Publications by authors named "Sheri L Spunt"

148 Publications

A Retrospective Comparative Analysis of Outcomes and Prognostic Factors in Adult and Pediatric Patients with Osteosarcoma.

Curr Oncol 2021 Dec 12;28(6):5304-5317. Epub 2021 Dec 12.

Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94304, USA.

Osteosarcoma is the most common primary bone malignancy in both children and adults. Despite introduction of intensive multimodal treatment with chemotherapy and surgery, outcomes are still poor, especially for patients with metastatic disease and adults. Hence, there is an ongoing need for better prognostic markers and outcome data to inform management decisions in both the adult and pediatric setting. Here, we retrospectively analyzed 112 patients with bone osteosarcoma treated at two large adult and pediatric tertiary academic centers between 1989 and 2019. Patients were divided into an adult (≥18 years) and pediatric (<18 years) cohort for comparison. Our aim was to evaluate predictors of outcomes in pediatric and adult patients, with a specific focus on the role of methotrexate when added to a combination of doxorubicin-cisplatin; the prognostic value of tumor necrosis after neoadjuvant chemotherapy; and outlining any differences in outcomes between adults and pediatric patients that could inform clinical management. Adult patients treated with methotrexate-doxorubicin-cisplatin and those treated with doxorubicin-cisplatin had similar 5-year PFS (26%, 95%CI: 45.5%-10% vs. 50%, 95%CI: 69.6%-26.2%, = 0.1) and 5-year OS (63%, 95%CI: 82%-34%, vs. 78%, 95%CI: 90.6%-52.6%, = 0.5). In the adult cohort, there was no difference between patients with ≥90% necrosis and <90% necrosis in either 5-year PFS (42%, 95%CI: 71.1%-11.3% vs. 38%, 95%CI: 57.7%-18.2%, = 0.4) or 5-year OS (85%, 95%CI: 97.8%-33.4% vs. 56%, 95%CI: 76.8%-27.6%, = 0.4). In the pediatric cohort, compared to patients with <90% necrosis, those with ≥90% necrosis had significantly better 5-year PFS (30%, 95%CI: 49.3%-14.1% vs. 55%, 95%CI: 73.9%-38.5%, = 0.003) and 5-year OS (64%, 95%CI: 80.8%-41.1% vs. 78%, 95%CI: 92%-60.9%, = 0.04). Adult and pediatric patients had similar 5-year OS (69%, 95%CI: 83.2%-49.8% vs. 73%, 95%CI: 83.2%-59.3%, = 0.8) and 5-year PFS (37%, 95%CI: 52.4%-22.9% vs. 43%, 95%CI: 56.2%-30.4% = 0.3) even though the proportion of patients with ≥90% necrosis after neoadjuvant chemotherapy was higher for children compared to adults (60.3% vs. 30%, OR: 3.54, 95%CI: 1.38-8.46, = 0.006). In conclusion, in adult patients, the addition of methotrexate to doxorubicin and cisplatin did not correlate with a significant survival benefit, questioning the therapeutic value of methotrexate overall. Our study confirms the prognostic utility of percent tumor necrosis after neoadjuvant chemotherapy in pediatric patients but not in adult patients. Lastly, this is one of the few reported studies where patients with osteosarcoma younger and older than 18 years had similar PFS and OS.
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http://dx.doi.org/10.3390/curroncol28060443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700626PMC
December 2021

Treatment at Specialized Cancer Centers Is Associated with Improved Survival in Adolescent and Young Adults with Soft Tissue Sarcoma.

J Adolesc Young Adult Oncol 2021 Dec 15. Epub 2021 Dec 15.

Division of Hematology/Oncology, Center for Oncology, Hematology Outcomes Research and Training (COHORT), University of California Davis School of Medicine, Sacramento, California, USA.

