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To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors.

PURPOSE In 2006, Children's Oncology Group (COG) reclassified subgroups of toddlers diagnosed with neuroblastoma from high-risk to intermediate-risk, when the age cutoff for high-risk assignment was raised from 365 days (12 months) to 547 days (18 months). The primary aim of this retrospective study was to determine if excellent outcome was maintained after assigned reduction of therapy. PATIENTS AND METHODS Children RESULTS For 12-18mo/Stage4/FavBiology, 5-year EFS/OS (± SE) before (≤2006; n = 40) versus after (>2006; n = 55) assigned reduction in therapy was similar: 89% ± 5.1%/89% ± 5.1% versus 87% ± 4.6%/94% ± 3.2% ( P = .7; P = .4, respectively). For 12-18mo/Stage3/ MYCN-NA/Unfav, the 5-year EFS and OS were both 100%, before (n = 6) and after (n = 4) 2006. The 12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/ MYCN-NA/Unfav classified as high-risk ≤2006 had an EFS/OS of 91% ± 4.4%/91% ± 4.5% versus 38% ± 1.3%/43% ± 1.3% for all other high-risk patients 2006 had an EFS/OS of 88% ± 4.3%/95% ± 2.9% versus 88% ± 0.9%/95% ± 0.6% for all other intermediate-risk patients CONCLUSION Excellent outcome was maintained among subsets of toddlers with neuroblastoma assigned to reduced treatment after reclassification of risk group from high to intermediate on the basis of new age cutoffs. Importantly, as documented in prior trials, intermediate-risk therapy is not associated with the degree of acute toxicity and late effects commonly observed with high-risk regimens.

Context Children with cancer and cardiac disease suffer with high symptom burden at end of life (EOL). Little is known about the EOL experience for children with other complex chronic conditions (CCCs). Objectives To evaluate symptoms and suffering at EOL for children with noncancer, noncardiac CCCs as well as parental distress related to child suffering. Methods This study is a secondary data analysis of a cross-sectional, single-center survey of bereaved parents of children with CCCs who died between 2006 to 2015. The primary outcome was parent-reported child suffering in the final two days of life. Results Among 211 eligible parents contacted for participation, 114 completed the survey, and 99 had complete primary outcome data (participation rate 47%). Most children had congenital/chromosomal (42%) or progressive central nervous system (22%) conditions. Twenty-eight percent of parents reported high child suffering in the final two days of life. Parents reported that pain and difficulty breathing caused the greatest suffering for children and distress among themselves. Some parents also reported distress related to uncertainty about child suffering. Parents were less likely to report high child suffering if they were confident in knowing what to expect when their child was dying (AOR 0.20; 95% CI 0.07–0.60) or felt prepared for medical problems at EOL (AOR 0.12; 95% CI 0.04–0.42). Conclusion Nearly one-third of parents of children with CCCs report high suffering in their child's final days of life. Parent preparedness was associated with lower perceived child suffering. Future research should target symptoms contributing to parent and child distress and assess whether enhancing parent preparedness reduces perceived child suffering.

Outcomes for patients with INRGSS metastatic special (MS) metastatic pattern neuroblastoma at initial diagnosis are well described. Prognosis after an initial event (relapse, progression, secondary malignancy) is unclear.We investigated characteristics of MS pattern neuroblastoma patients in the International Neuroblastoma Risk Group database who subsequently experienced an event. Post-event overall survival (OS) ± standard error was calculated overall and by diagnosis era: before 2000 versus 2001 or after. Cox models were used to identify factors prognostic of post-event OS.Among 209 patients with an event, 88% were less than 365 days old at diagnosis; tumors were MYCN amplified in 24% and diploid in 33%. The median (range) time from diagnosis to first event was 8.16 months (7 days to 11.24 years). Of 96 patients with known relapse/progression pattern, 75% were metastatic or primary plus metastatic. Five-year post-event OS was 53% ± 3.6% and was higher for 2001 and afterwards (62% ± 5.0%) compared to before 2001 (44% ± 4.9%; p = .0046). In patients diagnosed in 2001 and after, older age, Hispanic ethnicity, MYCN amplification, 1p LOH, diploidy, high Mitotic Karyorrhexis Index, high lactate dehydrogenase (LDH), unfavorable histology, and longer time to first event were prognostic of worse post-event OS. Independent adverse prognostic factors on multivariable testing were non-White race, MYCN amplification, and diploidy.Patients diagnosed in and after 2001 have substantially better post-event OS compared to before 2001. In those diagnosed in and after 2001, most well-accepted prognostic factors for OS at diagnosis are also prognostic of post-event OS. Future studies may evaluate strategies to improve outcomes in this rare population.

