SMAD2 and SMAD3 differentially regulate adiposity and the growth of subcutaneous white adipose tissue.

Adipose tissue is the primary site of energy storage, playing important roles in health. While adipose research largely focuses on obesity, fat also has other critical functions, producing adipocytokines and contributing to normal nutrient metabolism, which in turn play important roles in satiety and total energy homeostasis. SMAD2/3 proteins are downstream mediators of activin signaling, which regulate critical preadipocyte and mature adipocyte functions. Smad2 global knockout mice exhibit embryonic lethality, whereas global loss of Smad3 protects mice against diet-induced obesity. The direct contributions of Smad2 and Smad3 in adipose tissues, however, are unknown. Here, we sought to determine the primary effects of adipocyte-selective reduction of Smad2 or Smad3 on diet-induced adiposity using Smad2 or Smad3 "floxed" mice intercrossed with Adiponectin-Cre mice. Additionally, we examined visceral and subcutaneous preadipocyte differentiation efficiency in vitro. Almost all wild type subcutaneous preadipocytes differentiated into mature adipocytes. In contrast, visceral preadipocytes differentiated poorly. Exogenous activin A suppressed differentiation of preadipocytes from both depots. Smad2 conditional knockout (Smad2cKO) mice did not exhibit significant effects on weight gain, irrespective of diet, whereas Smad3 conditional knockout (Smad3cKO) male mice displayed a trend of reduced body weight on high-fat diet. On both diets, Smad3cKO mice displayed an adipose depot-selective phenotype, with a significant reduction in subcutaneous fat mass but not visceral fat mass. Our data suggest that Smad3 is an important contributor to the maintenance of subcutaneous white adipose tissue in a sex-selective fashion. These findings have implications for understanding SMAD-mediated, depot selective regulation of adipocyte growth and differentiation.

Respiratory Syncytial Virus Disease Severity Is Associated with Distinct CD8+ T-Cell Profiles.

Rationale: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although T-helper type 2 (Th2) cell pathology is implicated in severe disease, the mechanisms underlying the development of immunopathology are incompletely understood.Objectives: We aimed to identify local immune responses associated with severe RSV in infants. Our hypothesis was that disease severity would correlate with enhanced Th2 cellular responses.Methods: Nasal aspirates were collected from infants hospitalized with severe (admitted to the pediatric ICU) or moderate (maintained in the general ward) RSV disease at 5 to 9 days after enrollment. The immune response was investigated by evaluating T-lymphocyte cellularity, cytokine concentration, and viral load.Measurements and Main Results: Patients with severe disease had increased proportions of CD8 (cluster of differentiation 8)-positive T cells expressing IL-4 (Tc2) and reduced proportions of CD8+ T cells expressing IFNγ (Tc1). Nasal aspirates from patients with severe disease had reduced concentrations of IL-17. Patients with greater frequencies of Tc1, CD8+ T cells expressing IL-17 (Tc17), and CD4+ T cells expressing IL-17 (Th17) had shorter durations of hospitalization.Conclusions: Severe RSV disease was associated with distinct T-cell profiles. Tc1, Tc17, and Th17 were associated with shorter hospital stay and may play a protective role, whereas Tc2 cells may play a previously underappreciated role in pathology.

Waitlist management in a pediatric weight management clinic: implementing an orientation session.

BACKGROUND: This study evaluates implementation of an orientation session to address a waitlist of more than 2000 referrals to a pediatric weight management clinic in the Mid-South United States. METHODS: An hour-long group-based orientation to the pediatric weight management clinic was implemented to provide information about the structure and expectations of the clinic as well as education on healthy lifestyle recommendations. Families were contacted from the waitlist by telephone and invited to attend an orientation session prior to scheduling a clinic appointment. RESULTS: Of 2251 patients contacted from the waitlist, 768 scheduled an orientation session, of which 264 (34 %) attended. Of the 264 orientation participants, 246 (93 %) scheduled a clinic appointment. Of those, 193 (79 %) completed a clinic visit. Waitlist times decreased from 297.8 ± 219.4 days prior to implementation of orientation sessions to 104.1 ± 219.4 days after. CONCLUSIONS: Orientation has been an effective and efficient way to triage patient referrals while maximizing attendance in limited clinic slots for patients and families demonstrating interest and motivation. Elements of this approach are likely generalizable to other pediatric clinical settings that must strategically manage a large volume of patient referrals.

