One children's hospital planning and development process to adhere to the FDA recommendation that babies and young children undergo thyroid function testing after receiving an injection of iodine-containing contrast media for medical imaging.

The United States (US) Food and Drug Administration (FDA) has issued multiple statements and guidelines since 2015 on the topic of thyroid function testing in babies and children through 3 years old after receiving iodinated contrast media for medical imaging exams. In April 2023, the FDA adjusted this recommendation to target babies and young children younger than 4 years of age who have a history of prematurity, very low birth weight, or underlying conditions which affect thyroid gland function, largely in response to solid arguments from expert statements from the American College of Radiology (ACR) which is endorsed by the Society for Pediatric Radiology (SPR), Pediatric Endocrinology Society (PES), and the Society for Cardiovascular Angiography & Intervention (SCAI). Herein we describe our approach and development of a clinical care guideline along with the steps necessary for implementation of the plan including alterations in ordering exams requiring iodinated contrast media, automatic triggering of lab orders, reporting, and follow-up, to address the 2022 FDA guidance statement to monitor thyroid function in children after receiving iodinated contrast media. The newly implemented clinical care guideline at Ann and Robert H. Lurie Children's Hospital of Chicago remains applicable following the 2023 updated recommendation from the FDA. We will track patients less than 3 months of age who undergo thyroid function testing following computed tomography (CT), interventional radiology, and cardiac catheterization exams for which an iodinated contrast media is administered as a clinical care quality initiative.

The long-term efficacy and safety of nilotinib in pediatric patients with CML: a 5-year update of the DIALOG study.

The efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.

Reproductive late effects after hematopoietic stem cell transplant in pediatric, adolescent, and young adult cancer survivors.

Reproductive late effects after hematopoietic stem cell transplant can have a significant impact on cancer survivors' quality of life. Potential late effects include gonadal insufficiency, genital graft-versus-host disease, uterine injury, psychosexual dysfunction, and an increased risk of breast and cervical cancer in patients treated with total body irradiation. Despite guidelines, screening and treatment are not standardized among at-risk patients. Provider barriers include lack of knowledge of at-risk therapies and evidenced-based guidelines. Patient barriers include a reluctance to report symptoms and lack of awareness of treatment options. System barriers include inefficient implementation of screening tools and poor dissemination of guidelines to providers who serve as the medical home for survivors. This review guides the clinician in identifying and managing reproductive late effects after hematopoietic stem cell transplant to improve outcomes.

Prevalence of Abnormal Hemoglobin A1c Values in Single Ventricle Patients Following Fontan Palliation.

Fontan palliation has improved survival in single ventricle patients. However, Fontan patients are subject to long-term morbidity. A few previous studies suggest Fontan patients have an increased risk of abnormal glucose metabolism without a clear mechanism. We aim to evaluate the prevalence and severity of abnormal hemoglobin A1c (HbA1c) values in Fontan patients and identify associated factors. Single-center retrospective cross-sectional cohort study including Fontan patients and documented HbA1c testing. Univariate demographic, anthropometric, and laboratory variable comparisons were completed and a stepwise selection multivariate regression model was attempted. The study included 414 Fontan patients, median age of 19 years (range 3-59 years). Of these, 190 patients (60.5% male) had at least one HbA1c. Abnormal HbA1c (> 5.6%) was found in 36% (n = 70) and diabetic-range HbA1c (≥ 6.5%) in 4.7% (n = 9). Factors associated with abnormal HbA1c included non-white race (63% vs 45%, p = 0.018), female sex (49% vs 34%, p = 0.050), elevated adult BMI [29.6 (± 8.4) vs 24.8 (± 4.8), p = < 0.0001], elevated blood glucose [108.7 (± 47.3) vs 91.1 (± 17.9), p = < 0.0001], and elevated triglycerides [101.5 (± 52.9) vs 84.1 (± 50.9), p = 0.029]. There were no significant differences found between the two HbA1c groups regarding cardiac diagnoses or surgical factors including type of stage 1 procedure, type of stage 3 procedure, or fenestration of Fontan. Patient age at time of initial Fontan procedure and time since initial Fontan showed no association with abnormal glucose metabolism. Obesity (BMI z-score ≥ 1.6 in children and BMI ≥ 30 in adults) was correlated with abnormal HbA1c (p = 0.008, 95%CI 0.069-0.45). There is a high prevalence of elevated HbA1c values in Fontan patients with modifiable associated factors, such as obesity and hypertriglyceridemia. Further investigation is needed to identify additional associated factors for abnormal glucose metabolism and determine its clinical significance. Lastly, we propose a new management protocol to screen for abnormal glucose metabolism.

