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PURPOSE To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens. METHODS Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents. RESULTS Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity. CONCLUSION With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Background: Allogeneic hematopoietic cell transplantation (HCT) recipients have increased risk of developing glucose intolerance and diabetes mellitus (DM). The strongest risk factor for glucose intolerance is being overweight/obese, as determined by body mass index (BMI), which does not account for differences in body composition. We examined the association between body composition measures from pre-HCT CT and early-onset (≤30 days) de novo glucose intolerance after HCT, and determined its impact on nonrelapse mortality (NRM). Methods: This study included 749 patients without pre-HCT DM. Skeletal muscle loss [abnormal skeletal muscle gauge (SMG)] and abnormal visceral adiposity (VA) were defined by sex-specific tertiles. Fine–Gray proportional subdistribution HR estimates and 95% confidence intervals (CI) were obtained to determine the association between muscle loss and VA and development of glucose intolerance. 1 year NRM was calculated for patients alive at day 30. Results: Median age at HCT was 50.2 years. By day 30, 8.1% of patients developed glucose intolerance and 731 remained alive. In multivariable analysis, abnormal SMG was associated with increased risk of glucose intolerance in nonoverweight (BMI < 25 kg/m2) patients (HR = 3.00; 95% CI, 1.15–7.81; P = 0.024); abnormal VA was associated with increased risk of glucose intolerance in overweight/obese patients (HR = 2.26; 95% CI, 1.24–4.12; P = 0.008). Glucose intolerance was independently associated with NRM (HR = 1.88; 95% CI, 1.05–3.39; P = 0.035). Conclusions: Abnormal SMG and VA were associated with glucose intolerance in nonoverweight and overweight/obese patients, respectively, which contributed to increased risk of 1 year NRM. Impact: This information may guide personalized interventions to decrease the risk of adverse outcomes after HCT. See related commentary by Giri and Williams, p. 2002

PURPOSE In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. METHODS Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant ( H-K-NRAS), BRAF-mutant ( BRAF p.V600E), and RET/ NTRK fusion ( RET, NTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed. RESULTS Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with RET/ NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mut subgroups. CONCLUSION Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with RET/ NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

PURPOSE To characterize germline genetic risk factors of diabetes mellitus among long-term survivors of childhood cancer. METHODS Adult survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS) Original Cohort (n = 5,083; 383 with diabetes) were used to conduct a discovery genome-wide association study. Replication was performed using the CCSS Expansion (n = 2,588; 40 with diabetes) and the St Jude Lifetime (SJLIFE; n = 3,351; 208 with diabetes) cohorts. Risk prediction models, stratified on exposure to abdominal radiation, were calculated using logistic regression including attained age, sex and body mass index, diagnosis, alkylating chemotherapy, age at cancer diagnosis, and a polygenic risk score (PRS) on the basis of 395 diabetes variants from the general population. Area under the receiver operating characteristic curve (AUC) was calculated for models on the basis of traditional risk factors, clinical risk factors, and PRS. RESULTS There was a genome-wide significant association of rs55849673-A with diabetes among survivors (odds ratio, 2.9; 95% CI, 2.0 to 4.2; P = 3.7 × 10−8), which is related to expression of ERCC6L2 in the Genotype-Tissue Expression project. The association of rs55849673-A was observed largely among survivors not exposed to abdominal radiation (odds ratio = 3.5, P = 1.1 × 10−7) and the frequency of rs55849673-A was consistently higher among diabetic survivors in the CCSS Expansion and SJLIFE cohorts. Risk prediction models including traditional diabetes risk factors, clinical risk factors and PRS had an optimism-corrected AUC of 0.801, with an AUC of 0.751 in survivors treated with abdominal radiation versus 0.813 in survivors who did not receive abdominal radiation. CONCLUSION There is evidence for a novel locus of diabetes among survivors not exposed to abdominal radiation. Further refinement and validation of clinic-based risk prediction models for diabetes among long-term survivors of childhood cancer is warranted.

Context Pediatric thyroid cancer (TC) incidence rates are increasing, yet TC has one of the highest survival rates. Despite increased prevalence, little is known about youth adjustment to TC, particularly compared to other pediatric cancers. Objective The current study sought to describe health-related quality of life (HRQoL) in pediatric TC patients early after diagnosis compared to other pediatric cancer patients and healthy youth and examine predictors of HRQoL. Methods Pediatric TC patients (ages 8.5–23.4 years) and their caregivers from a pediatric thyroid center completed psychosocial questionnaires as part of a clinic-based screening program around time of surgery. TC HRQoL was compared to other pediatric cancer and healthy youth reported norms. Clinical and demographic data extracted from the medical record were examined for predictors of HRQoL. The main outcome measures included the Pediatric Quality of Life Inventory (PedsQL) and Distress Thermometer. Results Findings evidenced significantly higher HRQoL for TC patients than other pediatric cancers for all but emotional and school functioning. Compared to healthy youth, TC patients reported significantly lower functioning, except comparable social functioning. No significant differences in HRQoL were identified based on disease severity, thyroid disease history, or treatment. Patient distress was associated with HRQoL. Conclusion The findings suggest general resilience in TC patients compared to youth with other cancers, yet worse HRQoL than peers. Early universal screening is warranted due to a short TC treatment regimen. If administrative barriers preclude comprehensive screening, the single-item Distress Thermometer may identify patients for further comprehensive screening.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Introduction: The diagnostic utility of molecular profiling for the evaluation of indeterminate pediatric thyroid nodules is unclear. We aimed to assess pediatric cases with indeterminate thyroid fine-needle aspiration (FNA) alongside clinicopathologic features and mutational analysis. Methods: A retrospective review of 126 patients with indeterminate cytology who underwent FNA between January 2010 and December 2021 at the Children’s Hospital of Philadelphia was performed. Indeterminate cases defined by The Bethesda System for Reporting Thyroid Cytopathology (AUS/FLUS or TBSRTC III; FN/SFN or TBSRTC IV; SM or TBSRTC V) were correlated to clinicopathologic and genetic characteristics. Results: Of the 114 surgical cases, 48% were malignant, with the majority of malignant cases diagnosed as follicular variant of papillary thyroid carcinoma (28/55). Risk of malignancy increased with TBSRTC category: 23% for AUS/FLUS, 51% for FN/SFN, and 100% for SM nodules. There were significant differences in surgical approach (p < 0.01), performance of lymph node dissection (p < 0.01), histological diagnosis (p < 0.01), primary tumor focality/laterality (p = 0.04), and lymphatic invasion (p = 0.02) based on TBSRTC classification, with resultant differences in post-surgical risk stratification per American Thyroid Association (ATA) Pediatric Guidelines (p = 0.01). Approximately 89% (49/55) of cases were classified as ATA low risk, and 5 of 6 patients with ATA intermediate- or high-risk disease had SM cytology. Somatic molecular testing was performed in 40% (51/126) of tumors; 77% (27/35) of malignant cases and 38% (6/16) of benign cases harbored driver alteration(s). Of the driver-positive malignant cases, 52% (14/27) were associated with low risk (DICER1, PTEN, RAS, and TSHR mutations), 33% (9/27) were associated with high risk (BRAF mutations and ALK, NTRK, and RET fusions), and 15% (4/27) had unreported risk for invasive disease (APC, BLM, and PPM1D mutations and TG-FGFR1 fusion). Incidence of high-risk drivers increased with TBSRTC category. Approximately 23% (8/35) of patients harboring thyroid malignancy did not have an identifiable driver alteration. Conclusions: Molecular analysis is useful to discriminate benign and malignant thyroid nodules with indeterminate cytology. Patients with driver genetic alteration(s) and indeterminate cytology should consider surgical management secondary to the high incidence (82%; 27/33) of thyroid malignancy in these patients.

