Embryonal sarcoma of the liver in pediatric and young adult patients: A report from Children's Oncology Group study ARST0332.

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.

Clinical features and outcomes of young patients with low-grade non-rhabdomyosarcoma soft tissue sarcomas treated with a risk-based strategy: A report from Children's Oncology Group study ARST0332.

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.

Opportunities for Improving Detection of Cancer Predisposition Syndromes in Pediatric Solid Tumor Patients.

BACKGROUND: Detection of cancer predisposition syndromes (CPS) depends on identifying risk factors, including tumor type, family history, and physical findings, to prompt referral for genetic counseling/testing. Whether pediatric oncology providers (POPs) collect adequate family history information is unknown. METHODS: A single-institution retrospective chart review of solid tumor patients <18 years of age referred for a CPS evaluation between January 1, 2017 and January 31, 2019 was performed. POP adherence to American Society of Clinical Oncology (ASCO) family history collection recommendations was measured and compared with genetic counselor performance. Whether sufficient family history was documented to satisfy the criteria of three genetic counseling referral guidelines [American College of Medical Genetics (ACMG), updated Jongmans (UJ), and McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG)] was evaluated. RESULTS: POPs and genetic counselors achieved all 6 ASCO family history metrics in 3% and 99% of 129 eligible cases, respectively. POPs failed to document sufficient family history to satisfy genetic counseling referral criteria in most cases (74% ACMG, 73% UJ, 79% MIPOGG). CONCLUSIONS: POPs perform poorly in family history collection, raising concern that some patients at risk for a CPS based on their family history may not be referred for genetic counseling/testing. Interventions to improve family history collection are needed to enhance CPS detection.

Favorable Outcome of High-grade Endometrial Stromal Sarcoma in an Adolescent.

High-grade endometrial stromal sarcoma is a rare and aggressive soft tissue tumor characterized by YWHAE::NUTM2A/B translocations, diagnosis at a median of 50-60 years, and a poor prognosis (overall survival 30%-40%). We describe a 16-year-old patient with high-grade endometrial stromal sarcoma and regional nodal and pulmonary metastases who is a long-term survivor after grossly complete tumor resection, intensive chemotherapy, and pelvic radiotherapy. We discovered a previously undescribed YWHAE::NUTM2E translocation in the tumor. Our patient's favorable outcome suggests that intensive multimodality therapy with curative intent is appropriate for young patients with high-grade endometrial stromal sarcoma and highlights the importance of fertility preservation.

The bodily threat monitoring scale: Development and preliminary validation in adult and childhood cancer survivors.

OBJECTIVE: Bodily threat monitoring is a core clinical feature of Fear of cancer recurrence (FCR) and is targeted in psycho-oncology treatments, yet no comprehensive self-report measure exists. The aim of this study was the theory-informed development and initial validation of the Bodily Threat Monitoring Scale (BTMS). METHODS: Adult survivors of breast and gynaecological cancers (Study 1: N = 306, age = 37-81 years) and childhood cancer survivors (Study 2: N = 126, age = 10-25 years) completed the BTMS, designed to assess how individuals monitor for and interpret uncertain symptoms as indicating that something is wrong with their body. Participants completed measures to assess construct and criterion validity of the BTMS, and childhood cancer survivors (Study 2) completed the BTMS again 2 weeks later to assess test-retest reliability. RESULTS: The 19-item BTMS demonstrated excellent internal consistency across adult and childhood cancer samples (α = 0.90-0.96). Factor analyses indicated two subscales capturing 1. Monitoring of bodily sensations and 2. Threatening interpretations of bodily sensations. Two-week stability estimates were acceptable. For construct validity, the BTMS correlated with body vigilance and anxiety sensitivity. The BTMS also demonstrated criterion validity, yielding significant associations with FCR, intolerance of uncertainty, help-seeking behaviours, and quality of life. The BTMS was associated with FCR while controlling for body vigilance and anxiety sensitivity, indicating a unique contribution of this theory-informed measure. CONCLUSIONS: The BTMS shows evidence of sound psychometric properties and could be used to elucidate the role of bodily threat monitoring in the maintenance and management of FCR.

