Lindsey Hornung

Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies.

BACKGROUND AND OBJECTIVES: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days. METHODS: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m2 per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths. RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/laboratory toxicity in 3%. No toxicity-related deaths occurred. CONCLUSIONS: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.

Outcomes of Donor Lymphocyte Infusion for Treatment of Mixed Donor Chimerism after a Reduced-Intensity Preparative Regimen for Pediatric Patients with Nonmalignant Diseases

Mixed donor chimerism is increasingly common in the pediatric hematopoietic stem cell transplantation (HSCT) setting because of the increased use of reduced-intensity preparative regimens for nonmalignant diseases. Donor lymphocyte infusion (DLI) is potentially useful in the treatment of mixed donor chimerism, but little are data available on the use of DLI in this setting. We conducted a retrospective review of 27 pediatric patients who received DLI for mixed donor chimerism between January 2006 and December 2010 after receiving a preparative regimen of alemtuzumab, fludarabine, and melphalan. Twenty-one patients (78%) were alive at a median of 35 months post-transplant. Seven patients (26%) sustained full donor chimerism after DLI only at a median of 35 months post-HSCT. Nine patients (33%) continued with mixed donor chimerism (median, 38% [range, 18% to 70%]) at a median of 37 months after DLI only. Five patients underwent unconditioned stem cell boosts or second conditioned transplants after no improvement in donor chimerism was seen following DLI. Donor source appeared to contribute to outcomes after DLI; patients with mismatched unrelated donors had earlier first decline in chimerism and timing of first DLI, a higher response rate to DLI, and an increased rate of graft-versus-host disease (GVHD). There was no response to DLI in patients with matched sibling donors. Ten patients, all with improvement in chimerism after DLI, developed acute GVHD after DLI, with 3 having grade III GVHD. Three patients developed chronic GVHD after DLI. These data illustrate the potential efficacy of DLI in the treatment of mixed donor chimerism after a reduced-intensity preparative regimen.

Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis.

Objectives The aim of this study was to determine if comprehensive genetic testing was useful to identify genetic variants that discriminate chronic pancreatitis (CP) from acute recurrent pancreatitis (ARP) in a pediatric population. Methods We conducted a retrospective review of 50 patients enrolled in our institutional pancreatitis registry between April 2013 and January 2015. Genetic analysis of PRSS1, CFTR, SPINK1, and CTRC classified variants as mutations or variants of unknown clinical significance and the minor allele frequency of variants in our cohort was obtained. Results Genetic testing was obtained in 16/16 (100%) of CP and 29/34 (85%) of ARP patients. A total of 39 genetic variants were found in 27 (60%) of 45 subjects tested with 5 (11%) subjects having 2 different genes affected. Variant frequency was greatest in patients for CFTR (17/45, 38%) followed by SPINK1 (11/44, 25%), CTRC (2/27, 7%), and PRSS1 (2/44, 4%). CFTR variants were more likely in those with CP compared to ARP (63% and 24%, P = 0.01). Conclusions This study is the first to find a higher rate of CFTR mutations in CP versus ARP groups using comprehensive genetic testing in a pediatric population.

Rapid Deterioration of Insulin Secretion in Obese Adolescents Preceding the Onset of Type 2 Diabetes

OBJECTIVE To identify pathophysiologic changes that lead to the onset of type 2 diabetes (T2DM) in adolescents. STUDY DESIGN Obese adolescents with normal glucose tolerance (n = 41) were studied longitudinally over the course of 4 years with serial measure of the acute insulin response to glucose (AIRg) as well as proinsulin (PI) concentrations. Insulin resistance was estimated with the homeostatic model assessment of insulin resistance (HOMA-IR), the disposition index (DI) computed as AIRg × 1/HOMA-IR, and intravenous glucose tolerance estimated as the glucose disappearance constant. RESULTS Four adolescents developed diabetes mellitus (DM) during the study, and the rest of the cohort remained nondiabetic. Baseline PI exceeded the IQR of the nondiabetic group in 3 of 4 subjects with DM, and all had >85% reduction from baseline AIRg, and DI, within 6 months of diagnosis. All the subjects with DM gained weight over the course of the study, but these changes paralleled those for the nondiabetic group. HOMA-IR increased substantially in 1 of the subjects with DM at the time of diagnosis but was comparable with baseline in the other 3. The DI and glucose disappearance constant of the subjects with DM was less than the 10th percentile of the nondiabetic group before and after diagnosis. CONCLUSION Conversion from normal glucose tolerance to T2DM in adolescents can occur rapidly, and the onset of T2DM is heralded by a substantial decrease in AIRg and DI, as well as increased release of PI. These results support loss of β-cell function as the proximate step in the development of T2DM in this age group.

Utility of Direct Pancreatic Function Testing in Children.

Objectives Exocrine pancreatic insufficiency (EPI) can have a significant impact on a childs growth and nutrition. Our aim was to evaluate the utility of direct endoscopic pancreatic function testing (ePFT) in pediatrics. Methods A single-center retrospective chart review was performed of children who underwent ePFT from December 2007 through February 2015. Endoscopic pancreatic function testings were performed by 1 of 2 methods: (1) intravenous cholecystokinin, followed by the collection of a single duodenal aspirate at 10 minutes, or (2) intravenous cholecystokinin or secretin, followed by the collection of 3 duodenal aspirates at a 5, 10, and 15 minutes. Samples were tested for pH and enzyme activities. Results A total of 508 ePFTs were performed (481 single-sample tests, 27 multiple-sample tests). Based on the multiple-sample group, enzyme levels for chymotrypsin, amylase, and lipase peaked at 5 minutes, followed by a decrease in activity over time. Exocrine pancreatic sufficiency was identified in 373 (73.4%) and EPI in 93 (18.3%). Exocrine pancreatic sufficiency analysis found all pancreatic enzyme activities significantly increase with age: trypsin, chymotrypsin, amylase, and lipase, (P < 0.05). Conclusions Endoscopic pancreatic function testing can be used in the evaluation of EPI in children. Normative data suggest that pancreatic enzyme activities mature with age.

