Diagnostic classification of childhood cancer using multiscale transcriptomics.

The causes of pediatric cancers' distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were divided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional diversity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types.

DICER1 RNase IIIb domain mutations trigger widespread miRNA dysregulation and MAPK activation in pediatric thyroid cancer.

DICER1 is a highly conserved RNase III endoribonuclease essential for the biogenesis of single-stranded mature microRNAs (miRNAs) from stem-loop precursor miRNAs. Somatic mutations in the RNase IIIb domain of DICER1 impair its ability to generate mature 5p miRNAs and are believed to drive tumorigenesis in DICER1 syndrome-associated and sporadic thyroid tumors. However, the DICER1-driven specific changes in miRNAs and resulting changes in gene expression are poorly understood in thyroid tissue. In this study, we profiled the miRNA (n=2,083) and mRNA (n=2,559) transcriptomes of 20 non-neoplastic, 8 adenomatous and 60 pediatric thyroid cancers (13 follicular thyroid cancers [FTC] and 47 papillary thyroid cancers [PTC]) of which 8 had DICER1 RNase IIIb mutations. All DICER1-mutant differentiated thyroid cancers (DTC) were follicular patterned (six follicular variant PTC and two FTC), none had lymph node metastasis. We demonstrate that DICER1 pathogenic somatic mutations were associated with a global reduction of 5p-derived miRNAs, including those particularly abundant in the non-neoplastic thyroid tissue such as let-7 and mir-30 families, known for their tumor suppressor function. There was also an unexpected increase of 3p miRNAs, possibly associated with DICER1 mRNA expression increase in tumors harboring RNase IIIb mutations. These abnormally expressed 3p miRNAs, which are otherwise low or absent in DICER1-wt DTC and non-neoplastic thyroid tissues, make up exceptional markers for malignant thyroid tumors harboring DICER1 RNase IIIb mutations. The extensive disarray in the miRNA transcriptome results in gene expression changes, which were indicative of positive regulation of cell-cycle. Moreover, differentially expressed genes point to increased MAPK signaling output and loss of thyroid differentiation comparable to the RAS-like subgroup of PTC (as coined by The Cancer Genome Atlas), which is reflective of the more indolent clinical behavior of these tumors.

The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.

The Impact of Hospital Surgical Volume on Healthcare Utilization Outcomes After Pediatric Thyroidectomy.

BACKGROUND: A positive relationship between an individual surgeon's operative volume and clinical outcomes after pediatric and adult thyroidectomy is well-established. The impact of a hospital's pediatric operative volume on surgical outcomes and healthcare utilization, however, are infrequently reported. We investigated associations between hospital volume and healthcare utilization outcomes following pediatric thyroidectomy in Canada's largest province, Ontario. METHODS: Retrospective analysis of administrative and health-related population-level data from 1993 to 2017. A cohort of 1908 pediatric (<18 years) index thyroidectomies was established. Hospital volume was defined per-case as thyroidectomies performed in the preceding year. Healthcare utilization outcomes: length of stay (LOS), same day surgery (SDS), readmission, and emergency department (ED) visits were measured. Multivariate analysis adjusted for patient-level, disease and hospital-level co-variates. RESULTS: Hospitals with the lowest volume of pediatric thyroidectomies, accounted for 30% of thyroidectomies province-wide and performed 0-1 thyroidectomies/year. The highest-volume hospitals performed 19-60 cases/year. LOS was 0.64 days longer in the highest, versus the lowest quartile. SDS was 83% less likely at the highest, versus the lowest quartile. Hospital volume was not associated with rate of readmission or ED visits. Increased ED visits were, however, associated with male sex, increased material deprivation, and rurality. CONCLUSIONS: Increased hospital pediatric surgical volume was associated with increased LOS and lower likelihood of SDS. This may reflect patient complexity at such centers. In this cohort, low-volume hospitals were not associated with poorer healthcare utilization outcomes. Further study of groups disproportionately accessing the ED post-operatively may help direct resources to these populations.

Incidental Parathyroidectomy Among Pediatric Patients Undergoing Thyroid Surgery.

