A comprehensive analysis of neuroblastoma incidence, survival, and racial and ethnic disparities from 2001 to 2019.

BACKGROUND: We characterize the incidence and 5-year survival of children and adolescents with neuroblastoma stratified by demographic and clinical factors based on the comprehensive data from United States Cancer Statistics (USCS) and the National Program of Cancer Registries (NPCR). METHODS: We analyzed the incidence of neuroblastoma from USCS (2003-2019) and survival data from NPCR (2001-2018) for patients less than 20 years old. Incidence trends were calculated by average annual percent change (AAPC) using joinpoint regression. Differences in relative survival were estimated comparing non-overlapping confidence intervals (CI). RESULTS: We identified 11,543 primary neuroblastoma cases in USCS. Age-adjusted incidence was 8.3 per million persons [95% CI: 8.2, 8.5], with an AAPC of 0.4% [95% CI: -0.1, 0.9]. Five-year relative survival from the NPCR dataset (n = 10,676) was 79.7% [95% CI: 78.9, 80.5]. Patients aged less than 1 year had the highest 5-year relative survival (92.5%). Five-year relative survival was higher for non-Hispanic White patients (80.7%) or Hispanic patients (80.8%) compared to non-Hispanic Black patients (72.6%). CONCLUSION: Neuroblastoma incidence was stable during 2003-2019. Differences in relative survival exist by sex, age, race/ethnicity, and stage; patients who were male, older, non-Hispanic Black, or with distant disease had worse survival. Future studies could seek to assess the upstream factors driving disparities in survival, and evaluate interventions to address inequities and improve survival across all groups.

Neuroblastoma in the Era of Precision Medicine: A Clinical Review.

The latest advances in treatment for patients with neuroblastoma are constantly being incorporated into clinical trials and clinical practice standards, resulting in incremental improvements in the survival of patients over time. Survivors of high-risk neuroblastoma (HRNBL), however, continue to develop treatment-related late effects. Additionally, for the majority of the nearly 50% of patients with HRNBL who experience relapse, no curative therapy currently exists. As technologies in diagnostic and molecular profiling techniques rapidly advance, so does the discovery of potential treatment targets. Here, we discuss the current clinical landscape of therapies for neuroblastoma in the era of precision medicine.

Treatment of High-Risk Neuroblastoma.

High-risk neuroblastoma is a highly aggressive solid tumor that most commonly presents in early childhood. Advances in treatment through decades of clinical trials and research have led to improved outcomes. This review provides an overview of the current state of treatment for high-risk neuroblastoma.

Renal function in abdominal neuroblastoma patients undergoing proton radiotherapy.

BACKGROUND: The purpose of this study is to analyze renal function outcomes in abdominal neuroblastoma patients undergoing proton therapy (PT). PROCEDURE: From 2011 to 2019, two single-institution Institutional Review Board-approved protocols prospectively enrolled neuroblastoma patients for data collection. To assess renal function, serum creatinine (Cr), blood urea nitrogen (BUN), and creatinine clearance (CrCl) before proton therapy (pre-PT) were compared with the values at last follow-up. RESULTS: A total of 30 children with abdominal neuroblastoma with median age 3.5 years (range, 0.9-9.1) at time of PT were included in this study. All patients underwent chemotherapy and resection of primary tumor prior to PT. Two patients required radical nephrectomy. Median follow-up after PT was 35 months. Mean dose to ipsilateral and contralateral kidney was 13.9 and 5.4 Gy, respectively. No patients developed hypertension or renal dysfunction during follow-up. There was no statistically significant change in serum BUN (p = .508), CrCl (p = .280), or eGFR (p = .246) between pre-PT and last follow-up. CONCLUSION: At a median follow-up of almost 3 years, renal toxicity was uncommon after PT. Longer follow-up and larger patient cohort data are needed to further assess impact of PT on renal function in this population.

Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor.