OBJECTIVE Rheumatoid arthritis (RA) is associated with low muscle density due to the accumulation of intramuscular fat. The present study was undertaken to identify predictors of changes in muscle density and to determine whether low muscle density predicted changes in strength and physical function. METHODS Patients with RA, ages 18-70 years, completed whole-body dual-energy x-ray absorptiometry and peripheral quantitative computed tomography to quantify lean and fat mass indices and muscle density. Dynamometry was used to measure strength at the hand, knee, and lower leg. Disability and physical function were measured with the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB). Assessments were performed at baseline and at follow-up. Regression analyses assessed associations between patient characteristics, muscle density, and deteriorations in strength and function. RESULTS Muscle density was assessed at baseline in 107 patients with RA. Seventy-nine of these patients (74%) returned for a follow-up assessment at a median follow-up time of 2.71 years (interquartile range 2.35-3.57). Factors associated with declines in muscle density included female sex, higher disease activity, smoking, and lower insulin-like growth factor 1 (IGF-1) levels. Greater muscle density Z score at baseline (per 1 SD) was associated with less worsening per year according to HAQ, SPPB, and 4-meter walk time scores and a lower risk of a clinically important worsening in HAQ score (odds ratio [OR] 1.90 [95% confidence interval (95% CI) 1.06, 3.42]; P = 0.03) and walking speed (OR 2.87 [95% CI 1.05, 7.89]; P = 0.04). CONCLUSION Worsening of skeletal muscle density occurred in patients with higher disease activity, in smokers, and in those with lower IGF-1. Low muscle density was associated with worsening of physical function. Interventions addressing reductions in muscle quality might prevent functional decline.

Introduction: Risk of malignancy for pediatric thyroid nodules classified according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is not well defined. Correlations between risk of malignancy and ancillary clinical data remain inconclusive. We report a single institutional experience of fine-needle aspiration (FNA) to improve upon current management paradigm of thyroid nodules. Methods: A retrospective chart review of 575 thyroid nodules was performed of 324 patients who underwent 340 FNAs between 2008 and 2018 at the Children’s Hospital of Philadelphia. Demographics, ultrasound (US) characteristics, FNA cytology, surgical pathology, and ancillary data were reviewed. Results: The rate of malignancy according to TBSRTC was 0.0% for category I, 0.8% for category II, 15.6% for category III, 54.5% for category IV, 100.0% for category V, and 100.0% for category VI. The cumulative Thyroid Imaging Reporting and Data System (TI-RADS) score was significantly correlated with benign and malignant nodules on pathology (p < 2.2e−16). Distribution of TI-RADS for cytologically indeterminate nodules with benign or malignant pathology revealed significant differences for composition (p = 3.20e−8) and echogenic foci (p = 0.005) but not for echogenicity (p = 0.445), shape (p = 0.160), margins (p = 0.220), and size (p = 0.105). Distributions of thyroid-stimulating hormone levels between benign and malignant patients was significant (p = 1.58e−3). Conclusions: Nodules with TI-RADS scores >3 should undergo FNA, irrespective of size; surgical resection is recommended for nodules classified as TBSRTC category IV and V due to high risk of malignancy. US surveillance instead of FNA can be performed for nodules with TI-RADS scores ≤3.

Childhood cancer survivors (CCS) are at increased risk for thyroid disease, and many require definitive management with thyroid surgery. Despite this, there is limited evidence on surgical outcomes among CCS. We sought to evaluate postoperative outcomes at our institution among CCS undergoing thyroid surgery compared to patients without a history of primary childhood malignancy.Medical records were reviewed for 638 patients treated at the Children's Hospital of Philadelphia Pediatric Thyroid Center between 2009 and 2020. Rates of surgical complications, including recurrent laryngeal nerve (RLN) paralysis and hypoparathyroidism, among CCS were compared to patients with sporadic/familial thyroid cancer, Graves' disease, and other benign thyroid conditions. Operative time and intraoperative parathyroid hormone levels were also evaluated.There were no significant differences in long-term surgical complication rates, such as permanent RLN paralysis and hypoparathyroidism, between CCS and patients without a history of primary childhood malignancy (all p .05). For all surgical outcomes, there were no significant differences in complication rates when CCS were compared to those undergoing surgery for sporadic/familial thyroid cancer or Graves' disease (all p .05). CCS with benign final pathology had significantly higher rates of transient hypoparathyroidism compared to patients with benign thyroid conditions (p .001).Our study suggests that CCS are not at higher risk of long-term complications from thyroid surgery when treated by high-volume surgeons within a multidisciplinary team.