OBJECTIVE: To evaluate rates of incidental parathyroidectomy(IP) and to determine risk factors among children undergoing thyroid surgery. STUDY DESIGN: Retrospective case-control study. METHODS: Pediatric patients undergoing thyroidectomy with or without neck dissection were included in this retrospective cohort study over a 20 year period. Demographics, clinical features, and surgical outcomes were evaluated. The primary outcome was the presence of parathyroid tissue in the surgical specimen. RESULTS: Two hundred and eighty-six patients were included (100 cases with ≥1 parathyroid gland found in the pathology specimen and 186 controls). The most common surgical indication was cancer (49%), followed by benign nodule (25%). Hemithyroidectomy was performed in 119 (42%) patients, total thyroidectomy in 138 (48%), and completion in 29 (10%). Central neck dissection (CND) and lateral neck dissection were performed in 41% and 13%, respectively. 27 (9%) patients had parathyroid reimplantation. On univariable analysis, diagnosis, adenopathy on preoperative ultrasound, extent of thyroidectomy, neck dissection, and parathyroid reimplantation were significant predictors of IP. On multivariate analysis, CND > 5 nodes were the sole predictor of IP. Patients with IP were more likely to require postoperative calcium/vitamin D supplementation compared to those without (44% vs. 16%; P < .001). CONCLUSIONS: Incidental parathyroidectomy during pediatric thyroidectomy is relatively common. CND was independently predictive of IP. There were increased rates of postoperative hypocalcemia when 1 or more parathyroid gland was identified in the specimen. Reimplantation of 1 parathyroid gland was predictive of another gland in the specimen. Anticipating outcomes may help optimize patient care by allowing for early supplementation, frequent monitoring, and consideration of ancillary monitoring modalities in high-risk procedures. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 132:2262-2269, 2022.

Timing of Childhood-Onset Systemic Lupus Erythematosus Diagnosis Relative to Menarche and the Impact on Final Adult Height.

OBJECTIVE: The aim of this study was to examine the impact of timing of a childhood-onset systemic lupus erythematosus (SLE) diagnosis relative to menarchal status, on final height, accounting for disease-associated factors. METHODS: We conducted a cohort study of female patients age <18 years at childhood-onset SLE diagnosis, followed at a tertiary care pediatric center from July 1982 to March 2016 and restricted to patients with documented age of menarche and final height. We compared final height between patients diagnosed pre- and postmenarche. We tested the association of the timing of childhood-onset SLE diagnosis with final height, adjusted for ethnicity, in linear regression models. We performed subgroup analyses of patients with growth during follow-up, additionally adjusting for average daily corticosteroid dose and disease activity. RESULTS: Of 401 female childhood-onset SLE patients in the study, 115 patients (29%) were diagnosed premenarche and 286 (71%) postmenarche. Patients diagnosed premenarche were older at menarche compared with patients diagnosed postmenarche (mean ± SD age 13.5 ± 1.4 versus 12.5 ± 1.3 years; P < 0.001). The mean ± SD final height for girls diagnosed postmenarche (161.4 ± 6.9 cm) was greater than for those diagnosed premenarche (158.8 ± 7.3 cm; P = 0.001). In regression analysis, those diagnosed postmenarche were significantly taller than those diagnosed premenarche, as adjusted for ethnicity and disease severity (mean ± SD ß = 2.6 ± 0.7 cm; P = 0.0006). CONCLUSION: In this large cohort study of girls with childhood-onset SLE, patients diagnosed postmenarche achieved a taller final height than those diagnosed premenarche, even after accounting for ethnicity and disease severity.

Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes.

IMPORTANCE: Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. OBJECTIVE: To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. DESIGN, SETTING, AND PARTICIPANTS: In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied. EXPOSURES: Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results. MAIN OUTCOMES AND MEASURES: The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator. RESULTS: In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations. CONCLUSIONS AND RELEVANCE: In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.

Diverse Oncogenic Fusions and Distinct Gene Expression Patterns Define the Genomic Landscape of Pediatric Papillary Thyroid Carcinoma.