Elevated Levels of Type 2 Respiratory Innate Lymphoid Cells in Human Infants with Severe Respiratory Syncytial Virus Bronchiolitis.

Rationale: Studies of the immune responses at the site of respiratory syncytial virus (RSV) infection are sparse despite nearly five decades of research into understanding RSV disease.Objectives: To investigate the role of mucosal innate immune responses to RSV and respiratory viral load in infants hospitalized with the natural disease.Methods: Cytokines, viral load, and type 2 innate lymphoid cell (ILC2) levels in nasal aspirates, collected within 24 hours of enrollment, from infants hospitalized with RSV infection were quantified.Measurements and Main Results: RSV severity in infants was categorized based on admission to the general ward (moderate) or the pediatric ICU (severe). Evaluable subjects included 30 patients with severe and 63 patients with moderate disease (median age, 74 d; range, 9-297 d). ILC2s were found in the nasal aspirates of patients with severe disease (0.051% of total respiratory CD45+ cells) to a significantly greater extent than in patients with moderate disease (0.018%, P = 0.004). Levels of IL-4, IL-13, IL-33, and IL-1ß were significantly higher in nasal aspirates of patients with severe disease compared with those of patients with moderate disease. Factors associated with disease severity were gestational age (odds ratio, 0.49; 95% confidence interval, 0.29-0.82; P = 0.007) and IL-4 (odds ratio, 9.67; 95% confidence interval, 2.45-38.15; P = 0.001).Conclusions: This study shows, for the first time, that elevated levels of ILC2s is associated with infant RSV severity. The findings highlight the dominance of type-2 responses to RSV infection in infants and suggest an important role of ILC2 in shaping the immune response early during RSV infection.

Predictors of an Extended Length of Stay following an Elective Craniotomy in Children and Young Adults.

BACKGROUND: Length of stay (LOS) is now a generally accepted clinical metric within the USA. An extended LOS following an elective craniotomy can significantly impact overall costs. Few studies have evaluated predictors of an extended LOS in pediatric neurosurgical patients. OBJECTIVE: The aim of the study was to determine predictors of an extended hospital LOS following an elective craniotomy in children and young adults. METHODS: All pediatric patients and young adults undergoing an elective craniotomy between January 1, 2010, and April 1, 2019, were retrospectively identified using a prospectively maintained database. Demographic, clinical, radiological, and surgical data were collected. The primary outcome was extended LOS, defined as a postsurgical stay greater than 7 days. Bivariate and multivariable analyses were performed. RESULTS: A total of 1,498 patients underwent 1,720 elective craniotomies during the study period over the course of 1,698 hospitalizations with a median LOS of 4 days (interquartile range 3-6 days). Of these encounters, 218 (12.8%) had a prolonged LOS. Multivariable analysis demonstrated that non-Caucasian race (OR = 1.9 [African American]; OR = 1.6 [other]), the presence of an existing shunt (OR = 1.8), the type of craniotomy (OR = 0.3 [vascular relative to Chiari]), and the presence of a postoperative complication (OR = 14.7) were associated with an extended LOS. CONCLUSIONS: Inherent and modifiable factors predict a hospital stay of more than a week in children and young adults undergoing an elective craniotomy.

Psychosocial Functioning After One Year of Interdisciplinary Pediatric Weight Management.