PURPOSE: Although chemoimmunotherapy is widely used for treatment of children with relapsed high-risk neuroblastoma (HRNB), little is known about timing, duration, and evolution of response after irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) therapy. PATIENTS AND METHODS: Patients eligible for this retrospective study were age < 30 years at diagnosis of HRNB and received ≥ 1 cycle of I/T/DIN/GM-CSF for relapsed or progressive disease. Patients with primary refractory disease who progressed through induction were excluded. Responses were evaluated using the International Neuroblastoma Response Criteria. RESULTS: One hundred forty-six patients were included. Tumors were MYCN-amplified in 50 of 134 (37%). Seventy-one patients (49%) had an objective response to I/T/DIN/GM-CSF (objective response; 29% complete response, 14% partial response [PR], 5% minor response [MR], 21% stable disease [SD], and 30% progressive disease). Of patients with SD or better at first post-I/T/DIN/GM-CSF disease evaluation, 22% had an improved response per International Neuroblastoma Response Criteria on subsequent evaluation (13% of patients with initial SD, 33% with MR, and 41% with PR). Patients received a median of 4.5 (range, 1-31) cycles. The median progression-free survival (PFS) was 13.1 months, and the 1-year PFS and 2-year PFS were 50% and 28%, respectively. The median duration of response was 15.9 months; the median PFS off all anticancer therapy was 10.4 months after discontinuation of I/T/DIN/GM-CSF. CONCLUSION: Approximately half of patients receiving I/T/DIN/GM-CSF for relapsed HRNB had objective responses. Patients with initial SD were unlikely to have an objective response, but > 1 of 3 patients with MR/PR on first evaluation ultimately had complete response. I/T/DIN/GM-CSF was associated with extended PFS in responders both during and after discontinuation of treatment. This study establishes a new comparator for response and survival in patients with relapsed HRNB.

ERK Inhibitor Ulixertinib Inhibits High-Risk Neuroblastoma Growth In Vitro and In Vivo.

Neuroblastoma (NB) is a pediatric tumor of the peripheral nervous system. Approximately 80% of relapsed NB show RAS-MAPK pathway mutations that activate ERK, resulting in the promotion of cell proliferation and drug resistance. Ulixertinib, a first-in-class ERK-specific inhibitor, has shown promising antitumor activity in phase 1 clinical trials for advanced solid tumors. Here, we show that ulixertinib significantly and dose-dependently inhibits cell proliferation and colony formation in different NB cell lines, including PDX cells. Transcriptomic analysis revealed that ulixertinib extensively inhibits different oncogenic and neuronal developmental pathways, including EGFR, VEGF, WNT, MAPK, NGF, and NTRK1. The proteomic analysis further revealed that ulixertinib inhibits the cell cycle and promotes apoptosis in NB cells. Additionally, ulixertinib treatment significantly sensitized NB cells to the conventional chemotherapeutic agent doxorubicin. Furthermore, ulixertinib potently inhibited NB tumor growth and prolonged the overall survival of the treated mice in two different NB mice models. Our preclinical study demonstrates that ulixertinib, either as a single agent or in combination with current therapies, is a novel and practical therapeutic approach for NB.

Case report: Spindle cell neoplasm presenting as a spontaneous intestinal perforation in a term infant.

Spontaneous intestinal perforations in the neonatal population are mostly associated with low birth weight, prematurity, and necrotizing enterocolitis. Spontaneous intestinal perforation in the absence of these risk factors is extremely rare and should raise clinical concern for an underlying bowel pathology. Here we present a unique case of a normal-weight, full-term girl with spontaneous intestinal perforation due to a spindle cell neoplasm with a novel BRAF mutation and infantile fibrosarcoma-like morphology. Though rare, malignancy should be considered in the differential diagnosis for bowel perforation in an otherwise healthy, term infant as complete surgical excision can be curative.

Efficacy of post-induction therapy for high-risk neuroblastoma patients with end-induction residual disease.

BACKGROUND: High-risk neuroblastoma patients with end-induction residual disease commonly receive post-induction therapy in an effort to increase survival by improving the response before autologous stem cell transplantation (ASCT). The authors conducted a multicenter, retrospective study to investigate the efficacy of this approach. METHODS: Patients diagnosed between 2008 and 2018 without progressive disease with a partial response or worse at end-induction were stratified according to the post-induction treatment: 1) no additional therapy before ASCT (cohort 1), 2) post-induction "bridge" therapy before ASCT (cohort 2), and 3) post-induction therapy without ASCT (cohort 3). χ2 tests were used to compare patient characteristics. Three-year event-free survival (EFS) and overall survival (OS) were estimated by the Kaplan-Meier method and survival curves were compared by log-rank test. RESULTS: The study cohort consisted of 201 patients: cohort 1 (n = 123), cohort 2 (n = 51), and cohort 3 (n = 27). Although the end-induction response was better for cohort 1 than cohorts 2 and 3, the outcomes for cohorts 1 and 2 were not significantly different (P = .77 for EFS and P = .85 for OS). Inferior outcomes were observed for cohort 3 (P < .001 for EFS and P = .06 for OS). Among patients with end-induction stable metastatic disease, 3-year EFS was significantly improved for cohort 2 versus cohort 1 (P = .04). Cohort 3 patients with a complete response at metastatic sites after post-induction therapy had significantly better 3-year EFS than those with residual metastatic disease (P = .01). CONCLUSIONS: Prospective studies to confirm the benefits of bridge treatment and the prognostic significance of metastatic response observed in this study are warranted.

MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma.

Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.

Incidence and 5-year survival of children and adolescents with hepatoblastoma in the United States.

OBJECTIVE: Hepatoblastoma (HB) is the most common pediatric primary malignant liver tumor, its incidence has been increasing worldwide, but recent changes in incidence and outcomes with high population coverage are not well characterized. METHODS: We defined the incidence of HB diagnosed during 2003-2017 from United States Cancer Statistics (USCS) database, and survival during 2001-2016 from the National Program of Cancer Registries (NPCR). Data were stratified by sex, race/ethnicity, age, tumor stage, county population, and diagnosis year. Incidence trends were assessed by calculating average annual percent change (AAPC) using Joinpoint regression. Differences in overall 5-year survival were estimated using Cox regression analysis. RESULTS: 2178 HB cases with an annual incidence rate of 1.76 per million persons were identified and incidence increased over time (AAPC = 2.2, 95% confidence interval [CI], 0.9-3.6). The 5-year relative survival was 76.9% (95% CI: 74.9-78.8) and the risk of death was lower for cases diagnosed after 2009 (hazard ratio [HR] = 0.77, 95% CI: 0.63-0.94), higher for ages 3-7 years and 8-19 years compared to 0-2 years (HR = 1.38, 95% CI: 1.10-1.76 and 1.83, 95% CI: 1.31-2.70, respectively), for distant compared to locoregional stage (HR = 2.77, 95% CI: 2.27-3.36), and for non-Hispanic Black compared to non-Hispanic White cases (HR = 1.39, 95% CI: 1.02-1.84). CONCLUSIONS: HB incidence increased, and survival improved over the study period. Disparities in survival exist by age, race or ethnicity, and stage. Further studies could identify factors affecting increases in HB cases, inform future interventions, and address disparities in outcomes.

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG).

BACKGROUND: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. METHODS: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D. RESULTS: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). CONCLUSIONS: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.

Associations of demographic and perinatal factors with childhood neuroblastoma in Texas, 1995-2011.

BACKGROUND: Neuroblastoma, the most common extracranial solid tumor in children, contributes disproportionately to childhood cancer mortality and few risk factors have been identified. Our objective was to evaluate associations between parental and infant characteristics and neuroblastoma incidence. METHODS: Children born in Texas between January 1995 and December 2011 were eligible for the present study. Cases (N = 637) were diagnosed with neuroblastoma in Texas during the same period; controls (N = 6370) matched on year of birth were randomly selected from birth certificates that did not link to a record in the Texas Cancer Registry. We obtained data on birth and parental demographic/reproductive characteristics from birth certificates, and estimated odds ratios (OR) and 95% confidence intervals (CIs) for neuroblastoma using logistic regression. RESULTS: Gestational age 34-36 weeks at birth was associated with neuroblastoma (OR 1.45, CI 1.09-1.90), whereas female sex was inversely associated (OR 0.68, CI 0.58-0.81). Relative to children of non-Hispanic White women, children of Hispanic (OR 0.53, CI 0.43-0.64) or non-Hispanic Black (OR 0.52, CI 0.38-0.71) women were at reduced odds of neuroblastoma. When maternal and paternal race/ethnicity were evaluated jointly, similar patterns were observed (two non-Hispanic Black parents: OR 0.55, 95%CI 0.36-0.79; two Hispanic parents: OR 0.53, 95%CI 0.41-0.67). Older maternal age was also positively associated with neuroblastoma (OR 1.41, CI 1.04-1.90 for 35-39 years; OR 1.62, CI 0.87-2.81 for ≥40 years, relative to 25-29 years). CONCLUSIONS: Findings provide further evidence of racial/ethnic disparities in neuroblastoma incidence, determinants of which are unknown. In contrast to most published studies, we observed an association between maternal age and neuroblastoma. Further studies with more robust control for confounding are warranted.

Characteristics of benign neuroblastic tumors: Is surgery always necessary?

