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Purpose: To investigate the use of a complex multigradient echo (mGRE) acquisition and an autoregressive moving average (ARMA) model for simultaneous susceptibility and R 2 measurements for the assessment of liver iron content (LIC) in patients with iron overload.Materials and Methods: Fifty magnetic resonance imaging (MRI) exams with magnitude and phase mGRE images were processed using the ARMA model, which provides fat-separated field maps, R 2 maps, and T(1) -W imaging. The LIC was calculated by measuring the susceptibility between the liver and the right transverse abdominal muscle from the field maps. The relationship between LIC derived from susceptibility measurements and LIC from R 2 measurements was determined using linear least-squares regression analysis.Results: LIC measured from R 2 is highly correlated to the LIC with the susceptibility method (mg/g dry = 8.99 ± 0.15 × [mg Fe/mL of wet liver] -2.38 ± 0.29, R(2) = 0.94). The field inhomogeneity in the liver is correlated with R 2 (R(2) = 0.85).Conclusion: By using the ARMA model on complex mGRE images, both susceptibility and R 2-based LIC measurements can be made simultaneously. The susceptibility measurement can be used to help verify R 2 measurements in the assessment of iron overload. [ABSTRACT FROM AUTHOR]

Background: Patients treated for cancer have a higher incidence of focal liver lesions than the general population and there is often concern for a malignant etiology. This can result in patient, caregiver and physician anxiety and is managed by a "wait and watch" approach, or immediate additional imaging, or biopsy, depending on the degree of clinical concern. Because it is a low-cost, easily accessible, radiation and sedation free modality, we investigated the value of contrast enhanced ultrasound (CEUS) to accurately distinguish benign from malignant liver lesions in patients treated for childhood malignancies., Methods: We performed an IRB approved retrospective study of 68 subjects who were newly diagnosed, on treatment or off treatment for a pediatric malignancy and had liver lesions discovered on CT, MRI or non-contrast ultrasound and subsequently underwent CEUS between September 2013 and September 2021. Two experienced pediatric radiologists and a radiology trainee, blinded to the etiology of the liver lesions, independently reviewed the CEUS examinations and categorized lesions as benign, indeterminate, or malignant. The reference standard was biopsy for 19 lesions and clinical follow-up for 49. The sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy of CEUS were calculated using only the benign and malignant CEUS classifications. Inter-reviewer agreement was assessed by Cohen's kappa statistic., Results: There were 26 males and 42 females, mean age, 14.9 years (range, 1-52 years). Fifty subjects were off therapy, twelve receiving treatment, and six with newly diagnosed cancer. By the reference standard, 59 (87%) lesions were benign and 9 (13%) were malignant. Sensitivities of CEUS for the three reviewers ranged from 83 to 100% (95% CI, 35.9-100%), specificities from 93.1 to 96.0% (95% CI, 83.5-99.6%), PPV 60.0-71.4% (95% CI, 29.0-96.3%), NPV 98.0-100% (95% CI, 89.2-100%) and accuracy from 93.8 to 94.6% (95% CI, 85.1-99.7%). The kappa statistic for agreement between the two experienced radiologists was moderate at 0.58., Conclusions: CEUS is highly accurate in distinguishing benign from malignant etiologies of liver lesions in patients treated for pediatric malignancies., (© 2024. The Author(s).)

Background: In retrospective analyses, the Pediatric Oncology Group [POG) and the Federation National des Centres de Lutte Contre le Cancer (FNCLCC) histologic grade predict outcome in pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), but prospective data on grading, clinical features, and outcomes of low-grade NRSTS are limited., Methods: We analyzed patients less than 30 years of age enrolled on Children's Oncology Group (COG) study ARST0332 (NCT00346164) with POG grade 1 or 2 NRSTS. Low-risk patients were treated with surgery alone. Intermediate-/high-risk patients received ifosfamide/doxorubicin and radiotherapy, with definitive resection either before or after 12 weeks of chemoradiotherapy., Results: Estimated 5-year event-free and overall survival were 90% and 100% low risk (n = 80), 55% and 78% intermediate risk (n = 15), and 25% and 25% high risk (n = 4). In low-risk patients, only local recurrence was seen in 10%; none with margins greater than 1 mm recurred locally. Sixteen of 17 intermediate-/high-risk patients who completed neoadjuvant chemoradiotherapy underwent gross total tumor resection, 80% with negative margins. Intermediate-/high-risk group events included one local and seven metastatic recurrences. Had the FNCLCC grading system been used to direct treatment, 29% of low-risk (surgery alone) patients would have received radiotherapy ± chemotherapy., Conclusions: Most low-risk patients with completely resected POG low-grade NRSTS are successfully treated with surgery alone, and surgical margins greater than 1 mm may be sufficient to prevent local recurrence. Patients with intermediate- and high-risk low-grade NRSTS have outcomes similar to patients with high-grade histology, and require more effective therapies. Use of the current FNCLCC grading system may result in overtreatment of low-risk NRSTS curable with surgery alone., (© 2024 Wiley Periodicals LLC.)

Background: Embryonal sarcoma of the liver (ESL) is a rare mesenchymal tumor most common in childhood; the optimal treatment approach is uncertain. The clinical features and outcomes of patients with ESL enrolled in a Children's Oncology Group (COG) clinical trial that evaluated a risk-based strategy for treating soft tissue sarcomas in patients aged <30 years were evaluated., Methods: This subset analysis included patients with ESL enrolled in COG study ARST0332. Central review of records, pathology, and imaging confirmed the diagnosis, presenting features, and surgery extent and complications. All patients received dose-intensive ifosfamide/doxorubicin chemotherapy, with cycle timing dependent on surgery and radiotherapy. Tumor resection occurred before study entry or after four cycles of chemotherapy; radiotherapy for residual tumor was optional., Results: Thirty-nine eligible/evaluable patients with ESL were analyzed. All tumors were >10 cm in diameter; four were metastatic. Tumor resection was performed upfront in 23 and delayed in 16. Positive surgical margins (n = 6) and intraoperative tumor rupture (n = 6) occurred only in upfront resections. Eight patients received radiotherapy. Estimated 5-year event-free and overall survival were 79% (95% confidence interval [CI], 65%-93%) and 95% (95% CI, 87%-100%), respectively. Positive margins increased the local recurrence risk. One of 13 patients with documented hemorrhagic ascites and/or tumor rupture developed extrahepatic intra-abdominal tumor recurrence., Conclusions: The treatment strategy used in ARST0332 achieved favorable outcomes for patients with ESL despite a substantial proportion having high-risk disease features. Deferring tumor resection until after neoadjuvant chemotherapy may decrease the risk of intraoperative tumor rupture and improve the likelihood of adequate surgical margins., (© 2024 American Cancer Society.)

