Novel Use of Dasiglucagon, a Soluble Glucagon Analog, for the Treatment of Hyperinsulinemic Hypoglycemia Secondary to Suspected Insulinoma: A Case Report.

INTRODUCTION: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. In adolescents and adults, hyperinsulinemic hypoglycemia is most frequently caused by an insulin-producing tumor. CASE PRESENTATION: A 17-year-old, previously healthy male presented with recurrent and severe episodes of hypoglycemia. Diagnostic evaluation was consistent with hyperinsulinemic hypoglycemia, and an insulinoma was suspected. Multiple imaging studies and surgical exploration failed to identify a lesion. Over the course of months, the patient was found to be refractory to conventional medical interventions. CONCLUSION: Upon approval from the US Food and Drug Administration and the Institutional Review Board, the patient was treated with dasiglucagon, a novel soluble glucagon analog, under a single-patient Investigational New Drug. The patient has tolerated the medication and has been able to achieve appropriate glycemic control.

Langerhans Cell Histiocytosis With Thyroid Involvement on 18 F-FDG PET/MR.

ABSTRACT: An 18-month-old otherwise healthy girl presented with 1 month of neck swelling. Based on ultrasonography that showed diffusely enlarged heterogeneous thyroid gland, a presumed diagnosis of thyroid cancer was made. Subsequent core needle biopsy revealed Langerhans cell histiocytosis extensively involving the thyroid. 18 F-FDG PET/MR was performed for staging and to evaluate the local extent of the disease in the neck. PET/MR demonstrated a hypermetabolic neck mass inseparable from the thyroid gland. The mass encased the major vessels, trachea, and esophagus without compression or invasion. Osseous involvement was excluded by both skeletal survey and PET/MR.

Rates of Intervention and Cancer Detection on Initial versus Subsequent Whole-body MRI Screening in Li-Fraumeni Syndrome.

Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WB-MRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult patients with LFS (n = 182) were reviewed, including instances of WB-MRI screening and interventions based on screening results. For each WB-MRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WB-MRI. Of the total cohort (n = 182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WB-MRI screenings, with a mean of 3.8 ± 1.9 (adults) and 4.0 ± 2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, P = 0.0026) and stable for children (19%, P = NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WB-MRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3%-4% initial, 6%-10% subsequent) for both children and adults. These findings provide important data for counseling patients with LFS about screening outcomes. PREVENTION RELEVANCE: The cancer detection rate, burden of recommended interventions, and rate of false-positive findings found on subsequent WB-MRI screenings in patients with LFS are not well understood. Our findings suggest that annual WB-MRI screening has clinical utility and likely does not result in an unnecessary invasive intervention burden for patients.

Outcomes of ATA Low-Risk Pediatric Thyroid Cancer Patients Not Treated With Radioactive Iodine Therapy.

CONTEXT: The American Thyroid Association (ATA) Pediatric Guidelines recommend patients not receive radioactive iodine therapy (RAIT) for differentiated thyroid cancer (DTC) confined to the thyroid. Since publication, there is ongoing concern whether withholding RAIT will result in a lower rate of remission. OBJECTIVE: This study explores whether ATA low-risk patients treated with and without RAIT achieved similar remission rates. METHODS: Medical records of patients <19 years old diagnosed with DTC and treated with total thyroidectomy between 2010 and 2020 were reviewed. Multivariate logistic regression was performed to evaluate factors influencing RAIT administration and remission rate. RESULTS: Ninety-five patients with ATA low-risk DTC were analyzed: 53% (50/95) and 47% (45/95) were treated with and without RAIT, respectively. RAIT was used to treat 82% of patients before 2015 compared with 33% of patients after 2015 (P < .01). No significant difference in 1-year remission rate was found between patients treated with and without RAIT, 70% (35/50) vs 69% (31/45), respectively. With longer surveillance, remission rates increased to 82% and 76% for patients treated with and without RAIT, respectively. Median follow-up was 5.8 years (IQR 4.3-7.9, range 0.9-10.9) and 3.6 years (IQR 2.7-6.6; range 0.9-9.3) for both cohorts. No risk factors for persistent or indeterminate disease status were found, including RAIT administration, N1a disease, and surgery after 2015. CONCLUSION: Withholding RAIT for pediatric patients with ATA low-risk DTC avoids exposure to radiation and does not have a negative impact on remission rates. Dynamic risk stratification at 1-year after initial treatment is a suitable time point to assess the impact of withholding RAIT for these patients.

Role of MRI radiomics for the prediction of MYCN amplification in neuroblastomas.