Perioperative outcomes in children with Hashimoto's thyroiditis undergoing total thyroidectomy.

BACKGROUND: Hashimoto's thyroiditis (HT) affects 1-2 % of the pediatric population. In adults with HT, thyroidectomy is considered challenging and prone to postoperative complications due to the chronic inflammatory process. However, the complications of thyroidectomy among children with HT have not been established. The objective of our study was to evaluate whether children with HT undergoing total thyroidectomy for presumed thyroid cancer have higher complication rates than children without HT. METHODS: A retrospective cohort study of children who underwent total thyroidectomy by high-volume pediatric otolaryngologists between 2014 and 2021. RESULTS: 111 patients met inclusion criteria, 15 of these were diagnosed with HT preoperatively. Operative time and length of admission were similar among the groups. Postoperatively, patients with HT were more likely to have low levels of parathyroid hormone (60 % vs 26 %, p = 0.014) and transient hypocalcemia compared to non-HT patients, present with symptomatic hypocalcemia (67 % vs 27 %, p = 0.006), demonstrate EKG changes (20 % vs 6.3 %, p = 0.035) within 24 h of surgery, and to require both oral and intravenous calcium supplements (80 % vs 35 %, p = 0.001 and 60 % vs 22 % p = 0.004 respectively). Persistent hypocalcemia at 6 months follow-up, and recurrent laryngeal nerve paralysis rates were similar between groups. Parathyroid tissue was found in the thyroid specimen of 9 (60 %) HT patients vs 34 (35 %) non-HT patients (p = 0.069). CONCLUSIONS: The risk of permanent complications among children with HT following thyroidectomy is low. However, patients with HT are more likely to develop symptomatic transient hypocalcemia and to require oral and intravenous calcium supplements in the immediate post-operative period compared to non-HT patients. Tailoring a perioperative treatment protocol to optimize calcium levels may be considered for children with HT.

Total Thyroidectomy and Subsequent Weight Gain in Pediatric Populations.

OBJECTIVE: To evaluate weight gain in children post-thyroidectomy and identify predictors. METHODS: Charts from patients at a tertiary health care facility who underwent total thyroidectomy from 2014 to 2020 were reviewed for Body Mass Index z-scores (BMIz) at the time of thyroidectomy and at 1 and 2-year post-operation intervals. Patient demographic information, comorbidities, pre- and postoperative thyroid stimulating hormone, and postoperative free T4 levels were also extracted. Patients with other known endocrine abnormalities, chronic kidney disease, or without sufficient follow-up were excluded. RESULTS: A total of 56 patients (ages 3-17 years old) met the inclusion criteria (n = 17 Graves' disease; n = 39 presumed cancer). Over the first year, average BMIz significantly increased in patients with Graves' disease (∆BMIz = 0.45 ± 0.77, p = 0.03), Hispanic ethnicity (∆BMIz = 0.43 ± 0.68, p = 0.004), Medicaid/no insurance coverage (∆BMIz = 0.33 ± 0.74, p = 0.038), age <13 years at thyroidectomy (∆BMIz = 0.35 ± 0.68, p = 0.016), and persistent postoperative hypothyroidism (∆BMIz = 0.41 ± 0.41, p = 0.012). These changes remained significant after the second year. Age at thyroidectomy correlated negatively with ∆BMIz only after the first year (r = -0.40, p = 0.002). Regression analysis, controlling for Graves' status, persistent postoperative hypothyroidism, and insurance coverage, identified age at thyroidectomy as a significant predictor of ∆BMIz after the first year (b = -0.06, p = 0.004) and Hispanic ethnicity as a significant predictor after the second year (b = 0.60, p = 0.003). CONCLUSION: A small increase in BMIz post-thyroidectomy was observed across several patient subgroups. Younger age at thyroidectomy and Hispanic ethnicity were associated with increased BMIz in the first 2 years post-thyroidectomy. LEVEL OF EVIDENCE: Level 4 - Historically controlled cohort Laryngoscope, 133:1518-1523, 2023.