Background: Local control for patients with Ewing sarcoma (EWS) who present with large tumors are suboptimal when treated with standard radiation therapy (RT) doses of 54-55.8 Gy. The purpose of this study is to determine local control and toxicity of dose-escalated RT for tumors ≥8 cm (greatest diameter at diagnosis) in pediatric and young adult patients with EWS., Methods: Eligible patients ≤30 years old with newly diagnosed EWS ≥8 cm treated with definitive conformal or intensity modulated photon, or proton radiation therapy techniques were included. All patients in the study received dose-escalated RT doses. Outcomes included overall survival (OS), event-free survival (EFS), local failure rates, and toxicity., Results: Thirty-two patients were included, 20 patients presented with metastatic disease and 12 patients with localized disease. The median RT dose was 64.8 Gy (range, 59.4-69.4 Gy) with variability of doses to protect normal surrounding tissues. All patients received systemic chemotherapy. The 5-year OS and EFS for the cohort was 64.2% and 42%, respectively. The 5-year cumulative incidence of local failure was 6.6%. There were two combined local and distant failures with no isolated local failures. Twenty-nine patients experienced short term toxicity, 90% of those being radiation dermatitis. Twenty-seven patients experienced long-term toxicity, with only one experiencing grade 4 toxicity, a secondary malignancy after therapy., Conclusion: This study demonstrates that definitive RT for pediatric and young adult patients with EWS ≥8 cm provides high rates of local control, while maintaining a tolerable toxicity profile., (© 2024 American Cancer Society.)

Background: Clearing all pulmonary metastases is essential for curing pediatric solid tumors. However, intraoperative localization of such pulmonary nodules can be challenging. Therefore, an intraoperative tool that localizes pulmonary metastases is needed to improve diagnostic and therapeutic resections. Indocyanine green (ICG) real-time fluorescence imaging is used for this purpose in adult solid tumors, but its utility in pediatric solid tumors has not been determined., Methods: A single-center, open-label, nonrandomized, prospective clinical trial (NCT04084067) was conducted to assess the ability of ICG to localize pulmonary metastases of pediatric solid tumors. Patients with pulmonary lesions who required resection, either for therapeutic or diagnostic intent, were included. Patients received a 15-minute intravenous infusion of ICG (1.5 mg/kg), and pulmonary metastasectomy was performed the following day. A near-infrared spectroscopy iridium system was optimized to detect ICG, and all procedures were photo-documented and recorded., Results: ICG-guided pulmonary metastasectomies were performed in 12 patients (median age: 10.5 years). A total of 79 nodules were visualized, 13 of which were not detected by preoperative imaging. Histologic examination confirmed the following histologies: hepatoblastoma (n = 3), osteosarcoma (n = 2), and one each of rhabdomyosarcoma, Ewing sarcoma, inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, and papillary thyroid carcinoma. ICG guidance failed to localize pulmonary metastases in five (42%) patients who had inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, or papillary thyroid carcinoma., Conclusions: ICG-guided identification of pulmonary nodules is not feasible for all pediatric solid tumors. However, it may localize most metastatic hepatic tumors and high-grade sarcomas in children., (© 2023 Wiley Periodicals LLC.)

Rhabdomyosarcoma is the most common soft-tissue neoplasm in the pediatric population. The survival of children with rhabdomyosarcoma has only marginally improved over the past 25 years and remains poor for those with metastatic disease. A significant challenge to advances in treatment of rhabdomyosarcoma is the relative rarity of this disease, necessitating years to complete clinical trials. Progress can be accelerated by international cooperation and sharing national experiences. This necessitates agreement on a common language to describe patient cohorts and consensus standards to guide diagnosis, treatment, and response assessment. These goals formed the premise for creating the INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) in 2017. Multidisciplinary members of this consortium have since developed international consensus statements on the diagnosis, treatment, and management of pediatric soft-tissue sarcomas. Herein, members of the INSTRuCT Diagnostic Imaging Working Group present international consensus recommendations for imaging of patients with rhabdomyosarcoma at diagnosis, at staging, and during and after completion of therapy. The intent is to promote a standardized imaging approach to pediatric patients with this malignancy to create more-reliable comparisons of results of clinical trials internationally, thereby accelerating progress in managing rhabdomyosarcoma and improving survival., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Malignant primary bone tumors are uncommon in the pediatric population, accounting for 3%-5% of all pediatric malignancies. Osteosarcoma and Ewing sarcoma comprise 90% of malignant primary bone tumors in children and adolescents. This paper provides consensus-based recommendations for imaging in children with osteosarcoma and Ewing sarcoma at diagnosis, during therapy, and after therapy., (© 2022 Wiley Periodicals LLC.)

Pediatric soft tissue tumors of the extremity include rhabdomyosarcoma and nonrhabdomyosarcoma neoplasms. This manuscript provides consensus-based imaging recommendations for imaging evaluation at diagnosis, during treatment, and following completion of therapy for patients with a soft tissue tumor of the extremity., (© 2022 Wiley Periodicals LLC.)

Objective: Recent increased awareness and research studies reflect possible associations between opioid exposure and cancer outcomes. Children with neuroblastoma (NB) often require opioid treatment for pain. However, associations between tumor response to chemotherapy and opioid exposure have not been investigated in clinical settings., Methods: This is a single-institution retrospective review of patients with NB treated between 2013 and 2016. We evaluated opioid consumption quantified in morphine equivalent doses (mg/kg) based on nurse- or patient-controlled analgesia during antibody infusions. We also analyzed their associations with change in primary tumor volume and total tumor burden., Results: Of 42 patients given opioids for pain related to anti-disialoganglioside monoclonal antibodies (anti-GD2 mAb), data completion was achieved for 36, and details of statistical analyses were entered. Median total weight-based morphine equivalent (over 8 days) was 4.71 mg/kg (interquartile range 3.49-7.96). We found a statistically insignificant weak negative relationship between total weight-based morphine equivalents and tumor volume ratio (correlation coefficient -.0103, p-value .9525) and a statistically insignificant weak positive relationship between total weight-based morphine equivalent and Curie score ratio (correlation coefficient .1096, p-value .5247)., Conclusion: Our study found no statistically significant correlation between opioid consumption and natural killer (NK) cell-mediated killing of NB cells as measured by effects on tumor volume/tumor load., (© 2022 Wiley Periodicals LLC.)