Youth with obesity are more likely than normal-weight peers to experience psychosocial problems. Empirically-based recommendations for addressing pediatric obesity include intensive interdisciplinary weight management comprising medical, behavioral health, nutrition, and exercise components. The present study examined changes in psychosocial functioning associated with frequency of participation in an interdisciplinary pediatric weight management program. Participants were 86 patients (55.8% females; median age = 11.5 years; 67.4% Non-Hispanic Black; median BMI percentile = 99.5) enrolled in an interdisciplinary pediatric weight management program for at least one year. Psychosocial functioning was measured with the Pediatric Symptom Checklist (PSC-17), a caregiver-completed mental health screen that assesses internalizing, externalizing, and attention difficulties as well as global functioning. The PSC-17 was completed at the initial clinic visit (baseline) and repeated one-year later (annual). The Wilcoxon Signed Rank test indicated that annual PSC-17 scores were significantly lower than baseline scores across all domains. Spearman correlation coefficients revealed no significant association between total number of clinic visits and PSC-17 global or subscale scores. However, the number of visits for exercise-only sessions was significantly correlated with caregiver-reported improvement in internalizing behaviors. Findings suggest that participation in interdisciplinary pediatric weight management may improve psychosocial functioning in youth with obesity and that attending supervised exercise sessions may be especially beneficial for improving internalizing behavior symptoms.

Big Data Research in Pediatric Neurosurgery: Content, Statistical Output, and Bibliometric Analysis.

BACKGROUND/AIMS: We sought to describe pediatric "big data" publications since 2000, their statistical output, and clinical implications. METHODS: We searched 4 major North American neurosurgical journals for articles utilizing non-neurosurgery-specific databases for clinical pediatric neurosurgery research. Articles were analyzed for descriptive and statistical information. We analyzed effect sizes (ESs), confidence intervals (CIs), and p values for clinical relevance. A bibliometric analysis was performed using several key citation metrics. RESULTS: We identified 74 articles, which constituted 1.7% of all pediatric articles (n = 4,436) published, with an exponential increase after 2013 (53/74, 72%). The Healthcare Cost and Utilization Project (HCUP) databases were most frequently utilized (n = 33); hydrocephalus (n = 19) was the most common study topic. The statistical output (n = 49 studies with 464 ESs, 456 CIs, and 389 p values) demonstrated that the majority of the ESs (253/464, 55%) were categorized as small; half or more of the CI spread (CIS) values and p values were high (274/456, 60%) and very strong (195/389, 50%), respectively. Associations with a combination of medium-to-large ESs (i.e., magnitude of difference), medium-to-high CISs (i.e., precision), and strong-to-very strong p values comprised only 20% (75/381) of the reported ESs. The total number of citations for the 74 articles was 1,115 (range per article, 0-129), with the median number of citations per article being 8.5. Four studies had > 50 citations, and 2 of them had > 100 citations. The calculated h-index was 16, h-core citations were 718, the e-index was 21.5, and the Google i10-index was 34. CONCLUSIONS: There has been a dramatic increase in the use of "big data" in the pediatric neurosurgical literature. Reported associations that may, as a group, be of greatest interest to practitioners represented only 20% of the total output from these publications. Citations were weighted towards a few highly cited publications.

A Collaborative Behavioral Model for Psychiatric Visits in a Pediatric Emergency Department.

OBJECTIVES: Psychiatric pediatric emergency department (PED) visits are associated with extended length of stay (LOS) compared with nonpsychiatric visits. To address delays in definitive care, our PED incorporated a Collaborative Behavioral Model for patients with a psychiatric complaint. We evaluated LOS and 6-month readmission by comparing patients who received a psychiatric consultation through the model with a control group of nonpsychiatric patients. In addition, we assessed the utilization of laboratory tests and imaging and the impact of testing on final patient disposition. METHODS: A matched-pair retrospective chart review of psychiatric PED visits was conducted for visits from January 1, 2009, to December 31, 2013. Patients who received a psychiatric diagnosis and consultation through the Collaborative Behavioral Model were included. Participants were matched with a control group of similar patients who did not receive a psychiatric diagnosis. RESULTS: One hundred forty-seven patients met all the inclusion criteria. There was no statistical difference in median LOS for patients who received a psychiatric consultation versus nonpsychiatric visits (204 vs 200 minutes; P = 0.35). The 6-month PED readmission rate for psychiatric visits was significantly less than that in the control group (18% vs 32%; P = 0.003). Of the laboratory and imaging studies performed, 1 abnormal laboratory test (1%) and no imaging studies resulted in a change in patient management. CONCLUSIONS: Collaborative models, with specialized psychiatric components, can better coordinate the care of mental health visits by providing focused interventions that promote efficient disposition. In addition, laboratory and imaging studies resulted in few changes in management or final disposition.