Short-Term Complications After Total Thyroidectomy in Children.

INTRODUCTION: Total thyroidectomy for benign disease is becoming more common among children. The purpose of this study was to evaluate 30-day outcomes in children undergoing total thyroidectomy and determine if the short-term outcomes are different in those with a malignant versus benign indication for surgery. METHODS: This retrospective cohort study used the American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-Pediatric) to identify all children who underwent total thyroidectomy from 2015 to 2019. Fisher's exact test was used to compare postoperative outcomes between benign and malignant indications for thyroidectomy. RESULTS: Among 1595 total thyroidectomy patients, 1091 (68.4%) had a benign indication and 504 (31.6%) had a malignant indication. There were 1234 (77.4%) females, and the median age was 14.9 y (interquartile range [IQR] 12.5, 16.6). Average length of stay (LOS) was similar between cohorts (1.7 d for benign and 1.9 d for malignant, P = 0.30). Parathyroid auto-transplantation was performed in 71 (6.5%) patients in the benign cohort and 43 (8.6%) in the malignant cohort (P = 0.15). The most common complications were readmissions (23 [2.1%] benign and 15 [3.0%] malignant, P = 0.29) and reoperations (7 [0.6%] benign and 5 [1.0%] malignant, P = 0.54). Complication profiles were similar between benign and malignant cohorts (2.8% and 4.6%, respectively [P = 0.10]). CONCLUSIONS: Children undergoing total thyroidectomy for benign and malignant indications have low rates of 30-d postoperative complications, suggesting that total thyroidectomy is a safe option for children with benign disease. Evaluation of long-term outcomes is needed.

Abnormal TSH Prior to Surgery in Children with Graves' Disease Predicts Abnormal TSH Following Thyroidectomy.

OBJECTIVE: To identify variables that are associated with poor compliance to thyroid hormone replacement therapy in children after total thyroidectomy. METHOD: A retrospective cohort study of children who underwent total thyroidectomy by high-volume pediatric otolaryngologists between 1/2014 and 9/2021. Postoperative poor compliance was characterized by at least three separate measurements of high TSH levels not associated with radioactive iodine treatment. RESULTS: There were 100 patients, ages 3-20 years old who met inclusion criteria; 44 patients underwent thyroidectomy for cancer diagnosis, and 56 for Graves' disease. The mean follow-up time was 36.5 months (range 3.0-95.6 months). Overall, 42 patients (42%) were found to have at least three measurements of high TSH during follow-up, and 29 patients (29%) were diagnosed with clinical hypothyroidism. Sex, race, income, insurance type, and benign versus malignant etiology for thyroidectomy were not associated with adherence to therapy. Multivariate regression analysis identified patients with Graves' disease and hyperthyroidism at the time of surgery and Hispanic ethnicity to be associated with postoperative clinical hypothyroidism (OR 9.38, 95% CI 2.16-49.2, p = 0.004 and OR 6.15, 95% CI 1.21-36.0, p = 0.033, respectively). CONCLUSIONS: Preoperative hyperthyroidism in patients with Graves' disease and Hispanic ethnicity were predictors of postoperative TSH abnormalities. Preoperative counseling for patients and their families on the implications of total thyroidectomy and the need for life-long medications postoperatively is necessary. Efforts should be made to evaluate and improve adherence to therapy pre-and postoperatively in patients with Graves' disease. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2402-2406, 2023.