Soft tissue sarcomas (STS) are a heterogeneous group of tumors whose management benefits from a multidisciplinary therapeutic approach. Published data suggest that cancer treatment at a specialized cancer center (SCC) can improve survival in other cancers. Therefore, we examined the impact of the location of treatment on survival in children and adolescents and young adults (AYAs) with STS. We performed a population-based analysis of children and AYAs hospitalized within 1 year of diagnosis with first primary STS (2000-2014) using the California Cancer Registry linked with hospitalization data. Patients were categorized based on receiving all inpatient treatments at a SCC versus part/none. Multivariable Cox proportional hazards regression identified factors associated with overall and STS-specific survival by age group. Results are presented as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Of the 1,674 patients with STS, 142 were children (0-14) and 1,532 were AYAs (15-39) and 89.4% and 40.4% received all inpatient treatments at a SCC, respectively. Overall, the 5-year survival was improved for patients who received all inpatient care at a SCC (59.8% vs. those who received part/none, 50.7%). Multivariable regression analysis found that having all treatments at a SCC was associated with better overall survival (HR, 0.79, CI: 0.65-0.95) in AYAs, but not in children. Our findings demonstrate that treatment for STS at a SCC is associated with better survival in AYAs. Eliminating barriers to treatment of AYAs with STS at SCCs could improve survival in this population.
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http://dx.doi.org/10.1089/jayao.2021.0110DOI Listing
December 2021

Validation of Deep Learning-based Augmentation for Reduced F-FDG Dose for PET/MRI in Children and Young Adults with Lymphoma.

Radiol Artif Intell 2021 Nov 6;3(6):e200232. Epub 2021 Oct 6.

Department of Radiology, Molecular Imaging Program at Stanford (A.J.T., F.S., K.Y., A.M.M., M.M., A.C., H.E.D.L.), Department of Pediatrics, Division of Hematology/Oncology, Lucile Packard Children's Hospital (S.L.S., A.P., H.E.D.L.), and Department of Biomedical Data Science (Y.L., Q.Z.), Stanford University, 725 Welch Rd, Stanford, CA 94304; and Subtle Medical, Menlo Park, Calif (P.G.).

Purpose: To investigate if a deep learning convolutional neural network (CNN) could enable low-dose fluorine 18 (F) fluorodeoxyglucose (FDG) PET/MRI for correct treatment response assessment of children and young adults with lymphoma.

Materials And Methods: In this secondary analysis of prospectively collected data (ClinicalTrials.gov identifier: NCT01542879), 20 patients with lymphoma (mean age, 16.4 years ± 6.4 [standard deviation]) underwent F-FDG PET/MRI between July 2015 and August 2019 at baseline and after induction chemotherapy. Full-dose F-FDG PET data (3 MBq/kg) were simulated to lower F-FDG doses based on the percentage of coincidence events (representing simulated 75%, 50%, 25%, 12.5%, and 6.25% F-FDG dose [hereafter referred to as 75%, 50%, 25%, 12.5%, and 6.25%, respectively]). A U.S. Food and Drug Administration-approved CNN was used to augment input simulated low-dose scans to full-dose scans. For each follow-up scan after induction chemotherapy, the standardized uptake value (SUV) response score was calculated as the maximum SUV (SUV) of the tumor normalized to the mean liver SUV; tumor response was classified as adequate or inadequate. Sensitivity and specificity in the detection of correct response status were computed using full-dose PET as the reference standard.

Results: With decreasing simulated radiotracer doses, tumor SUV increased. A dose below 75% of the full dose led to erroneous upstaging of adequate responders to inadequate responders (43% [six of 14 patients] for 75%; 93% [13 of 14 patients] for 50%; and 100% [14 of 14 patients] below 50%; < .05 for all). CNN-enhanced low-dose PET/MRI scans at 75% and 50% enabled correct response assessments for all patients. Use of the CNN augmentation for assessing adequate and inadequate responses resulted in identical sensitivities (100%) and specificities (100%) between the assessment of 100% full-dose PET, augmented 75%, and augmented 50% images.

Conclusion: CNN enhancement of PET/MRI scans may enable 50% F-FDG dose reduction with correct treatment response assessment of children and young adults with lymphoma. Pediatrics, PET/MRI, Computer Applications Detection/Diagnosis, Lymphoma, Tumor Response, Whole-Body Imaging, Technology AssessmentClinical trial registration no: NCT01542879 © RSNA, 2021.
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http://dx.doi.org/10.1148/ryai.2021200232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637226PMC
November 2021

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

Histopathology 2021 Nov 29. Epub 2021 Nov 29.

Department of Pathology, Oregon Health & Sciences University, Portland, OR, USA.

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.
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http://dx.doi.org/10.1111/his.14603DOI Listing
November 2021

Synovial Sarcoma in Children, Adolescents, and Young Adults: A Report From the Children's Oncology Group ARST0332 Study.