BACKGROUND: Accurate and precise methods to predict growth remain lacking. Diffusion tensor imaging (DTI) depicts the columnar structure of the physis and metaphyseal spongiosa and provides measures of tract volume and length that may help predict growth. PURPOSE: To validate physeal DTI metrics as predictors of height velocity (1-year height gain from time of MRI examination) and total height gain (height gain from time of MRI examination until growth stops) and compare the prediction accuracy with bone age–based models. MATERIALS AND METHODS: Femoral DTI studies (b values = 0 and 600 sec/mm(2); directions = 20) of healthy children who underwent MRI of the knee between February 2012 and December 2016 were retrospectively analyzed. Children with height measured at MRI and either 1 year later (height velocity) or after growth cessation (total height gain, mean = 34 months from MRI) were included. Physeal DTI tract volume and length were correlated with height velocity and total height gain. Multilinear regression was used to assess the potential of DTI metrics in the prediction of both parameters. Bland-Altman plots were used to compare root mean square error (RMSE) and bias in height prediction using DTI versus bone age methods. RESULTS: Eighty-nine children (mean age, 13 years ± 3 [SD]; 47 boys) had height velocity measured, and 70 (mean age, 14 years ± 1; 36 girls) had total height gain measured. Tract volumes correlated with height velocity (r(2) = 0.49) and total height gain (r(2) = 0.46) (P < .001 for both) after controlling for age and sex. Tract volume was the strongest predictor for height velocity and total height gain. An optimal multilinear model including tract volume improved prediction of height velocity (R(2) = 0.63, RMSE = 1.7 cm) and total height gain (R(2) = 0.59, RMSE = 1.8 cm) compared with bone age–based methods (height velocity: R(2) = 0.32, RMSE = 2.9 cm; total height gain: R(2) = 0.42, RMSE = 5.0 cm). CONCLUSION: Models using tract volume derived from diffusion tensor imaging may perform better than bone age–based models in children for the prediction of height velocity and total height gain. © RSNA, 2022

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a common therapy for pediatric hematologic malignancies. With improved supportive care, addressing treatment-related late effects is at the forefront of survivor long-term health and quality of life. We previously demonstrated that alloHSCT survivors had increased adiposity, decreased lean mass, and lower bone density and strength, 7 years (median) from alloHSCT compared to their healthy peers. Yet it is unknown whether these deficits persist. Our longitudinal study characterized changes in muscle and bone over a period of 3.4 (range, 2.0 to 4.9) years in 47 childhood alloHSCT survivors, age 5-26 years at baseline (34% female). Tibia cortical bone geometry and volumetric density and lower leg muscle cross-sectional area (MCSA) were assessed via peripheral quantitative computed tomography (pQCT). Anthropometric and pQCT measurements were converted to age, sex, and ancestry-specific standard deviation scores, adjusted for leg length. Muscle-specific force was assessed as strength relative to MCSA adjusted for leg length (strength Z-score). Measurements were compared to a healthy reference cohort (n = 921), age 5-30 years (52% female). At baseline and follow-up, alloHSCT survivors demonstrated lower height Z-scores, weight Z-scores, and leg length Z-scores compared to the healthy reference cohort. Deficits in MCSA, trabecular volumetric bone density, and cortical bone size and estimated strength (section modulus) were evident in survivors (all p 0.05). Between the two study time points, anthropometric, muscle, and bone Z-scores did not change significantly in alloHSCT survivors. Approximately 15% and 17% of alloHSCT survivors had MCSA and section modulus Z-score -2.0, at baseline and follow-up, respectively. Furthermore, those with a history of total body irradiation compared to those without demonstrated lower MCSA at follow-up. The persistent muscle and bone deficits in pediatric alloHSCT survivors support the need for strategies to improve bone and muscle health in this at-risk population. © 2022 American Society for Bone and Mineral Research (ASBMR).

Background The number of patients undergoing autologous haematopoietic cell transplant (HCT) is growing, but little is known about the factors that predict adverse outcomes. Low muscle mass and obesity are associated with disability and premature mortality in individuals with non‐malignant diseases and may predict outcomes after autologous HCT. Methods This was a retrospective cohort study of 320 patients who underwent autologous HCT for Hodgkin or non‐Hodgkin lymphoma between 2009 and 2014. Sarcopenia {skeletal muscle index male

Background: Malnutrition (under and overnutrition) occurs in children with solid tumors and has been linked with adverse outcomes during and after treatment. Assessment of nutritional status (NS) can be challenging due to large tumor burdens, atypical growth patterns and different methods for assessing NS. Methods: Retrospective longitudinal study of children with solid tumors (n=61). Anthropometric data assessed [(diagnosis, after diagnosis (1.5, 3, 6 and 12 months, 5 years), end of treatment (EOT), initial cancer survivorship program (CSP) visit]. Registered dietitian nutritionist nutritional assessment (NA) during treatment and Intensity of Treatment Rating (ITR) documented. Results: At diagnosis, prevalence of undernutrition [(Z-score -1.0 to -2.99)] and overnutrition (Z-score ≥ +2.0) were 13.8% and 8.6%, respectively; weight status categories, 8.6%, 6.9%/13.8% were underweight, overweight/obese, respectively. Weight loss and decreased weight-for-age Z-score (WAZ) occurred in 31.9% and 74.5% patients, respectively, at 1.5 months. At EOT, compared to diagnosis, WAZ and height-for-age Z-score (HAZ) decreased and BMIZ increased. From EOT to CSP visit, overweight/obesity doubled, 7.7%/5.8% and 15.2/11.9%, respectively. Thirty-one percent of patients received a NA, occurring at lowest WAZ. Over 50% had ITR of level 3 or 4 and 88.9% had NA in level 4. Conclusions: Suboptimal NS continues at diagnosis, during treatment and survivorship. Normalized measures, accounting for expected growth, should be used instead of raw numbers. More than one nutrition indicator will identify atypical growth patterns and a proactive approach would help prevent malnutrition. Evidence based research is essential and collaboration necessary to meet the needs of this population.

Neuroblastoma is the most common extracranial solid tumor in children. Those with high-risk disease are treated with multimodal therapy, including high-dose chemotherapy, stem cell transplant, radiation, and immunotherapy that have led to multiple long-term complications in survivors. In the late 1990s, consolidation therapy involved myeloablative conditioning including total body irradiation (TBI) with autologous stem cell rescue. Recognizing the significant long-term toxicities of exposure to TBI, more contemporary treatment protocols have removed this from conditioning regimens. This study examines an expanded cohort of 48 high-risk neuroblastoma patients to identify differences in the late effect profiles for those treated with TBI and those treated without TBI.Data on the study cohort were collected from clinic charts, provider documentation in the electronic medical record of visits to survivorship clinic, including all subspecialists, and ancillary reports of laboratory and diagnostic tests done as part of risk-based screening at each visit.All 48 survivors of BMT for high-risk neuroblastoma had numerous late effects of therapy, with 73% having between five and 10 late effects. TBI impacted some late effects significantly, including growth hormone deficiency (GHD), bone outcomes, and cataracts.Although high-risk neuroblastoma survivors treated with TBI have significant late effects, those treated without TBI also continue to have significant morbidity related to high-dose chemotherapy and local radiation. A multidisciplinary care team assists in providing comprehensive care to those survivors who are at highest risk for significant late effects.