PURPOSE: Ganglioneuroma (GN) and ganglioneuroblastoma-intermixed (GNB-I) represent benign variants of neuroblastic tumors in children; however, differentiating from more aggressive histological variants of GNB including the nodular subtype (GNB-N) prior to resection can be challenging, even with biopsy. Currently, no standard treatment guidelines exist. The purpose of this study was to identify pre-operative characteristics of benign neuroblastic tumors and evaluate outcomes for patients who underwent surgical resection or observation. METHODS: Retrospective chart review of children treated at a single institution between 2009 and 2019 for non-metastatic tumor with a tissue diagnosis of GN, GNB-N or GNB-I. Demographics, imaging, labs, operative details and outcomes were recorded and analyzed. RESULTS: Of 53 patients, 45% were male. The most common tumor location was abdomen (49%), followed by thorax (34%). Forty-five percent had at least one image defined risk factor. Biopsy was performed in 32% (17/53) and upfront surgery in 68% (36/53). Three patients (3/53, 5.6%) with biopsy demonstrating GN tumors were observed due to high surgical risk. Pathology of resected specimens demonstrated GN in 52% (26/50) and GNB-I or GNB-N in 48% (24/50). The majority of GNB tumors (75% (18/24) were GNB-I and 25% (6/24) were GNB-N. Therefore, 88% of the resected tumors were benign spectrum neuroblastic tumors (GN & GNB-I). Seven (7/50, 14%) patients experienced perioperative complication (temporary paralysis, Horner's syndrome, chylothorax, vocal cord paralysis). Recurrence was noted in 1 patient with GN (1/50, 2%) and 3 with GNB-N (3/50, 6%). There were no tumor-related deaths. Patients with GN were older than those with GNB (8.8 years (IQR 6-11.25) vs 5.6 years for GN (IQR 3-7); p = 0.01). GNB tumors were also more likely to have calcifications on imaging (63% vs. 38%, p = .01) and more commonly had MIBG avidity (88% vs 66%, p = .04). There were no significant differences in tumor size or symptoms at presentation. CONCLUSIONS: In children with neuroblastic tumors, older age, CT without tumor calcifications, lack of MIBG avidity, and/or normal urine catecholamines may indicate benign GN. Close observation could be considered for asymptomatic patients meeting these criteria with biopsy-proven GN, with resection reserved for progressive growth or symptom development. However, larger, multicenter studies are needed for further validation. LEVEL OF EVIDENCE: IV.

Preventing Home Medication Administration Errors.

Medication administration errors that take place in the home are common, especially when liquid preparations are used and complex medication schedules with multiple medications are involved; children with chronic conditions are disproportionately affected. Parents and other caregivers with low health literacy and/or limited English proficiency are at higher risk for making errors in administering medications to children in their care. Recommended strategies to reduce home medication errors relate to provider prescribing practices; health literacy-informed verbal counseling strategies (eg, teachback and showback) and written patient education materials (eg, pictographic information) for patients and/or caregivers across settings (inpatient, outpatient, emergency care, pharmacy); dosing-tool provision for liquid medication measurement; review of medication lists with patients and/or caregivers (medication reconciliation) that includes prescription and over-the-counter medications, as well as vitamins and supplements; leveraging the medical home; engaging adolescents and their adult caregivers; training of providers; safe disposal of medications; regulations related to medication dosing tools, labeling, packaging, and informational materials; use of electronic health records and other technologies; and research to identify novel ways to support safe home medication administration.

Thoracoscopic Resection of Thoracic Inlet Neuroblastic Tumors in Young Children.

Background: Thoracic inlet (TI) tumors are rare, and can be particularly challenging to resect due to proximity to mediastinal vessels and nerves. Traditional resection is typically performed through "trapdoor" or sternoclavicular incisions. The purpose of our study was to evaluate the feasibility and effectiveness of thoracoscopic resection of this group of tumors. Methods: We performed a single-center retrospective chart review for children who presented with TI neuroblastic tumors between 2011 and 2020. Demographics, tumor characteristics, treatment, operative complications, and outcomes were collected and analyzed. Results: Eight patients were identified. The median age at diagnosis was 13 months (interquartile range [IQR] 6-32) with median tumor size at diagnosis of 4.1 cm (IQR 3.6-4.4). Neoadjuvant chemotherapy was given in 50% (4/8) with 38% (3/8) undergoing upfront surgery; 1 patient was observed without chemotherapy or surgery. Ultimately, 6 patients had thoracoscopic resection. For thoracoscopic resections, median intraoperative estimated blood loss was 15 mL (IQR 10-28), median operative room time was 199 minutes (IQR 152-259), and median hospital length of stay was 2 days (IQR 2-3). There were two complications: one recurrent laryngeal nerve injury and one new-onset Horner's syndrome. Complete gross total resection was achieved for all children and there were no recurrences or mortalities with a median follow-up of 3 years. Conclusion: Thoracoscopic resection for TI neuroblastic tumors is feasible with minimal morbidity and can lead to adequate oncological resection.

Recommendations for Age-Appropriate Testing, Timing, and Frequency of Audiologic Monitoring During Childhood Cancer Treatment: An International Society of Paediatric Oncology Supportive Care Consensus Report.