J Clin Oncol 2021 12 8;39(35):3927-3937. Epub 2021 Oct 8.

Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA.

Purpose: Synovial sarcoma (SS) is the second most common malignant soft tissue tumor in children. ARST0332 evaluated a risk-based treatment strategy for young patients with soft tissue sarcoma designed to limit therapy for low-risk (LR) disease and to test neoadjuvant chemoradiotherapy for unresected higher-risk disease.

Methods: Newly diagnosed patients with SS age < 30 years were assigned to four treatment arms based on disease features: A (surgery only), B (55.8 Gy radiotherapy [RT]), C (ifosfamide and doxorubicin [ID] chemotherapy plus 55.8 Gy RT), and D (neoadjuvant ID and 45 Gy RT, then surgery and RT boost based on margins followed by adjuvant ID). Patients treated in Arms A and B were considered LR, arms C and D without metastases as intermediate-risk (IR), and those with metastases as high-risk (HR).

Results: Of the 146 patients with SS enrolled, 138 were eligible and evaluable: LR (46), IR (71), and HR (21). Tumors were 80% extremity, 70% > 5 cm, 70% high-grade, 62% invasive, 95% deep, and 15% metastatic. Treatment was on arm A (29.7%), B (3.6%), C (16.7%), and D (50%). There were no toxic deaths and four unexpected grade 4 adverse events. By risk group, at a median follow-up of 6.8 years, estimated 5-year event-free survival was LR 82%, IR 70%, and HR 8%, and overall survival was LR 98%, IR 89%, and HR 13%. After accounting for the features that defined risk category, none of the other patient or disease characteristics (age, sex, tumor site, tumor invasiveness, and depth) improved the risk stratification model.

Conclusion: The risk-based treatment strategy used in ARST0332 produced favorable outcomes in patients with nonmetastatic SS relative to historical controls despite using RT less frequently and at lower doses. The outcome for metastatic SS remains unsatisfactory and new therapies are urgently needed.
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http://dx.doi.org/10.1200/JCO.21.01628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660012PMC
December 2021

Patients with nonmetastatic embryonal rhabdomyosarcoma arising in the biliary tract should be treated on low-risk clinical trials.

Authors:
Sheri L Spunt

Pediatr Blood Cancer 2022 01 6;69(1):e29399. Epub 2021 Oct 6.

Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.

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http://dx.doi.org/10.1002/pbc.29399DOI Listing
January 2022

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

Pediatr Blood Cancer 2021 Dec 26;68(12):e29346. Epub 2021 Sep 26.

Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.

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.
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http://dx.doi.org/10.1002/pbc.29346DOI Listing
December 2021

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

Pediatr Radiol 2021 12 19;51(13):2521-2529. Epub 2021 Aug 19.

Department of Radiology, Pediatric Molecular Imaging Program, Stanford University, 725 Welch Road, Stanford, CA, 94304, USA.

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.
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http://dx.doi.org/10.1007/s00247-021-05156-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602726PMC
December 2021

Metastatic pediatric sclerosing epithelioid fibrosarcoma.

Cold Spring Harb Mol Case Stud 2021 10 19;7(5). Epub 2021 Oct 19.

University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare and aggressive soft-tissue sarcoma thought to originate in fibroblasts of the tissues comprising tendons, ligaments, and muscles. Minimally responsive to conventional cytotoxic chemotherapies, >50% of SEF patients experience local recurrence and/or metastatic disease. SEF is most commonly discovered in middle-aged and elderly adults, but also rarely in children. A common gene fusion occurring between the and genes has been observed in 80%-90% of SEF cases. We describe here the youngest SEF patient reported to date (a 3-yr-old Caucasian male) who presented with numerous bony and lung metastases. Additionally, we perform a comprehensive literature review of all SEF-related articles published since the disease was first characterized. Finally, we describe the generation of an SEF primary cell line, the first such culture to be reported. The patient described here experienced persistent disease progression despite aggressive treatment including multiple resections, radiotherapy, and numerous chemotherapies and targeted therapeutics. Untreated and locally recurrent tumor and metastatic tissue were sequenced by whole-genome, whole-exome, and deep-transcriptome next-generation sequencing with comparison to a patient-matched normal blood sample. Consistent across all sequencing analyses was the disease-defining - fusion as a single feature consensus. We provide an analysis of our genomic findings and discuss potential therapeutic strategies for SEF.
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http://dx.doi.org/10.1101/mcs.a006093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8559621PMC
October 2021

A Comprehensive Circulating Tumor DNA Assay for Detection of Translocation and Copy-Number Changes in Pediatric Sarcomas.