Introduction: Thyroid lobectomy reduces risks of surgical complications and need for levothyroxine (LT4). We aimed at identifying the clinical course and risk factors for postlobectomy hypothyroidism to optimize surgical counseling and management in pediatric patients undergoing lobectomy. Methods: Clinical and biochemical presentations pre- and postlobectomy were retrospectively reviewed for 110 patients who underwent thyroid lobectomy between 2008 and 2020 at the Children's Hospital of Philadelphia. Results: Approximately 28.2% of patients (31/110) developed postlobectomy hypothyroidism defined by an elevated thyrotropin (TSH) level, including 24.5% (27/110) with subclinical hypothyroidism (TSH >4.5 and 10.0 mIU/L). LT4 was initiated in 12.7% (14/110) of cases. Most patients (81.6%; 84/103) recovered euthyroidism within 12 months postlobectomy. When excluding patients with autonomous nodule(s), median preoperative TSH was 1.09 (interquartile range [IQR] = 0.70–1.77) mIU/L and 1.80 (IQR = 1.02–2.68) mIU/L in euthyroid and hypothyroid patients, respectively, with multivariate logistic regression confirming the association between an increased preoperative TSH and postlobectomy hypothyroidism (odds ratio = 1.8 [confidence interval 1.08–3.13], p = 0.024). Of the patients who underwent thyroid lobectomy and developed postoperative hypothyroidism (n = 31), 38.7% (12/31) had a preoperative diagnosis of an autonomously functioning thyroid nodule. Conclusions: Thyroid function should be evaluated postlobectomy to assess the need for LT4. LT4 should be considered if the TSH remains elevated, especially if an upward trend is observed or TSH is >10.0 mIU/L. Suppressed preoperative TSH associated with autonomous nodules is an independent risk factor for postlobectomy hypothyroidism.

Importance The current recommendation for pediatric patients with papillary thyroid cancer (PTC) is a total thyroidectomy. This recommendation applies to all stages of PTC, including papillary thyroid microcarcinoma (≤1 cm, T1a) tumors. Objective To evaluate the characteristics of American Joint Committee on Cancer T1 PTC tumors in a large pediatric population and to identify a subgroup of patients who may benefit from a thyroid lobectomy instead of a total thyroidectomy. Design, Setting, and Participants This retrospective cohort study was conducted from January 1, 2009, to May 31, 2020. The study took place at a tertiary care medical center and included 102 patients who were surgically treated for T1 PTC: 52 with stage T1a (≤1 cm) tumors and 50 with stage T1b (>1 cm but ≤2 cm) tumors. Main Outcomes and Measures Primary outcomes included the presence of bilateral disease and lymph node metastasis. Results A total of 102 patients (mean age, 15.3 years [range, 9.7-18.9 years]; 84 girls [82.4%]) were included in the analysis. Among 52 patients with T1a tumors, 10 (19.2%) had bilateral disease, and 15 (28.8%) had central neck lymph node (N1a) metastasis. Among 50 patients with T1b tumors, 10 (20%) had bilateral and 13 (26%) had N1a disease. Of those with T1a, unilateral multifocality was associated with bilateral disease (odds ratio [OR], 2.1; 95% CI, 1.3-3.4) and N1a disease (OR, 5.1; 95% CI, 1.5-17.6). Both N1a disease (OR, 20.0; 95% CI, 3.5-115.0) and ≥4 positive lymph nodes (OR, 8.6; 95% CI, 1.2-60.9) were associated with bilateral disease. In patients with no pathologic evidence of lymph node metastasis (N0), there was a 95% rate of unilateral PTC. In patients with T1b tumors, unilateral multifocality was also associated with bilateral disease (OR, 1.8; 95% CI, 1.3-2.7). Patients with T1b tumors had an increased risk of lateral (N1b) neck lymph node metastasis when compared with those with T1a tumors (OR, 3.7; 95% CI, 1.0-14.5). Conclusions and Relevance The findings of this cohort study suggest that, in patients with unifocal T1a PTC without clinically evident nodal disease on preoperative ultrasonography, a thyroid lobectomy and central neck dissection may be considered. If there is no evidence of unilateral multifocality or if there are fewer than 4 positive lymph nodes on postoperative pathology, then close observation may be considered. These findings have substantial clinical implications and may result in practice changes regarding the extent of thyroid surgery on low-stage pediatric PTC.

BackgroundIn 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathological classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer and investigate if mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC.MethodsSomatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant (H-K-NRAS), BRAF-mutant (BRAF p.V600E) and RET/NTRK fusion (RET, NTRK1 and NTRK3 fusions) to determine differences between subtype classification in regard to pathological data (AJCC TNM) as well as response to therapy 1-year after initial treatment had been completed.ResultsMutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1-year. Patients with RET/NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at one year than patients within RAS- or BRAF-mut subgroups.ConclusionsOur data supports that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathological classification with patients with RET/NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

Background Survival from paediatric high‐risk neuroblastoma (HR‐NBL) has increased, but cis‐retinoic acid (cis‐RA), the cornerstone of HR‐NBL therapy, can cause osteoporosis and premature physeal closure and is a potential threat to skeletal structure in HR‐NBL survivors. Sarcopenia is associated with increased morbidity in survivors of paediatric malignancies. Low muscle mass may be associated with poor prognosis in HR‐NBL patients but has not been studied in these survivors. The study objective was to assess bone density, body composition and muscle strength in HR‐NBL survivors compared with controls. Methods This prospective cross‐sectional study assessed areal bone mineral density (aBMD) of the whole body, lumbar spine, total hip, femoral neck, distal 1/3 and ultradistal radius and body composition (muscle and fat mass) using dual‐energy X‐ray absorptiometry (DXA) and lower leg muscle strength using a dynamometer. Measures expressed as sex‐specific standard deviation scores (Z‐scores) included aBMD (adjusted for height Z‐score), bone mineral apparent density (BMAD), leg lean mass (adjusted for leg length), whole‐body fat mass index (FMI) and ankle dorsiflexion peak torque adjusted for leg length (strength‐Z). Muscle‐specific force was assessed as strength relative to leg lean mass. Outcomes were compared between HR‐NBL survivors and controls using Student's t‐test or Mann–Whitney U test. Linear regression models examined correlations between DXA and dynamometer outcomes. Results We enrolled 20 survivors of HR‐NBL treated with cis‐RA [13 male; mean age: 12.4 ± 1.6 years; median (range) age at therapy initiation: 2.6 (0.3–9.1) years] and 20 age‐, sex‐ and race‐matched controls. Height‐Z was significantly lower in HR‐NBL survivors compared with controls (−1.73 ± 1.38 vs. 0.34 ± 1.12, P