OBJECTIVES: We evaluate MR radiomics and develop machine learning-based classifiers to predict MYCN amplification in neuroblastomas. METHODS: A total of 120 patients with neuroblastomas and baseline MR imaging examination available were identified of whom 74 (mean age ± standard deviation [SD] of 6 years and 2 months ± 4 years and 9 months; 43 females and 31 males, 14 MYCN amplified) underwent imaging at our institution. This was therefore used to develop radiomics models. The model was tested in a cohort of children with the same diagnosis but imaged elsewhere (n = 46, mean age ± SD: 5 years 11 months ± 3 years 9 months, 26 females and 14 MYCN amplified). Whole tumour volumes of interest were adopted to extract first-order histogram and second-order radiomics features. Interclass correlation coefficient and maximum relevance and minimum redundancy algorithm were applied for feature selection. Logistic regression, support vector machine, and random forest were employed as the classifiers. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic accuracy of the classifiers on the external test set. RESULTS: The logistic regression model and the random forest both showed an AUC of 0.75. The support vector machine classifier obtained an AUC of 0.78 on the test set with a sensitivity of 64% and a specificity of 72%. CONCLUSION: The study provides preliminary retrospective evidence demonstrating the feasibility of MRI radiomics in predicting MYCN amplification in neuroblastomas. Future studies are needed to explore the correlation between other imaging features and genetic markers and to develop multiclass predictive models. KEY POINTS: • MYCN amplification in neuroblastomas is an important determinant of disease prognosis. • Radiomics analysis of pre-treatment MR examinations can be used to predict MYCN amplification in neuroblastomas. • Radiomics machine learning models showed good generalisability to external test set, demonstrating reproducibility of the computational models.

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988 .

Neuroblastic Tumor Recurrence Associated With Opsoclonus Myoclonus Ataxia Syndrome Relapse a Decade After Initial Resection and Treatments.

Opsoclonus myoclonus ataxia syndrome (OMAS) is a rare disorder that causes significant neurodevelopmental sequelae in children. Approximately half of pediatric OMAS cases are paraneoplastic, typically associated with localized neuroblastic tumors. Since early persistence or relapse of OMAS symptoms is common even after tumor resection, OMAS relapses may not routinely prompt reevaluation for recurrent tumors. We report a 12-year-old girl with neuroblastic tumor recurrence associated with OMAS relapse a decade after initial treatment. Providers should be aware of tumor recurrence as a trigger for distant OMAS relapse, raising intriguing questions about the role of immune surveillance and control of neuroblastic tumors.

Comparison of whole-body DW-MRI with 2-[18F]FDG PET for staging and treatment monitoring of children with Langerhans cell histiocytosis.

PURPOSE: To assess and compare the diagnostic accuracy of whole-body (WB) DW-MRI with 2-[18F]FDG PET for staging and treatment monitoring of children with Langerhans cell histiocytosis (LCH). METHODS: Twenty-three children with LCH underwent 2-[18F]FDG PET and WB DW-MRI at baseline. Two nuclear medicine physicians and two radiologists independently assessed presence/absence of tumors in 8 anatomical areas. Sixteen children also performed 2-[18F]FDG PET and WB DW-MRI at follow-up. One radiologist and one nuclear medicine physician revised follow-up scans and collected changes in tumor apparent diffusion (ADC) and standardized uptake values (SUV) before and after therapy in all detectable lesions. 2-[18F]FDG PET results were considered the standard of reference for tumor detection and evaluation of treatment response according to Lugano criteria. Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of WB DW-MRI at baseline were calculated, and the 95% confidence intervals were estimated by using the Clopper-Pearson (exact) method; changes in tumor SUVs and ADC were compared using a Mann-Whitney U test. Agreement between reviewers was assessed with a Cohen's weighted kappa coefficient. Analyses were conducted using SAS software version 9.4. RESULTS: Agreement between reviewers was perfect (kappa coefficient = 1) for all analyzed regions but spine and neck (kappa coefficient = 0.89 and 0.83, respectively) for 2-[18F]FDG PET images, and abdomen and pelvis (kappa coefficient = 0.65 and 0.88, respectively) for WB DW-MRI. Sensitivity and specificity were 95.5% and 100% for WB DW-MRI compared to 2-[18F]FDG PET. Pre to post-treatment changes in SUVratio and ADCmean were inversely correlated for all lesions (r: -0.27, p = 0·06) and significantly different between responders and non-responders to chemotherapy (p = 0.0006 and p = 0·003 for SUVratio and ADCmean, respectively). CONCLUSION: Our study showed that WB DW-MRI has similar accuracy to 2-[18F]FDG PET for staging and treatment monitoring of LCH in children. While 2-[18F]FDG PET remains an approved radiological examination for assessing metabolically active disease, WB DW-MRI could be considered as an alternative approach without radiation exposure. The combination of both modalities might have advantages over either approach alone.

