/15 [80%]; P < .001) and outpatient referral (C1: 3/47 [6%], C2:5/8 [63%]; P < .01). IMPLICATIONS FOR PRACTICE: Neonatal AKI guideline implementation was associated with improvements in recognition, diagnosis, and inpatient and outpatient nephrology consultation. Early recognition and diagnosis along with specialist referral may improve outcomes among neonatal AKI survivors, ensuring appropriate future monitoring and long-term follow-up. IMPLICATIONS FOR RESEARCH: Future research should continue to determine the long-term implications of early diagnosis of AKI and appropriate subspecialty care with follow-up.

Maternal Epidural Steroids to Prevent Neonatal Exposure to Hyperthermia and Inflammation.

BACKGROUND: Epidural analgesia is associated with a fourfold increased rate of intrapartum fever. The likely pathophysiology is a noninfectious maternal inflammatory activation. Safe interventions to reduce maternal and neonatal exposures to intrapartum fever and inflammation are needed. OBJECTIVE: The purpose of this study was to determine if prophylactic epidural steroids decrease fetal exposure to hyperthermia and inflammatory cytokines following epidural analgesia. STUDY DESIGN: This is a randomized, double-blinded, placebo controlled trial. Term nulliparous women requesting epidural analgesia received 80 mg methylprednisolone or preservative-free normal saline via the epidural catheter at placement. The primary outcome was maternal temperature >100.4°F. Secondary outcomes included fetal exposure to inflammation as assessed by cord blood interleukin-6 (IL-6) levels and rates of funisitis. Power analysis estimated a sample size requirement of 276, but new Food and Drug Administration (FDA) recommendations advising a black box warning on epidural steroids resulted in early study termination. RESULTS: A total of 116 subjects were enrolled: 58 treatments and 58 placebos. There was no difference in the rate of maternal intrapartum fever or cord blood IL-6 levels between treatment arms. No complications listed in the FDA warning occurred. CONCLUSION: Prophylactic epidural methylprednisolone was not effective in reducing intrapartum fever or neonatal inflammation following epidural analgesia. Alternate mechanisms and preventative strategies should be considered.

Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.

Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families.

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination.

To be effective, the adaptive immune response requires a large repertoire of antigen receptors, which are generated through V(D)J recombination in lymphoid precursors. These precursors must be protected from DNA damage-induced cell death, however, because V(D)J recombination generates double-strand breaks and may activate p53. Here we show that the BTB/POZ domain protein Miz-1 restricts p53-dependent induction of apoptosis in both pro-B and DN3a pre-T cells that actively rearrange antigen receptor genes. Miz-1 exerts this function by directly activating the gene for ribosomal protein L22 (Rpl22), which binds to p53 mRNA and negatively regulates its translation. This mechanism limits p53 expression levels and thus contains its apoptosis-inducing functions in lymphocytes, precisely at differentiation stages in which V(D)J recombination occurs.

Cytomegalovirus-Induced Hemophagocytic Lymphohistiocytosis in an Extreme Preterm Infant: Recognition and Therapy Leading to Recovery.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that can be triggered by cytomegalovirus, a relatively common infectious exposure to neonates. The clinical presentation is common to many acute illnesses seen in extreme premature infants; however, there are key clinical and laboratory findings that can lead to the diagnosis. PURPOSE: We present a case of an extreme premature infant of 25 weeks' gestation who developed cytomegalovirus-induced HLH. Using the current published protocols that are used in pediatric cancer can be adapted for use in a premature infant, which led to remission of HLH and eventual discharge from the neonatal intensive care unit. IMPLICATIONS FOR PRACTICE: There are published treatment protocols used in pediatric oncology that when initiated early can lead to favorable outcomes and remission in even the most fragile neonates. IMPLICATIONS FOR RESEARCH: Additional studies are needed on the pharmacokinetics, dosing, and side effects on medications used for treatment of HLH in preterm infants. Additional research is needed to improve the clinician's ability to reach the diagnosis as well as define treatment strategies that provide optimal outcomes.

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.

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.

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.

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, 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.

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.

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.

Infectious, autoimmune and allergic diseases and risk of Hodgkin lymphoma in children and adolescents: a Children's Oncology Group study.

An infectious origin for pediatric Hodgkin lymphoma (HL) has long been suspected and Epstein-Barr virus (EBV) has been implicated in a subset of cases. Increased HL incidence in children with congenital and acquired immunodeficiencies, consistent associations between autoimmune diseases and adult HL and genome-wide association and other genetic studies together suggest immune dysregulation is involved in lymphomagenesis. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL diagnosed in 1989-2003 at 0-14 years at Children's Oncology Group institutions. Parents of 517 cases and 784 controls completed telephone interviews, including items regarding medical histories. Tumor EBV status was determined for 355 cases. Using conditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for risk of HL. Cases were more likely to have had an infection>1 year prior to HL diagnosis (OR=1.69, 95% CI: 0.98-2.91); case siblings were also more likely to have had a prior infection (OR=2.04, 95% CI: 1.01-4.14). Parental history of autoimmunity associated with increased EBV+ HL risk (OR=2.97, 95% CI: 1.34-6.58), while having a parent (OR=1.47, 95% CI: 1.01-2.14) or sibling (OR=1.62, 95% CI: 1.11-2.36) with an allergy was associated with EBV - HL. These results may indicate true increased risk for infections and increased risk with family history of autoimmune and allergic conditions that varies by tumor EBV status, or they may be attributable to inaccurate recall. In addition to employing biomarkers to confirm the role of immune-modulating conditions in pediatric HL, future studies should focus on family based designs.

Anthropometric, medical history and lifestyle risk factors for myeloproliferative neoplasms in the Iowa Women's Health Study cohort.

Classical myeloproliferative neoplasms (MPNs) are composed of essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), the etiology of which is largely unknown. We investigated the role of anthropometric, medical and lifestyle factors with risk of MPN in a prospective cohort of 27,370 women aged 55-69 years at enrollment. After >250,000 person-years of follow-up, 257 cases of MPN were identified (172 ET, 64 PV, 21 MF). Risk factor profiles were mostly unique for the two most common types, ET and PV. ET was associated with energy balance factors including body mass index (RR = 1.52 for >29.3 vs. <23.4 kg/m(2) ; p-trend = 0.042), physical activity (RR = 0.66 for high vs. low; p-trend = 0.04) and adult onset diabetes (RR = 1.82; p = 0.009), while PV was not. PV was associated with current smoking (RR = 2.83; p-trend = 0.016), while ET was not. Regular use of aspirin was associated with lower risk of ET (RR = 0.68; p = 0.017). These results broadly held in multivariate models. Our results suggest distinct etiologies for these MPN subtypes and raise mechanistic hypotheses related to obesity-related inflammatory pathways for ET and smoking-related carcinogenic pathways for PV. Regular aspirin use may lower risk for ET.

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.

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.

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.