Background Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for diabetes mellitus, but the association between risk and radiation dose and volume is unclear. Methods Participants included 20 762 5-year survivors of childhood cancer (4568 exposed to abdRT) and 4853 siblings. For abdRT, we estimated maximum dose to abdomen; mean doses for whole pancreas, pancreatic head, body, tail; and percent pancreas volume receiving no less than 10, 20, and 30 Gy. Relative risks (RRs) were estimated with a Poisson model using generalized estimating equations, adjusted for attained age. All statistical tests were two-sided. Results Survivors exposed to abdRT (median age = 31.6 years, range = 10.2–58.3 years) were 2.92-fold more likely than siblings (95% confidence interval [CI] = 2.02 to 4.23) and 1.60-times more likely than survivors not exposed to abdRT (95%CI = 1.24 to 2.05) to develop diabetes. Among survivors treated with abdRT, greater attained age (RRper 10 years = 2.11, 95% CI = 1.70 to 2.62), higher body mass index (RRBMI 30+ = 5.00, 95% CI = 3.19 to 7.83 with referenceBMI 18.5–24.9), and increasing pancreatic tail dose were associated with increased diabetes risk in a multivariable model; an interaction was identified between younger age at cancer diagnosis and pancreatic tail dose with much higher diabetes risk associated with increasing pancreatic tail dose among those diagnosed at the youngest ages (P < .001). Radiation dose and volume to other regions of the pancreas were not statistically significantly associated with risk. Conclusions Among survivors treated with abdRT, diabetes risk was associated with higher pancreatic tail dose, especially at younger ages. Targeted interventions are needed to improve cardiometabolic health among those at highest risk.

BACKGROUND: The survival of patients with high-risk neuroblastoma has increased with multimodal therapy, but most survivors demonstrate growth failure. OBJECTIVE: To assess physeal abnormalities in children with high-risk neuroblastoma in comparison to normal controls by using diffusion tensor imaging (DTI) of the distal femoral physis and adjacent metaphysis. MATERIALS AND METHODS: We prospectively obtained physeal DTI at 3.0 T in 20 subjects (mean age: 12.4 years, 7 females) with high-risk neuroblastoma treated with high-dose cis-retinoic acid, and 20 age-and gender-matched controls. We compared fractional anisotropy (FA), normalized tract volume (cm(3)/cm(2)) and tract concentration (tracts/cm(2)) between the groups, in relation to height Z-score and response to growth hormone therapy. Tractography images were evaluated qualitatively. RESULTS: DTI parameters were significantly lower in high-risk neuroblastoma survivors compared to controls (P0.31; P

10049 Background: Childhood cancer survivors (CCS) are at risk for radiotherapy (RT) late effects, including second malignancies. Optimal screening for thyroid cancer (TC) in CCS post-RT remains controversial. We assessed the clinical benefit of thyroid ultrasound (US) surveillance in CCS exposed to RT. Methods: 316 CCS (175 males) were prospectively surveilled with thyroid US between 2002 and 2021 at the Children’s Hospital of Philadelphia. Patients were screened upon referral to the Survivorship Program. Thyroid US, clinicopathologic features, and endocrine-related outcomes were ascertained. Outcomes were compared using primary CCS diagnosis age cohorts of ≤ 3, > 3 to ≤ 10, and > 10 years. Risk factors for thyroid nodule(s) and TC were evaluated using Kruskal Wallis and ANOVA [OR (95% CI)]. Results: The most common CCS diagnoses were leukemia (32%), CNS tumor (26%), and neuroblastoma (18%). Patients received TBI (43%) and/or RT to craniospinal (43%), chest (13%), and neck regions (7%). About 48% (n = 152) of patients presented thyroid nodule(s) (Table). Forty-six patients underwent surgery, and 28 had TC, including 19 with ATA low-risk, 2 with ATA intermediate-risk, and 7 with ATA high-risk disease. Of the 9 patients with intermediate- or high-risk disease, 5 were ≤ 3 years, 3 were > 3 to ≤ 10 years, and 1 was > 10 years at the time of RT exposure. Eight patients with TC demonstrated pathogenic variant(s). RT exposure at ≤ 3 years old conferred 2-fold increased risk for nodule(s) compared to RT at > 10 years [OR = 2.14 (1.44-2.84) p = 0.03]. Female sex [OR = 1.73 (1.25-2.21) p = 0.02] and greater interval between RT and first US [OR = 1.10 (1.04-1.15) p = 0.001] were additional independent risk factors. Conclusions: Younger age at RT exposure is associated with increased risk of and shorter latency for developing TC. Thyroid US surveillance appears most beneficial in CCS exposed to RT ≤ 3 years old in an effort to diagnose TC at an earlier stage prior to metastasis. [Table: see text]

Skeletal abnormalities are common in children and adolescents diagnosed and treated for a malignancy. The spectrum ranges from mild pain to debilitating osteonecrosis and fractures. In this review, we summarize the impact of cancer therapy on the developing skeleton, provide an update on therapeutic strategies for prevention and treatment, and discuss the most recent advances in musculoskeletal research. Early recognition of skeletal abnormalities and strategies to optimize bone health are essential to prevent long-term skeletal sequelae and diminished quality of life in childhood cancer survivors.