The effect of hyperthyroidism at thyroidectomy on complication rates in children with Graves' disease.

BACKGROUND: Graves' disease (GD) is the most common cause of childhood hyperthyroidism. Surgery is often chosen as a treatment modality given the high relapse rates and side effects of antithyroid drugs and has shown to be safe and efficacious. The goal of our study was to evaluate whether hyperthyroidism at time of thyroidectomy is associated with higher intra and postoperative complication rates. METHODS: A retrospective cohort study of children who underwent thyroidectomy for GD by high-volume pediatric otolaryngologists between 2014 and 2021. RESULTS: 64 patients met inclusion criteria. Patients with hyperthyroidism (defined as free T4≥1.63 ng/dL) were more likely to be treated with beta-blocker preoperatively compared to the euthyroid group (20/24 patients (83%) vs 23/40 patients (58%) respectively, p = 0.035). Twenty (83%) patients with hyperthyroidism and 39 euthyroid patients (98%) were treated with methimazole prior to surgery. Intraoperative tachycardia was noted in 5% of euthyroid patients and 20.8% of patients with hyperthyroidism. The mean peak heart rate intra-operatively and the number of patients with heart rate ≥120bmp were significantly higher for patients with hyperthyroidism (96.5 ± 16.2 vs 87.6 ± 22.1bpm, p = 0.02). Two patients required administration of esmolol during surgery for heart rate control, both with hyperthyroidism. Intra-operative peak systolic blood pressure, operative time, estimated blood loss, persistent hypocalcemia, length of admission and recurrent laryngeal nerve paralysis rates were similar among groups. CONCLUSIONS: Hyperthyroidism at surgery is associated with increased heart rate intraoperatively, with no increased risk for other complications. While optimizing thyroid hormone levels before surgery should be pursued in all children, our data suggest that hyperthyroidism should not delay the surgery.

The 2015 American Thyroid Association guidelines and trends in hemithyroidectomy utilization for pediatric thyroid cancer.

BACKGROUND: In 2015, the American Thyroid Association (ATA) released its inaugural recommendations for the management of thyroid cancer in children. We aim to evaluate whether there has been a change in hemithyroidectomy utilization for pediatric differentiated thyroid cancer, and the association between those changes and the release of the ATA guidelines. METHODS: The National Cancer Database was queried and identified 4776 patients ≤18 years old with differentiated thyroid cancer. Causal impact time-series analysis and logistic analysis were utilized to assess factors associated with use of hemithyroidectomy. RESULTS: Post-2015 hemithyroidectomy rate was greater than predicted based on preguideline trends (predicted: 8.4%, actual: 12.6%, p = 0.001). In logistic analysis of factors associated with hemithyroidectomy use, we find that Papillary histology, tumor size >1 cm, nodal examination, and positive nodes were associated with lower rate of hemithyroidectomy (OR: 0.23, 0.51, 0.62, and 0.18, respectively). CONCLUSION: There has been a significant increase in hemithyroidectomy utilization for pediatric differentiated thyroid cancer.

Surgeon perceptions of volume threshold and essential practices for pediatric thyroidectomy✰.