Background: The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease., Methods: In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility., Results: One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively., Conclusions: The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials., (© 2021 American Cancer Society.)

Purpose: Image-defined risk factors (IDRFs) are associated with surgical risks in neuroblastoma. We sought to evaluate the impact of neoadjuvant therapy on IDRFs and associated ability to achieve gross total resection (GTR) of locoregional disease in patients with high-risk neuroblastoma., Methods: We retrospectively reviewed charts of patients treated on four consecutive high-risk neuroblastoma protocols over a 20-year period at a single institution. The number of IDRFs at diagnosis and just prior to surgery, and the percent decrease of tumor volume from just prior to surgery to the end of induction were determined., Results: Eighty-eight patients were included. There were 438 IDRFs (average 5.0 ± 3.1 per patient) at diagnosis and 198 (average 2.3 ± 1.9 per patient) after neoadjuvant chemotherapy (p < 0.01). A reduction in IDRFs was seen in 81.8% of patients with average decrease of 2.9 ± 2.5 per patient. The average percent reduction in tumor volume was 89.8 ± 18.9% and correlated with the number of IDRFs present after chemotherapy (p < 0.01). Three or fewer IDRFs prior to surgery was associated with the highest odds ratio for > 90% GTR at 9.33 [95% confidence interval 3.14-31.5]., Conclusion: Neoadjuvant chemotherapy reduced the number of IDRFs in the majority of patients with high-risk neuroblastoma. The number of IDRFs present after neoadjuvant therapy correlated with the extent of resection., (© 2021. Society of Surgical Oncology.)

Pulmonary complications are common in children following hematopoietic cell transplantation (HCT) and contribute to their morbidity and mortality. Early diagnosis is essential for management and prevention of progression of lung injury and damage. In many cases, diagnosis can be challenging and may require diagnostic imaging and more invasive testing such as bronchoscopy and lung biopsy. We report the case of a 12-year-old girl who developed recurrent episodes of acute respiratory failure requiring intensive care unit admission in the post-HCT phase and describe the diagnostic and multidisciplinary approach for her management. In addition, we review the diagnostic approach of pulmonary complications post-HCT and highlight the utility and risks of bronchoscopy and lung biopsy in these children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Elbahlawan, McArthur, Morin, Abdelhafeez, McCarville, Ruiz, Srinivasan and Qudeimat.)

Contrast-enhanced ultrasound (CEUS) has been increasingly used in pediatric radiology practice worldwide. For nearly two decades, CEUS applications have been performed with the off-label use of gas-containing second-generation ultrasound contrast agents (UCAs). Since 2016, the United States Food and Drug Administration (FDA) has approved the UCA Lumason for three pediatric indications: the evaluation of focal liver lesions and echocardiography via intravenous administration and the assessment of vesicoureteral reflux via intravesical application (contrast-enhanced voiding urosonography, ceVUS). Prior to the FDA approval of Lumason, numerous studies with the use of second-generation UCAs had been conducted in adults and children. Comprehensive protocols for clinical safety evaluations have demonstrated the highly favorable safety profile of UCA for intravenous, intravesical and other intracavitary uses. The safety data on CEUS continue to accumulate as this imaging modality is increasingly utilized in clinical settings worldwide. As of August 2021, 57 pediatric-only original research studies encompassing a total of 4,518 children with 4,906 intravenous CEUS examinations had been published. As in adults, there were a few adverse events; the majority of these were non-serious, although very rarely serious anaphylactic reactions were reported. In the published pediatric-only intravenous CEUS studies included in our analysis, the overall incidence rate of serious adverse events was 0.22% (10/4,518) of children and 0.20% (10/4,906) of all CEUS examinations. Non-serious adverse events from the intravenous CEUS were observed in 1.20% (54/4,518) of children and 1.10% (54/4,906) of CEUS examinations. During the same time period, 31 studies with the intravesical use of UCA were conducted in 12,362 children. A few non-serious adverse events were encountered (0.31%; 38/12,362), but these were most likely attributable to the bladder catheterization rather than the UCA. Other developing clinical applications of UCA in children, including intracavitary and intralymphatic, are ongoing. To date, no serious adverse events have been reported with these applications. This article reviews the existing pediatric CEUS literature and provides an overview of safety-related information reported from UCA uses in children., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Contrast-enhanced ultrasound (CEUS) utilization is expanding rapidly, particularly in children, in whom the modality offers the important advantages of dynamic evaluation of the vasculature, portability, lack of ionizing radiation, and lack of need for sedation. Accumulating data establish an excellent safety profile of ultrasound contrast agents (UCAs) in children. Although UCAs have been FDA-approved only for IV use in children for characterizing focal liver lesions and for use in children during echocardiography, off-label applications are expanding the diagnostic potential of ultrasound. Focal liver lesion evaluation is the most common use of CEUS, and the American College of Radiology Pediatric LI-RADS Working Group recommends including CEUS for evaluation of a newly discovered focal liver lesion in many circumstances. Data also support the role of CEUS in hemodynamically stable children with blunt abdominal trauma, and CEUS is becoming a potential alternative to CT in this setting. Additional potential applications that require further study include evaluation of pathology in the lung, spleen, brain, pancreas, bowel, kidney, female pelvis, and scrotum. This article explores the implementation of CEUS in children, describing basic principles of UCAs and CEUS technique and summarizing current and potential IV diagnostic applications based on pediatric-specific supporting evidence.