Background Pediatric melanoma is rare and diagnostically challenging. Objective To characterize clinical and histopathologic features of fatal pediatric melanomas. Methods Multicenter retrospective study of fatal melanoma cases in patients younger than 20 years diagnosed between 1994 and 2017. Results Of 38 cases of fatal pediatric melanoma identified, 57% presented in white patients and 19% in Hispanic patients. The average age at diagnosis was 12.7 years (range, 0.0-19.9 y), and the average age at death was 15.6 years (range, 1.2-26.2 y). Among cases with known identifiable subtypes, 50% were nodular (8/16), 31% were superficial spreading (5/16), and 19% were spitzoid melanoma (3/16). One fourth (10/38) of melanomas arose in association with congenital melanocytic nevi. Limitations Retrospective nature, cohort size, and potential referral bias. Conclusions Pediatric melanoma can be fatal in diverse clinical presentations, including a striking prevalence of Hispanic patients compared to adult disease, and with a range of clinical subtypes, although no fatal cases of spitzoid melanoma were diagnosed during childhood.

Background: Some research indicated that hypothyroidism has huge adverse effects for the metabolic, cardiovascular, respiratory, and immune systems. However, there is no confirmed conclusion for the effect of cardiovascular surgery. This cohort study aims to investigate the prognosis of hypothyroidism patient at the age under 65-year-old after coronary artery bypass grafting (CABG) surgery. Method: From the National Health Insurance Research Database of Taiwan, 1586 patients with hypothyroidism who underwent elective CABG surgery were selected, along with 6334 patients who underwent surgery in a ratio of 1:4 sex-, age- and index year-matched controls, who were out of hypothyroidism. We used Cox proportional hazard analysis to compare the rate of 30-day, 5-year mortality, post-operative atrial fibrillation, respiratory complication during an average of 10-year follow-up. Result: Post-CABG patients had more hospital days, which was associated with hypothyroidism, male, DM and higher CCI_R (p < 0.001). Post-CABG patients had more inpatient respiratory complications, which was associated with hypothyroidism (p = 0.041), DM and CCI_R (p < 0.001, p = 0.046), and there was no difference in 1-year respiratory complication, tracheostomy in the same hospital course and within 1 year, repeated PCI, Af, CVVH, cerebral infarction, 30-day and 5-year mortality rate. Conclusions: Hypothyroidism correlates to post-CABG ventilator-related complications and pneumonia, and prolonged hospital days, but no effect on 30-day, 5-year mortality, post-operative atrial fibrillation and cerebral infarction rate. Thyroid function survey might include routinely preoperative survey for CABG outcome prognosis.

Current screening guidelines may not be adequate to identify iron deficiency (ID) and iron deficiency anemia (IDA) in adolescent and young adults. Adolescent and young adult outpatients from 4 hospital-based clinics (N = 493) reported on diet, health, and bleeding, and had phlebotomy for iron and hematologic tests. We examined sex-specific factors associated with ID and IDA and ability of universal and risk factor–based screening using hemoglobin and hemoglobin plus ferritin to detect ID and IDA. Among females (n = 350), 34.6% had ID and 6.3% had IDA. Nearly 1 in 3 females with ID had no risk factors. Among males, 12.6% had ID; none had IDA. More than 1 in 3 males with ID did not have risk factors. Current screening approaches would have missed ID in 47% to 82% of females and 95% to 100% of males. ID was prevalent in both male and female adolescents and young adult outpatients. New approaches to screening for ID are needed to accurately evaluate iron status in this population.

BACKGROUND Pharmacokinetic modeling for previously reported phase 1A data of pan-RAF inhibitor DAY101 in RAS/RAF/MEK/ERK pathway-altered tumors suggested a correlation between higher doses and improved efficacy without clear safety data. The protocol was amended to explore differential dosing across different body surface areas (BSA). METHODS Eligible patients were < 25 years old with radiographically recurrent/progressive RAS/RAF/MEK/ERK pathway-altered tumors. We applied a novel modification of a TITE-BOIN design to determine recommended phase 2 dosing of oral, weekly DAY101 in evaluable patients within two BSA subgroups: ≤ 1.5 m2 or > 1.5 m2. Target toxicity probability was closest to 20%. We tested 420 and 530 mg/m2. Dose limiting toxicities (DLTs) were determined within Cycle 1. Evaluable patients had either ‘complete’ or ‘partial’ information. Complete information meant patient had a DLT or received 3 of 4 planned doses with no DLT. Partial information meant patient received only 1 or 2 doses or did not complete the DLT observation period. Three patients with complete information at a given dose level were required before dose escalation. The primary endpoint driving dose escalation was time from start of Cycle 1 to first DLT or, if no DLT, time from start of Cycle 1 to minimum of date of last contact or end of Cycle 1. RESULTS We treated 35 eligible patients: 21 KIAA1549:BRAF-, 9 BRAFV600E-, 4 novel RAF- and one FGFR1-altered tumors. Histologically, cohort included 30 LGGs, 4 high grade gliomas and 1 soft tissue sarcoma. There were 6 DLTs: 3 in each BSA subgroup, all at 530 mg/m2/dose, all grade 3, and 5 known side effects ( 2 fatigue, 3 rash, 1 menorrhagia). CONCLUSIONS Oral weekly DAY101 is well tolerated. The TITE model recommends 530 mg/m2/dose PO weekly for patients with BSA < 1.5m2 and 420 mg/m2/dose PO weekly for patients with BSA >1.5m2.