Neoadjuvant pazopanib in nonrhabdomyosarcoma soft tissue sarcomas (ARST1321): A report of major wound complications from the Children's Oncology Group and NRG Oncology.

BACKGROUND AND OBJECTIVES: The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/- chemotherapy for soft tissue sarcoma. METHODS: Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy. RESULTS: Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites. CONCLUSION: The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

Tyrosine kinase inhibitor therapy in pediatric sarcoma: Prognostic implications of pulmonary metastatic cavitation.

PURPOSES: This study aims to ascertain the prevalence of cavitations in pulmonary metastases among pediatric and young adult patients with sarcoma undergoing tyrosine kinase inhibitor (TKI) therapy, and assess whether cavitation can predict clinical response and survival outcomes. METHODS: In a single-center retrospective analysis, we examined chest computed tomography (CT) scans of 17 patients (median age 16 years; age range: 4-25 years) with histopathologically confirmed bone (n = 10) or soft tissue (n = 7) sarcoma who underwent TKI treatment for lung metastases. The interval between TKI initiation and the onset of lung nodule cavitation and tumor regrowth were assessed. The combination of all imaging studies and clinical data served as the reference standard for clinical responses. Progression-free survival (PFS) was compared between patients with cavitating and solid nodules using Kaplan-Meier survival analysis and log-rank test. RESULTS: Five out of 17 patients (29%) exhibited cavitation of pulmonary nodules during TKI therapy. The median time from TKI initiation to the first observed cavitation was 79 days (range: 46-261 days). At the time of cavitation, all patients demonstrated stable disease. When the cavities began to fill with solid tumor, 60% (3/5) of patients exhibited progression in other pulmonary nodules. The median PFS for patients with cavitated pulmonary nodules after TKI treatment (6.7 months) was significantly longer compared to patients without cavitated nodules (3.8 months; log-rank p-value = .03). CONCLUSIONS: Cavitation of metastatic pulmonary nodules in sarcoma patients undergoing TKI treatment is indicative of non-progressive disease, and significantly correlates with PFS.

PET/MR of pediatric bone tumors: what the radiologist needs to know.

Integrated 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/magnetic resonance (MR) imaging can provide "one stop" local tumor and whole-body staging in one session, thereby streamlining imaging evaluations and avoiding duplicate anesthesia in young children. 18F-FDG PET/MR scans have the benefit of lower radiation, superior soft tissue contrast, and increased patient convenience compared to 18F-FDG PET/computerized tomography scans. This article reviews the 18F-FDG PET/MR imaging technique, reporting requirements, and imaging characteristics of the most common pediatric bone tumors, including osteosarcoma, Ewing sarcoma, primary bone lymphoma, bone and bone marrow metastases, and Langerhans cell histiocytosis.

Detection of bone marrow metastases in children and young adults with solid cancers with diffusion-weighted MRI.

OBJECTIVE: To compare the diagnostic accuracy of diffusion-weighted (DW)-MRI with b-values of 50 s/mm2 and 800 s/mm2 for the detection of bone marrow metastases in children and young adults with solid malignancies. METHODS: In an institutional review board-approved prospective study, we performed 51 whole-body DW-MRI scans in 19 children and young adults (14 males, 5 females; age range: 1-25 years) with metastasized cancers before (n = 19 scans) and after (n = 32 scans) chemotherapy. Two readers determined the presence of focal bone marrow lesions in 10 anatomical areas. A third reader measured ADC and SNR of focal lesions and normal marrow. Simultaneously acquired 18F-FDG-PET scans served as the standard of reference. Data of b = 50 s/mm2 and 800 s/mm2 images were compared with the Wilcoxon signed-rank test. Inter-reader agreement was evaluated with weighted kappa statistics. RESULTS: The SNR of bone marrow metastases was significantly higher compared to normal bone marrow on b = 50 s/mm2 (mean ± SD: 978.436 ± 1239.436 vs. 108.881 ± 109.813, p < 0.001) and b = 800 s/mm2 DW-MRI (499.638 ± 612.721 vs. 86.280 ± 89.120; p < 0.001). On 30 out of 32 post-treatment DW-MRI scans, reconverted marrow demonstrated low signal with low ADC values (0.385 × 10-3 ± 0.168 × 10-3mm2/s). The same number of metastases (556/588; 94.6%; p > 0.99) was detected on b = 50 s/mm2 and 800 s/mm2 images. However, both normal marrow and metastases exhibited low signals on ADC maps, limiting the ability to delineate metastases. The inter-reader agreement was substantial, with a weighted kappa of 0.783 and 0.778, respectively. CONCLUSION: Bone marrow metastases in children and young adults can be equally well detected on b = 50 s/mm2 and 800 s/mm2 images, but ADC values can be misleading.