Mol Cancer Ther 2021 10 5;20(10):2016-2025. Epub 2021 Aug 5.

Division of Hematology/Oncology, Department of Pediatrics, University of California San Francisco, San Fransisco, California.

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy-number changes. We applied Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy-number alterations (CNA). We analyzed 64 prospectively collected plasma samples from 17 patients with pediatric sarcoma. Translocations were detected in the pretreatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy-number changes in the pretreatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and CNAs in the plasma of patients with pediatric sarcoma. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0987DOI Listing
October 2021

Paediatric non-rhabdomyosarcoma soft tissue sarcomas: towards global collaboration.

Lancet Child Adolesc Health 2021 08 30;5(8):532-533. Epub 2021 Jun 30.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

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http://dx.doi.org/10.1016/S2352-4642(21)00178-4DOI Listing
August 2021

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

Pediatr Radiol 2022 Feb 27;52(2):354-366. Epub 2021 May 27.

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Lucile Packard Children's Hospital, Stanford University, 725 Welch Road, Stanford, CA, 94305-5614, USA.

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.
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http://dx.doi.org/10.1007/s00247-021-05098-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626538PMC
February 2022

Local Control For High-Grade Nonrhabdomyosarcoma Soft Tissue Sarcoma Assigned to Radiation Therapy on ARST0332: A Report From the Childrens Oncology Group.

Int J Radiat Oncol Biol Phys 2021 07 3;110(3):821-830. Epub 2021 Feb 3.

Department of Orthopedics, University of California Davis, Sacramento, California.

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.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767764PMC
July 2021

Metabolic response as assessed by F-fluorodeoxyglucose positron emission tomography-computed tomography does not predict outcome in patients with intermediate- or high-risk rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

Cancer Med 2021 02 19;10(3):857-866. Epub 2020 Dec 19.

Seattle Children's Hospital, Seattle, WA, USA.

Background: Strategies to optimize management in rhabdomyosarcoma (RMS) include risk stratification to assign therapy aiming to minimize treatment morbidity yet improve outcomes. This analysis evaluated the relationship between complete metabolic response (CMR) as assessed by F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET) imaging and event-free survival (EFS) in intermediate-risk (IR) and high-risk (HR) RMS patients.

Methods: FDG-PET imaging characteristics, including assessment of CMR and maximum standard uptake values (SUVmax) of the primary tumor, were evaluated by central review. Institutional reports of SUVmax were used when SUVmax values could not be determined by central review. One hundred and thirty IR and 105 HR patients had FDG-PET scans submitted for central review or had SUVmax data available from institutional report at any time point. A Cox proportional hazards regression model was used to evaluate the relationship between these parameters and EFS.

Results: SUVmax at study entry did not correlate with EFS for IR (p = 0.32) or HR (p = 0.86) patients. Compared to patients who did not achieve a CMR, EFS was not superior for IR patients who achieved a CMR at weeks 4 (p = 0.66) or 15 (p = 0.46), nor for HR patients who achieved CMR at week 6 (p = 0.75) or 19 (p = 0.28). Change in SUVmax at week 4 (p = 0.21) or 15 (p = 0.91) for IR patients or at week 6 (p = 0.75) or 19 (p = 0.61) for HR patients did not correlate with EFS.

Conclusion: Based on these data, FDG-PET does not appear to predict EFS in IR or HR-RMS. It remains to be determined whether FDG-PET has a role in predicting survival outcomes in other RMS subpopulations.
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http://dx.doi.org/10.1002/cam4.3667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897958PMC
February 2021

Symptom appraisal in uncertainty: a theory-driven thematic analysis with survivors of childhood cancer.

Psychol Health 2021 10 19;36(10):1182-1199. Epub 2020 Oct 19.

Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Objective: Somatic symptoms capture attention, demand interpretation, and promote health behaviors. Symptom appraisal is particularly impactful within uncertain health contexts such as cancer survivorship. Yet, little is known about how individuals make sense of somatic symptoms within uncertain health contexts, nor how this process guides health behaviors.

