Identifying clinical practice guidelines for the supportive care of children with cancer: A report from the Children's Oncology Group.

Providing evidence-based supportive care for children with cancer has the potential to optimize treatment outcomes and improve quality of life. The Children's Oncology Group (COG) Supportive Care Guidelines Subcommittee conducted a systematic review to identify current supportive care clinical practice guidelines (CPGs) relevant to childhood cancer or pediatric hematopoietic stem cell transplant. Only 22 papers met the 2011 Institute of Medicine criteria to be considered a CPG. The results highlight the paucity of CPGs available to pediatric oncology healthcare professionals and the pressing need to create CPGs using current methodological standards.

Barriers to Medication Access in Pediatric Oncology in the United States.

Timely medication access in pediatric oncology is important; yet barriers are poorly described. We surveyed pediatric oncology health care providers at National Cancer Institute Community Oncology Research Program sites on their experience with the impact of drug acquisition difficulties, prior authorization (PA) requests, insurance denials, and patient copays leading to deviations or delays from prescribed treatment for their pediatric/adolescent/young adult patients in calendar year 2016. PA requests, the most frequently cited issue, created a deviation or delay from planned chemotherapy and supportive care treatment in at least 61% of respondents. Half of the respondents believed that PA-induced delays had a negative impact on care. Two-thirds of respondents felt that delays in starting therapy due to barriers in medication access created psychologic or emotional distress for the patient or family. Pediatric cancer patients may be receiving inferior care as a result of barriers to medication access.

Early-stage Hodgkin lymphoma in the modern era: simulation modelling to delineate long-term patient outcomes.

We developed a novel simulation model integrating multiple data sets to project long-term outcomes with contemporary therapy for early-stage Hodgkin lymphoma (ESHL), namely combined modality therapy (CMT) versus chemotherapy alone (CA) via 18 F-fluorodeoxyglucose positron emission tomography response-adaption. The model incorporated 3-year progression-free survival (PFS), probability of cure with/without relapse, frequency of severe late effects (LEs), and 35-year probability of LEs. Furthermore, we generated estimates for quality-adjusted life years (QALYs) and unadjusted survival (life years, LY) and used model projections to compare outcomes for CMTversusCA for two index patients. Patient 1: a 25-year-old male with favourable ESHL (stage IA); Patient 2: a 25-year-old female with unfavourable ESHL (stage IIB). Sensitivity analyses assessed the impact of alternative assumptions for LE probabilities. For Patient 1, CMT was superior to CA (CMT incremental gain = 0·11 QALYs, 0·21 LYs). For Patient 2, CA was superior to CMT (CA incremental gain = 0·37 QALYs, 0·92 LYs). For Patient 1, the advantage of CMT changed minimally when the proportion of severe LEs was reduced from 20% to 5% (0·15 QALYs, 0·43 LYs), whereas increasing the severity proportion for Patient 2's LEs from 20% to 80% enhanced the advantage of CA (1·1 QALYs, 6·5 LYs). Collectively, this detailed simulation model quantified the long-term impact that varied host factors and alternative contemporary treatments have in ESHL.

Multisite external validation of a risk prediction model for the diagnosis of blood stream infections in febrile pediatric oncology patients without severe neutropenia.

BACKGROUND: Pediatric oncology patients are at an increased risk of invasive bacterial infection due to immunosuppression. The risk of such infection in the absence of severe neutropenia (absolute neutrophil count ≥ 500/µL) is not well established and a validated prediction model for blood stream infection (BSI) risk offers clinical usefulness. METHODS: A 6-site retrospective external validation was conducted using a previously published risk prediction model for BSI in febrile pediatric oncology patients without severe neutropenia: the Esbenshade/Vanderbilt (EsVan) model. A reduced model (EsVan2) excluding 2 less clinically reliable variables also was created using the initial EsVan model derivative cohort, and was validated using all 5 external validation cohorts. One data set was used only in sensitivity analyses due to missing some variables. RESULTS: From the 5 primary data sets, there were a total of 1197 febrile episodes and 76 episodes of bacteremia. The overall C statistic for predicting bacteremia was 0.695, with a calibration slope of 0.50 for the original model and a calibration slope of 1.0 when recalibration was applied to the model. The model performed better in predicting high-risk bacteremia (gram-negative or Staphylococcus aureus infection) versus BSI alone, with a C statistic of 0.801 and a calibration slope of 0.65. The EsVan2 model outperformed the EsVan model across data sets with a C statistic of 0.733 for predicting BSI and a C statistic of 0.841 for high-risk BSI. CONCLUSIONS: The results of this external validation demonstrated that the EsVan and EsVan2 models are able to predict BSI across multiple performance sites and, once validated and implemented prospectively, could assist in decision making in clinical practice. Cancer 2017;123:3781-3790. © 2017 American Cancer Society.

Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model.

Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.

Intravenous Iron Sucrose for Children With Iron Deficiency Anemia.

Iron deficiency anemia (IDA) is the most common nutritional deficiency in children. Most children with IDA are treated with oral iron preparations. However, intravenous (IV) iron is an alternative for children with severe IDA who have difficulty in adhering to or absorbing oral iron. We sought to describe the safety and effectiveness of IV iron sucrose for treatment of IDA in children. Pharmacy records of children who received IV iron sucrose at a children's hospital between 2004 and 2014 were reviewed. Laboratory markers of anemia and iron studies were obtained and preinfusion and postinfusion values were compared. Records were also reviewed for adverse reactions. A total of 142 patients received IV iron sucrose over 10 years. The mean age was 11 years, 9 months. One patient of 142 developed cough and wheezing during the infusion. No other adverse events were found. IV iron sucrose resulted in a statistically significant and clinically meaningful increase in hemoglobin, mean corpuscular volume, serum iron, ferritin, and % iron saturation, with a corresponding decrease in total iron binding capacity. The use of IV iron sucrose in pediatric patients with IDA is safe and leads to a moderate increase in hemoglobin and substantial improvement in iron studies.

Discovery of 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis.

Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.

Food craving and obesity in survivors of pediatric ALL and lymphoma.

Cancer treatment can impact the hypothalamic-pituitary region of the developing brain, impairing appetite regulation and causing food craving in children who have survived cancer. We assessed food craving using a modified Food Craving Inventory in 22 survivors of pediatric acute lymphoblastic leukemia (ALL) and lymphoma (median age = 11.7 years) and evaluated its association with treatment exposure and changes in weight status over a one-year period. Mean total craving score was 2.1 (SD = 0.7). Survivors reported significantly higher mean craving score for fast-foods [2.6 (SD = 0.9)] than for sweets [2.1 (SD = 0.8)], carbohydrates [2.0 (SD = 0.6)], and fats [1.8 (SD = 0.7)] (all P values < 0.05). Results from multivariate linear regression indicated that survivors diagnosed at an older age (≥4.5 years) experienced higher frequencies of food craving than those diagnosed at a younger age (<4.5 years) (ß = 0.88, 95% CI: 0.42, 1.34). Food craving, however, was not significantly associated with survivors' weight status over 12 months of follow-up. Food craving alone does not appear to explain the obesity risk in this sample of childhood cancer survivors. The role of food craving in shaping eating behavior and obesity risk needs to be further evaluated in a large cohort of childhood cancer survivors.

Growth patterns during and after treatment in patients with pediatric ALL: A meta-analysis.

BACKGROUND: Survivors of pediatric acute lymphoblastic leukemia (ALL) have a significantly higher body mass index (BMI) than their peers. Understanding the critical time periods in which patients with pediatric ALL are vulnerable to unhealthy weight gain will lay the groundwork for developing effectively timed interventions. PROCEDURE: We determined the growth patterns of patients with pediatric ALL during and after treatment through the conduct of a systematic review and meta-analysis. A search of MEDLINE, Scopus, and Web of Science was performed from its inception through May 2014. Studies met the inclusion criteria if they included at least 10 patients of pediatric ALL, and longitudinally assessed BMI at diagnosis and at least one time point after diagnosis RESULTS: Twenty-one studies met the inclusion criteria for the systematic review and 16 were included in meta-analysis. The mean increase in BMI z-score during treatment in 1,514 patients with pediatric ALL was 0.81 (95% CI: 0.25-1.38). Specifically, patients experienced substantial weight gain in early treatment (Δ = 0.41, 95% CI: -0.34, 1.17) and again during maintenance (Δ = 0.34, 95% CI:-0.22, 0.90). The mean increase in BMI z-score ranged between 0.52 and 0.89 beyond treatment completion. Subgroup analyses found unhealthy weight gain occurred regardless of patients' receipt of cranial radiation therapy, sex, and, weight status at diagnosis. CONCLUSIONS: Patients with pediatric ALL experience unhealthy weight gain early in treatment, and increases in weight are maintained beyond treatment completion. Preventing early onset of obesity is a priority for improving the care and outcomes for patients with pediatric ALL.

Using nonrandomized studies to inform complex clinical decisions: the thorny issue of cranial radiation therapy for T-cell acute lymphoblastic leukemia.