INTRODUCTION: The topics of sub-specialization and regionalization of care have garnered increased attention among pediatric surgeons. Thyroid surgeries are one such sub-specialty and are commonly concentrated within practices. A national survey was conducted examining current surgeon practices and beliefs surrounding pediatric thyroid surgery. METHODS: Non-resident members of the American Pediatric Surgical Association (APSA) were surveyed in October 2020. Respondents were stratified based on self-reported thyroid surgical experience. Those who performed thyroid surgery were asked about surgical technique and operative practices; those who did not were asked about referral patterns. All respondents were asked about perceptions surrounding the volume-outcome relationship for pediatric thyroid surgery. RESULTS: Among 1015 APSA members, 405 (40%) responded, with 79% (317/400) practicing at academic hospitals, 58% (232/401) practicing in major metropolitan area, and 41% (161/392) with over 10 years of attending pediatric surgery experience. Most respondents (88%, n = 356) agreed that thyroid surgery volume affects outcome, though wide variation was reported in the annual case threshold for "high volume" surgery. Eighty-four respondents (21%) reported performing ≥ 1 pediatric thyroid surgery in the past year. Of these, 82% routinely use recurrent laryngeal nerve monitoring, 32% routinely send hemithyroidectomy patients home the same day, and there was little consensus surrounding postoperative hypocalcemia management. The majority of respondents endorse performing thyroid procedures with a colleague. CONCLUSIONS: Pediatric thyroid surgery appears to be performed by a subset of active pediatric surgeons, most of whom endorse the use of a dual operating team. More evidence is needed to build consensus around additional perioperative practices.

Effect of surgeon volume on pediatric thyroid surgery outcomes: A systematic review.

BACKGROUND: Pediatric thyroidectomy has been identified as a surgical procedure that may benefit from concentrating cases to high-volume surgeons. This systematic review aimed to address the definition of "high-volume surgeon" for pediatric thyroidectomy and to examine the relationship between surgeon volume and outcomes. METHODS: PubMed, Embase, Cochrane Library, Scopus, Web of Science, ClinicalTrials.gov, and OpenGrey databases were searched for through February 2020 for studies which reported on pediatric thyroidectomy and specified surgeon volume and surgical outcomes. RESULTS: Ten studies, encompassing 6430 patients, were included in the review. Five single-center retrospective studies reported only on high-volume surgeons, one single center retrospective study reported on only low-volume surgeons, and four national database studies (2 cross sectional, 2 retrospective reviews) reported outcomes for both high-volume and low-volume surgeons. Majority of patients underwent total thyroidectomy (54.9%); common indications for surgery were malignancy (41.7%) and hyperthyroidism/thyroiditis (40.5%). Rates of transient hypocalcemia (11.4% - 74.2%), transient recurrent laryngeal nerve injury (0% - 9.7%), and bleeding (0.5% - 4.3%) varied across studies. Definitions for high-volume pediatric thyroid surgeons ranged from ≥9 annual pediatric thyroid operations to >200 annual thyroid operations (with >30 pediatric cases). Four studies reported significantly better outcomes, including lower post-operative complications and shorter length of hospital stay, for patients treated by high-volume surgeons. CONCLUSIONS: Despite significant variation in caseloads to define volume, pediatric thyroid patients have generally better outcomes when operated on by higher volume surgeons. Concentration thyroidectomy cases to a smaller cohort of surgeons within pediatric practices may confer improved outcomes. LEVEL OF EVIDENCE: Systematic Reviews and Meta-Analyses; Level IV.

A phase 2 study of nilotinib in pediatric patients with CML: long-term update on growth retardation and safety.

The phase 2, open-label study (DIALOG) of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) met its coprimary end points, showing sustained nilotinib efficacy in patients with newly diagnosed (ND) or imatinib/dasatinib resistant/intolerant (R/I) CML. This update assessed growth and safety profiles in patients who had completed ≥48, 28-day treatment cycles of nilotinib 230 mg/m2 twice daily, or previously discontinued the study. Height was assessed regularly and reported using standard deviation scores (SDSs) based on World Health Organization growth charts. All data were summarized descriptively (cutoff, 6 March 2019). Overall, 33 patients in the R/I cohort and 25 patients in the ND cohort received nilotinib. Each cohort showed a negative slope in height SDS over the course of the study, indicating attenuated growth rates during nilotinib treatment: overall median change from baseline in height SDS after 48 cycles was -0.54 SDS (range, - 1.6 to 0.4) and -0.91 SDS (-1.4 to -0.1) in R/I and ND cohorts, respectively. Patients in the R/I cohort were shorter at baseline than those in the ND cohort, and remained so throughout the study. The most common all-cause adverse events were increased blood bilirubin (53.4%), headache (46.6%), pyrexia (37.9%), and increased alanine transferase (36.2%). Apart from the impact on growth, the safety profile of nilotinib was generally consistent with previous reports. This study was registered on www.clinicaltrials.gov at #NCT01844765.