Platelet Transfusions in the PICU: Does Disease Severity Matter?

OBJECTIVES: Pediatric intensivists frequently prescribe platelet transfusions to critically ill children, but there are limited data on platelet transfusion practice and platelet transfusion-related outcomes in the PICU. In this study, we evaluated the current platelet transfusion practice and platelet transfusion-related outcomes in the PICU. DESIGN: Institutional review board-approved, retrospective cohort study from January 2010 to March 2016. SETTING: Tertiary-level PICU. PATIENTS: Children less than 19 years old who received platelet transfusions in the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-six percent (1,547/4,339) of platelet transfusions in the institution were given to 2.4% of PICU patients (232/9,659). The patients who received a platelet transfusion (platelet transfusions, n = 232) compared with those who did not receive platelets (no platelet transfusions, n = 9,427) were younger, had similar gender distribution, had a higher median Pediatric Risk of Mortality-3 score, and stayed longer in the PICU. Fifty percent of platelet transfusions were prescribed prophylactically for thrombocytopenia to patients without extracorporeal membrane oxygenation support. The mortality was higher for platelet transfusions group (30% vs 2.3%) with an 18 times increased unadjusted odds of mortality when compared with no platelet transfusion group (odds ratio, 18.2; 95% CI, 13.3-24.8; p < 0.0001). In a multiple logistic regression analysis, the predicted probability of dying for platelet transfusion group compared with no platelet transfusion group depended on the median Pediatric Risk of Mortality-3 score. Patients who received platelet transfusion versus no platelet transfusion have increased odds of dying at lower median Pediatric Risk of Mortality-3 scores, but decreased odds of dying at higher median Pediatric Risk of Mortality-3 scores. CONCLUSIONS: This PICU cohort demonstrates that the odds or predicted probability of dying change in patients who received platelet transfusions based on underlying disease severity measured by Pediatric Risk of Mortality-3 score compared with patients who did not receive platelet transfusions. A large, prospective trial is required to confirm this association and determine whether to consider underlying disease severity in estimating risks and benefits of prophylactic platelet transfusions in critically ill children.

Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33.

Respiratory syncytial virus (RSV) is the most common cause of infant hospitalizations and severe RSV infections are a significant risk factor for childhood asthma. The pathogenic mechanisms responsible for RSV induced immunopathophysiology remain elusive. Using an age-appropriate mouse model of RSV, we show that IL-33 plays a critical role in the immunopathogenesis of severe RSV, which is associated with higher group 2 innate lymphoid cells (ILC2s) specifically in neonates. Infection with RSV induced rapid IL-33 expression and an increase in ILC2 numbers in the lungs of neonatal mice; this was not observed in adult mice. Blocking IL-33 with antibodies or using an IL-33 receptor knockout mouse during infection was sufficient to inhibit RSV immunopathogenesis (i.e., airway hyperresponsiveness, Th2 inflammation, eosinophilia, and mucus hyperproduction); whereas administration of IL-33 to adult mice during RSV infection was sufficient to induce RSV disease. Additionally, elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV; these cytokines declined during convalescence. In summary, IL-33 is necessary, either directly or indirectly, to induce ILC2s and the Th2 biased immunopathophysiology observed following neonatal RSV infection. This study provides a mechanism involving IL-33 and ILC2s in RSV mediated human asthma.

Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants-A Randomized Controlled Trial.

