Clinical updates and surveillance recommendations for DNA replication-repair deficiency syndromes in children and young adults.

Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2 or MLH1 genes, and/ or in the polymerase-proofreading genes, POLE and POLD1. RRD predisposition syndromes [constitutional MMR deficiency (CMMRD), Lynch, polymerase-proofreading associated polyposis (PPAP)] share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with CMMRD, new data combining clinical insights and cancer genomics have revealed genotype-phenotype associations, helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/ genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and PPAP syndromes harbouring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations regarding genetic counselling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance, develop prevention strategies, and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally.

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.

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.

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 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 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.

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.

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.

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.

Pilot study for comparative assessment of dual-energy computed tomography and single-photon emission computed tomography V/Q scanning for lung perfusion evaluation in infants.

OBJECTIVE: To evaluate clinical applications of dual-energy computed tomography (DECT) in pediatric-specific lung diseases and compare ventilation and perfusion findings with those from single-photon emission computed tomography (SPECT-CT) V/Q. METHODS: All patients at our institution who underwent exams using both techniques within a 3-month period were included in this study. Two readers independently described findings for DECT, and two other readers independently analyzed the SPECT-CT V/Q scan data. All findings were compared between readers and disagreements were reassessed and resolved by consensus. Inter-modality agreements are described throughout this study. RESULTS: Eight patients were included for evaluation. The median age for DECT scanning was 3.5 months (IQR = 2). Five of these patients were scanned for both DECT and SPECT-CT V/Q studies the same day, and three had a time gap of 7, 65, and 94 days between studies. The most common indications were chronic lung disease (5/8; 63%) and pulmonary hypertension (6/8; 75%). DECT and SPECT-CT V/Q identified perfusion abnormalities in concordant lobes in most patients (7/8; 88%). In one case, atelectasis limited DECT perfusion assessment. Three patients ultimately underwent lobectomy with corresponding perfusion abnormalities identified by all reviewers on both DECT and SPECT-CT V/Q in all resected lobes. CONCLUSION: DECT is a feasible technique that could be considered as an alternative for SPECT-CT V/Q for lung perfusion evaluation in infants.

Case Report: Two Distinct Focal Congenital Hyperinsulinism Lesions Resulting From Separate Genetic Events.

Focal hyperinsulinism (HI) comprises nearly 50% of all surgically treated HI cases and is cured if the focal lesion can be completely resected. Pre-operative localization of the lesion is thus critical. Few cases of hyperinsulinism with multiple focal lesions have been reported, and assessment of the molecular mechanisms driving this rare occurrence has been limited. We present two cases of multifocal HI, each resulting from two independent, pancreatic focal lesions. 18Fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography detected both lesions preoperatively in one patient, whereas identification of the second lesion was an incidental finding during surgical exploration in the other. Complete resection of the focal lesions resulted in cure of the HI in both cases. In each patient, genetic testing of the individual focal lesions revealed different regions of loss of heterozygosity for the maternal 11p15 allele, confirming that each lesion arose from independent somatic events in the setting of a paternally inherited germline ABCC8 mutation. These cases highlight the importance of a multidisciplinary and personalized approach to the management of infants with HI.

18F-6-Fluoro-l-Dopa PET/CT Imaging of Congenital Hyperinsulinism.

Congenital hyperinsulinism is characterized by persistent hypoglycemia due to inappropriate excess secretion of insulin resulting in hyperinsulinemic hypoglycemia. The clinical course varies from mild to severe, with a significant risk for brain damage. Imaging plays a valuable role in the care of infants and children with severe hypoglycemia unresponsive to medical therapy. 18F-6-fluoro-l-dopa PET/CT is the method of choice for the detection and localization of a focal lesion of hyperinsulinism. Surgical resection of a focal lesion can lead to a cure with limited pancreatectomy. This article reviews the role of 18F-6-fluoro-l-dopa PET/CT in the management of this vulnerable population.

Neuroblastoma Shown on 18F-DOPA PET/CT Performed to Evaluate Congenital Hyperinsulinism.

ABSTRACT: 18F-DOPA PET/CT was performed to evaluate congenital hyperinsulinism in a 55-day-old boy with hypoglycemia. The images revealed not only a focal 18F-DOPA-avid lesion in the pancreas but also in a left thoracic paraspinal neuroblastoma.