The addition of contrast US to an existing pediatric US service requires several preparatory steps. This overview provides a guide to simplify the process. Initially, it is important to communicate to all stakeholders the justifications for pediatric contrast US, including (1) its comparable or better diagnostic results relative to other modalities; (2) its reduction in procedural sedation or anesthesia by avoiding MRI or CT; (3) its reduction or elimination of radiation exposure by not having to perform fluoroscopy or CT; (4) the higher safety profile of US contrast agents (UCA) compared to other contrast agents; (5) the improved exam comfort and ease inherent to US, leading to better patient and family experience, including bedside US exams for children who cannot be transported; (6) the need for another diagnostic option in light of increasing demand by parents and providers; and (7) its status as an approved and reimbursable exam. It is necessary to have an UCA incorporated into the pharmacy formulary noting that only SonoVue/Lumason is currently approved for pediatric use. In the United States this UCA is approved for intravenous administration for cardiac and liver imaging and for vesicoureteric reflux detection with intravesical application. In Europe and China it is only approved for the intravesical use in children. All other applications are off-label. The US scanner needs to be equipped with contrast-specific software. The UCA has to be prepared just before the exam and it is important to strictly follow the steps as outlined in the packaging inserts in order to prevent premature destruction of the microbubbles. The initial training in contrast US is best focused on the frontline staff actually performing the US studies; these might be sonographers, pediatric or interventional radiologists, or trainees. It is important from the outset to educate the referring physicians about contrast US. It is helpful to participate in existing contrast US courses, particularly those with hands-on components., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Gray-scale and color/power Doppler ultrasound (US) are the first-line imaging modalities to evaluate the spleen, gallbladder and pancreas in children. The increasing use of contrast-enhanced ultrasound (CEUS) as a reliable and safe method to evaluate liver lesions in the pediatric population promises potential for imaging other internal organs. Although CEUS applications of the spleen, gallbladder and pancreas have been well described in adults, they have not been fully explored in children. In this manuscript, we present an overview of the applications of CEUS for normal variants and diseases affecting the spleen, gallbladder and pancreas. We highlight a variety of cases as examples of how CEUS can serve in the diagnosis and follow-up for such diseases in children. Our discussion includes specific examination techniques; presentation of the main imaging findings in various benign and malignant lesions of the spleen, gallbladder and pancreas in children; and acknowledgment of the limitations of CEUS for these organs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The role of contrast-enhanced ultrasound (CEUS) imaging is being widely explored by various groups for its use in the pediatric population. Clinical implementation of new diagnostic or therapeutic techniques requires extensive and meticulous preclinical testing and evaluation. The impact of CEUS will be determined in part by the extent to which studies are oriented specifically toward a pediatric population. Rather than simply applying principles and techniques used in the adult population, these studies are expected to advance and augment preexisting knowledge with pediatric-specific information. To further develop this imaging modality for use in children, pediatric-focused preclinical research is essential. In this paper we describe the development and implementation of the pediatric-specific preclinical animal and phantom models that are being used to evaluate CEUS with the goal of clinical translation to children., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Contrast-enhanced ultrasound (CEUS) is increasingly being used in children. One of the most common referrals for CEUS performance is characterization of indeterminate focal liver lesions and follow-up of known liver lesions. In this setting, CEUS is performed with intravenous administration of ultrasound contrast agents (UCAs). When injected into a vein, UCA microbubbles remain confined within the vascular network until they dissipate. Therefore, visualization of UCA within the tissues and lesions corresponds to true blood flow. CEUS enables continuous, real-time observation of the enhancement pattern of a focal liver lesion, allowing in most cases for a definite diagnosis and obviating the need for further cross-sectional imaging or other interventional procedures. The recent approval of Lumason (Bracco Diagnostics, Monroe Township, NJ) for pediatric liver CEUS applications has spurred the widespread use of CEUS. In this review article we describe the role of CEUS in pediatric liver applications, focusing on the examination technique and interpretation of main imaging findings of the most commonly encountered benign and malignant focal liver lesions. We also compare the diagnostic performance of CEUS with other imaging modalities for accurate characterization of focal liver lesions., (© 2021. The Author(s).)

For two decades, pediatric contrast US has been well accepted throughout Europe and other parts of the world outside the United States because of its high diagnostic efficacy and extremely favorable safety profile. This includes intravenous (IV) administration, contrast-enhanced US (CEUS) and the intravesical application, contrast-enhanced voiding urosonography (ceVUS). However, the breakthrough for pediatric contrast US in the United States did not come until 2016, when the U.S. Food and Drug Administration (FDA) approved the first pediatric indication for a US contrast agent. This initial approval covered the use of Lumason (Bracco Diagnostics, Monroe Township, NJ) for the evaluation of focal liver lesions via IV administration in children. A second pediatric indication followed shortly thereafter, when the FDA extended the use of Lumason for assessing known or suspected vesicoureteral reflux via intravesical application in children. Both initial pediatric approvals were granted without prospective pediatric clinical trials, based instead on published literature describing favorable safety and efficacy in children. Three years later, in 2019, the FDA approved Lumason for pediatric echocardiography following a clinical trial involving a total of 12 subjects at 2 sites. The story of how we achieved these FDA approvals spans more than a decade and involves the extraordinary dedication of two professional societies, namely the International Contrast Ultrasound Society (ICUS) and the Society for Pediatric Radiology (SPR). Credit also must be given to the FDA staff for their commitment to the welfare of children and their openness to compelling evidence that contrast US is a safe, reliable, radiation-free imaging option for our pediatric patients. Understanding the history of this approval process will impact the practical application of US contrast agents, particularly when expanding off-label indications in the pediatric population. This article describes the background of the FDA's approval of pediatric contrast US applications to better illuminate the potential pathways to approvals of future indications., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: Mark D. KrailoConsulting or Advisory Role: Merck Sharp & DohmeTravel, Accommodations, Expenses: Merck Sharp & Dohme Emilia M. PintoPatents, Royalties, Other Intellectual Property: Genotyping assays to identify mutations in XAF1 pending to St Jude Children's Research Hospital Farzana PashankarConsulting or Advisory Role: Novartis David MalkinConsulting or Advisory Role: Bayer Jonathan D. WassermanConsulting or Advisory Role: Bayer Gerard ZambettiResearch Funding: Johnson & JohnsonPatents, Royalties, Other Intellectual Property: MCL1 antibody license (Rockland Labs) to St Jude Children's Research Hospital. I receive small royalty on an annual basis, Patent pending for Genotyping assays to identify mutations in XAF1 Provisional application #62/659,427; Foreign filing April 18, 2019 Alberto S. PappoHonoraria: Bayer, RocheConsulting or Advisory Role: Merck, Loxo/Bayer, EUSA Pharma, DebbioNo other potential conflicts of interest were reported.