OBJECTIVE: To compare the effect of initiating human milk fortification at 2 different feeding volumes on feeding intolerance and the time to reach full feeding volume. STUDY DESIGN: Very low birth weight infants (n = 100) were prospectively randomized to early fortification (EF) (beginning at a feeding volume of 20 mL/kg/d) or delayed fortification (at a feeding volume of 100 mL/kg/d). We employed a standardized feeding protocol and parenteral nutrition guidelines for the nutritional management of all study infants. RESULTS: The median days to reach full feeding volumes were equivalent in the 2 groups (20 vs 20, P = .45). No significant difference was observed in the total number of episodes of feeding intolerance (58 vs 57). Two cases of necrotizing enterocolitis (Bell stage ≥2) and deaths occurred in each group. Median daily protein intake (g/kg/d) was higher in EF group in week 1 (3.3 [3.2, 3.5] vs 3.1 [2.9, 3.3], P < .001), week 2 (3.6 [3.5, 3.8] vs 3.2 [2.9, 3.4], P < .001), and week 3 (3.7 [3.4, 3.9] vs 3.5 [2.8, 3.8], P = .006). Cumulative protein intake (g/kg) in the first 4 weeks of life was higher in EF group (98.6 [93.8, 104] vs 89.6 [84.2, 96.4], P < .001). CONCLUSIONS: Very early human milk fortification may improve early protein intake in very low birth weight infants without increasing frequencies of adverse events. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01988792.

Diagnostic Utility of Three-Dimensional Rotational Angiography in Congenital Cardiac Catheterization.

We evaluated the diagnostic utility of the three modalities of three-dimensional rotational angiography (3DRA): rotational angiography (RA), multiplanar reformat (MPR) and three-dimensional angiographic reconstruction (3D-R) in pediatric cardiac catheterization. The 3DRA studies were classified by anatomy of interest based on our injection protocol: pulmonary arteries (PA), aorta, cavopulmonary connection (CPC), and others. Retrospective review of 3DRA images by two reviewers for each modality was conducted with grading as inferior, similar, or superior in comparison with the diagnostic quality of fixed-plane angiography (FPA). The percentages of grades for each modality were averaged. Weighted kappa statistic was used to evaluate inter-rater reliability. In total, 114 3DRA studies were performed on 87 patients between August 2010 and March 2012. Median age was 2.7 years (1 day-48.4 years) and median weight 12.1 kg (3.6-106.5 kg). For RA: 79.4 % of the studies were of diagnostic quality and 52.2 % were superior; 3D-R: 82 % were of diagnostic quality and 65.8 % were superior; and MPR: 83.5 % were of diagnostic quality and 63 % were superior. Overall 3DRA technologies (RA, 3D-R, MPR) were of diagnostic quality or better in 111/114 (97.4 %) studies and 103/114 (90.4 %) were judged superior. Most common reasons for inferior grading were limited opacification and metallic artifact. In pediatric cardiac catheterization, 3DRA imaging was of diagnostic quality and frequently provided additional clinically relevant data when compared to FPA.

Use of Vertical Expandable Prosthetic Titanium Rib (VEPTR) in the Treatment of Congenital Scoliosis Without Fused Ribs.

BACKGROUND: Although the vertical expandable prosthetic titanium rib (VEPTR) has been shown to be useful in treating congenital scoliosis (CS) with fused ribs, no studies to date have specifically evaluated the efficacy of VEPTR in the treatment of CS without fused ribs. The purpose of this study was to determine the effectiveness of VEPTR in sagittal/coronal curve correction and spine growth and compare its complication rate to the use of VEPTR in other conditions and to other treatment methods used for CS. METHODS: A multicenter database was queried for patients with CS without fused ribs treated with VEPTR. Anteroposterior (AP) and lateral radiographs were used to measure parameters at 3 timepoints (preoperative, immediate postoperative, and latest follow-up): coronal Cobb angle, sagittal kyphosis, and thoracic and lumbar spine heights. Clinical data included age, time to follow-up, and complications. RESULTS: Twenty-five patients (13 females, 12 males) were identified. The average age at implantation was 5.7 years, with an average follow-up of 50 months. Several parameters improved from preoperative to latest follow-up: coronal Cobb angle (69 to 54 degrees, P<0.0001), thoracic spine height (T1-T12) in the AP (13.3 to 15.9 cm, P<0.0001) and lateral (14.8 to 17.4 cm, P=0.0024) planes, and lumbar spine height (L1-S1) in the AP (8.8 to 11.4 cm, P<0.0001) and lateral (9.9 to 11.9 cm, P=0.0002) planes. Kyphosis increased over the study period (36 to 41 degrees, P=0.6). Fifteen patients (60%) had 41 complications (average 2.75; range, 1 to 12). Twenty-eight complications (68%) were device-related, and 13 (32%) were disease-related. The most common complications were infection, wound dehiscence, and device migration. Six complications (15%) altered the course of treatment. Thoracic spine height increased 79% of expected growth. CONCLUSION: VEPTR is an effective treatment for patients with CS without fused ribs, as evidenced by improved radiographic parameters and increased spinal height, with a complication rate which is high but similar to other methods of treatment. LEVEL OF EVIDENCE: Level IV-case series.