Imaging of pediatric pancreas tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Primary pancreatic tumors in children are rare with an overall age-adjusted incidence of 0.018 new cases per 100,000 pediatric patients. The most prevalent histologic type is the solid pseudopapillary neoplasm, followed by pancreatoblastoma. This paper describes relevant imaging modalities and presents consensus-based recommendations for imaging at diagnosis and follow-up.

Imaging of pediatric extragonadal pelvic soft tissue tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

The most common pediatric extragonadal pelvic cancers include germ cell tumors, sacrococcygeal teratomas, and rhabdomyosarcomas (arising from the urinary bladder, prostate, paratesticular tissues, vagina, uterus, and perineum). This paper describes the radiological and nuclear medicine features of these entities and provides consensus-based recommendations for the assessment at diagnosis, during, and after treatment.

Imaging of pediatric pulmonary tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Pediatric pulmonary malignancy can be primary or metastatic, with the latter being by far the more common. With a few exceptions, there are no well-established evidence-based guidelines for imaging pediatric pulmonary malignancies, although computed tomography (CT) is used in almost all cases. The aim of this article is to provide general imaging guidelines for pediatric pulmonary malignancies, including minimum standards for cross-sectional imaging techniques and specific imaging recommendations for select entities.

Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.

Objective: Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital HI have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI. Design: The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined. Methods: We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK). Results: Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic. Conclusion: These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI that lack an identifiable germ-line mutation and that partial pancreatectomy may be curative for these cases.

Intrascrotal Lipoblastoma: A Rare Cause of Paratesticular Mass in a Pediatric Patient.

There is a broad differential diagnosis for a pre-pubertal child presenting with a scrotal mass including both benign and malignant etiologies. Lipoblastomas are rare benign neoplasms originating from fat cells that occur most commonly on the trunk or extremities of young children. There have been less than 20 cases of scrotal lipoblastomas reported in the literature, with the majority occurring in children less than 3 years of age. Here we present a unique case of an 18-month male presenting with a paratesticular mass found to be a lipoblastoma on final pathology.

Whole-tumour apparent diffusion coefficient (ADC) histogram analysis to identify MYCN-amplification in neuroblastomas: preliminary results.

OBJECTIVES: To determine the role of apparent diffusion coefficient (ADC) histogram analysis in the identification of MYCN-amplification status in neuroblastomas. METHODS: We retrospectively evaluated imaging records from 62 patients with neuroblastomas (median age: 15 months (interquartile range (IQR): 7-24 months); 38 females) who underwent magnetic resonance imaging at our institution before the initiation of any therapy or biopsy. Fourteen patients had MYCN-amplified (MYCNA) neuroblastoma. Histogram parameters of ADC maps from the entire tumour was obtained from the baseline images and the normalised images. The Mann-Whitney U test was used to compare the absolute and normalised histogram parameters amongst neuroblastomas with and without MYCN-amplification. Receiver operating characteristic (ROC) curves and area under the curves (AUC) were generated for the statistically significant histogram parameters. Cut-offs obtained from the ROC curves were evaluated on an external validation set (n-15, MYCNA-6, F-7, age 24 months (10-60)). A logistic regression model was trained to predict MYCNA by combining statistically significant histogram parameters and was evaluated on the validation set. RESULTS: MYCN-amplified neuroblastomas had statistically significant higher maximum ADC and lower minimum ADC than non-amplified neuroblastomas. They also demonstrated higher entropy, variance, energy, and lower uniformity than non-amplified neoplasms (p > 0.05). Energy, entropy, and maximum ADC had AUC of 0.85, 0.79, and 0.82, respectively. CONCLUSIONS: Whole tumour ADC histogram analysis of neuroblastomas can differentiate between tumours with and without MYCN-amplification. These parameters can help identify areas for targeted biopsies or can be used to predict subtypes of these high-risk tumours before biopsy results are available. KEY POINTS: • MYCN-amplification significantly affects treatment decisions in neuroblastomas. • MYCN-amplified neuroblastomas had significantly different ADC histogram metrics as compared to tumours without amplification. • ADC histogram metrics can be used to predict MYCN-amplification status based on imaging.

Working from home during the COVID-19 pandemic: surveys of the Society for Pediatric Radiology and the Society of Chiefs of Radiology at Children's Hospitals.