Purpose: The ARST0332 trial for pediatric and young adults with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based on extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR)., Methods and Materials: Patients aged <30 years with high-grade NRSTS received RT (55.8 Gy) for R1 ≤5 cm tumor (arm B); RT (55.8 Gy)/CT for R0/R1 >5 cm tumor (arm C); or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and postoperative boost to 10.8 Gy R0 <5 mm margins/R1 or 19.8 Gy for R2/unresected tumors (arm D)., Results: One hundred ninety-three eligible patients had 24 LRs (arm B 1/15 [6.7%], arm C 7/65 [10.8%], arm D 16/113 [14.2%]) at median time to LR of 1.1 years (range, 0.11-5.27). Of 95 eligible for delayed surgery after neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. Overall LC after RT were as follows: R0, 106 of 109 (97%); R1, 51 of 60 (85%); and R2/unresectable, 2 of 6 (33%). LR predictors include extent of delayed resection (P <.001), imaging response before delayed surgery (P < .001), histologic subtype (P <.001), and no RT (P = .046). The 5-year event-free survival was significantly lower (P = .0003) for patients unable to undergo R0/R1 resection., Conclusions: Risk-based treatment for young patients with high-grade NRSTS treated on ARST0332 produced very high LC, particularly after R0 resection (97%), despite lower-than-standard RT doses. Neoadjuvant CT/RT enabled delayed R0/R1 resection in most patients and is preferred over adjuvant therapy due to the lower RT dose delivered., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Children with sickle cell anaemia (SCA) and conditional transcranial Doppler (TCD) flow velocities (conditional: 170-199 cm/s; normal: <170 cm/s) have an increased risk of stroke. The Sickle Cell Clinical Research and Intervention Program (SCCRIP), a lifetime observational study, assessed the influence of haematological markers on TCD velocities. In children (≤16 years) with SCA (HbSS/HbSβ 0 -thalassaemia) and conditional TCD velocities (n = 32), increases in haemoglobin and in fetal haemoglobin after hydroxyurea initiation were significantly associated with decreases in TCD velocities. The benefit of pharmacological intervention to increase haemoglobin and fetal haemoglobin and normalise TCD velocities was demonstrated in this real-world dataset., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Acute pancreatitis (AP) due to chemotherapy-induced pancreatic injury is a common side effect of treatment for acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The American College of Radiology recommends ultrasound (US) for initial imaging of AP in all populations to assess for ductal obstruction. However, US may be insensitive to diagnose and assess chemotherapy-associated AP., Methods and Materials: The institutional review board approved this retrospective study. Patients with ALL and AP were identified from protocol databases, using Common Terminology Criteria for Adverse Events (CTCAE) version 3. Chemotherapy dosing, amylase/lipase levels, clinical symptoms, and US/computed tomography (CT) reports within 10 days of diagnosis were recorded. All CT images were reviewed for revised Atlanta classification and CT severity index (CTSI)., Results: Sixty-nine patients, aged 2-21 years, experienced 88 episodes of AP, undergoing 98 US and 44 CT. Seventy-two events (82%) occurred within 30 days of asparaginase administration. Sixty-nine episodes (78%) were initially diagnosed by the presence of abdominal pain and pancreatic enzyme elevation. Overall sensitivities for AP detection were 47% using US and 98% for CT. US sensitivity was greatest in CTCAE grade 4 (86%) and necrotizing pancreatitis (67%)., Conclusions: Most cases of AP in children with ALL can be diagnosed with clinical history and labs. US has limited sensitivity in detecting pancreatitis in this population. Imaging to diagnose AP in this patient population could be limited to clinically equivocal cases., (© 2020 Wiley Periodicals LLC.)

Background: Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murine Ewing sarcoma model. Based on these data, we conducted a phase I trial of talazoparib and irinotecan with/without temozolomide in paediatric patients with recurrent/refractory solid malignancies., Patients and Methods: Cohorts of 3-6 patients with recurrent/refractory solid malignancies received escalating doses of oral talazoparib and intravenous irinotecan (arm A) and oral talazoparib, oral temozolomide and intravenous irinotecan (arm B) in a 3 + 3 design. Talazoparib was administered on days 1-6, and intravenous irinotecan and oral temozolomide were administered on days 2-6, of a 21-day course. Serum for talazoparib and irinotecan pharmacokinetics was obtained during course 1. UGT1A1 polymorphism and Schlafen family member 11 (SLFN11) immunohistochemical staining were performed., Results: Forty-one patients (20 males; median age, 14.6 years; 24 with recurrent disease) were evaluable for dose escalation. Twenty-nine and 12 patients were treated on arm A and arm B, respectively, for a total of 208 courses. The most common diagnosis was Ewing sarcoma (53%). The most common ≥grade III haematologic toxicities in arms A and B included neutropenia (78% and 31%, respectively) and thrombocytopenia (42% and 31%, respectively). In arms A and B, febrile neutropenia (24% and 14%, respectively) and diarrhoea (21% and 7%, respectively) were the most common ≥grade III non-hematologic toxicities. Six patients (Ewing sarcoma [5 patients] and synovial sarcoma [1 patient]) had a response (1 with a complete response, 5 with a partial response). The objective response rates were 10.3% (arm A) and 25% (arm B). Pharmacokinetic testing demonstrated no evidence of drug-drug interaction between talazoparib and irinotecan. UGT1A1 was not related to response. SLFN11 positivity was associated with best response to therapy., Conclusions: The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted., Competing Interests: Conflict of interest statement The authors declare no potential conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

BCOR internal tandem duplications (ITDs) and rearrangements are implicated in the oncogenesis of a subset of undifferentiated sarcomas. To date, BCOR ITD sarcomas have been exclusively found in non-appendicular infantile soft tissues, whereas BCOR-rearranged sarcomas occur in both bones and soft tissues affecting a wider patient age range. Little is known about patient outcome in BCOR ITD sarcomas. We present a BCOR-expressing, primary bone, undifferentiated sarcoma case involving an adolescent male's left tibia that, unexpectedly, harbored a BCOR ITD instead of a BCOR rearrangement. Furthermore, the patient achieved a partial histologic response after receiving a Ewing sarcoma chemotherapy regimen. Our case expands the clinical spectrum of BCOR ITD sarcomas and suggests that childhood and adult BCOR-expressing sarcomas with an undifferentiated histology should be considered for both BCOR rearrangement and ITD screening. Accurate BCOR mutation identification in undifferentiated sarcomas is essential to define their clinical spectrum and to develop effective management strategies.