BACKGROUND: There are no randomized controlled trials to inform the decision of which cranial radiation therapy (CRT) strategy to apply to pediatric patients with T-cell acute lymphoblastic leukemia (ALL). PROCEDURE: We performed a decision analysis using a Markov model in which we compared the life expectancy and quality-adjusted life expectancy when administering one of three CRT strategies to a cohort of patients with T-cell ALL: (1) omission of CRT for all patients; (2) CRT only for those with evidence of leukemic involvement in the central nervous system at diagnosis (therapeutic strategy); or (3) CRT for all (prophylactic strategy). RESULTS: When considering plausible event-free survival rates and late mortality after cure for groups of pediatric patients with T-cell ALL, the strategies of omitting CRT, administering therapeutic CRT, and administering prophylactic CRT result in similar short-term (7-year) survival. When considering the increased contribution of deaths from late effects, the strategy of prophylactic CRT is associated with lower life expectancy when compared to the other two strategies. The Monte Carlo probabilistic sensitivity analysis demonstrated that the strategy of prophylactic CRT was the preferred strategy only 5% of the time. CONCLUSIONS: Similar short-term survival may be expected when comparing the strategies of total omission of CRT, therapeutic CRT, and prophylactic CRT for patients with T-cell ALL. Long-term survival is likely inferior for the strategy of prophylactic CRT. The synthesis of nonrandomized trials and the application of decision analysis can help inform complex decision making in pediatric oncology.

Comparison of childhood cancer survivors' nutritional intake with US dietary guidelines.

BACKGROUND: Despite improved survival, childhood cancer survivors experience significantly elevated risk of premature mortality and serious morbidity due to chronic health conditions. Poor diet quality can exacerbate chronic health conditions in the survivors but their nutritional intake has not been adequately studied. PROCEDURE: We assessed the Healthy Eating Index 2010 (HEI-2010) in 22 survivors of pediatric acute lymphoblastic leukemia and lymphoma (median age = 11.7 years) and compared survivors' dietary intake to the 2010 Dietary Guidelines for Americans. Dietary data were collected using repeated 24 hr dietary recalls over a 1-year period, which were averaged to estimate habitual intake. RESULTS: The mean HEI-2010 in childhood cancer survivors was 52.7, about 50 percent of the maximum score. Long-term survivors (time from diagnosis ≥10 years) had a significantly lower HEI-2010 than recent survivors (time from diagnosis <5 years) (ß = -11.5, 95% CI: -22.1, -0.9, P = 0.047). For individual food groups and nutrients, survivors had a particularly poor adherence to green vegetables and beans, total vegetables, and whole fruits. None of the survivors met the guidelines for dietary fiber and potassium intake. Only 4%, 19%, 24%, and 29% met the guidelines for vitamin D, sodium, calcium, and saturated fat intake. The average intake in relative to the recommended intake was 32% for vitamin D, 50% for potassium, 63% for fiber, and 85% for calcium, but was 115% for saturated fat and 143% for sodium. CONCLUSIONS: Childhood cancer survivors, in particular long-term survivors, have a poor adherence to the US dietary guidelines.

Assessing Dietary Intake in Childhood Cancer Survivors: Food Frequency Questionnaire Versus 24-Hour Diet Recalls.

Cancer diagnosis and treatment may influence dietary intake. The validity of using self-reported methods to quantify dietary intake has not been evaluated in childhood cancer survivors. We validated total energy intake (EI) reported from Food Frequency Questionnaire (FFQ) and repeated 24-hour diet recalls (24HRs) against total energy expenditure (TEE) measured using the doubly labeled water method in 16 childhood cancer survivors. Dietary underreporting, assessed by (EI-TEE)/TEE × 100%, was 22% for FFQ and 1% for repeated 24HRs. FFQ significantly underestimates dietary intake and should not be used to assess the absolute intake of foods and nutrients in childhood cancer survivors.

Population genomics of domestic and wild yeasts.

Since the completion of the genome sequence of Saccharomyces cerevisiae in 1996 (refs 1, 2), there has been a large increase in complete genome sequences, accompanied by great advances in our understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions, population structure and sexual versus asexual reproduction. Less well understood at the whole genome level are the evolutionary processes acting within populations and species that lead to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to fourfold or more coverage of the genome sequences of over seventy isolates of the baker's yeast S. cerevisiae and its closest relative, Saccharomyces paradoxus. We examine variation in gene content, single nucleotide polymorphisms, nucleotide insertions and deletions, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. S. paradoxus populations are well delineated along geographic boundaries, whereas the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.

Low Levels of Energy Expenditure in Childhood Cancer Survivors: Implications for Obesity Prevention.