ALK rearrangements in infantile fibrosarcoma-like spindle cell tumours of soft tissue and kidney.

AIMS: Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated 'NTRK-rearranged' spindle cell neoplasms. These two groups of tumours demonstrate overlapping morphologies and harbour alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1 and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of paediatric tumours with clinicopathological features not typical for inflammatory myofibroblastic tumour, but rather with similarities to cCMN/IFS harbouring ALK fusions. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumours occurred in patients aged from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumours arose in soft tissues and two in the kidney. Morphological features included spindle to ovoid cells arranged in long fascicles or haphazardly within a myxoid to collagenised stroma; a subset of cases had either dilated, ectatic vessels or focal perivascular hyalinosis. By immunohistochemistry, all cases tested showed cytoplasmic expression of anaplastic lymphoma kinase (ALK) and one case demonstrated co-expression of CD34 and S100. CONCLUSIONS: This series of ALK-rearranged IFS-like tumours expands the spectrum of targetable kinases altered in these tumours and reinforces the potential overlap between IFS/cCMN-like tumours and the provisional entity of 'NTRK-rearranged' spindle cell neoplasms.

Smartphone-based Ecological Momentary Assessment to study "scanxiety" among Adolescent and Young Adult survivors of childhood cancer: A feasibility study.

OBJECTIVE: Scan-related anxiety ("scanxiety") refers to the fear, stress, and anxiety in anticipation of tests and scans in follow-up cancer care. This study assessed the feasibility of Ecological Momentary Assessment (EMA) for real-world, real-time capture of scanxiety using patients' personal smartphone. METHODS: Adolescent and Young Adult survivors of childhood cancer were prompted to complete EMA surveys on a smartphone app three times per day for 11 days (33 surveys total) around their routine surveillance scans. Participants provided structured feedback on the EMA protocol. RESULTS: Thirty out of 46 contacted survivors (65%) enrolled, exceeding the preregistered feasibility cutoff of 55%. The survey completion rate (83%) greatly exceeded the preregistered feasibility cutoff of 65%. Participants generally found the smartphone app easy and enjoyable to use and reported low levels of distress from answering surveys. Participants reported significantly more daily fear of cancer recurrence (FCR) and negative affect in the days before compared to the days after surveillance scans, aligning with the expected trajectory of scanxiety. Participants who reported greater FCR and scanxiety using comprehensive measures at baseline also reported significantly more daily FCR around their surveillance scans, indicating validity of EMA items. Bodily threat monitoring was prospectively and concurrently associated with daily FCR, thus warranting further investigation as a risk factor for scanxiety. CONCLUSIONS: Findings indicate the feasibility, acceptability, and validity of EMA as a research tool to capture the dynamics and potential risk factors for scanxiety.

Diagnostic Accuracy of 2-[18F]FDG-PET and whole-body DW-MRI for the detection of bone marrow metastases in children and young adults.