Objective Rheumatoid arthritis (RA) is associated with adverse body composition profiles and low muscle density due to the accumulation of intramuscular fat. Linear regression was used to assess differences between RA patients and controls and to determine associations between muscle density, strength, and physical functioning. Methods Patients with RA, ages 18-70 years, and healthy control subjects underwent whole-body dual x-ray absorptiometry and peripheral quantitative computed tomography, in order to quantify the appendicular lean mass index (ALMI) and the fat mass index (FMI), visceral fat area, and muscle density. Dynamometry was used to measure hand grip strength and muscle strength at the knee and lower leg. Disability and physical functioning were measured using the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB). Linear regression analyses were performed to assess differences related to RA and associations between muscle density, strength, and function. Results The study group included 103 patients with RA (51 men) and 428 healthy control subjects. Among patients with RA, low muscle density was associated with higher disease activity, C-reactive protein and interleukin-6 levels, greater total and visceral fat area, lower ALMI Z scores, physical inactivity, and long-term use of glucocorticoids (>1 year). Patients with low ALMI Z scores had lower muscle density Z scores compared with reference participants with similarly low ALMI scores. Low muscle density was independently associated with lower muscle strength, higher HAQ scores, and lower SPPB scores, after adjustment for ALMI and FMI Z scores. Conclusion The low muscle density observed in patients with RA was associated with low muscle mass, excess adiposity, poor strength, and greater disability. Interventions to address poor muscle quality could potentially affect important functional outcomes.

Annual gains in BMC and areal bone mineral density (aBMD) in children vary with age, pubertal status, height-velocity, and lean body mass accrual (LBM velocity). Evaluating bone accrual in children with bone health-threatening conditions requires consideration of these determinants. The objective of this study was to develop prediction equations for calculating BMC/aBMD velocity SD scores (velocity-Z) and to evaluate bone accrual in youth with health conditions. Bone and body compositions via DXA were obtained for up to six annual intervals in healthy youth (n = 2014) enrolled in the Bone Mineral Density in Childhood Study (BMDCS) . Longitudinal statistical methods were used to develop sex- and pubertal-status-specific reference equations for calculating velocity-Z for total body less head-BMC and lumbar spine (LS), total hip (TotHip), femoral neck, and 1/3-radius aBMD. Equations accounted for (1) height velocity, (2) height velocity and weight velocity, or (3) height velocity and LBM velocity. These equations were then applied to observational, single-center, 12-month longitudinal data from youth with cystic fibrosis (CF; n = 65), acute lymphoblastic leukemia (ALL) survivors (n = 45), or Crohn disease (CD) initiating infliximab (n = 72). Associations between BMC/aBMD-Z change (conventional pediatric bone health monitoring method) and BMC/aBMD velocity-Z were assessed. The BMC/aBMD velocity-Z for CF, ALL, and CD was compared with BMDCS. Annual changes in the BMC/aBMD-Z and the BMC/aBMD velocity-Z were strongly correlated, but not equivalent; LS aBMD-Z = 1 equated with LS aBMD velocity-Z = -3. In CF, BMC/aBMD velocity-Z was normal. In posttherapy ALL, BMC/aBMD velocity-Z was increased, particularly at TotHip (1.01 [-.047; 1.7], p < 0.0001). In CD, BMC/aBMD velocity-Z was increased at all skeletal sites. LBM-velocity adjustment attenuated these increases (eg, TotHip aBMD velocity-Z: 1.13 [0.004; 2.34] versus 1.52 [0.3; 2.85], p < 0.0001). Methods for quantifying the BMC/aBMD velocity that account for maturation and body composition changes provide a framework for evaluating childhood bone accretion and may provide insight into mechanisms contributing to altered accrual in chronic childhood conditions. © 2018 American Society for Bone and Mineral Research.

Endocrine late effects, including reproductive disorders and secondary thyroid cancer, have been reported in up to 50 %childhood cancer survivors (CCS) more than 5 years after treatment. Most endocrine disorders are amenable to treatment; awareness of symptoms is therefore of great importance. Recognition of these symptoms may be delayed however because many are nonspecific. Timely treatment of endocrine disorders improves quality of life in CCS and prevents possible consequences, such as short stature, bone and cardiovascular disorders, and depression. At-risk CCS must therefore be regularly and systematically monitored. This article provides a summary of the most commonly reported endocrine late effects in CCS.

Differentiated thyroid cancer (DTC) is the most common childhood thyroid malignancy. The standard of care for pediatric DTC is total thyroidectomy followed by radioactive iodine (RAI) treatment when indicated. Molecular changes and potential therapeutic targets have been recently described in pediatric thyroid cancer. Pediatric oncologists are increasingly involved in the evaluation of thyroid nodules in childhood cancer survivors and in the management of advanced thyroid cancer. In 2015, the American Thyroid Association published management guidelines for children with DTC. We provide an overview of the current standard of care and highlight available targeted therapies for progressive or RAI refractory DTC.

Summary Background Cancer treatment can cause gonadal impairment. Acute ovarian failure is defined as the permanent loss of ovarian function within 5 years of cancer diagnosis. We aimed to develop and validate risk prediction tools to provide accurate clinical guidance for paediatric patients with cancer. Methods In this cohort study, prediction models of acute ovarian failure risk were developed using eligible female US and Canadian participants in the Childhood Cancer Survivor Study (CCSS) cohort and validated in the St Jude Lifetime Cohort (SJLIFE) Study. 5-year survivors from the CCSS cohort were included if they were at least 18 years old at their most recent follow-up and had complete treatment exposure and adequate menstrual history (including age at menarche, current menstrual status, age at last menstruation, and menopausal aetiology) information available. Participants in the SJLIFE cohort were at least 10-year survivors. Participants were excluded from the prediction analysis if they had an ovarian hormone deficiency, had missing exposure information, or had indeterminate ovarian status. The outcome of acute ovarian failure was defined as permanent loss of ovarian function within 5 years of cancer diagnosis or no menarche after cancer treatment by the age of 18 years. Logistic regression, random forest, and support vector machines were used as candidate methods to develop the risk prediction models in the CCSS cohort. Prediction performance was evaluated internally (in the CCSS cohort) and externally (in the SJLIFE cohort) using the areas under the receiver operating characteristic curve (AUC) and the precision-recall curve (average precision [AP; average positive predictive value]). Findings Data from the CCSS cohort were collected for participants followed up between Nov 3, 1992, and Nov 25, 2016, and from the SJLIFE cohort for participants followed up between Oct 17, 2007, and April 16, 2012. Of 11 336 female CCSS participants, 5886 (51·9%) met all inclusion criteria for analysis. 1644 participants were identified from the SJLIFE cohort, of whom 875 (53·2%) were eligible for analysis. 353 (6·0%) of analysed CCSS participants and 50 (5·7%) of analysed SJLIFE participants had acute ovarian failure. The overall median follow-up for the CCSS cohort was 23·9 years (IQR 20·4–27·9), and for SJLIFE it was 23·9 years (19·0–30·0). The three candidate methods (logistic regression, random forest, and support vector machines) yielded similar results, and a prescribed dose model with abdominal and pelvic radiation doses and an ovarian dose model with ovarian radiation dosimetry using logistic regression were selected. Common predictors in both models were history of haematopoietic stem-cell transplantation, cumulative alkylating drug dose, and an interaction between age at cancer diagnosis and haematopoietic stem-cell transplant. External validation of the model in the SJLIFE cohort produced an estimated AUC of 0·94 (95% CI 0·90–0·98) and AP of 0·68 (95% CI 0·53–0·81) for the ovarian dose model, and AUC of 0·96 (0·94–0·97) and AP of 0·46 (0·34–0·61) for the prescribed dose model. Based on these models, an online risk calculator has been developed for clinical use. Interpretation Both acute ovarian failure risk prediction models performed well. The ovarian dose model is preferred if ovarian radiation dosimetry is available. The models, along with the online risk calculator, could help clinical discussions regarding the need for fertility preservation interventions in girls and young women newly diagnosed with cancer. Funding Canadian Institutes of Health Research, Women and Children's Health Research Institute, National Cancer Institute, and American Lebanese Syrian Associated Charities.