10013 Background: In 2006, COG reclassified subgroups of toddlers diagnosed with neuroblastoma from high-(HR) to intermediate-risk (IR), when the age cut-off for increased risk was raised from 365 days (12 mo) to 547 days (18 mo) (London, J Clin Onc 2005). The aim of this retrospective study was to determine if excellent outcome was maintained after a reduction of therapy. Methods: Children < 3 yrs old at diagnosis, enrolled on a COG biology study from 1990-2018, were eligible (n = 9,189). Therapy was reduced for two “cohorts of interest” based on the age cut-off change: 365-546 days old with INSS stage 4, MYCN not amplified, favorable INPC, hyperdiploid tumors (12-18mo/Stage4/FavBiology); and, 365-546 days old with INSS stage 3 tumors with non-amplified MYCN and unfavorable INPC (12-18mo/Stage3/NotAmp/UnfavINPC). Log rank tests compared event-free (EFS) and overall survival (OS) curves. Results: In the cohorts of interest, patient (pt) characteristics were similar for ≤2006 vs > 2006. For 12-18mo/Stage4/FavBiology, 5-year EFS and OS (± std error) before (≤2006; n = 40) versus after (> 2006; n = 55) the reduction in therapy were similar: 89±5.1% versus 87±4.6% (p = 0.7), and 89±5.1% versus 94±3.2% (p = 0.4), respectively (Table). For 12-18mo/Stage3/NotAmp/UnfavINPC, the 5-year EFS and OS were both 100%, before (n = 6) and after (n = 4) 2006. For the combined cohorts for ≤2006 versus > 2006, EFS and OS were 91±4.4% versus 88±4.3% (p = 0.6), and 91±4.5% versus 95±2.9% (p = 0.5), respectively. Within HR pts diagnosed ≤2006, EFS/OS were 91±4.4%/91±4.5% for (12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/NotAmp/UnfavINPC) vs 38±1.3%/43±1.3% for all other HR pts < 3 yrs old (p < 0.0001; Table). Within IR pts diagnosed > 2006, EFS/OS were 88±4.3%/95±2.9% for (12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/NotAmp/UnfavINPC) vs 88±0.9%/95±0.6% for all other IR pts < 3 yrs old (p = 0.9). Conclusions: Our 19 year study demonstrates that excellent outcome is maintained among toddlers with Stage4/FavBiology and Stage3/Not Amp/Unfav INPC neuroblastoma with a significant reduction of therapy from high- to intermediate-risk treatment. Importantly, pts were likely spared acute toxicity and late effects known to be associated with HR therapy. Efforts to identify additional pt cohorts who may not require HR therapy to achieve long-term survival are critical to improve the long-term health of children with neuroblastoma. [Table: see text]