Design: 25 adolescent and young adult survivors of childhood cancer completed semi-structured interviews regarding how they appraise and respond to changing somatic sensations within the uncertain context of survivorship.

Main Outcome Measures: Interviews were transcribed verbatim and subjected to a hybrid deductive-inductive thematic analysis, guided by the Cancer Threat Interpretation model.

Results: We constructed three themes. S (theme 1) captured that participants described commonly interpreting and worrying about everyday sensations as indicating cancer recurrence or new illness. (theme 2) captured participants' felt need to employ cognitive and behavioral strategies to determine whether somatic sensations indicated a credible health threat. These two themes are qualified by the final theme, (theme 3), which captured participants' recognition that post-cancer symptoms are wily and influenced by psychological factors such as anxiety.

Conclusions: These data highlight that making sense of everday somatic sensations can be particularly challenging following an experience of cancer. There is a need for novel symptom management approaches that target how somatic sensations are appraised and responded to as signals of bodily threat.
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http://dx.doi.org/10.1080/08870446.2020.1836180DOI Listing
October 2021

Do qualitative interviews cause distress in adolescents and young adults asked to discuss fears of cancer recurrence?

Psychooncology 2021 01 15;30(1):123-126. Epub 2020 Sep 15.

Department of Medical Oncology, Stanford University School of Medicine, Stanford, California, USA.

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http://dx.doi.org/10.1002/pon.5544DOI Listing
January 2021

Long-term renal function after treatment for unilateral, nonsyndromic Wilms tumor. A report from the St. Jude Lifetime Cohort Study.

Pediatr Blood Cancer 2020 10 24;67(10):e28271. Epub 2020 Jul 24.

Department of Epidemiology and Cancer Control, and Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, and the Department of Pediatrics, University of Tennessee College of Medicine, Memphis, Tennessee.

Background: The impact of specific treatment modalities on long-term renal function and blood pressure among adult survivors of Wilms tumor (WT) has not been well documented.

Methods: Among 40 WT survivors and 35 noncancer controls, we estimated the glomerular filtration rate (eGFR) using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equations with and without cystatin C, obtained 24-hour ambulatory blood pressure readings, and, among survivors only, measured Tc diethylenetriamine pentaacetic acid (DTPA) plasma clearance. Survivors were treated with unilateral nephrectomy and nonnephrotoxic chemotherapy. Twenty received whole abdomen radiation therapy (WART) [median -16.5 Gray (Gy)], and 20 received no radiation therapy. Pairwise comparisons between survivors treated with and without WART, and each group to controls were performed using two-sample t tests.

Results: Twenty-six (65%) WT survivors were female, and 33 (83%) were non-Hispanic white. GFR estimated with creatinine or creatinine + cystatin C was decreased among irradiated survivors compared with controls. No irradiated or unirradiated participant had an eGFR (creatinine + cystatin C) < 60 mL/min/1.73 m . The prevalence of hypertension was significantly increased among unirradiated (25%) and irradiated survivors (35%) compared with controls (0%). Of the 24-hour ambulatory blood pressure monitoring parameters evaluated, only mean sleep period diastolic blood pressure load of those who received WART was significantly different from that of controls.

Conclusions: Chronic kidney disease was infrequent in long-term survivors of unilateral nonsyndromic WT, whether treated with WART or no radiation. The prevalence of hypertension was increased in both groups compared with controls, emphasizing the need for ongoing monitoring of renal and cardiovascular health.
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http://dx.doi.org/10.1002/pbc.28271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735383PMC
October 2020

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.

Lancet Oncol 2020 08 20;21(8):1110-1122. Epub 2020 Jul 20.

Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

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/m per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m 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/m 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.
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http://dx.doi.org/10.1016/S1470-2045(20)30325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745646PMC
August 2020

A Rare Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.

Cancer Res 2020 09 16;80(17):3732-3744. Epub 2020 Jul 16.

Cohen Children's Medical Center of New York, New Hyde Park, New York.

Germline mutations in cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of . The majority of families were of Ashkenazi Jewish descent, and the c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including , and ) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE: c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484045PMC
September 2020

Results of a Randomized, Double-Blinded, Placebo-Controlled, Phase 2.5 Study of Saracatinib (AZD0530), in Patients with Recurrent Osteosarcoma Localized to the Lung.