OBJECTIVES: To compare the diagnostic accuracy of 2-[18F]fluoro-2-deoxy-D-glucose-enhanced positron emission tomography (2-[18F]FDG-PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) for the detection of bone marrow metastases in children and young adults with solid malignancies. METHODS: In this cross-sectional single-center institutional review board-approved study, we investigated twenty-three children and young adults (mean age, 16.8 years ± 5.1 [standard deviation]; age range, 7-25 years; 16 males, 7 females) with 925 bone marrow metastases who underwent 66 simultaneous 2-[18F]FDG-PET and DW-MRI scans including 23 baseline scans and 43 follow-up scans after chemotherapy between May 2015 and July 2020. Four reviewers evaluated all foci of bone marrow metastasis on 2-[18F]FDG-PET and DW-MRI to assess concordance and measured the tumor-to-bone marrow contrast. Results were assessed with a one-sample Wilcoxon test and generalized estimation equation. Bone marrow biopsies and follow-up imaging served as the standard of reference. RESULTS: The reviewers detected 884 (884/925, 95.5%) bone marrow metastases on 2-[18F]FDG-PET and 893 (893/925, 96.5%) bone marrow metastases on DW-MRI. We found different "blind spots" for 2-[18F]FDG-PET and MRI: 2-[18F]FDG-PET missed subcentimeter lesions while DW-MRI missed lesions in small bones. Sensitivity and specificity were 91.0% and 100% for 18F-FDG-PET, 89.1% and 100.0% for DW-MRI, and 100.0% and 100.0% for combined modalities, respectively. The diagnostic accuracy of combined 2-[18F]FDG-PET/MRI (100.0%) was significantly higher compared to either 2-[18F]FDG-PET (96.9%, p < 0.001) or DW-MRI (96.3%, p < 0.001). CONCLUSIONS: Both 2-[18F]FDG-PET and DW-MRI can miss bone marrow metastases. The combination of both imaging techniques detected significantly more lesions than either technique alone. KEY POINTS: • DW-MRI and 2-[18F]FDG-PET have different strengths and limitations for the detection of bone marrow metastases in children and young adults with solid tumors. • Both modalities can miss bone marrow metastases, although the "blind spot" of each modality is different. • A combined PET/MR imaging approach will achieve maximum sensitivity and specificity for the detection of bone marrow metastases in children with solid tumors.

How to stop using gadolinium chelates for magnetic resonance imaging: clinical-translational experiences with ferumoxytol.

Gadolinium chelates have been used as standard contrast agents for clinical MRI for several decades. However, several investigators recently reported that rare Earth metals such as gadolinium are deposited in the brain for months or years. This is particularly concerning for children, whose developing brain is more vulnerable to exogenous toxins compared to adults. Therefore, a search is under way for alternative MR imaging biomarkers. The United States Food and Drug Administration (FDA)-approved iron supplement ferumoxytol can solve this unmet clinical need: ferumoxytol consists of iron oxide nanoparticles that can be detected with MRI and provide significant T1- and T2-signal enhancement of vessels and soft tissues. Several investigators including our research group have started to use ferumoxytol off-label as a new contrast agent for MRI. This article reviews the existing literature on the biodistribution of ferumoxytol in children and compares the diagnostic accuracy of ferumoxytol- and gadolinium-chelate-enhanced MRI. Iron oxide nanoparticles represent a promising new class of contrast agents for pediatric MRI that can be metabolized and are not deposited in the brain.

Dermatologic toxicities of targeted antineoplastic agents and immune checkpoint inhibitor therapy in pediatric patients: A systematic review.

Cutaneous adverse events (cAEs) from targeted antineoplastic agents and immune checkpoint inhibitors are common in children with cancer and may lead to dose reduction or cessation of critical oncologic treatment. Timely diagnosis and proper management of cAEs in pediatric oncology patients is essential to optimize ongoing cancer-directed therapy and improve quality of life. This systematic review of published studies summarizes dermatologic toxicities to targeted anticancer treatments and immune checkpoint inhibitors.

Ferumoxytol magnetic resonance imaging detects joint and pleural infiltration of bone sarcomas in pediatric and young adult patients.