10044 Background: Neuroblastoma (NB) presenting with INRGSS MS metastatic pattern highlights the extreme heterogeneity within NB and subsequent difficulty in risk assignment. Depending on tumor biology, patients with stage MS disease may be classified as very-low risk or as high-risk. While outcomes at initial diagnosis have been well-described, outcomes after relapse are less well defined. Methods: From the INRG Data Commons, we investigated clinical and biological characteristics of patients diagnosed 1984-2021 with stage MS pattern NB (INSS stage 4s, INSS stage 4 or INRG stage MS) who subsequently experienced disease relapse or progression, excluding patients whose first event was death. Using Kaplan-Meier methods, post-relapse overall survival (OS)± standard error (SE) was calculated from the time of first relapse/progression until death or last contact, overall and by era of diagnosis: < 2000 vs ≥2001. Univariate Cox models were used to identify factors prognostic of post-relapse OS. Results: 209 patients met eligibility criteria,103 diagnosed < 2001 and 106 ≥2001. Of patients diagnosed ≥2001, 89% (n = 94) were < 365 days old at diagnosis; tumors were MYCN amplified in 21% (21/102) and diploid in 31% (20/64). Of this same cohort, time from initial diagnosis to relapse was < 6 months in 40% (n = 42), 6-12 months in 25% (n = 26), and > 12 months in 36% (n = 38) of patients. Of 60 patients with known site of relapse/progression diagnosed ≥2001, 73% (44) were metastatic (29) or primary plus metastatic (15). Among these, 16% (5/32) remained stage MS pattern while 84% (27/32) had metastatic sites beyond MS sites. Five-year post-relapse OS±SE was 53±3.5% overall (n = 209), and higher for those diagnosed ≥2001 (62±5.0%; n = 106) compared to those diagnosed < 2001 (44±4.9%; n = 103) (p = 0.0046). In patients diagnosed ≥2001, factors prognostic of superior post-relapse OS included: age < 365 days; not Hispanic; MYCN non-amplified; no 1p loss/aberration, hyperdiploidy; low/intermediate MKI; LDH < 1400 U/L, favorable INPC histology; and < 12 months from initial diagnosis to first relapse. Conclusions: Most patients with relapsed stage MS NB have metastatic relapse and these relapses more commonly occur at sites outside liver, skin, and bone marrow. Patients diagnosed ≥2001 with MS pattern NB have substantially better post-relapse OS compared to those diagnosed < 2001. In the cohort of patients with MS pattern NB diagnosed ≥2001, most of the well-accepted prognostic factors for OS at diagnosis are also prognostic of post-relapse OS.

e23507 Background: Ewing sarcoma (EwS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. CDK4 is a known genomic vulnerability in EwS, but an unappealing monotherapy target given propensity for innate resistance. In laboratory studies to identify targets synergistic with CDK4 inhibition, IGF-1R scored highly. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF-1R monoclonal antibody) for patients with relapsed or refractory EwS. Methods: This was a prospective open-label, non-randomized, single-center, phase 2 study (NCT04129151) for patients with relapsed EwS and RECIST measurable disease. Patients with relapsed EwS ≥12 years and a documented fusion consistent with EwS were eligible. Patients initially received Palbociclib 125 mg on days 1-21 and ganitumab 18 mg/kg on days 1 and 15 of a 28-day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A one-stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. Results: Ten evaluable patients enrolled between 5/2019-8/2021. The study closed 12/2021 due to lack of ganitumab drug supply. The median age at enrollment was 25.7 years (range 12.3-40.1; Table). The median duration of therapy was 2.5 months (range = 0.9-10.8). There were no complete or partial responders. Three of 10 patients had stable disease for > 4 cycles and 2 had stable disease at completion of planned therapy or study closure. 6-month PFS was 30±14.5%. Two patients had cycle 1 hematologic DLTs triggering the pre-defined toxicity rule; the palbociclib dose was subsequently reduced to 100 mg daily for 21 days. Among the remaining 8 patients, two had cycle 1 hematologic DLTs at the 100 mg dose. 80% of patients had grade 3/4 AEs; the most commons AEs were neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Total IGF-1 testing demonstrated intrapatient elevations in serum levels after a single cycle of therapy. Analysis of serial ctDNA samples is ongoing. Conclusions: Four responders out of 15 were required to reject the null hypothesis of a 10% response rate. With 0/10 responders, we concluded that this combination lacked adequate therapeutic activity for further study. The combination was tolerable at a palbociclib dose of 100 mg, with primarily hematologic toxicity in patients with relapsed EwS. Clinical trial information: NCT04129151. [Table: see text]

Background To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). Methods Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. Results Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. Conclusion Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

This quality improvement study examines disparities in proton radiotherapy use in patients enrolled in Children’s Oncology Group Trials

Transplant-associated thrombotic microangiopathy (TA-TMA) is a well-recognized complication of hematopoietic cell transplantation (HCT). Diagnosis is challenging and in the absence of a tissue biopsy, TA-TMA is provisionally diagnosed by meeting clinical criteria. In this study, we describe the prevalence, outcomes, and risk factors for meeting 2 different diagnostic criteria for TA-TMA and for increased transplant-related mortality (TRM). In this retrospective study of 307 pediatric HCT patients, records were reviewed for the first 100 days after HCT. Patients who were diagnosed with TA-TMA by a provider during this time were included. In addition, the Cho et al criteria (2010) and Jodele et al (2014) TA-TMA criteria were applied retrospectively. Eight patients (2.6%) were diagnosed with TA-TMA by their provider. However, on retrospective review, 20% and 36% met the Cho and Jodele criteria for TA-TMA, respectively. Overall survival was significantly worse (P < .0001) and TRM was significantly higher in patients who met criteria for TA-TMA (MC-TA-TMA) (P < .0001). After controlling for comorbid conditions, MC-TA-TMA (hazard ratio [HR], 10.9; P = .0001) and grade 3/4 acute graft-versus-host-disease (aGVHD) (HR 3.5; P = .01) remained independently associated with increased TRM. Among allogeneic HCT recipients, features associated with an increased risk for MC-TA-TMA included ≥2 HCT, concurrent grade 3/4 aGVHD and concurrent infections. Among patients who MC-TA-TMA, LDH ≥2 times the upper limit of normal (P = .001), the need for ≥2 antihypertensive medications (P < .0001), and acute kidney injury (P = .003) were associated with significantly increased TRM.