Childhood cancer survivors are at an increased risk of obesity but causes for this elevated risk are uncertain. We evaluated total energy expenditure in childhood cancer survivors using the doubly labeled water method in a cross-sectional study of 17 survivors of pediatric leukemia or lymphoma (median age, 11.5 y). Mean total energy expenditure was 2073 kcal/d, which was nearly 500 kcal/d lower than estimated energy requirements with recommended levels of physical activity. This energy gap is likely to contribute to the risk of obesity in this population and future trials are needed to assess implications and potential treatment strategies.

Cranial radiation for pediatric T-lineage acute lymphoblastic leukemia: a systematic review and meta-analysis.

There are heterogeneous approaches to cranial radiation therapy (CRT) for T-lineage acute lymphoblastic leukemia (T-ALL). We performed a systematic review of studies that specified a radiation strategy and reported survival for pediatric T-ALL. Our analysis included 62 publications reporting 78 treatment groups (patient n = 5844). The average event-free survival (EFS) was higher by 6% per 5 years (P < 0.001). Adjusting for year, EFS differed by radiation strategy. Compared to the reference group (CRT for all) which had a year-adjusted EFS of 65% (95% confidence interval, CI: 61-69%) the adjusted EFS was significantly worse (rate difference (RD) = -9%, 95% CI: -15 to -2%) among studies that used a risk-directed approach to CRT (P = 0.004). The adjusted EFS for the other strategies were not significantly different compared to the reference group: CRT for central nervous system positive patients only (RD = -3%, 95% CI: -14 to 7%, P = 0.49); CRT omitted for all patients (RD = 5%, 95% CI: -4 to 15%, P = 0.33). CRT may not be necessary with current chemotherapy for T-ALL. These findings, however, are susceptible to bias and caution should be applied in drawing conclusions on the comparative effectiveness of alternative CRT strategies.

Comparable survival for pediatric acute myeloid leukemia with poor-risk cytogenetics following chemotherapy, matched related donor, or unrelated donor transplantation.

BACKGROUND: We sought to better define the role of hematopoietic cell transplantation (HCT) in first remission (CR1) for high-risk pediatric acute myeloid leukemia (AML). PROCEDURES: Outcomes were compared among patients aged less than 21 years with cytogenetically defined poor-risk AML treated with chemotherapy, matched related (MRD), or unrelated donor (URD) transplantation in CR1. Poor-risk cytogenetics was defined as monosomy 7/del7q, monosomy 5/del 5q, abnormalities of 3q, t(6;9)(p23;q34), or complex karyotype. Included are patients treated on Children's Oncology Group trials or reported to the Center for International Blood and Marrow Transplant Research from 1989 to 2006. RESULTS: Of the 233 patients, 123 received chemotherapy, 55 received MRD HCT, and 55 received URD HCT. The 5-year overall survival from the time of consolidation chemotherapy or transplant conditioning was similar: chemotherapy (43% ± 9%), MRD (46% ± 14%), or URD (50% ± 14%), P = 0.99. Similarly, multivariate analysis demonstrated no significant differences in survival [(reference group = chemotherapy); MRD HR 1.08, P = 0.76; URD HR 1.13, P = 0.67] despite lower relapse risk with URD HCT (HR = 0.43, P = 0.01). CONCLUSIONS: Our findings do not provide support for the preferential use of HCT over chemotherapy alone for children with cytogenetically defined poor-risk AML in CR1.

Predictors of being overweight or obese in survivors of pediatric acute lymphoblastic leukemia (ALL).

BACKGROUND: A high prevalence of obesity has been increasingly recognized in survivors of pediatric ALL. However, longitudinal patterns of weight change during and after treatment, and associated factors, are less well elucidated. PROCEDURE: In a retrospective cohort of 83 pediatric patients with ALL diagnosed between 1985 and 2010, we examined body mass index (BMI) status at several key time points: diagnosis; end of induction; end of consolidation; every 6 months during maintenance; and yearly for up to 5 years post-treatment. RESULTS: At diagnosis, 21% were overweight (BMI = 85-94.9th percentile) or obese (BMI ≥ 95th percentile). At the end of treatment and 5 years post-treatment, approximately 40% were overweight or obese. The mean BMI z-score was 0.2 (58th percentile) at diagnosis and increased significantly during induction (Δ = 0.5, P < 0.0001). It increased again during the first 6 months of maintenance (Δ = 0.2, P < 0.01) and did not significantly change over the remainder of maintenance (BMI z-score at the end of treatment = 0.8, 79th percentile) and 5 years post-treatment (BMI z-score = 0.7, 76th percentile). High BMI z-score at diagnosis was associated with an increased risk of being overweight/obese at treatment completion (OR = 2.9, 95% CI: 1.6-5.1). Weight gain during treatment was associated with being overweight/obese 5 years post-treatment (OR = 3.8, 95% CI: 1.1-12.5). CONCLUSION: Children with ALL are at risk of becoming overweight/obese early in treatment. Increases in weight are maintained throughout treatment and beyond. Lifestyle interventions are needed targeting weight control early during treatment, particularly for patients overweight/obese at diagnosis and those who experience substantial weight gain during treatment.