IMPORTANCE: Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on. OBJECTIVE: To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice. METHODS: An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel. FINDINGS: The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources. CONCLUSIONS AND RELEVANCE: This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens.

The Anti-Tumor Activity of the NEDD8 Inhibitor Pevonedistat in Neuroblastoma.

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin-RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136-400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53MUT) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53WT) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.

Role of anticoagulation in the management of tumor thrombus: A 10-year single-center experience.

BACKGROUND: Children with cancer diagnosis are overall at a higher risk of thrombosis. For a newly diagnosed blood clot, patients are commonly started on anticoagulants to prevent further extension and embolization of the clot. In the rare instance that a pediatric patient has a tumor thrombus, role of anticoagulation is less clear. PROCEDURE/METHODS: Patients under 21 years of age with a finding of tumor thrombus on imaging from 2010 to 2020 at Texas Children's Hospital were identified and their medical records were reviewed. RESULTS: A total of 50 patients were identified. Most thrombi were incidental findings at diagnosis; however, two patients presented with pulmonary embolism (PE). Inferior vena cava extension was noted in 36% of the patients, and 24% patients had an intracardiac tumor thrombus. Anticoagulation was initiated in 10 patients (20%). There was no difference in the rate of bland thrombus formation and/or embolization in patients who did or did not receive anticoagulation. However, three of the six patients with asymptomatic tumor thrombus who were started on anticoagulation had bleeding complications compared to only two patients in the no anticoagulation cohort (p < .05). CONCLUSION: Children with intravascular extension of solid tumors were not commonly started on anticoagulation at the time of diagnosis, irrespective of the extent of tumor thrombus. Furthermore, we observed a significant trend toward higher incidence of bleeding complications after initiation of anticoagulation for asymptomatic tumor thrombus. There is inadequate evidence at this time to support routine initiation of anticoagulation in pediatric patients with intravascular extension of solid tumors.

Genomic analysis and preclinical xenograft model development identify potential therapeutic targets for MYOD1-mutant soft-tissue sarcoma of childhood.

The myogenic differentiation 1 gene (MYOD1) p.L122R somatic mutation was first discovered in a subset of clinically aggressive embryonal rhabdomyosarcomas and has since been described in both pediatric and adult spindle cell/sclerosing rhabdomyosarcomas. Relatively little is known about the clinical, molecular, and histopathological features of these tumors in children. In order to further characterize the genomic and clinical features of pediatric MYOD1-mutant sarcomas, we evaluated a cohort of soft-tissue sarcoma patients treated at Texas Children's Hospital. Tumor DNA was subjected to next-generation panel sequencing and/or Sanger sequencing of the MYOD1 hotspot mutation. The MYOD1 p.L122R mutation was identified in six tumors, with a variant allele fraction greater than 0.8 in three cases, suggestive of loss of heterozygosity. One sclerosing rhabdomyosarcoma lacking the MYOD1 hotspot mutation was observed to have a MYOD1 copy number gain, also with evidence of loss of heterozygosity. Cancer gene panel sequencing revealed potentially targetable alterations in six of seven (86%) patients with MYOD1 alterations, including four patients with an alteration in the PI3K-AKT pathway: two hotspot PIK3CA mutations and deletions in PTEN and TSC2. On histopathologic review, MYOD1-altered tumors exhibited spindle and/or round cells and varying degrees of hyaline sclerosis. At last follow-up, six patients had died of disease and the seventh progressed early and was subsequently lost to follow-up. Both pre- and post-therapy patient-derived xenograft models were generated from one patient's tumor. These models were confirmed to harbor the MYOD1 and PIK3CA mutations seen in the primary tumor and were shown to be sensitive to PI3K/mTOR inhibition in vitro and in vivo. In conclusion, this study adds to recent reports describing the clinicopathologic and genomic features of MYOD1-altered soft-tissue sarcomas in children, including dismal prognosis and potential molecular targets for therapy. The novel preclinical models developed will facilitate further biological and preclinical study of this rare and aggressive tumor. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Peptide receptor radionuclide therapy for treatment of metastatic neuroendocrine tumors in children.

Neuroendocrine tumors (NETs) of the pancreas and midgut are extremely rare in children, and patients presenting with metastatic disease have poor survival. Given this rarity, treatments are extrapolated from guidelines for adults with NET. Recent clinical trials in adults with NETs have shown that the addition of peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE resulted in a disease control rate of nearly 80%, with minimal side effects. We report our experience using 177 Lu-DOTATATE to treat two pediatric patients with metastatic NET.