PURPOSE: To correlate MR imaging findings with molecular analyses in DIPG. METHODS: Baseline MR imaging studies, including standard pre- and post-contrast MR sequences, were reviewed from patients included in our multi-institutional, IRB-approved DIPG trial NCT01182350. Prospectively acquired imaging data were analyzed after study closure, including FLAIR/T2 tumor volume; tumor volume enhancement and cyst/necrosis; median, mean, mode, skewness, and kurtosis of apparent diffusion coefficient (ADC) tumor volume based on both FLAIR and enhancement at baseline. Whole-genome and RNA-sequencing identified histone mutations. We applied univariate Cox proportional-hazards regression modeling to test the association of imaging predictors with overall (OS) and progression-free survival (PFS). Wilcoxon rank-sum, Kruskal-Wallis, and Fisher’s exact tests compared imaging measures between groups. RESULTS: Fifty patients underwent biopsy and MRI. Median age at trial registration was 6 years (range,3.3–17.5 years); 52% of patients were female. Molecular subgroup study assignments for 48 patients’ tumors were as follows: 28 in MGMT-/EGFR-, 14 in MGMT-/EGFR+, 3 in MGMT+/EGFR-, and 3 in MGMT+/EGFR+. Further genetic testing identified mutations in histones, PDGFRA, ACVR1, TP53, EGFR, PPM1D, FGFR, and/or PI3K. Twenty-three tumors possessed histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HISTH3C. Median follow-up time was 11 months (range,0.4–33 months). Poorer OS (p=0.01) and PFS (p=0.001) were significantly associated with increased enhancing tumor volume. Enhancing tumor volume also differed significantly across molecular subgroups (p=0.047). Tumor enhancement, mode, skewness, and kurtosis ADC-FLAIR differed significantly (p≤0.048) between patients with H3F3A and HIST1H3B mutations. Tumor enhancement, median, mode, skewness, and kurtosis ADC-FLAIR also differed significantly (p≤0.048) between patients with H3F3A and HIST1H3B or HISTH3C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters correlate to molecular subgroups in DIPG. Further studies are required to verify and refine these findings in a larger cohort.

TPS10055 Background: Several aggressive pediatric and young adult cancers are characterized by SMARCB1 inactivation resulting in loss of INI1 expression, including rhabdoid tumors, epithelioid sarcoma and undifferentiated chordoma. These malignancies are associated with a poor prognosis and few effective treatment options for relapsed or refractory disease. Prior studies and emerging data suggest INI1-negative cancers may be uniquely susceptible to treatment with immune checkpoint inhibitors: Many INI1-negative pediatric tumors express PD-L1 and are infiltrated by immune cells, and there are reports of patients with advanced INI1-negative cancers with clinical responses to immune checkpoint blockade (Forrest et al. Clinical Cancer Research, 2020). We hypothesize that INI1 loss predicts tumor response to immune checkpoint inhibition (ICI). Methods: This is an ongoing multicenter, phase II, open-label clinical trial to evaluate the activity of nivolumab and ipilimumab in patients aged 6 months to 30 years with relapsed or refractory INI1-negative cancers (NCT04416568). The study enrolls patients in 2 strata: extracranial solid tumors in Stratum 1 and intracranial solid tumors in Stratum 2. Patients treated with prior ICI are excluded. Patients are treated with intravenous (IV) nivolumab 3mg/kg plus ipilimumab 1mg/kg IV every 3 weeks for 4 cycles followed by nivolumab 3mg/kg (max dose 240mg) IV every 2 weeks for up to 1-year. The primary objective is to evaluate the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) for Stratum 1 and by Response Assessment in Neuro-Oncology (RANO) criteria for Stratum 2. The trial has a 2-stage design targeting a 25% or greater response rate, with each stratum assessed independently. The analysis for Stage 1 in a given Stratum will be performed after 10 patients are enrolled. If a sufficient number of responders are observed, an additional 10 patients will be enrolled at Stage 2. Secondary endpoints include progression-free survival, overall survival, and disease control rate at 12 months. Correlative aims include assessing tissue and blood biomarkers associated with treatment response. Enrollment began 14 Aug 2020 and is ongoing. Clinical trial information: NCT04416568.