MR imaging artifacts and parallel imaging techniques with calibration scanning: a new twist on old problems.

The application of parallel magnetic resonance (MR) imaging is increasing as clinicians continue to strive for improved spatial and temporal resolution, benefits that arise from the use of fewer phase encodings during imaging. To reconstruct images, extra information is needed to map the spatial sensitivity of each coil element, which may be accomplished by acquiring a calibration image in one common implementation of parallel MR imaging. Although obtaining a quick calibration image is an efficient method for gathering this information, corruption of the image or disharmony with subsequent images may lead to errors in reconstruction. Although conventional MR imaging sequences may be employed with parallel MR imaging, the altered image reconstruction introduces several new artifacts and changes the appearance of conventional artifacts. The altered appearance of traditional artifacts may obscure the source of the problem, and, in some cases, the severity of artifacts associated with parallel MR imaging may be exacerbated, hindering image interpretation. Several artifacts arise in the context of parallel MR imaging, including both traditional artifacts and those associated with parallel MR imaging.

Hyperhemolysis in sickle cell disease.

An 18-year-old female with sickle cell disease presented with thigh pain, dark urine, and hematuria within 72 hours of receiving a blood transfusion. Her clinical picture was consistent with hemolysis. Subsequent laboratory workup, however, demonstrated reticulocytopenia without evidence of an antibody-mediated transfusion reaction. As her hemoglobin continued to decrease, she was treated with IVIG and steroids for presumed hyperhemolysis. Clinicians should have a high index of suspicion for hyperhemolysis in sickle cell patients with evidence of hemolysis after a recent transfusion. Differentiating hyperhemolysis from other hemolytic syndromes is critical; transfusions in a hyperhemolytic episode can accelerate hemolysis causing life-threatening anemia.

Interim 1-Year Radiographic and Clinical Outcomes Following Anterior Cervical Discectomy and Fusion Using Hydroxyapatite-Infused Polyetheretherketone Interbody Cages.

BACKGROUND: This is a multicenter observational registry analysis of 1-year radiographic and clinical outcomes following anterior cervical discectomy and fusion (ACDF) using hydroxyapatite (HA)-infused polyetheretherketone (PEEK) intervertebral cages. METHODS: Radiographic and clinical outcome data were collected preoperatively and at 6 weeks, 3 months, 6 months, and 12 months postoperatively. To assess fusion, dynamic flexion-extension radiographs were independently evaluated with a validated method. Clinical outcomes were assessed using the following disease-specific measures: Neck Disability Index (NDI) and visual analog scale (VAS) for neck, left arm, and right arm pain. Patient satisfaction was also evaluated. RESULTS: A total of 789 ACDF patients (men: 51.5%/women: 48.5%; mean body mass index: 29.9 kg/m2) were included at the time of analysis, and 1565 segments have been operated. Successful fusion was confirmed in 91.3% of all operated levels after 6 months and 92.2% after 12 months. Mean NDI scores improved significantly (P < 0.01) preoperatively (46.3, n = 771) to postoperatively (12 months: 25.2, n = 281). Consistently, mean VAS neck (preoperative: 64.2, n = 770; 12 months: 28.6, n = 278), VAS right arm (preoperative: 42.6, n = 766; 12 months: 20.4, n = 277), and VAS left arm (preoperative: 41.1, n = 768; 12 months: 20.8, n = 277) decreased significantly (P < 0.01). Patients reported high satisfaction rates after surgery with no significant changes in postoperative patient satisfaction between 6 weeks and 12 months (95.1%, n = 273). CONCLUSIONS: ACDF with HA-infused PEEK cages demonstrates promising radiographic and clinical outcomes, supporting the potential benefits of incorporating HA into PEEK cages to enhance fusion rates and improve patient outcomes. CLINICAL RELEVANCE: This study demonstrates a >90% fusion rate by level with reliable improvements in patient reported outcomes, along with a high rate of patient satisfaction, in a large patient cohort undergoing ACDF with HA-infused PEEK cages. LEVEL OF EVIDENCE: 2 .