BACKGROUND: The diagnosis of joint infiltration by a malignant bone tumor affects surgical management. The specificity of standard magnetic resonance imaging (MRI) for diagnosing joint infiltration is limited. During our MRI evaluations with ferumoxytol nanoparticles of pediatric and young adult patients with bone sarcomas, we observed a surprising marked T1 enhancement of joint and pleural effusions in some patients but not in others. OBJECTIVE: To evaluate if nanoparticle extravasation differed between joints and pleura with and without tumor infiltration. MATERIALS AND METHODS: We retrospectively identified 15 pediatric and young adult patients (mean age: 16±4 years) with bone sarcomas who underwent 18 MRI scans at 1 h (n=7) or 24 h (n=11) after intravenous ferumoxytol infusion. Twelve patients also received a gadolinium-enhanced MRI. We determined tumor invasion into the joint or pleural space based on histology (n=11) and imaging findings (n=4). We compared the signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) of the joint or pleural fluid for tumors with and without invasion using a Mann-Whitney U test. RESULTS: MRI scans 24 h after intravenous ferumoxytol infusion demonstrated a positive T1 enhancement of the effusion in all joints and pleural spaces with tumor infiltration and no joint or pleural space without infiltration. Corresponding SNR (P=0.004) and CNR (P=0.004) values were significantly higher for joints and pleural spaces with tumor infiltration than without. By contrast, unenhanced MRI, gadolinium-enhanced MRI and 1-h post-contrast ferumoxytol MRI did not show any enhancement of the joint or pleural effusion, with or without tumor infiltration. CONCLUSION: This pilot study suggests that 24-h post-contrast ferumoxytol MRI scans can noninvasively differentiate between joints with and without tumor infiltration.

A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study.

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/m2 per dose intravenously on days 1-3 and five cycles of doxorubicin 37·5 mg/m2 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.

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. METHODS: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. FINDINGS: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. INTERPRETATION: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

Therapy Response Assessment of Pediatric Tumors with Whole-Body Diffusion-weighted MRI and FDG PET/MRI.

Background Whole-body diffusion-weighted (DW) MRI can help detect cancer with high sensitivity. However, the assessment of therapy response often requires information about tumor metabolism, which is measured with fluorine 18 fluorodeoxyglucose (FDG) PET. Purpose To compare tumor therapy response with whole-body DW MRI and FDG PET/MRI in children and young adults. Materials and Methods In this prospective, nonrandomized multicenter study, 56 children and young adults (31 male and 25 female participants; mean age, 15 years ± 4 [standard deviation]; age range, 6-22 years) with lymphoma or sarcoma underwent 112 simultaneous whole-body DW MRI and FDG PET/MRI between June 2015 and December 2018 before and after induction chemotherapy (ClinicalTrials.gov identifier: NCT01542879). The authors measured minimum tumor apparent diffusion coefficients (ADCs) and maximum standardized uptake value (SUV) of up to six target lesions and assessed therapy response after induction chemotherapy according to the Lugano classification or PET Response Criteria in Solid Tumors. The authors evaluated agreements between whole-body DW MRI- and FDG PET/MRI-based response classifications with Krippendorff α statistics. Differences in minimum ADC and maximum SUV between responders and nonresponders and comparison of timing for discordant and concordant response assessments after induction chemotherapy were evaluated with the Wilcoxon test. Results Good agreement existed between treatment response assessments after induction chemotherapy with whole-body DW MRI and FDG PET/MRI (α = 0.88). Clinical response prediction according to maximum SUV (area under the receiver operating characteristic curve = 100%; 95% confidence interval [CI]: 99%, 100%) and minimum ADC (area under the receiver operating characteristic curve = 98%; 95% CI: 94%, 100%) were similar (P = .37). Sensitivity and specificity were 96% (54 of 56 participants; 95% CI: 86%, 99%) and 100% (56 of 56 participants; 95% CI: 54%, 100%), respectively, for DW MRI and 100% (56 of 56 participants; 95% CI: 93%, 100%) and 100% (56 of 56 participants; 95% CI: 54%, 100%) for FDG PET/MRI. In eight of 56 patients who underwent imaging after induction chemotherapy in the early posttreatment phase, chemotherapy-induced changes in tumor metabolism preceded changes in proton diffusion (P = .002). Conclusion Whole-body diffusion-weighted MRI showed significant agreement with fluorine 18 fluorodeoxyglucose PET/MRI for treatment response assessment in children and young adults. © RSNA, 2020 Online supplemental material is available for this article.

Comparison of ferumoxytol- and gadolinium chelate-enhanced MRI for assessment of sarcomas in children and adolescents.