Sarcoma 2020 30;2020:7935475. Epub 2020 Apr 30.

Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California Children's Hospital Los Angeles, 4650 Sunset Blvd Mail Stop 57, Los Angeles, CA 90027, USA.

Purpose: Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. . Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles.

Results: Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (=0.47). Median OS was not reached in either arm.

Conclusions: Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.
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http://dx.doi.org/10.1155/2020/7935475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211262PMC
April 2020

Differentiation of benign and malignant lymph nodes in pediatric patients on ferumoxytol-enhanced PET/MRI.

Theranostics 2020 18;10(8):3612-3621. Epub 2020 Feb 18.

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, USA.

The composition of lymph nodes in pediatric patients is different from that in adults. Most notably, normal lymph nodes in children contain less macrophages. Therefore, previously described biodistributions of iron oxide nanoparticles in benign and malignant lymph nodes of adult patients may not apply to children. The purpose of our study was to evaluate if the iron supplement ferumoxytol improves the differentiation of benign and malignant lymph nodes in pediatric cancer patients on F-FDG PET/MRI. We conducted a prospective clinical trial from May 2015 to December 2018 to investigate the value of ferumoxytol nanoparticles for staging of children with cancer with F-FDG PET/MRI. Ferumoxytol is an FDA-approved iron supplement for the treatment of anemia and has been used "off-label" as an MRI contrast agent in this study. Forty-two children (7-18 years, 29 male, 13 female) received a F-FDG PET/MRI at 2 (n=20) or 24 hours (h) (n=22) after intravenous injection of ferumoxytol (dose 5 mg Fe/kg). The morphology of benign and malignant lymph nodes on ferumoxytol-enhanced T2-FSE sequences at 2 and 24 h were compared using a linear regression analysis. In addition, ADCmean-values, SUV-ratio (SUV lesion/SUV liver) and R2*-relaxation rate of benign and malignant lymph nodes were compared with a Mann-Whitney-U test. The accuracy of different criteria was assessed with a receiver operating characteristics (ROC) curve. Follow-up imaging for at least 6 months served as the standard of reference. We examined a total of 613 lymph nodes, of which 464 (75.7%) were benign and 149 (24.3%) were malignant. On ferumoxytol-enhanced T2-FSE images, benign lymph nodes showed a hypointense hilum and hyperintense parenchyma, while malignant lymph nodes showed no discernible hilum. This pattern was not significantly different at 2 h and 24 h postcontrast (p=0.82). Benign and malignant lymph nodes showed significantly different ferumoxytol enhancement patterns, ADCmean values of 1578 and 852 x10 mm/s, mean SUV-ratios of 0.5 and 2.8, and mean R2*-relaxation rate of 127.8 and 84.4 Hertz (Hz), respectively (all p<0.001). The accuracy of ADCmean, SUV-ratio and pattern (area under the curve (AUC): 0.99; 0.98; 0.97, respectively) was not significantly different (p=0.07). Compared to these three parameters, the accuracy of R2* was significantly lower (AUC: 0.93; p=0.001). Lymph nodes in children show different ferumoxytol-enhancement patterns on MRI than previously reported for adult patients. We found high accuracy (>90%) of ADCmean, SUV-ratio, pattern, and R2* measurements for the characterization of benign and malignant lymph nodes in children. Ferumoxytol nanoparticle accumulation at the hilum can be used to diagnose a benign lymph node. In the future, the delivery of clinically applicable nanoparticles to the hilum of benign lymph nodes could be harnessed to deliver theranostic drugs for immune cell priming.
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http://dx.doi.org/10.7150/thno.40606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069081PMC
April 2021

Undifferentiated small round cell sarcoma in a young male: a case report.

Cold Spring Harb Mol Case Stud 2020 02 3;6(1). Epub 2020 Feb 3.

Children's Cancer Therapy Development Institute, Beaverton, Oregon 97005, USA.