Changes in the Treatment of Pediatric Femoral Fractures: 15-Year Trends From United States Kids' Inpatient Database (KID) 1997 to 2012.

BACKGROUND: The options for treating femoral fractures in children and adolescents have evolved over the last 2 decades to include a variety of nonoperative and operative methods. The purpose of this study was to identify changes in the types of treatment for pediatric femoral fractures in the United States from 1997 to 2012. METHODS: From discharge estimates for 1997, 2000, 2003, 2006, 2009, and 2012 in the Kids' Inpatient Database, data were extracted using the International Classification of Diseases, 9th revision, and Clinical Modification for pediatric femoral fracture treatments. Patients included were 0 to 17 years old and were categorized into 5 age groups: younger than 1, 1 to 4, 5 to 9, 10 to 14, and 15 to 17 years. RESULTS: A total of 74,483 estimated discharges were recorded for pediatric patients with femoral fractures in the database for years 1997, 2000, 2003, 2006, 2009, and 2012. A total of 12,986 pediatric femoral fractures were estimated for 1997 and 9813 for 2012, which was statistically different (P<0.0001). Significantly fewer fractures were treated with closed reduction alone in 2012 than in 1997 in age groups 5 to 9, 10 to 14, and 15 to 17 years. Children aged 5 to 9 had more frequent open reduction and internal fixation in 2012 than in 1997, whereas adolescents aged 15 to 17 had less frequent open reduction and internal fixation in 2012 than in 1997. CONCLUSIONS: Although the number of femoral shaft fractures overall has decreased, the frequency of operative treatment has increased significantly in patients 5 to 9 years of age. Knowledge of these trends can guide educational efforts and resource allocation, but further study is necessary to determine procedure-specific (eg, nailing, plating, external fixation) trends and their clinical and economic impacts. LEVEL OF EVIDENCE: Level III-case series.

Allergic reactions and antiasparaginase antibodies in children with high-risk acute lymphoblastic leukemia: A children's oncology group report.

BACKGROUND: The objectives of this study were to assess the incidence of clinical allergy and end-induction antiasparaginase (anti-ASNase) antibodies in children with high-risk acute lymphoblastic leukemia treated with pegylated (PEG) Escherichia coli ASNase and to determine whether they carry any prognostic significance. METHODS: Of 2057 eligible patients, 1155 were allocated to augmented arms in which PEG ASNase replaced native ASNase postinduction. Erwinia chrysanthemi (Erwinia) ASNase could be used to replace native ASNase after allergy, if available. Allergy and survival data were complete for 990 patients. End-induction antibody titers were available for 600 patients. RESULTS: During the consolidation phase, 289 of 990 patients (29.2%) had an allergic reaction. There were fewer allergic reactions to Erwinia ASNase than to native ASNase (odds ratio, 4.33; P < .0001) or PEG ASNase (odds ratio, 3.08; P < .0001) only during phase 1 of interim maintenance. There was no significant difference in 5-year event-free survival (EFS) between patients who received PEG ASNase throughout the entire study postinduction versus those who developed an allergic reaction to PEG ASNase during consolidation phase and subsequently received Erwinia ASNase (80.8% ± 2.8% and 81.6% ± 3.8%, respectively; P = .66). Patients who had positive antibody titers postinduction were more likely to have an allergic reaction to PEG ASNase (odds ratio, 2.4; P < .001). The 5-year EFS rate between patients who had negative versus positive antibody titers (80% ± 2.6% and 77.7% ± 4.3%, respectively; P = .68) and between patients who did not receive any ASNase postconsolidation and those who received PEG ASNase throughout the study (P = .22) were significantly different. CONCLUSIONS: The current results demonstrate differences in the incidence rates of toxicity between ASNase preparations but not in EFS. The presence of anti-ASNase antibodies did not affect EFS.