Pediatric papillary thyroid carcinoma (PPTC) is clinically distinct from adult-onset disease. Although there are higher rates of metastasis and recurrence in PPTC, prognosis remains highly favorable. Molecular characterization of PPTC has been lacking. Historically, only 40% to 50% of childhood papillary thyroid carcinoma (PTC) were known to be driven by genomic variants common to adult PTC; oncogenic drivers in the remainder were unknown. This contrasts with approximately 90% of adult PTC driven by a discrete number of variants. In this study, 52 PPTCs underwent candidate gene testing, followed in a subset by whole-exome and transcriptome sequencing. Within these samples, candidate gene testing identified variants in 31 (60%) tumors, while exome and transcriptome sequencing identified oncogenic variants in 19 of 21 (90%) remaining tumors. The latter were enriched for oncogenic fusions, with 11 nonrecurrent fusion transcripts, including two previously undescribed fusions, STRN-RET and TG-PBF. Most fusions were associated with 3' receptor tyrosine kinase (RTK) moieties: RET, MET, ALK, and NTRK3. For advanced (distally metastatic) tumors, a driver variant was described in 91%. Gene expression analysis defined three clusters that demonstrated distinct expression of genes involved in thyroid differentiation and MAPK signaling. Among RET-CCDC6-driven tumors, gene expression in pediatric tumors was distinguishable from that in adults. Collectively, these results show that the genomic landscape of pediatric PTC is different from adult PTC. Moreover, they identify genomic drivers in 98% of PPTCs, predominantly oncogenic fusion transcripts involving RTKs, with a pronounced impact on gene expression. Notably, most advanced tumors were driven by a variant for which targeted systemic therapy exists. SIGNIFICANCE: This study highlights important distinctions between the genomes and transcriptomes of pediatric and adult papillary thyroid carcinoma, with implications for understanding the biology, diagnosis, and treatment of advanced disease in children.

Predicting Malignancy in Pediatric Thyroid Nodules: Early Experience With Machine Learning for Clinical Decision Support.

OBJECTIVE: To develop a machine learning tool to integrate clinical data for the prediction of non-benign thyroid cytology and histology. CONTEXT: Papillary thyroid carcinoma is the most common endocrine malignancy. Since most nodules are benign, the challenge for the clinician is to identify those most likely to harbor malignancy while limiting exposure to surgical risks among those with benign nodules. METHODS: Random forests (augmented to select features based on our clinical measure of interest), in conjunction with interpretable rule sets, were used on demographic, ultrasound, and biopsy data of thyroid nodules from children younger than 18 years at a tertiary pediatric hospital. Accuracy, false-positive rate (FPR), false-negative rate (FNR), and area under the receiver operator curve (AUROC) are reported. RESULTS: Our models predict nonbenign cytology and malignant histology better than historical outcomes. Specifically, we expect a 68.04% improvement in the FPR, 11.90% increase in accuracy, and 24.85% increase in AUROC for biopsy predictions in 67 patients (28 with benign and 39 with nonbenign histology). We expect a 23.22% decrease in FPR, 32.19% increase in accuracy, and 3.84% decrease in AUROC for surgery prediction in 53 patients (42 with benign and 11 with nonbenign histology). This improvement comes at the expense of the FNR, for which we expect 10.27% with malignancy would be discouraged from performing biopsy, and 11.67% from surgery. Given the small number of patients, these improvements are estimates and are not tested on an independent test set. CONCLUSION: This work presents a first attempt at developing an interpretable machine learning based clinical tool to aid clinicians. Future work will involve sourcing more data and developing probabilistic estimates for predictions.

Routine T4 No More? Reducing Excess Thyroid Hormone Testing at a Pediatric Tertiary Care Hospital.