-rearranged sarcomas (CRSs) have recently been characterized as a distinct sarcoma subgroup with a less favorable prognosis compared to other small round cell sarcomas. CRSs share morphologic features with Ewing's sarcoma and prior to 2013 were grouped under undifferentiated sarcomas with round cell phenotype by the WHO classification. In this report, whole-genome sequencing and RNA sequencing were performed for an adolescent male patient with CRS who was diagnosed with undifferentiated pleomorphic sarcoma (UPS) by three contemporary institutions. Somatic mutation analysis identified mutations in , , and in pre- and post-treatment tissue samples, as well as a fusion that was confirmed by qPCR and DUX4 immunohistochemistry. Of particular interest was the overexpression of the translation factor , which has oncogenic properties and has recently been identified as a target of the investigational agent plitidepsin. This case may provide a valuable waypoint in the understanding and classification of CRSs and may provide a rationale for targeting eEF1A1 in similar soft tissue sarcoma cases.
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http://dx.doi.org/10.1101/mcs.a004812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996518PMC
February 2020

Efficacy and Safety of Limited-Margin Conformal Radiation Therapy for Pediatric Rhabdomyosarcoma: Long-Term Results of a Phase 2 Study.

Int J Radiat Oncol Biol Phys 2020 05 25;107(1):172-180. Epub 2020 Jan 25.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. Electronic address:

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 [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.
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http://dx.doi.org/10.1016/j.ijrobp.2020.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668436PMC
May 2020

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

Pediatr Blood Cancer 2020 04 15;67(4):e28150. Epub 2020 Jan 15.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

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.
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http://dx.doi.org/10.1002/pbc.28150DOI Listing
April 2020

Epigenetic Targeting of -Associated Gene Expression Signature in Human Neuroblastoma with Overexpression.

Cancer Res 2020 03 3;80(5):1024-1035. Epub 2020 Jan 3.

Department of Surgery, Stanford University School of Medicine, Stanford, California.

Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-sequencing data from 498 patients with neuroblastoma and revealed a differentially overexpressed gene signature in MYCN nonamplified neuroblastomas with telomerase reverse transcriptase () gene overexpression and coordinated activation of oncogenic signaling pathways, including E2Fs, Wnt, Myc, and the DNA repair pathway. Promoter rearrangement of the gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis in neuroblastoma, but -associated oncogenic signaling remains unclear. ChIP-seq analysis of the human CLB-GA neuroblastoma cells harboring rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in and multiple -associated genes. Brd4 and cyclin-dependent kinases (CDK) had critical regulatory roles in the expression and chromatin activation of and multiple -associated genes. Epigenetically targeting Brd4 or CDKs with their respective inhibitors suppressed the expression of and multiple -associated genes in neuroblastoma with overexpression or MYCN amplification. ChIP-seq and ChIP-qPCR provided evidence that the CDK inhibitor directly inhibited Brd4 recruitment to activate chromatin globally. Therefore, inhibiting Brd4 and CDK concurrently with AZD5153 and dinaciclib would be most effective in tumor growth suppression, which we demonstrated in neuroblastoma cell lines, primary human cells, and xenografts. In summary, we describe a unique mechanism in neuroblastoma with overexpression and an epigenetically targeted novel therapeutic strategy. SIGNIFICANCE: Epigenetically cotargeting Brd4 and Cdks suppresses human neuroblastoma with overexpression by inhibiting the -associated gene expression networks.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056551PMC
March 2020

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

Eur Radiol 2020 Mar 16;30(3):1790-1803. Epub 2019 Dec 16.

Department of Radiology, Pediatric Molecular Imaging Program at Stanford (PedsMIPS), Stanford University, Stanford, CA, USA.

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.
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http://dx.doi.org/10.1007/s00330-019-06569-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035151PMC
March 2020

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.

Lancet Oncol 2020 01 27;21(1):145-161. Epub 2019 Nov 27.

Seattle Children's Hospital, Seattle, WA, USA.

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 per dose intravenously on days 1-3 and five cycles of doxorubicin 37·5 mg/m 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.
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http://dx.doi.org/10.1016/S1470-2045(19)30672-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946838PMC
January 2020

Comparative Tumor RNA Sequencing Analysis for Difficult-to-Treat Pediatric and Young Adult Patients With Cancer.

JAMA Netw Open 2019 10 2;2(10):e1913968. Epub 2019 Oct 2.

CHOC Children's Hospital, Hyundai Cancer Institute, Orange, California.

Importance: Pediatric cancers are epigenetic diseases; therefore, considering tumor gene expression information is necessary for a complete understanding of the tumorigenic processes.