BACKGROUND: Due to the COVID-19 pandemic, some pediatric radiologists have shifted to working from home; the long-term ramifications for pediatric radiologists and departments have not yet been defined. OBJECTIVE: To characterize experiences of working from home associated with the COVID-19 pandemic and guide expectations after the pandemic is controlled, via separate surveys of Society for Pediatric Radiology (SPR) and Society of Chiefs of Radiology at Children's Hospitals (SCORCH) members. MATERIALS AND METHODS: Two separate surveys were conducted. In the first, SPR members were surveyed Jan. 11 through Feb. 8, 2021. The response rate was 17.0% (255 of 1,501). Survey questions included demographics, information on the ability to work from home and subjective experiences ranked on a scale of 0 to 10. The survey enabled segregation and comparison of responses between those with and without home PACS. In the second survey, SCORCH members were surveyed Dec. 8, 2020, through Jan. 8, 2021. The response rate was 51.5% (51/99). Survey questions included the logistics of working from home, technical specifications and the expectations on clinical duties performed from home. The Wilcoxon rank test was used to determine statistical significance of compared variables between respondents with and without home PACS in SPR members, and expectations between SPR and SCORCH members. Descriptive statistics summarized demographic questions and free text responses. RESULTS: The majority of member respondents (81.2%, 207/255) had a home PACS and most departments provided home PACS to faculty (94.1%, 48/51). Overall, radiologists who could work from home were satisfied with their ability to work from home (mean rating: 8.3/10) and were significantly more satisfied than predicted by those without home PACS (5.9/10, P<0.0001). Respondents overwhelmingly indicated they were less able to teach trainees (mean rating: 2.7/10) and had decreased emotional engagement (mean rating: 4.4/10), but had improved research productivity and cognitive ability for research when working from home (mean rating for both: 5.3/10). Regarding the expectations of the ability to work from home after no longer needing to address the pandemic, department chairs generally favored fewer rotations from home, with 97.9% (47/48) indicating working from home should be 60% or fewer assignments, compared with 84.1% (164/195) of individual radiologists (P=0.071). CONCLUSIONS: Due to the COVID-19 pandemic, there has been a shift to working from home using PACS. Results of these SPR and SCORCH member surveys can help inform future decisions regarding pediatric radiologists working from home once the pandemic has been controlled.

Congenital hyperinsulinism: localization of a focal lesion with 18F-FDOPA positron emission tomography.

Hyperinsulinemic hypoglycemia of infancy, also known as congenital hyperinsulinism, is a group of disorders characterized by dysregulated insulin release. Neonates with severe, persistent hyperinsulinemic hypoglycemia who are unresponsive to medical therapy require pancreatectomy to prevent brain damage from hypoglycemia. To date, multiple genetic mutations and syndromes and several unique histopathological entities have been identified in children with hyperinsulinism. Histopathology is characterized as diffuse, focal or atypical. Surgical resection of a focal lesion results in a cure in up to 97% of these children. Imaging with 6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET) is the test of choice for identifying and localizing a focal lesion and has proved to be an invaluable guide for surgical resection. Genetic evaluation is essential for determining who will benefit from PET imaging. This article provides an approach to determine who should be imaged, how to set up a protocol and how to interpret the imaging findings. The diagnosis and management of this disorder require a multidisciplinary approach to prevent brain damage from hypoglycemia.

Deep learning-based automatic tumor burden assessment of pediatric high-grade gliomas, medulloblastomas, and other leptomeningeal seeding tumors.

BACKGROUND: Longitudinal measurement of tumor burden with magnetic resonance imaging (MRI) is an essential component of response assessment in pediatric brain tumors. We developed a fully automated pipeline for the segmentation of tumors in pediatric high-grade gliomas, medulloblastomas, and leptomeningeal seeding tumors. We further developed an algorithm for automatic 2D and volumetric size measurement of tumors. METHODS: The preoperative and postoperative cohorts were randomly split into training and testing sets in a 4:1 ratio. A 3D U-Net neural network was trained to automatically segment the tumor on T1 contrast-enhanced and T2/FLAIR images. The product of the maximum bidimensional diameters according to the RAPNO (Response Assessment in Pediatric Neuro-Oncology) criteria (AutoRAPNO) was determined. Performance was compared to that of 2 expert human raters who performed assessments independently. Volumetric measurements of predicted and expert segmentations were computationally derived and compared. RESULTS: A total of 794 preoperative MRIs from 794 patients and 1003 postoperative MRIs from 122 patients were included. There was excellent agreement of volumes between preoperative and postoperative predicted and manual segmentations, with intraclass correlation coefficients (ICCs) of 0.912 and 0.960 for the 2 preoperative and 0.947 and 0.896 for the 2 postoperative models. There was high agreement between AutoRAPNO scores on predicted segmentations and manually calculated scores based on manual segmentations (Rater 2 ICC = 0.909; Rater 3 ICC = 0.851). Lastly, the performance of AutoRAPNO was superior in repeatability to that of human raters for MRIs with multiple lesions. CONCLUSIONS: Our automated deep learning pipeline demonstrates potential utility for response assessment in pediatric brain tumors. The tool should be further validated in prospective studies.