OBJECTIVES: To promote resource stewardship in thyroid hormone testing at a pediatric tertiary care hospital. STUDY DESIGN: Quality improvement approaches generated 3 change ideas that were implemented simultaneously in the hospital electronic medical record: (1) a reflex free thyroxine (fT4), whereby fT4 is automatically reported if the thyroid-stimulating hormone is outside the normal range; (2) a forced-function for thyroid hormone ordering, whereby a provider must select an appropriate indication for ordering fT4 or triiodothyronine (T3); and (3) a clinical decision support message displayed at the time of ordering thyroid function tests. Laboratory data were audited to determine the mean number of fT4 and T3 tests performed per week as well as indications for testing. RESULTS: The mean number of fT4 and T3 tests processed per week decreased from 154 ± 21 and 11 ± 7, respectively, in the preintervention period, to 107 ± 12 (30% reduction) and 4 ± 3 (66% reduction) postintervention. These reductions were sustained for the full 20-week assessment period. Process and balancing measures revealed no unintended adverse consequences. Approximate cost savings were $43 000 per year. CONCLUSIONS: We describe the successful implementation of electronic medical record-based interventions (reflex fT4, forced-function selection of indication, decision support text) leading to sustained improvements in healthcare use, with significant associated cost-savings.

Treatment of Pediatric Adrenocortical Carcinoma With Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children's Oncology Group ARAR0332 Protocol.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare aggressive pediatric malignancy with distinct biology. Its treatment follows the principles developed for adults; pediatric-specific studies are scarce. PATIENTS AND METHODS: Prospective single-arm risk-stratified interventional study. Study objectives were (1) to describe the outcome of patients with stage I ACC treated with adrenalectomy alone; (2) to describe the outcome of stage II patients (completely resected > 200 cc or > 100 g) treated with adrenalectomy and retroperitoneal lymph node dissection; and (3) to describe the outcome of patients with stage III or IV treated with mitotane and chemotherapy. RESULTS: Between September 2006 and May 2013, 78 patients (77 eligible, 51 females) were enrolled. The 5-year event-free survival estimates for stages I (24 patients), II (15 patients), III (24 patients), and IV (14 patients) were 86.2%, 53.3%, 81%, and 7.1%, respectively. The corresponding 5-year overall survival estimates were 95.2%, 78.8%, 94.7%, and 15.6%, respectively. On univariate analysis, age, stage, presence of virilization, Cushing syndrome, or hypertension, germline TP53 status, and presence of a somatic ATRX mutation were associated with outcome. On multivariable analysis, only stage and age were significantly associated with outcome. The probabilities of mitotane and chemotherapy feasibility events were 10.5% and 31.6%, respectively. CONCLUSION: Outcome for children with stage I ACC is excellent with surgery. Outcome for patients with stage II disease is inferior despite retroperitoneal lymph node dissection. Patients with stage III ACC have an excellent outcome combining surgery and chemotherapy. Patients with stage IV ACC are older and have a poor outcome; new treatments should be explored for this high-risk group. The combination of mitotane and chemotherapy as prescribed in ARAR0332 resulted in significant toxicity; one third of patients with advanced disease could not complete the scheduled treatment.

Tumor surveillance for children and adolescents with cancer predisposition syndromes: The psychosocial impact reported by adolescents and caregivers.

PURPOSE: Individuals with cancer predisposition syndromes (CPS) are often followed in cancer screening programs, which aim to detect early stage tumors. While cancer surveillance has the potential to improve patient outcomes, its psychosocial impact is uncharacterized in the pediatric population. We examined the cancer surveillance experience from the perspectives of adolescents and parents of children at risk of developing cancer. PATIENTS AND METHODS: Using grounded theory and thematic analysis qualitative methodology, we conducted semi-structured interviews with parents and adolescents, separately. Interviews were transcribed verbatim and coded separately to derive overlapping and unique themes. RESULTS: We completed 20 semi-structured interviews (11 parents and nine adolescents). Positive experiences were related to feelings of reassurance and taking a proactive approach. Both adolescents and parents experienced worry, related to practical aspects of screening, and related to the reminder of cancer risk that manifests with surveillance appointments. This worry was cyclical, associated with appointments, and generally waned over time. Participants felt that the benefits of surveillance outweighed perceived challenges. Open communication with health care providers, and equipping parents/adolescents with vocabulary to discuss their diagnosis and care with others, were felt to be important for mitigating worries associated with cancer risk and surveillance. CONCLUSION: Parents and adolescents experience worry associated with surveillance for CPS, which may warrant regular psychosocial support, particularly during the first year following CPS diagnosis. Enhancing communication with the health care team and among and beyond immediate family members represents an additional important strategy to mitigate adverse experiences and perceptions.