Objective: To evaluate the feasibility and utility of incorporating comparative gene expression information into the precision medicine framework for difficult-to-treat pediatric and young adult patients with cancer.

Design, Setting, And Participants: This cohort study was conducted as a consortium between the University of California, Santa Cruz (UCSC) Treehouse Childhood Cancer Initiative and clinical genomic trials. RNA sequencing (RNA-Seq) data were obtained from the following 4 clinical sites and analyzed at UCSC: British Columbia Children's Hospital (n = 31), Lucile Packard Children's Hospital at Stanford University (n = 80), CHOC Children's Hospital and Hyundai Cancer Institute (n = 46), and the Pacific Pediatric Neuro-Oncology Consortium (n = 24). The study dates were January 1, 2016, to March 22, 2017.

Exposures: Participants underwent tumor RNA-Seq profiling as part of 4 separate clinical trials at partner hospitals. The UCSC either downloaded RNA-Seq data from a partner institution for analysis in the cloud or provided a Docker pipeline that performed the same analysis at a partner institution. The UCSC then compared each participant's tumor RNA-Seq profile with more than 11 000 uniformly analyzed tumor profiles from pediatric and young adult patients with cancer, downloaded from public data repositories. These comparisons were used to identify genes and pathways that are significantly overexpressed in each patient's tumor. Results of the UCSC analysis were presented to clinical partners.

Main Outcomes And Measures: Feasibility of a third-party institution (UCSC Treehouse Childhood Cancer Initiative) to obtain tumor RNA-Seq data from patients, conduct comparative analysis, and present analysis results to clinicians; and proportion of patients for whom comparative tumor gene expression analysis provided useful clinical and biological information.

Results: Among 144 samples from children and young adults (median age at diagnosis, 9 years; range, 0-26 years; 72 of 118 [61.0%] male [26 patients sex unknown]) with a relapsed, refractory, or rare cancer treated on precision medicine protocols, RNA-Seq-derived gene expression was potentially useful for 99 of 144 samples (68.8%) compared with DNA mutation information that was potentially useful for only 34 of 74 samples (45.9%).

Conclusions And Relevance: This study's findings suggest that tumor RNA-Seq comparisons may be feasible and highlight the potential clinical utility of incorporating such comparisons into the clinical genomic interpretation framework for difficult-to-treat pediatric and young adult patients with cancer. The study also highlights for the first time to date the potential clinical utility of harmonized publicly available genomic data sets.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.13968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822083PMC
October 2019

Data sharing for clinical utility.

Cold Spring Harb Mol Case Stud 2019 10 23;5(5). Epub 2019 Oct 23.

University of California Santa Cruz Genomics Institute, Santa Cruz, California 95064, USA.

Genomic data offer valuable insights that can be used to help find treatments and cures for disease. Precision medicine, defined by the NIH as "an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person," is gaining acceptance among physicians, who are beginning to integrate patient-centric data analysis into clinical decision-making. Although precision medicine makes use of various types of data, this piece focuses on molecular characterization data specifically, as the discoveries yielded from these data can advance thinking around clinical care for cancer patients. Our pediatrics genomics team at the University of California Santa Cruz Genomics Institute is uniquely situated to discuss the use of shared genomic data for clinical benefit because our collaborations with hospital partners in the United States and internationally rely on big-data comparative genomic analysis. Using shared data, Treehouse Childhood Cancer Initiative develops methods for comparative analysis of tumor RNA sequencing profiles from single patients for the purposes of identifying overexpressed oncogenes that could be targeted by therapies in the clinic. To enable and improve this analysis, we continuously increase the size of our data compendium by adding public pediatric tumor RNA sequencing data sets. We developed an approach for assessing the quality of shared RNA sequencing data to ensure the integrity of the data. In this approach we calculate the number of mapped exonic nonduplicate (MEND) reads, applying a 10 million MEND read minimum threshold for inclusion in our comparative analysis. In collaboration with Stanford University and Lucile Packard Children's Hospital Stanford, our team at Treehouse Childhood Cancer Initiative explores the value to researchers everywhere of shared genomic data for clinical utility and the challenges of data sharing that threaten to impede otherwise rapid advances in precision medicine. This Perspective offers recommendations for maximizing the use of genomic data to make discoveries that will benefit patients.
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http://dx.doi.org/10.1101/mcs.a004689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824251PMC
October 2019
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