Background: Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours., Methods: An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m 2 po twice daily, days 1-21) and low-dose cyclophosphamide (50 mg/m 2 po daily, days 1-21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1., Results: Twenty-four patients (15 males; median age 14.5 yrs; range 1-22 yr) received a median of 6 courses (range 1-18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6-95.6%) and 54% (95% CI 30.2-78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results., Conclusions: Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours., Competing Interests: Conflict of interest statement The authors declare no potential conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Our purpose was to assess disease outcomes and late toxicities in pediatric patients with rhabdomyosarcoma treated with conformal photon radiation therapy (RT)., Methods and Materials: Sixty-eight patients (median age, 6.9 years) were treated with conformal photon RT to the primary site on a prospective clinical trial. Target volumes included a 1-cm expansion encompassing microscopic disease. Prescribed doses were 36 Gy to this target volume and 50.4 Gy to gross residual disease. Chemotherapy consisted of vincristine/dactinomycin (n = 6), vincristine/dactinomycin/cyclophosphamide (n = 37), or vincristine/dactinomycin/cyclophosphamide-based combinations (n = 25). Patients were evaluated with primary-site magnetic resonance imaging, whole-body [ 18 F]fluorodeoxyglucose positron emission tomography, and chest computed tomography for 5 years after treatment., Results: Five-year disease-free survival was 88% for low-risk (n = 8), 76% for intermediate-risk (n = 37), and 36% for high-risk (n = 23) patients (P ≤ .01 for low risk/intermediate risk vs high risk). The cumulative incidence of local failure (LF) at 5 years for the entire cohort was 10.4%. Tumor size at diagnosis was a significant predictor of LF (P < .01). Patients with head and neck primary tumors (n = 31) had a 35% cumulative incidence of cataracts; the risk correlated with lens dose (P = .0025). Jaw dysfunction was more severe when the pterygoid and masseter muscles received a mean dose of >20 Gy (P = .013). Orbital hypoplasia developed more frequently after a mean bony orbit dose of >30 Gy (P = .041). Late toxicity in patients with genitourinary tumors included microscopic hematuria (9 of 14), bladder-wall thickening (10 of 14), and vaginal stenosis (2 of 5)., Conclusions: Long-term LF rates were low, and higher rates correlated with larger tumors. Treatment-related toxicities resulting in measurable functional deficits were not infrequent, despite the conformal RT approach., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Natural killer (NK) cells are one of the main effector populations of immunotherapy with monoclonal antibody and cytokines, used in combination with chemotherapy to treat children with high-risk neuroblastoma on this phase II trial. However, the impact of chemoimmunotherapy on NK cell kinetics, phenotype, and function is understudied., Methods: We prospectively examined NK cell properties from 63 children with newly diagnosed neuroblastoma enrolled in a phase II trial (NCT01857934) and correlated our findings with tumor volume reduction after 2 courses of chemoimmunotherapy. NK cell studies were conducted longitudinally during chemoimmunotherapy and autologous hematopoietic cell transplantation (autoHCT) with optional haploidentical NK cell infusion and additional immunotherapy., Results: Chemoimmunotherapy led to significant NK cytopenia, but complete NK cell recovery reliably occurred by day 21 of each therapy course as well as after autoHCT. Haploidentical NK cell infusion elevated the NK cell count transiently during autoHCT. NK cell cytotoxicity increased significantly during treatment compared with diagnosis. In addition, NK cells maintained their ability to respond to cytokine stimulation in culture longitudinally. Unsupervised cluster analysis of CD56 bright NK cell count and tumor volume at diagnosis and after two courses of chemoimmunotherapy identified two patient groups with distinct primary tumor sizes and therapy responses., Conclusion: After profound NK cytopenia due to chemoimmunotherapy, endogenously reconstituted NK cells exhibit enhanced NK cytotoxicity compared with pretherapy measurements. Our data suggest a relationship between CD56 bright expression and tumor size before and after two courses of chemoimmunotherapy; however, future studies are necessary to confirm this relationship and its predictive significance., Trial Registration Number: NCT01857934., Competing Interests: Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/purpose: MYCN-amplification in neuroblastoma is associated with an aggressive clinical phenotype. We evaluated the association of MYCN amplification with tumor response to neoadjuvant chemotherapy., Methods: Primary tumor response, assessed by percentage volume change on CT scan and degree of tumor resection, assessed by the operating surgeon, were retrospectively compared in 84 high-risk neuroblastoma patients. There were thirty-four (40%) with MYCN-amplified tumors and fifty (60%) with non-amplified tumors treated at our institution from 1999 to 2016. Metastatic disease response was assessed on MIBG scan by change in Curie score., Results: MYCN-amplification was associated with a greater mean percentage reduction in primary tumor volume after neoadjuvant chemotherapy (72.27% versus 46.83% [non-amplified tumors], p = 0.001). The percentage of patients with a Curie score > 2 at diagnosis who then had a score ≤ 2 after neoadjuvant chemotherapy was not significantly different (8 [61.5%] and 8 [34.8%], respectively, p = 0.37). Twenty-eight (85.7%) patients with MYCN-amplification had ≥90% surgical resection compared to 45 (91.84%) patients with non-amplified tumors (p = 0.303)., Conclusions: MYCN-amplification in high-risk neuroblastoma was associated with a better response of the primary tumor to neoadjuvant chemotherapy, but not metastatic sites, than in patients with non-amplified tumors. This did not significantly impact the ability to resect ≥90% of the primary tumor/locoregional disease., Type of Study: Treatment Study LEVEL OF EVIDENCE: Level III., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We developed a risk stratification system from known prognostic factors and assessed it in the context of risk-adapted therapy for young patients with NRSTS., Methods: In this prospective study, eligible patients enrolled in 159 hospitals in three countries were younger than 30 years, had a Lansky (patients ≤16 years) or Karnofsky (patients >16 years) performance status score of at least 50, and a new diagnosis of a WHO (2002 criteria) intermediate (rarely metastasising) or malignant soft-tissue tumour (apart from tumour types eligible for other Children's Oncology Group studies and tumours for which the therapy in this trial was deemed inappropriate), malignant peripheral nerve sheath tumour, non-metastatic and grossly resected dermatofibrosarcoma protuberans, undifferentiated embryonal sarcoma of the liver, or unclassified malignant soft-tissue sarcoma. Each patient was assigned to one of three risk groups and one of four treatment groups. Risk groups were: low (non-metastatic R0 or R1 low-grade, or ≤5 cm R1 high-grade tumour); intermediate (non-metastatic R0 or R1 >5 cm high-grade, or unresected tumour of any size or grade); or high (metastatic tumour). The treatment groups were surgery alone, radiotherapy (55·8 Gy), chemoradiotherapy (chemotherapy and 55·8 Gy radiotherapy), and neoadjuvant chemoradiotherapy (chemotherapy and 45 Gy radiotherapy, then surgery and radiotherapy boost based on margins with continued chemotherapy). Chemotherapy included six cycles of ifosfamide 3 g/m 2 per dose intravenously on days 1-3 and five cycles of doxorubicin 37·5 mg/m 2 per dose intravenously on days 1-2 every 3 weeks with sequence adjusted on the basis of timing of surgery or radiotherapy. The primary outcomes were event-free survival, overall survival, and the pattern of treatment failure. Analysis was done per protocol. This study has been completed and is registered with ClinicalTrials.gov, NCT00346164., Findings: Between Feb 5, 2007, and Feb 10, 2012, 550 eligible patients were enrolled, of whom 21 were treated in the incorrect group and excluded from this analysis. 529 evaluable patients were included in the analysis: low-risk (n=222), intermediate-risk (n=227), high-risk (n=80); surgery alone (n=205), radiotherapy (n=17), chemoradiotherapy (n=111), and neoadjuvant chemoradiotherapy (n=196). At a median follow-up of 6·5 years (IQR 4·9-7·9), 5-year event-free survival and overall survival were: 88·9% (95% CI 84·0-93·8) and 96·2% (93·2-99·2) in the low-risk group; 65·0% (58·2-71·8) and 79·2% (73·4-85·0) in the intermediate-risk group; and 21·2% (11·4-31·1) and 35·5% (23·6-47·4) in the high-risk group, respectively. Risk group predicted event-free survival and overall survival (p<0·0001). No deaths from toxic events during treatment were reported. Nine patients had unexpected grade 4 adverse events (chemoradiotherapy group, n=2; neoadjuvant chemoradiotherapy group, n=7), including three wound complications that required surgery (all in the neoadjuvant chemoradiotherapy group)., Interpretation: Pre-treatment clinical features can be used to effectively define treatment failure risk and to stratify young patients with NRSTS for risk-adapted therapy. Most low-risk patients can be cured without adjuvant therapy, thereby avoiding known long-term treatment complications. Survival remains suboptimal for intermediate-risk and high-risk patients and novel therapies are needed., Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation, American Lebanese Syrian Associated Charities., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: The treatment of childhood nasopharyngeal carcinoma has been adapted from adult regimens; pediatric-specific studies are limited. The ARAR0331 study sought to evaluate the impact of induction chemotherapy (IC) and concurrent chemoradiotherapy (CCR)., Patients and Methods: Patients with American Joint Committee on Cancer stages IIb to IV were scheduled to receive three cycles of IC with cisplatin and fluorouracil, followed by CCR with three cycles of cisplatin. Patients with complete or partial response to IC received 61.2 Gy to the nasopharynx and neck, and patients with stable disease received 71.2 Gy., Results: Between February 2006 and January 2012, 111 patients (75 male) were enrolled. Median age was 15 years, and 46.8% of the patients were African American. After a feasibility analysis, the study was amended to reduce cisplatin to two cycles during CCR. The 5-year event-free survival (EFS) and overall survival estimates were 84.3% and 89.2%, respectively. The 5-year EFS for stages IIb, III, and IV were 100%, 82.8%, and 82.7%, respectively. The 5-year cumulative incidence estimates of local, distant, and combined relapse were 3.7%, 8.7%, and 1.8%, respectively. Patients treated with three versus two CCR cycles of cisplatin had improved 5-year postinduction EFS (90.7% v 81.2%, P = .14)., Conclusion: Patients in ARAR0331 were characterized by advanced disease and by a high proportion of black children and adolescents. Treatment with IC and CRT resulted in excellent outcomes. A radiation dose reduction is possible for patients responding to IC. Although the outcomes are comparable, we observed a trend toward decreased EFS for patients assigned to receive fewer doses of cisplatin during CCR.