TPS11575 Background: Osteosarcoma is the most common primary bone tumor, occurring in children, adolescents, and young adults. In contrast to advances in treatment for most childhood cancers, there have been no significant improvements in osteosarcoma outcomes in the past 40 years. Forty percent of osteosarcoma patients will, at some point, have advanced disease which has a very poor outcome with a 5-year overall survival of approximately 20%. Genomic alterations and signatures associated with sensitivity to treatment with DNA damage response (DDR) inhibitors are observed frequently in osteosarcoma. Many osteosarcomas have a unique mutational signature (signature 3) similar to that seen in BRCA1 deficient cancer and response to PARP inhibitors has been seen in osteosarcoma cell lines. Additionally, ATRX, a protein involved in the alternative lengthening of telomeres (ALT), is often inactivated in osteosarcoma. Defects in the ALT pathway may sensitize tumor cells to ATR inhibitors and osteosarcoma cell lines have been shown to be sensitive to ATR inhibition. In vitro susceptibility of osteosarcoma cell lines to ATR and PARP inhibitors, the presence of mutations in genes involved in DDR and the presence of signature 3 in a subset of osteosarcomas serves as the basis for the development of this trial. Methods: This is an ongoing open label, multicenter, phase II clinical trial to evaluate the clinical activity of PARP inhibitor, olaparib, in combination with ATR inhibitor, ceralasertib, in 2 cohorts of patients aged 12-40 with recurrent osteosarcoma (NCT04417062). Patients with unresectable disease are enrolled into Cohort 1. Patients with resectable disease limited to the lung are enrolled into Cohort 2. Patients in both cohorts receive olaparib 300mg orally twice a day on days 1-28 and ceralasertib 160 mg orally once a day on days 1-7 of a 28-day cycle (adult maximum tolerated dose for the combination). For patients in Cohort 2, study treatment also includes surgical resection of lung metastases at protocol-specified timepoints. Patients can remain on treatment for up to 2 years if they have not progressed. For Cohort 1, the primary objective is to determine whether the combination treatment improves the 4-month event-free rate as compared to a historical benchmark from Children’s Oncology Group (COG) trials using a Simon’s two-stage design. In the first stage, ≥3 of 19 patients must be event-free at 4 months to proceed to stage 2. Enrollment into Cohort 2 continues as long as Cohort 1 enrollment is ongoing. For Cohort 2, the primary endpoint is the submission of paired pre- and post-treatment tumor samples for correlative studies. Secondary endpoints include objective response rate, event-free survival, and overall survival. Integrated correlative studies will assess tumor tissue for biomarkers of treatment response and measure circulating tumor DNA longitudinally. Enrollment began November 24, 2020 and is ongoing. Clinical trial information: NCT04417062.

10005 Background: Next generation sequencing (NGS) assays are now a standard part of clinical care for many adult solid cancers. The significance of molecular tumor profiling for the care of children with cancer is not well understood.We aimed to determine the clinical impact of identifying genomic alterations by NGS for young patients with relapsed, refractory, or high-risk extracranial solid tumors. Methods: We report on the first 389 participants in a prospective cohort study enrolling patients at 12 institutions with extracranial solid tumors diagnosed at age 30 years or less. Targeted DNA NGS was performed on one or more tumor samples from each patient. Selected patients also had tumors subjected to RNA sequencing. Test results were returned to the treating oncologist and follow-up treatment and response data were collected.Identified genomic alterations were classified according to evidence of impact on diagnosis, prognosis or response to targeted therapy matched to an identified alteration (matched targeted therapy, MTT) using established guidelines. Response to MTT was determined and reported as a response if either there was radiographic response according to RECIST or the duration of therapy was > 4 months. Results: Molecular tumor profiling (MTP) was successful in 345 (89%) patients (mean age 11 years at diagnosis; 65% with sarcoma). Two hundred and ninety-nine patients with MTP results (87%) had one or more alterations of clinical significance. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 208 (60%), 51 (15%) and 240 (70%) patients, respectively. Of the 240 patients with tumors harboring genomic alterations designated as having therapeutic impact, 23 (11%) had Tier 1 molecular findings. 205 patients were eligible to receive MTT based on having a molecular alteration with therapeutic significance and sufficient follow-up; 31 of these patients (15%) received MTT. Seven patients (23%) receiving MTT responded, 6 of these were kinase fusions. All of the responders received targeted therapy matched to a fusion and 78% of diagnostically significant alterations were fusions. Conclusions: Molecular tumor profiling has a significant impact on diagnosis and treatment recommendations for young patients with extracranial solid tumors. These results emphasize the importance of fusion detection for patients with sarcomas and rare tumors. Clinical trial information: NCT02520713.