Hypocalcemia prevention and management after thyroidectomy in children: A systematic review.

INTRODUCTION: Hypocalcemia is the most common complication following thyroidectomy in children. Guidelines to manage post-thyroidectomy hypocalcemia are available for adults, but not children. The objective of this review was to identify practices related to hypocalcemia prevention and management in pediatric patients. METHODS: We identified studies examining the prevention and management of hypocalcemia in pediatric patients post-thyroidectomy within PubMed, EMBASE, Web of Science and Cochrane databases. Three independent reviewers screened citations and reviewed full-text papers. RESULTS: A total of 15 studies were included, representing 1552 patients. The overall study quality was weak with lack of randomization and inconsistent outcome reporting. The pooled incidence of hypocalcemia from the 15 studies was 35.5% for transient hypocalcemia and 4.2% for permanent hypocalcemia. All studies discussed post-operative hypocalcemia treatment, with most patients requiring admission for intra-venous calcium therapy. One study described a protocol discharging asymptomatic patients on calcitriol and calcium. Three studies discussed preoperative calcium supplementation in patients at risk of hypocalcemia. No studies examined routine use of calcium and/or vitamin D supplementation to prevent post-operative hypocalcemia. CONCLUSION: A significant number of children undergoing thyroidectomy develop hypocalcemia. Despite this high incidence, our systematic review demonstrates significant practice variation surrounding post-thyroidectomy hypocalcemia prevention and management in children. LEVEL OF EVIDENCE: III (systematic review of studies of which some were case-control studies (III) and some were case series (IV)).

Extensive miRNA expression analysis in craniopharyngiomas.

PURPOSE: Craniopharyngiomas are benign tumors of the sellar or parasellar regions. They arise from the remnants of Rathke's pouch and are considered a "developmental disease." microRNAs are short non-coding RNAs that play a key regulatory role in the control of expression of entire gene networks. We performed an extensive analysis of miRNAs in craniopharyngiomas aiming to identify a miRNA expression signature that might aid in the prognosis of disease progression and outcome. METHODS: Thirty-seven craniopharyngioma samples from twenty-three patients, ten age-matched controls from autopsy, and ten infant controls from the developing pituitary from autopsy were evaluated for the expression of 754 miRNAs using TaqMan® Low Density Arrays (TLDAs) v2.0 (Applied Biosystems, Foster City, CA). RESULTS: Among the most differentially expressed miRNAs, downregulation of miR-132 appears to be a marker of aggressiveness and also plays a role in epithelial-mesenchymal transition. CONCLUSIONS: This is the first time that an extensive study of miRNA expression has been performed in craniopharyngiomas. Further research needs to be performed to investigate the potential role of miR-132 in the development and progression of craniopharyngiomas, and its value as a prognostic marker of aggressiveness.

Recognizing Endocrinopathies Associated With Tyrosine Kinase Inhibitor Therapy in Children With Chronic Myelogenous Leukemia.

Side effects of tyrosine kinase inhibitor (TKI) treatment vary in children and adults with chronic myelogenous leukemia (CML). As children have a much longer life expectancy than adults, TKI therapy may continue for decades and with long-term consequences that differ from adults. Children may develop endocrinopathies related to "off-target" effects of TKIs, such as delayed growth, changes in bone metabolism, thyroid abnormalities, and effects on puberty and fertility. These endocrinopathies present additional challenges for pediatric patients with CML. This review critically evaluates the literature on long-term endocrine side effects of TKIs in the pediatric CML population and provides suggested recommendations.