Purpose: We sought to evaluate whether combining a humanized antidisialoganglioside mAb (hu14.18K322A) with induction chemotherapy improves early responses and outcomes in children with newly diagnosed high-risk neuroblastoma., Patients and Methods: We conducted a prospective nonrandomized, single-arm, two-stage, phase II clinical trial. Six courses of induction chemotherapy were coadministered with hu14.18K322A and followed with granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose IL2. Consolidation was performed with a busulfan/melphalan preparative regimen. An additional course of hu14.18K322A was administered with parent-derived natural killer cells, when available, during consolidation. Hu14.18K322A, GM-CSF, IL2, and isotretinoin were then administered. Secondary outcomes included reduced tumor volume and semiquantitative 123 I-metaiodobenzylguanidine scoring [i.e., Curie scores (CS)] at the end of induction., Results: Forty-two patients received hu14.18K322A and induction chemotherapy. This regimen was well tolerated, with continuous-infusion narcotics adjusted to patient tolerance. Partial responses (PR) or better after the first two chemoimmunotherapy courses occurred in 32 patients [76.2%; 95% confidence interval (CI), 60.6-88.0]. This was accompanied by primary tumor volume reductions (median, -76%; range, -100% to 5%). Of 35 patients with stage IV disease who completed induction, 31 had end-of-induction CSs of 2 or less. No patients experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9-93.3)., Conclusions: Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma., (©2019 American Association for Cancer Research.)

