Hyperglycemia requiring insulin during acute lymphoblastic leukemia induction chemotherapy is associated with increased adverse outcomes and healthcare costs.

BACKGROUND: Hyperglycemia is a complication of induction chemotherapy in 10%-50% of pediatric patients with acute lymphoblastic leukemia (ALL). Though hyperglycemia in ALL patients is usually transient, it may be associated with adverse health outcomes. However, the risk factors for and consequences of hyperglycemia are poorly understood. We hypothesized that hyperglycemia significant enough to require insulin therapy during induction chemotherapy would be associated with increased morbidity and mortality in pediatric ALL patients during induction chemotherapy and in subsequent care. METHODS: We abstracted clinical and resource utilization data from the Pediatric Health Information System (PHIS) database utilizing ICD-9 codes and medication charges. We used logistic regression analysis to predict the development of hyperglycemia. The effects of hyperglycemia on binary and count adverse outcomes following induction chemotherapy were modeled using mixed-effect regression models. RESULTS: An increased risk of hyperglycemia requiring insulin was associated with older age, female sex, higher risk group and trisomy 21. Patients on insulin for hyperglycemia had increased mortality following induction chemotherapy. These patients were more likely to have subsequent infectious complications, need for bone marrow transplant, and risk of disease relapse. They also had greater length of inpatient stay, higher cost of care, and were more likely to require intensive care unit admission during induction chemotherapy. CONCLUSIONS: Hyperglycemia requiring insulin during induction chemotherapy in pediatric ALL is associated with an increased risk of short-term and long-term complications. Prospective studies are needed to analyze formal screening, preventive measures, and optimal management practices for hyperglycemia during ALL induction chemotherapy.

Relationship of adiponectin and leptin with autoimmunity in children with new-onset type 1 diabetes: a pilot study.

AIM: To explore racial differences in adiponectin, and leptin and their relationship with islet autoimmunity in children with new-onset type 1 diabetes (T1D). METHODS: Medical records were reviewed from a cohort of new-onset clinically diagnosed T1D subjects matched by race, age, gender, and year of diagnosis. Sera were available for 156 subjects (77 African American (AA), 79 Caucasian (C), 48% male, age of 11.1 ± 3.8 yr) and assayed for adiponectin and leptin prior to (D0), 3, 5 d, and 2-4 months (M3) after insulin therapy and islet autoantibodies to GAD, IA2, insulin, and ICA were measured at onset. RESULTS: Adiponectin levels increased significantly following insulin therapy by day 5 (D5) (D0: 13.7 ± 7.2 vs. D5: 21.3 ± 9.9 µg/mL, p < 0.0001), but no further significant increase from D5 to M3. At DO, AA had lower adiponectin levels (10.5 vs. 15.7 µg/mL, p = 0.01), were more often overweight than C (55 vs. 18%, BMI ≥ 85th‰) and fewer had positive autoantibodies (72 vs. 87%, p = 0.05). Racial differences in adipocytokines disappeared after adjustment for BMI. At M3, subjects with more number of positive autoantibodies had higher adiponectin levels (p = 0.043) and adiponectin/leptin ratio (ALR) (p = 0.01), and lower leptin levels (p = 0.016). CONCLUSION: Adiponectin levels increased acutely with insulin therapy. Significantly lower adiponectin levels in AA were related to greater adiposity and not race. These pilot data showing those with the fewest autoantibodies had the lowest adiponectin levels, supporting the concept that insulin-resistant subjects may present with clinical T1D at earlier stages of ß-cell damage.

Novel Inactivating Homozygous PAPSS2 Mutation in Two Siblings With Disproportionate Short Stature.

Background/Objective: Variants in PAPSS2 (3'-phosphoadenosine 5'-phosphosulfate synthetase 2) present with varying degrees of brachyolmia (short trunk, platyspondyly, mild long-bone abnormalities). Our objective is to present the phenotype of male and female siblings with the same novel inactivating variant in PAPSS2. Case Report: A Jordanian female (case 1), born to consanguineous parents, was referred at 10 years of age for short stature (SS). She had a normal laboratory workup, including normal growth hormone stimulation testing. Spinal x-rays done for clinical scoliosis revealed platyspondyly. She attained an adult height of 143.5 cm (-3 SD). Years later, her brother (case 2) was referred at 21 months of age for SS. His laboratory workup and bone age were normal. His growth velocity declined at 6 years of age, but normal growth factors did not suggest growth hormone deficiency. When he returned during puberty, disproportionate body measurements were noted. A skeletal survey revealed platyspondyly, increasing suspicion of growth plate pathology. Exome sequencing in the family revealed a homozygous variant, p.His496Pro (H496P) in PAPSS2 (NM_004670.3:c.1487A>C). Both parents carried the same variant. Discussion: PAPSS2 assists with the sulfonation of dehydroepiandrosterone (DHEA) to DHEA sulfate and the sulfonation of proteoglycans in the cartilage, necessary for endochondral bone formation. PAPSS2-inactivating variants present with skeletal dysplasia and elevated DHEA levels. Conclusion: This novel variant in PAPSS2 manifested with mild brachyolmia but disproportionate SS in male and female siblings. Biochemical phenotype with low circulating DHEA sulfate and high DHEA levels reflect a sulfonation defect.