Background: Gene variants with potential therapeutic significance have been reported in 30-60% of childhood malignancies. The 12-institution Genomic Assessment Informs Novel therapy (GAIN) consortium is conducting the individualized cancer therapy 2 (iCat2) study (NCT02520713) with the objective of evaluating the impact of tumor profiling on outcome. We provide an interim report on patients enrolled on the ongoing GAIN/iCat2 study. Methods and Objectives: Patients are eligible if they have a high-risk, recurrent/refractory (RR), or difficult-to-diagnose extracranial solid tumor diagnosed at ≤30 years and adequate sample available for sequencing. A next-generation targeted panel assay is performed. Results are returned with a GAIN report containing clinical interpretation, including an individualized cancer therapy (iCat) recommendation if there is evidence supporting a link between an identified variant and response to molecularly targeted therapy. iCat recommendations are tiered from 1 to 5 based on the level of clinical and preclinical support, with tier 1 being the highest and tier 5 the lowest. Potential extraordinary responders are selected for further review based on having treatment duration of ≥1 year for chemotherapy or ≥4 months or a partial response for targeted therapy. Results: 388 eligible patients were enrolled by 1/1/2019 with the most common diagnoses being osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. 366 patients (94%) have had at least one successful sequencing result, with 349 having molecular and GAIN reports suitable for inclusion in this analysis. 68% of patients (237/349) have received iCat recommendations, with 41% (143/349) having the highest tier of 1-2 and 27% (94/349) having a highest tier of 3-5. Common genes for which tier 1-2 iCat recommendations were made include TP53 (15%), SMARCB1 (4%), PIK3CA (3%), CDK4 (2%), and KRAS (2%). Common alterations for which tier 3-5 recommendations were made include EWSR1 fusions (12%), MYC/MYCN amplifications (8%), and CDKN2A deletions (7%). Of 170 RR patients with treatment follow-up data entered as of June 2019, 15% (25/170) have received matched targeted therapy. Six of these (24%) are considered extraordinary responders. Of note, extraordinary responses were also seen with some second-line chemotherapy and multitargeted kinase inhibitors. Conclusions: The proportion of patients with clinically significant gene variants is higher in this study than in some previous reports. Providing an iCat recommendation for alterations in genes such as TP53 where evidence is mixed, increased availability of molecularly targeted therapy trials, and more evidence may all be responsible for this increased rate. Reassessment of iCat recommendation tiers based on current evidence is ongoing. Extraordinary responses occur in a subset of children with extracranial solid malignancies who receive matched targeted therapy. Study enrollment is ongoing with further assessments of the impact of tumor profiling on outcome planned. Citation Format: Laura B. Corson, Alanna J. Church, Deirdre Reidy, Pei-Chi Kao, Wenjun Kang, Navin Pinto, Luke Maese, Theodore W. Laetsch, AeRang Kim, Susan I. Vear, Margaret E. Macy, Mark A. Applebaum, Lobin A. Lee, Duong Doan, R. Seth Pinches, Seong Choi, Suzanne J. Forrest, Catherine M. Clinton, Brian D. Crompton, Laura E. MacConaill, Samuel L. Volchenboum, Neal I. Lindeman, Steven G. DuBois, Wendy B. London, Katherine A. Janeway. Targeted sequencing in 388 patients with high-risk or recurrent/refractory pediatric extracranial solid malignancies: An interim report from the GAIN Consortium/iCat2 Study [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A28.

Background Transplant associated thrombotic microangiopathy (TA-TMA) is a well-recognized complication of hematopoietic cell transplantation (HCT) but is very challenging to diagnose. Outcomes are historically poor, though it is unclear if this is secondary to TA-TMA or to concurrent morbid conditions. We aimed to describe the prevalence and outcomes of TA-TMA at a single large pediatric center. Methods In this retrospective study, medical records of all children who received an HCT at Boston Children's Hospital from 1/2015-08/2017 were reviewed for evidence of TA-TMA in the first 100 days after HCT. Patients were diagnosed using "probable diagnostic TA-TMA criteria" (Cho et al, 2010). Patients who were both clinically diagnosed and retrospectively met criteria for TA-TMA were grouped together for analysis. Results 275 HCTs were performed in 232 patients. 37 patients (16%) met criteria for TA-TMA; 6 were clinically diagnosed and 31 retrospectively met criteria. TA-TMA was diagnosed a median of 26 days (range 11-97 days) after cell infusion. Patients with TA-TMA had significantly higher rates of aGVHD, ICU admissions, engraftment failure, bacterial and or viral infections in the first 100 days and were more likely to have an unrelated donor HCT, an HLA-loci mismatch of OS was significantly lower in patients with TA-TMA, with a one-year OS of 63.1% (95% CI=46.8-79.3%) vs 92.1% (87.9-96.2%), (p Of the 6 patients diagnosed with TA-TMA by providers, 4/6 were treated with eculizumab; 2 died of multiorgan failure and 2 remained dependent on eculizumab for ³2 years to maintain control of disease. The other 2 patients changed aGVHD prophylaxis resulting in TA-TMA resolution. Of the 31 patients who retrospectively met criteria none received TA-TMA directed therapy. One-year TRM was not significantly different between those diagnosed clinically versus retrospectively. Conclusion Most patients who met criteria for TA-TMA were retrospectively identified while being treated for another transplant complication (31/37), highlighting the challenge of a clinical diagnosis in the setting of non-specific criteria. Patients with TA-TMA had worse OS and increased TRM, even when adjusting for the development of aGVHD and engraftment failure (HR 9.1). It is important to develop multi-institutional, prospective studies to identify risk factors for TA-TMA and further study therapies and outcomes.