Background The recommendation for children with papillary thyroid cancer (PTC) is total thyroidectomy (TT) based on the incidence of bilateral disease. Evaluating this assumption, we reviewed the characteristics of bilateral PTC in a large cohort of children. Methods A retrospective chart review for patients surgically treated for PTC from 2009 to 2018 analyzing preoperative risk factors, ultrasound findings, and pathology results was performed. Bilateral disease was defined as pathologic PTC in the contralateral lobe, including microscopic disease. Results Of the 172 patients included, 38.4% had bilateral disease with 23% diagnosed postoperatively. Multifocal disease on ultrasound was associated with bilateral disease (OR 2.9, 95% CI 1.5–5.9, p = 0.002). Nodule dimension > 2 cm was associated with increased risk for postoperative bilateral disease (OR 3.5, 95% CI 1.6–7.4, p = 0.001). Patients with bilateral disease were more likely to have extrathyroidal extension, lymphovascular invasion, positive central lymph nodes, and extranodal extension (p Conclusion Thirty-eight percent of children were diagnosed with PTC demonstrate bilateral disease. Nearly one in four have occult bilateral disease. The features that predicted bilateral disease were multifocality, widely invasive PTC on ultrasound, and the presence of lymphadenopathy. Thus, TT is the appropriate surgical approach for pediatric patients with PTC. Type of Study Clinical Research, Retrospective Review. Level of Evidence Level IV.

Background Genetic alterations in multiple cell signaling pathways are involved in the molecular pathogenesis of thyroid cancer. Oncogene mutation testing and gene-expression profiling are routinely used for the preoperative risk management of adult thyroid nodules. In this study, we evaluated the potential value of miRNA biomarkers for the classification of pediatric thyroid lesions. Procedure Double-blind case-control study with 113 resected pediatric lesions: 66 malignant and 47 benign. Quantitative and qualitative molecular data generated with a 10-miRNA expression panel (ThyraMIR) and a next-generation sequencing oncogene panel (ThyGeNEXT) were compared with clinicopathological parameters. Results miRNAs were differentially expressed in benign versus malignant tumors with distinct expression patterns in different histopathology categories. The 10-miRNA classifier identified 39 (59%) malignant lesions with 100% specificity. A positive classifier score was associated with lymph node metastasis, extrathyroidal extension and intrathyroidal spread. Genetic alterations associated with increased risk for malignancy were detected in 35 (53%) malignant cases, 20 positive for point mutations in BRAF, HRAS, KRAS, NRAS, PIK3CA, or TERT and 15 positive for gene rearrangements involving ALK, NTRK3, PPARG, or RET. The 10-miRNA classifier correctly identified 11 mutation-negative malignant cases. The performance of the combined molecular test was 70% sensitivity and 96% specificity with an area under the curve of 0.924. Conclusions These data suggest that the regulatory miRNA pathways underlying thyroid tumorigenesis are similar in adults and children. miRNA expression can identify malignant lesions with high specificity, augment the diagnostic yield of mutation testing, and improve the molecular classification of pediatric thyroid nodules.

BACKGROUND Current methods to predict height and growth failure are imprecise. MRI measures of physeal cartilage are promising biomarkers for growth. PURPOSE In the physis, to assess how 3D MRI volume measurements, and diffusion tensor imaging (DTI) measurements (tract volume and length) correlate with growth parameters and detect differences in growth. We compared patients exposed to cis-retinoic acid, which causes physeal damage and growth failure, with normal subjects. STUDY TYPE Case-control. POPULATION Twenty pediatric neuroblastoma survivors treated with cis-retinoic acid and 20 age- and sex-matched controls. FIELD STRENGTH/SEQUENCE 3T; DTI and 3D double-echo steady-state (DESS) sequences. ASSESSMENT On distal femoral MR studies, physeal 3D volume and DTI tract measurements were calculated and compared to height. STATISTICAL TESTS We used partial Spearman correlation, analysis of covariance, logistic regression, Wald test, and the intraclass correlation coefficient (ICC). RESULTS The height percentile correlated most strongly with DTI tract volumes (r = 0.74), followed by mean tract length (r = 0.53) and 3D volume (r = 0.40) (all P

Endocrine complications are highly prevalent in childhood cancer survivors. Approximately 50% of survivors will experience at least one hormonal disorder over the course of their lives. Endocrine complications often are observed in survivors previously treated with radiation to the head, neck, or pelvis. We provide an overview the most common endocrine late effects seen in survivors, including hypothalamic-pituitary dysfunction, primary thyroid dysfunction, obesity, diabetes mellitus, metabolic syndrome, and decreased bone mineral density. Primary gonadal injury is discussed elsewhere in this series. Given a variable latency interval, a systematic approach where individuals are periodically screened on the basis of their risk factors can help to improve health outcomes by prompt diagnosis and treatment of evolving endocrinopathies. These recommendations must be revised in the future given changes and improvements in cancer treatment over time.