Bone health measures in glucocorticoid-treated ambulatory boys with Duchenne muscular dystrophy

Osteoporosis is a major problem in boys with Duchenne Muscular Dystrophy (DMD), attributable to muscle weakness and glucocorticoid therapy. Consensus regarding bone health assessment and management is lacking. Lumbar spine areal bone mineral density (defined as bone mass per area of bone) by dual-energy X-ray absorptiometry (DXA) is frequently the primary measure used, but has limitations for boys with DMD. We retrospectively studied 292 ambulant glucocorticoid-treated boys with DMD categorized by functional mobility score, FMS 1, 2 or 3. We assessed DXA whole body and lumbar spine areal bone mineral density and content Z-scores adjusted for age and height, lateral distal femur areal bone mineral density Z-scores, frequency of fractures, and osteoporosis by International Society for Clinical Densitometry 2013 criteria. Whole body and femoral DXA indices decreased, while spine fractures increased, with declining motor function. Lumbar spine areal bone mineral density Z-scores appeared to improve with declining motor function. Bone mineral content Z-scores were consistently lower than corresponding bone mineral density Z-scores. Our findings highlight the complexity of assessing bone health in boys with DMD. Bone health indices worsened with declining motor function in ambulant boys, but interpretation was affected by measure and skeletal site examined. Whole body bone mineral content may be a valuable measure in boys with DMD. Lumbar spine areal bone mineral density Z-score as an isolated measure could be misleading. Comprehensive management of osteoporosis in boys with DMD should include vertebral fracture assessment.

Timing of Cholecystectomy in Children With Biliary Pancreatitis.

Background: Biliary pancreatitis (BP) is common in adults and children. Current standard of care is to perform a cholecystectomy (CCE) to decrease the recurrence risk of pancreatitis. Controversy exists as to the timing of surgery, early versus delayed surgical intervention. Adult literature suggests a greater benefit of early CCE. Comparatively, there is limited pediatric literature as to the optimal timing of a CCE in children. We report a retrospective case series of children with BP who underwent early versus late CCE. Methods: A retrospective chart review was performed of children with BP for a period of 45 months. Reviewed information included patient demographics, timing of CCE, and the occurrence of adverse events preceding or following surgical intervention. Early CCE was defined as surgery during the index admission; late CCE was defined as surgery during a subsequent admission. Results: Nineteen children and adolescents (17 girls) were identified to have had BP with a subsequent CCE. Cholecystectomy was performed early in 9 patients with no adverse events. Ten patients had delayed surgery with 4 occurrences of adverse clinical events (recurrence of pancreatitis or biliary colic abdominal pain) while awaiting their CCE. Conclusions: Adverse biliary-related events occur at a higher rate in children with mild BP who undergo a delayed CCE when compared to early CCE performance. Early CCE is safe to perform in children with mild BP.

Growth hormone improves short stature in children with Diamond-Blackfan anemia

Diamond‐Blackfan anemia (DBA), an inherited marrow failure syndrome, has severe hypoplastic anemia in infancy and association with aplastic anemia, MDS/leukemia, and other malignancies. Short stature is present in most patients. Isolated cases have demonstrated improved growth on growth hormone (GH) therapy.

Low bone mineral density and fractures are highly prevalent in pediatric patients with spinal muscular atrophy regardless of disease severity

Patients with Spinal Muscular Atrophy (SMA) are at risk for poor bone health. The prevalence of fractures, low areal bone mineral density (aBMD; Z-score ≤-2.0) of the lateral distal femur and of osteoporosis by SMA subtype is not known. We aimed to describe the natural history of bone health in patients with SMA prior to bisphosphonate treatment. We reviewed data from 85 eligible patients with SMA ages 12 months to 18 years, seen at a single institution between January 2005 and July 2016. Fracture history was reported at annual clinic visits. aBMD was obtained from dual energy x-ray absorptiometry scans of the lumbar spine, total body, and lateral distal femur. 85% of patients had aBMD Z-scores ≤-2.0 SD and were progressively lower with worsening SMA severity. Longitudinal aBMD Z-scores of the lateral distal femur decreased with age. Fractures occurred in 38% (32/85) of patients with the femur being the most common location (25 of 57 fractures). Thirteen percent of patients fulfilled criteria for osteoporosis. Low aBMD and femur fractures are highly prevalent in all SMA subtypes from a young age; however, few patients met the criteria for osteoporosis. Poor bone health may be an under-recognized comorbidity of SMA.

G.P.171

Osteoporosis is a major problem in Duchenne Muscular Dystrophy (DMD) patients due to long term glucocorticoid (GC) therapy and immobility. There is neither age-specific prevalence data nor consensus on management of osteoporosis in DMD. To determine age-specific prevalence of osteoporosis and frequency of poor bone health indices in pediatric DMD patients. Methods: We retrospectively examined age-specific prevalence of osteoporosis and poor bone health indices in GC-treated DMD patients seen between January 2005 and July 2012 at Cincinnati Children’s Hospital. Outcomes of interest were fractures (total, vertebral, long bone), and low age- and height-adjusted z -scores ( z -scores also increased with age, and varied with site of measurement. Osteoporosis is frequent in DMD patients from a young age. Our study is the first to examine age-specific prevalence of osteoporosis and frequency of poor bone health indices throughout the pediatric age span in a large DMD cohort. These data also highlight the complexity of bone health measures, and the urgent need to improve detection, prevention and treatment of osteoporosis in DMD.