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients.

Neurotrophic tyrosine receptor kinase gene fusions (NTRK) are oncogenic drivers present at a low frequency in most tumour types (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., infantile fibrosarcoma [IFS]) and considered mutually exclusive with other common oncogenic drivers. Health Canada recently approved two tyrosine receptor kinase (TRK) inhibitors, larotrectinib (for adults and children) and entrectinib (for adults), for the treatment of solid tumours harbouring NTRK gene fusions. In Phase I/II trials, these TRK inhibitors have demonstrated promising overall response rates and tolerability in patients with TRK fusion cancer who have exhausted other treatment options. In these studies, children appear to have similar responses and tolerability to adults. In this report, we provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor for pediatric patients with solid tumours. We focus on three pediatric tumour types: non-rhabdomyosarcoma soft tissue sarcoma/unspecified spindle cell tumours including IFS, differentiated thyroid carcinoma, and glioma. We also propose a tumour-agnostic consensus based on the probability of the tumour harbouring an NTRK gene fusion. For children with locally advanced or metastatic TRK fusion cancer who have either failed upfront therapy or lack satisfactory treatment options, TRK inhibitor therapy should be considered.

Lung Metastasis in Children with Differentiated Thyroid Cancer: Factors Associated with Diagnosis and Outcomes of Therapy.

Background: Lung metastasis from differentiated thyroid cancer (DTC) in children and young adults (CAYA) is estimated at 25%, which is 3-4 times higher than in adults. Lung metastases may respond to radioactive iodine (RAI) therapy and overall survival is excellent. Associations with lung metastasis include lateral lymph node (LN) disease although CAYA data are limited. We investigated factors associated with lung metastasis in children and adolescents and described their presentation and outcome. Methods: A retrospective review of medical records from 1998 to 2017 in patients aged <18 years treated at a tertiary pediatric center was carried out. Data on age, clinical features at diagnosis, histology, biochemistry, imaging, RAI therapy, and outcome were collected. Results: Patients treated for DTC totaled 98 and 19 of 98 (19%) patients had lung metastasis; 17 of 19 (89%) patients were identified within 6 months from thyroidectomy. Patients with lung metastasis were younger (p < 0.001)-40% <13 years old had lung metastasis-and had a larger primary tumor diameter (p = 0.01). Absence of LN disease had negative predictive values ≥90% (p < 0.02). Patients with lung metastasis had a higher postoperative thyrotropin-stimulated thyroglobulin (Tg) (p < 0.001), ≥2 ng/mL in 10 of 11 (91%) patients, and 100% had an elevated preoperative Tg (>60 ng/mL). Post-therapy whole body scan (WBS) identified most metastasis (13 of 17 patients), which were mostly diffuse (11 of 19 patients). Discordant findings were found between WBS and computed tomography (CT) at diagnosis (2 patients), WBS and CT during surveillance (3 patients), and diagnostic and post-therapy WBS (2 patients). Final outcome was "excellent" in 3 of 19 (16%) patients, "biochemically persistent" in 1 of 19 (5%) patients, "structurally persistent" in 13 of 19 (68%) patients-including 1 death-and indeterminate in 2 of 19 (11%) patients. Postoperative Tg correlated with response to therapy. Lung metastasis pattern and RAI cumulative activity were not predictive of response to therapy. Conclusions: Lung metastases are mostly observed at diagnosis of DTC and higher suspicion should be maintained in CAYA who are younger, have LN disease, and have elevated postoperative Tg. Preoperative Tg shows promise as another predictive marker, but limited sample size precludes generalization. "Excellent" response to therapy is uncommon-multiple RAI courses do not necessarily improve outcome-response appears unrelated to RAI activity or metastasis pattern.

Early signs of metabolic syndrome in pediatric central nervous system tumor survivors after high-dose chemotherapy and autologous stem-cell transplantation and radiation.