Introduction: The American Joint Committee Cancer (AJCC) TNM system predicts survival in patients with differentiated thyroid cancer (DTC). In the eighth edition of the AJCC TNM, microscopic extrat...

CONTEXT: In adults, noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) is considered a low risk for metastasis and persistent/recurrent disease. OBJECTIVE: The goal of this study was to assess the clinical, sonographic, and histopathologic features of FVPTC in a pediatric cohort. DESIGN: A retrospective review of subjects

10014 Background: Childhood cancer survivors face increased risk for DM, a polygenic trait also attributable to cancer treatment exposures, particularly abdominal radiation. We aimed to characterize the role of genetic and treatment risk factors for DM among two large cohorts of childhood cancer survivors. Methods: We performed a nested case-control genome-wide association study for DM managed with oral medications in the original CCSS cohort (diagnosed 1970-1986). Logistic regression was conducted in the total sample (N = 5083) and stratified by 1) European ancestry (EA) and 2) abdominal radiation. Replication of suggestive variants (P < 1×10-7) using Fisher’s exact test was performed in independent cohorts: i) CCSS expansion diagnosed 1987-1999 (N = 2588) and ii) SJLIFE diagnosed 1962-2012 (N = 2182). To evaluate the effect of cancer treatment on the background genetic predisposition to DM, we estimated standardized effect sizes (Z’) among EA survivors in each abdominal radiation group for 398 index variants from the largest population-based EA DM study. Radiation group Z’ estimates were compared using linear regression. Results: In the original CCSS cohort we identified nine variants associated with DM and provide further support for four linked variants in the ERCC6L2 locus. Among all survivors, the rs55849673-A allele was associated with increased odds for DM among survivors in the original CCSS cohort (minor allele frequency [MAF]-cases = 0.055; MAF-controls = 0.024; adjusted odds ratio [aOR] = 2.9, 95% CI: 2.0-4.2, P = 3.7×10-8). Allele frequencies were consistent in the CCSS expansion (MAF-cases = 0.075; MAF-controls = 0.028; P = 0.07) and SJLIFE (MAF-cases = 0.036; MAF-controls = 0.027; P = 0.5). Additionally, rs55849673-A estimates were consistent among EA survivors and stronger among survivors not treated with abdominal radiation (MAF-cases = 0.052; MAF-controls = 0.021; aOR = 3.6, P = 1.6×10-6). Notably, in the CCSS expansion all rs55849673-A EA carriers who developed DM did not receive abdominal radiation (MAF-cases = 0.1; MAF-controls = 0.026; P = 0.04). More broadly, the Z’ of population-based DM index variants were 78% lower in survivors treated with abdominal radiation than survivors not treated with abdominal radiation (beta = 0.22; P = 0.01), indicating the background genetic risk for DM may be altered by treatment. Conclusions: We provide evidence for a novel locus of DM in childhood cancer survivors. This locus is a regulatory region associated with expression of ERCC6L2, a gene implicated in an East Asian population-based DM study. Taken together, our findings support the overwhelming effect of abdominal radiation on DM risk in childhood cancer survivors, relative to other risk factors, and provide insight on a genetic locus that may be useful for DM risk prediction in the context of cancer treatment.

Objective.Rheumatoid arthritis (RA) is associated with muscle loss, osteoporosis, and fracture. We examined associations between skeletal muscle mass, strength, and quality and trabecular and cortical bone deficits in patients with RA and healthy controls.Methods.Participants, ages 18–75 years, completed whole-body dual-energy x-ray absorptiometry and peripheral quantitative computed tomography (pQCT) of the tibia to quantify appendicular lean mass and fat mass indices (ALMI, FMI), muscle density at the lower leg, trabecular bone density, and cortical bone thickness. Age-, sex-, and race-specific Z scores were calculated based on distributions in controls. Associations between body composition and pQCT bone outcomes were assessed in patients with RA and controls. Linear regression analyses assessed differences in bone outcomes after considering differences in body mass index (BMI) and body composition.Results.The sample consisted of 112 patients with RA (55 men) and 412 controls (194 men). Compared to controls, patients with RA had greater BMI Z score (p < 0.001), lower ALMI Z score after adjustment for FMI (p = 0.02), lower muscle strength Z score (p = 0.01), and lower muscle density Z score (p < 0.001). Among RA, ALMI Z scores were positively associated with trabecular density [β: 0.29 (0.062–0.52); p = 0.01] and cortical thickness [β: 0.33 (0.13–0.53; p = 0.002]. Associations were similar in controls. Bone outcomes were inferior in patients with RA after adjusting for BMI, but similar to controls when adjusting for body composition. Radiographic damage and higher adiponectin levels were independently associated with inferior bone outcomes.Conclusion.Patients with RA exhibit deficits in cortical bone structure and trabecular density at the tibia and a preserved functional muscle-bone unit. A loss of mechanical loading may contribute to bone deficits.

OBJECTIVE: To create reference charts for sitting height to standing height ratio (SitHt/Ht) for children in the US, and to describe the trajectory of SitHt/Ht during puberty. STUDY DESIGN: This was a cross-sectional study using data from the 1988-1994 National Health and Nutrition Examination Survey III, a strategic random sample of the US population. Comparison between non-Hispanic White (NHW), non-Hispanic Black (NHB) and Mexican American groups was performed by ANOVA to determine if a single population reference chart could be used. ANOVA was used to compare SitHt/Ht in pre-, early, and late puberty. RESULTS: NHANES III recorded sitting height and standing height measurements in 9569 children aged 2-18 years of NHW (n = 2715), NHB (n = 3336), and Mexican American (n = 3518) ancestry. NHB children had lower SitHt/Ht than NHW and Mexican American children throughout childhood (P < .001). In both sexes, the SitHt/Ht decreased from prepuberty to early puberty and increased in late puberty. Sex-specific percentile charts of SitHt/Ht vs age were generated for NHB and for NHW and Mexican American youth combined. CONCLUSIONS: SitHt/Ht assessment can detect disproportionate short stature in children with skeletal dysplasia, but age-, sex-, and population-specific reference charts are required to interpret this measurement. NHB children in the US have significantly lower SitHt/Ht than other children, which adds complexity to interpretation. We recommend the use of standardized ancestry-specific reference charts in screening for skeletal dysplasias and have developed such charts in this study.