Decreased induction morbidity and mortality following modification to induction therapy in infants with acute lymphoblastic leukemia enrolled on AALL0631: a report from the Children's Oncology Group.

BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Intensification of therapy has resulted in fewer relapses but increased early deaths, resulting in failure to improve survival. PROCEDURE: AALL0631 is a Phase 3 study for infants (<366 days of age) with newly diagnosed ALL. Induction initially (Cohort 1) consisted of 3 weeks of therapy based on COG P9407. Due to excessive early mortality, induction was amended to a less intensive 5 weeks of therapy based on Interfant-99. Additionally, enhanced supportive care guidelines were incorporated with hospitalization during induction until evidence of marrow recovery and recommendations for prevention/treatment of infections (Cohort 2). RESULTS: Induction mortality was significantly lower for patients in Cohort 2 (2/123, 1.6%) versus Cohort 1 (4/26, 15.4%; P = 0.009). All induction deaths were infection related except one due to progressive disease (Cohort 2). Sterile site infections were lower for patients in Cohort 2 (24/123, 19.5%) versus Cohort 1 (15/26, 57.7%; P = 0.0002), with a significantly lower rate of Gram positive infections during induction for patients in Cohort 2, P = 0.0002. No clinically significant differences in grades 3-5 non-infectious toxicities were observed between the two cohorts. Higher complete response rates were observed at end induction intensification for Cohort 2 (week 9, 94/100, 94%) versus Cohort 1 (week 7, 17/25, 68%; P = 0.0.0012). CONCLUSION: De-intensification of induction therapy and enhanced supportive care guidelines significantly decreased induction mortality and sterile site infections, without decreasing complete remission rates.

Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3).

BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6-9 months of diagnosis is common. Approximately 75% of infants have MLL-rearranged (MLL-R) ALL with event free survival (EFS) ranging from 20% to 30%. Children's Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS. PROCEDURE: P9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty-seven infants were enrolled in the third cohort. RESULTS: We report an overall 5-year EFS and OS of 42.3 ± 6% and 52.9 ± 6.5% respectively. Poor prognostic factors included age ≤90 days at diagnosis, MLL-R ALL and white cell count ≥50,000/µl. For infants ≤90 days of age, the 5-year EFS was 15.5 ± 10.1% and 48.5 ± 6.7% for those >90 days (P < 0.0001). Among infants >90 days of age, 5-year EFS rates were 43.8 ± 8% for MLL-R versus 69.1 ± 13.6% for MLL-germline ALL (P < 0.0001). CONCLUSIONS: Age ≤90 days at diagnosis was the most important prognostic factor. Despite shortened therapy with early intensification, EFS remained less than 50% overall in MLL-R ALL.

Dose intensification of methotrexate and cytarabine during intensified continuation chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: POG 9406: a report from the Children's Oncology Group.

PURPOSE: To determine the efficacy and toxicity of higher dose versus standard dose intravenous methotrexate (MTX) and pulses of high-dose cytosine arabinoside with asparaginase versus standard dose cytosine arabinoside and teniposide during intensified continuation therapy for higher risk pediatric B-precursor acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: From 1994 to 1999, the Pediatric Oncology Group conducted a randomized phase III clinical trial in higher risk pediatric B-precursor ALL. A total of 784 patients were randomized in a 2×2 factorial design to receive MTX 1 g/m versus 2.5 g/m and to cytosine arabinoside/teniposide versus high-dose cytosine arabinoside/asparaginase during intensified continuation therapy. RESULTS: Patients receiving standard dose MTX had a 5-year disease-free survival (DFS) of 71.8±2.4%; patients receiving higher dose MTX had a 5-year DFS of 71.7±2.4% (P=0.55). Outcomes on cytosine arabinoside/teniposide (DFS of 70.4±2.4) were similar to higher dose cytosine arabinoside/asparaginase (DFS of 73.1±2.3%) (P=0.41). Overall survival rates were not different between MTX doses or cytosine arabinoside/teniposide versus cytosine arabinoside/asparaginase. CONCLUSIONS: Increasing MTX dosing to 2.5 g/m did not improve outcomes in higher risk pediatric B-precursor ALL. Giving high-dose cytarabine and asparaginase pulses instead of standard dose cytarabine and teniposide produced nonsignificant differences in outcomes, allowing for teniposide to be removed from ALL therapy.