PURPOSE: Cancer survivors treated with stem-cell transplant (SCT) and radiation therapy are at a high risk for late effects including the metabolic syndrome. This study reviewed the prevalence of the metabolic syndrome in pediatric central nervous system (CNS) tumor survivors treated with autologous SCT and craniospinal radiation. METHODS: A prospective, cross-sectional study in pediatric CNS tumor patients, who underwent a one-time evaluation at least 18 months post-autologous SCT for the presence of components of metabolic syndrome: obesity, hypertension, hyperlipidemia, and abnormal glucose levels. RESULTS: Twelve patients were evaluated, and two (16%) met full criteria for the metabolic syndrome. Seven patients (58%) had at least one component of metabolic syndrome: elevated glucose levels in 8% (1/12), obesity 17% (2/12), hypertriglyceridemia 17% (2/12), and reduced HDL cholesterol in 25% (3/12). None had hypertension. Nine patients (75%) demonstrated abnormal fasting lipid profiles with elevated total cholesterol levels, although only 25% (3/12) fulfilled criteria for a diagnosis of dyslipidemia. CONCLUSION: Pediatric CNS tumor survivors treated with autologous SCT and craniospinal radiation are at risk for early signs of metabolic syndrome, most commonly hyperlipidemia. Further studies evaluating the progression of these early signs to full criteria for the metabolic syndrome diagnosis are required.

Clinical Outcomes of Children With Adrenocortical Carcinoma in the Context of Germline TP53 Status.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy of the adrenal cortex. This study characterizes a single-institution cohort of children treated for ACC, and explores the relationship between clinical outcomes of ACC and germline TP53 mutation status. We performed a retrospective chart review of 23 consecutive pediatric patients with ACC treated at The Hospital for Sick Children, Toronto, Canada, between 1977 and 2017. Clinical, biochemical, radiologic, pathologic, and genetic data were collected for each patient. ACC diagnosis followed a bimodal age distribution of 0 to 6 (n=17) and 12+ (n=6) years, with a female:male ratio of 3.6:1. Ten of 20 patients tested for germline TP53 status carried a pathogenic (9) or likely pathogenic (1) variant, including all but 1 male patient. Only 3 patients died of ACC-related causes, each 5 months post-diagnosis. When treated with resection and combination chemotherapy, carriers of germline TP53 mutations may respond more favorably than their wild-type counterparts. In addition, the survival of patients reported in our cohort with high-stage ACC was appreciably greater than previously described (100.0% for stage II, 50.0% for stage III, and 42.9% for stage IV), favoring aggressive intervention in these patient populations.

Pulmonary and overall healthcare utilization after childhood and young adult thyroid cancer.

Differentiated thyroid carcinoma (DTC) in children, adolescents, and young adults is associated with excellent prognosis. However, little is known about the long-term utilization of healthcare resources among survivors. The objective of this study was to compare the utilization of healthcare resources among DTC survivors to the general population, with a focus on pulmonary-related resource utilization. Population-based linked data were used to retrospectively ascertain DTC patients from the Ontario Cancer Registry, age <30 years at diagnosis between 1992 and 2011. DTC cases were individually matched 1:10 to the general population on age, sex, diagnosis year, and rural status. Billing records for all-cause hospitalizations, emergency department visits, pulmonary subspecialist visits, and chest imaging were compared using incidence rate ratios (IRR). A total of 2456 individuals with DTC were identified, with women representing the majority (82.8%) of cases. Compared to controls, hospitalization and emergency department visit IRRs were 2.56 (95% CI, 2.49-2.63) and 2.22 (95% CI, 2.18-2.26), respectively. An excess of pulmonary diagnostic imaging was observed for chest radiography (IRR, 2.7; 95% CI, 2.6-2.8) and pulmonary CT's (IRR, 17.5; 95% CI, 15.8-19.3). Patients who underwent radioactive iodine therapy had a higher incidence of pulmonary-related healthcare utilization than those who did not. The highest healthcare utilization for all modalities was observed in the 30 to 90 days after DTC diagnosis with a steady decline further from diagnosis; however, elevated utilization was observed throughout the observation period. Health services utilization is high for primary DTC survivors, irrespective of the time since diagnosis. Radioactive iodine therapy is associated with higher rates of utilization. These findings have ramifications for treatment, surveillance and for policy formulation.

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or ß-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.