Molecular Characterization of Sporadic Pediatric Thyroid Carcinoma with the DNA/RNA ThyroSeq v2 Next-Generation Sequencing Assay.

The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n=18) were studied. We previously tested 15 cases by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not tested previously. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n=3) and TPR/NTRK1 (n=1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could identify only molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n=13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype, but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules to aid future classification, treatment, and clinical management recommendations.

Hypoglycemia: a complication of diabetes therapy in children.

The experience of hypoglycemia is probably the most feared and hated consequence of life with type 1 diabetes among pediatric patients and their parents. Although transient detrimental effects are clearly disturbing and may have severe results, there is surprisingly little evidence of long-term CNS damage, even after multiple hypoglycemic episodes, except in rare instances. Despite the latter evidence, we advocate that every treatment regimen be designed to prevent hypoglycemia without inducing unacceptable hyperglycemia and increasing the risk of micro- and macrovascular complications.

Can malignant thyroid nodules be distinguished from benign thyroid nodules in children and adolescents by clinical characteristics? A review of 89 pediatric patients with thyroid nodules.

BACKGROUND: Thyroid nodules are less common in children than adults, but the risk of malignancy in thyroid nodules is much higher in children. The ability to characterize pediatric thyroid nodules has improved with the use of ultrasound-guided fine-needle aspiration, the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) classification system, and expanded molecular testing. Nevertheless, stratification criteria to predict thyroid malignancy in children are poorly defined. Our objective was to determine if clinical presentation and molecular genetics could predict malignancy in pediatric thyroid nodules. METHODS: Retrospective chart review of patients ≤18 years of age at the Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center with the diagnosis of a thyroid nodule from January 2007 to January 2012 was conducted. Eighty-nine subjects fulfilled the inclusion criteria: 1) thyroid nodule ≥0.8 cm and biopsy (n=76), or 2) thyroid nodule ≥0.8 cm, no biopsy, and ultrasound follow-up for at least 2 years (n=13). RESULTS: Twenty-four (27%) of 89 patients were diagnosed with thyroid cancer (50% papillary thyroid carcinoma [PTC], 50% follicular variant of papillary thyroid carcinoma [FVPTC]). Features associated with malignancy included larger nodule size, palpable nodule, or palpable lymphadenopathy. There were no differences in presenting features between patients with PTC and those with FVPTC. Thyroid malignancy was diagnosed in all nine patients with a molecular abnormality (BRAF, RAS, RET/PTC, PAX8/PPARγ). CONCLUSIONS: Clinical features, FNA cytology, and molecular genetics are valuable tools to discriminate benign from malignant nodules in pediatric patients. This information is important to direct subsequent clinical management.

Preoperative cytology with molecular analysis to help guide surgery for pediatric thyroid nodules.

OBJECTIVES: To discuss the use of molecular mutation analysis in the surgical management of pediatric thyroid nodules. METHODS: This study is a case series with retrospective chart review performed at a tertiary children's hospital. Pediatric patients who presented to the Children's Hospital of Pittsburgh of UPMC with a thyroid nodule and had subsequent fine needle aspiration with positive molecular mutation between November 2009 and February 2012 were identified and charts were reviewed. Patient demographics, presenting signs, lab results, pathologic findings, and surgical outcomes were collected. RESULTS: 5 pediatric patients with positive molecular mutation studies on preoperative FNA were identified. FNA results were categorized as follows: suspicious for follicular neoplasm (n = 2), suspicious for malignant cells (n = 1), and positive for malignant cells (n = 2). The following molecular mutations were identified: BRAF (V600E) (n = 2), PAX8/PPARγ (n = 1), HRAS (n = 1), and RET/PTC (n = 1). A total thyroidectomy was performed on each patient. In all cases the final pathology was positive for malignancy (papillary thyroid carcinoma (PTC), n = 3; follicular variant of PTC, n = 2). Three of five patients had transient postsurgical hypocalcemia. There were no other postoperative complications. CONCLUSIONS: This series provides evidence that preoperative FNA with reflex molecular testing in pediatric thyroid nodules can help guide surgical decision making, reduce the need for repeat surgeries, and diminish the risk of complications from a staged procedure.