Cognitive effects of treatment of depression with repetitive transcranial magnetic stimulation.

BACKGROUND AND OBJECTIVE: We previously reported a randomized, sham-controlled trial of 5 Hz dorsolateral prefrontal left- and right-side repetitive transcranial magnetic stimulation (rTMS) in 48 participants with a medically refractory major depressive disorder. Depression improved most with right-side cranial stimulation, both rTMS and sham, and to a lesser degree with left rTMS. Because depression is often associated with cognitive impairment, in this study we sought to determine whether our earlier participants had treatment-induced changes in cognition, which cognitive domains (language, executive, visuospatial, verbal episodic memory, attention) were affected, and whether treatment-induced cognitive changes were related either to improvement in depression or to other treatment variables, such as right versus left treatment and rTMS versus sham. METHODS: We used hierarchical regression analyses to determine how variables measured at baseline or associated with treatment affected changes in neuropsychological functions. The variables were neuropsychological function in the 5 domains, severity of depression, change in depression with treatment, rTMS versus sham, laterality of stimulation, and rTMS-laterality interaction. RESULTS: Compared to sham, right rTMS was associated with 1.24 standard deviations greater gain in language function, 1.09 standard deviations greater gain in visuospatial function, and 2.38 standard deviations greater gain in verbal episodic memory than left rTMS. These improvements did not appear to be directly related to the relief from depression. CONCLUSIONS: Our results suggest that disorders of cognition and mood in depression may have different mechanisms, but right rTMS may treat both. We propose potential mechanisms underlying the right-side rTMS effect. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT00711568.

Modifications to induction therapy decrease risk of early death in infants with acute lymphoblastic leukemia treated on Children's Oncology Group P9407.

BACKGROUND: Infants (<366 days of age) with acute lymphoblastic leukemia (ALL) have a poor prognosis. Most treatment failures occur within 6-9 months of diagnosis, primarily from relapse. PROCEDURE: The Children's Oncology Group P9407 study was designed to test if early intensified treatment would improve outcome for infants with ALL. Due to a significant number of early deaths (< 90 days from enrollment), Induction therapy was amended three times. Cohorts 1 + 2 (n = 68), received identical Induction therapy except for reduced daunorubicin dose in Cohort 2. Cohort 3 (n = 141) received prednisone (40 mg/m(2)/day) instead of dexamethasone (10 mg/m(2)/day) and short infusion daunorubicin (30 minutes) instead of continuous infusion (48 hours), as well as additional supportive care measures throughout therapy. RESULTS: Early deaths occurred in 17/68 (25%) infants in Cohorts 1 + 2 and 8/141 (5.7%) infants in Cohort 3 (P < 0.0001). Among infants ≤90 days of age at diagnosis, early death occurred in 10/17 (58.8%) in Cohorts 1 + 2 and 4/27 (14.8%) in Cohort 3 (P = 0.006). Among infants >90 days of age at diagnosis, early death occurred in 7/51 (13.7%) in Cohorts 1 + 2 and 4/114 (3.5%) in Cohort 3 (P = 0.036). Bacterial, viral, and fungal infections were more common in Cohorts 1 + 2 versus Cohort 3. CONCLUSIONS: Early morbidity and mortality for infants with ALL were reduced by substitution of prednisone (40 mg/m(2)/day) for dexamethasone (10 mg/m(2)/day), the delivery of daunorubicin over 30 minutes instead of a continuous infusion for 48 hours, and the provision of more specific supportive care measures.