OBJECTIVES: We compared the value of ferumoxytol (FMX)- and gadolinium (Gd)-enhanced MRI for assessment of sarcomas in paediatric/adolescent patients and hypothesised that tumour size and morphological features can be equally well assessed with both protocols. METHODS: We conducted a retrospective study of paediatric/adolescent patients with newly diagnosed bone or soft tissue sarcomas and both pre-treatment FMX- and Gd-MRI scans, which were maximal 4 weeks apart. Both protocols included T1- and T2-weighted sequences. One reader assessed tumour volumes, signal-to-noise ratios (SNR) of the primary tumour and adjacent tissues and contrast-to-noise ratios (CNR) of FMX- and Gd-MRI scans. Additionally, four readers scored FMX- and Gd-MRI scans according to 15 diagnostic parameters, using a Likert scale. The results were pooled across readers and compared between FMX- and Gd-MRI scans. Statistical methods included multivariate analyses with different models. RESULTS: Twenty-two patients met inclusion criteria (16 males, 6 females; mean age 15.3 ± 5.0). Tumour volume was not significantly different on T1-LAVA (p = 0.721), T1-SE (p = 0.290) and T2-FSE (p = 0.609) sequences. Compared to Gd-MRI, FMX-MRI demonstrated significantly lower tumour SNR on T1-LAVA (p < 0.001), equal tumour SNR on T1-SE (p = 0.104) and T2-FSE (p = 0.305), significantly higher tumour-to-marrow CNR (p < 0.001) on T2-FSE as well as significantly higher tumour-to-liver (p = 0.021) and tumour-to-vessel (p = 0.003) CNR on T1-LAVA images. Peritumoural and marrow oedema enhanced significantly more on Gd-MRI compared to FMX-MRI (p < 0.001/p = 0.002, respectively). Tumour thrombi and neurovascular bundle involvement were assessed with a significantly higher confidence on FMX-MRI (both p < 0.001). CONCLUSIONS: FMX-MRI provides equal assessment of the extent of bone and soft tissue sarcomas compared to Gd-MRI with improved tumour delineation and improved evaluation of neurovascular involvement and tumour thrombi. Therefore, FMX-MRI is a possible alternative to Gd-MRI for tumour staging in paediatric/adolescent sarcoma patients. KEY POINTS: • Ferumoxytol can be used as an alterative to gadolinium chelates for MRI staging ofpaediatric sarcomas. • Ferumoxytol-enhanced MRI provides equal assessment of tumour size and other diagnostic parameters compared to gadolinium chelate-enhanced MRI. • Ferumoxytol-enhanced MRI provides improved delineation of sarcomas from bone marrow, liver and vessels compared to gadolinium chelate-enhanced MRI.

Clinical impact of post-induction resolution of pulmonary lesions in metastatic Ewing sarcoma.

BACKGROUND: Patients with metastatic Ewing sarcoma experience poor outcomes despite intensive systemic and local therapy. Early chemotherapy response of pulmonary metastases has been associated with prognosis in other pediatric malignancies. We reviewed the outcomes of patients with Ewing sarcoma and pulmonary metastases treated at our institution based on therapy received and early pulmonary response. MATERIALS AND METHODS: We retrospectively reviewed patients with newly diagnosed Ewing sarcoma and pulmonary metastases at St. Jude Children's Research Hospital between 1979 and 2015. Data obtained included demographic and treatment characteristics including chemotherapy, local control measures, whole lung irradiation (WLI) administration, autologous stem cell transplantation, and outcomes. Patients were evaluated for radiographic post-induction pulmonary complete response (CR). We estimated event-free survival (EFS) and overall survival (OS) and used Cox proportional hazards regression to examine the effects of clinical and treatment factors on outcomes. RESULTS: Fifty-four patients (median age, 12.9 years) were evaluated. Post-induction pulmonary CR was observed in 33 (61%) patients. WLI was delivered to 16 patients (4/33 with pulmonary CR and 12/21 with non-CR). At median 3.6 years follow-up, five-year EFS and OS were 30.8% ± 6.4% and 49.6% ± 7.1%, respectively. Post-induction pulmonary CR was associated with prolonged EFS (P < 0.001) but not improved OS (P = 0.065). Post-induction pulmonary CR was associated with a lower incidence of lung failure (P = 0.031). CONCLUSIONS: Post-induction pulmonary CR is associated with improved EFS in patients with Ewing sarcoma who present with pulmonary metastases.