Objective: To correlate imaging features of epithelioid sarcoma in children and young adults enrolled in Children's Oncology Group study ARST0332 with clinical and pathological findings., Materials and Methods: Fifteen patients (6 males; median age 16.1 years, range 6.5-24.8 years) with epithelioid sarcoma enrolled in ARST0332 had preoperative imaging (MRI, n=10; CT, n=5) that was reviewed by two radiologists who recorded numerous features including presence and percentage of tumor necrosis, presence of surrounding edema, and lymph node involvement. Discrepancies between reviewers were adjudicated by concurrent re-review. We correlated imaging findings with histological assessment of percentage tumor necrosis, proximal- vs. classic-type histology, lymph node involvement and recurrence., Results: Eleven patients (11/15, 73%) had proximal-type histology tumors. Ten of 14 tumors (71%) had imaging evidence of necrosis. Among the nine tumors with imaging and histological estimates of percentage necrosis, agreement was within 30% (in six tumors there was ≤10% difference between pathology and imaging). All 10 tumors imaged with MRI had surrounding edema. Four patients had biopsy-proven nodal involvement; all had necrotic nodes on imaging. There were four false-positives for nodal involvment by imaging. Twelve patients (12/15, 80%) had recurrences (local only, n=1; local and distant, n=1; distant only, n=10)., Conclusion: Proximal-type histology was prevalent in this young cohort with preoperative imaging. Necrosis is common in primary tumors and involved nodes. There is good agreement between histological and imaging estimates of primary tumor necrosis. Surrounding tumor edema is common in this tumor, which is known to spread along fascial planes.

Background: Data on the clinical features, optimal treatment and outcomes of paediatric patients with epithelioid sarcoma (ES) are limited and mostly retrospective., Methods: A subset analysis of ES patients < 30 years of age enrolled on two international prospective clinical trials conducted between 7/2005 and 11/2015 was performed. Risk-adapted therapy was based on tumour diameter, histologic grade, extent of surgery and presence/absence of metastases and included surgery ± radiotherapy for all patients with the addition of ifosfamide/doxorubicin chemotherapy for intermediate-/high-risk patients. Response to therapy, event-free and overall survival and pattern and predictors of treatment failure were evaluated., Results: Sixty-three ES patients (median age 13.1 years, 52% male) were eligible. Clinical features included the following: 68% extremity, median tumour diameter 3.5 cm, 56% high histologic grade, 14% nodal metastases, 14% distant metastases. Thirty-four low-risk patients underwent surgery (n = 30) or surgery/radiotherapy (n = 4); 16 intermediate-risk and 13 high-risk patients received chemotherapy ± surgery ± radiotherapy. Partial response was observed in 11/22 (50%) patients receiving neoadjuvant therapy. Events were local recurrence (n = 10) and distant recurrence (n = 15); estimated 5-year survival was 86.4%, 63.5% and 0%, respectively, for low-, intermediate- and high-risk patients. Locoregional nodal involvement, invasive tumour, high grade and lesser extent of resection predicted event-free survival in patients without metastases., Conclusions: Most low-risk ES patients who have undergone an adequate resection fare well without adjuvant therapy. Large tumour size, high histologic grade, tumour invasiveness, inadequate tumour resection and metastatic disease predict poorer outcomes in higher risk ES patients, for whom more effective therapies are needed., Clinical Trial Registration: COG ARST0332: ClinicalTrials.gov Identifier NCT00346164, EpSSG NRSTS 2005: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Hepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4-6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy., Methods: In this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m 2 per dose or 3·3 mg/kg per dose for children <10 kg) intravenously over 6 h on day 1; fluorouracil (600 mg/m 2 per dose or 20 mg/kg per dose for children <10 kg) intravenous push on day 2; and vincristine (1·5 mg/m 2 per day to a maximum dose of 2 mg, or 0·05 mg/kg per day for children <10 kg) intravenous push on days 2, 9, and 16. The primary outcome was investigator-assessed event-free survival. As prespecified by protocol, we analysed the primary endpoint 6 years after enrolment (cutoff date June 30, 2017). This trial is registered with ClinicalTrials.gov, number NCT00980460, and is now permanently closed to accrual., Findings: Between May 18, 2010, and May 28, 2014, 51 patients in 32 centres in two countries were enrolled into the low-risk stratum of this trial, of whom 49 received c hemotherapy treatment after surgery and were evaluable for activity and safety. Median follow-up time for all evaluable patients was 42 months (IQR 36-62). 4-year event-free survival was 92% (95% CI 79-97) and 5-year event-free survival was 88% (72-95). Two (4%) of 49 patients had surgical complications (bile leaks). The most common grade 3-4 adverse events were febrile neutropenia in seven (14%) patients, decreased neutrophil count in three (6%) patients, infections in four (8%) patients, and diarrhoea in four (8%) patients. Ototoxicity occurred in one (2%) patient. One (2%) patient of the three who relapsed in this cohort died from disease. Two (4%) patients died in clinical remission after therapy discontinuation. One patient died of pneumonia and bacterial sepsis 1 year after therapy discontinuation and another patient died of unrelated causes 57 months after therapy completion. There were no treatment-related deaths., Interpretation: Minimal postoperative chemotherapy with two cycles of cisplatin, fluorouracil, and vincristine can ensure disease control in patients with hepatoblastoma resected at diagnosis. Our results show that dose reduction of ototoxic agents is a safe, effective treatment for these children., Funding: National Institutes of Health., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The predictive value of Image-Defined Risk Factors (IDRFs) developed by the International Neuroblastoma Risk Group Task Force as it relates to primary-site management is undefined and may aid patient selection for de-escalation of adjuvant radiation therapy to the primary site in high-risk neuroblastoma., Methods and Materials: Patients (N = 76) with high-risk neuroblastoma treated on prospective trials at our institution from 1997 to 2014 were eligible for inclusion. IDRFs were defined based on pretherapy imaging. Overall survival, progression-free survival, and locoregional failure-free survival (LRFFS) were described using the Kaplan-Meier estimator and tested across strata by using the log-rank test., Results: Twenty of 76 patients (26%) experienced local (n = 6), regional (n = 6), or combined locoregional failure (n = 8) with or without distant failure. Ten (50%) of the locoregional failures had concurrent distant relapse. Of patients who completed all therapy, both those with no IDRFs and those with >90% resection had a 3-year LRFFS of 100%, with or without radiation therapy. Patients with either ≥1 IDRF or 90% tumor resection and no primary site IDRFs at diagnosis may be candidates for de-escalation of adjuvant primary-site radiation therapy, although validation of these findings in future studies is required., (Copyright © 2018 Elsevier Inc. All rights reserved.)