Background Biliary atresia (BA) is a paediatric cholestatic disease characterized by a progressive fibro-inflammation of the biliary tree. Current treatment of choice is to establish good bile flow via the Kasai operation. Aims We aimed to identify outcome-predictive serum biomarkers in BA infant. Methods Thirty-three BA children recruited from 1986 to 2007 served as the baseline-study group. An additional 11 children recruited from 2008 to 2011 served as the validation group. Serum samples were collected immediately before and 6 months after the Kasai operation for the assessment of serum cytokines, including tumour necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-10, IL-12p40 and IL-12p70 as the candidate biomarkers. Results Increased serum TGF-β levels indicated a lower Knodell hepatitis activity index at Kasai operation. The serum TGF-β levels declined after the operation. Serum IL-12p40 levels before the Kasai operation were higher in the subjects with a 3-month jaundice-free status than in others (P = 0.001). A serum pre-operative IL-12p40 level of 33 pg/ml was predictive of a 3-month jaundice-free status after surgery (positive predictive value=81.0%; negative predictive value=83.3%). This biomarker was also predictive of a better outcome, in terms of 3-year survival with native liver (risk ratio [RR = 4.00]; P

Background: Transplant associated thrombotic microangiopathy (TA-TMA) is a well-recognized complication of hematopoietic cell transplantation (HCT) and in a pediatric cohort, a prevalence rate of 39% is reported (Jodele, et al 2016). However, TA-TMA is challenging to diagnose as features are common to and may occur concurrently with many post HCT complications, i.e. acute graft versus host disease (aGVHD) and infection. Outcomes are historically poor, though it is unclear if this is secondary to TA-TMA or to concurrent morbid conditions. We aimed to describe the prevalence and outcomes of TA-TMA at a single large pediatric center. Methods: In this retrospective study, data were extracted from the medical records of all children who received an HCT at Boston Children's Hospital from 1/2015-08/2017. Records were reviewed for evidence of TA-TMA in the first 100 days after HCT. According to "probable diagnostic TA-TMA criteria" (Cho et al, 2010), all the following had to occur concurrently and during at least 2 consecutive time points: 1) elevated lactate dehydrogenase, 2) platelet count Results: 275 HCTs were performed in 232 patients. Among allogenic transplants (n=163), cell source was largely bone marrow (87%). Median follow up time of survivors was 1.3 years (range 0.04-2.9 years). Thirty-seven patients (16%) met criteria for TA-TMA; 6 were clinically diagnosed and 31 retrospectively met criteria. TA-TMA was diagnosed a median of 26 days (range 11-97 days) after cell infusion. Patients who met criteria for TA-TMA had significantly higher rates of aGVHD, ICU admissions, engraftment failure, bacterial and or viral infections in the first 100 days and were more likely to have an unrelated donor HCT, an HLA-loci mismatch of OS was significantly lower in patients with TA-TMA, with a one-year OS of 63.1% (95% CI=46.8-79.3%) vs 92.1% (87.9-96.2%), (log-rank p Of the 6 patients diagnosed with TA-TMA by providers, 4/6 were treated with eculizumab; 2 died of multiorgan failure and 2 remained dependent on eculizumab for ³2 years to maintain control of disease. The other 2 patients had aGVHD prophylaxis switched from cyclosporine to a different agent, resulting in TA-TMA resolution. TRM at 1 year was 33%. Of the 31 patients who retrospectively met criteria none received TA-TMA directed therapy. All were treated for the primary condition at the time of positive screening: aGVHD (n=9), engraftment failure (n=4), infection (n=6), multiorgan failure of unclear etiology (n=2) and other (n=16). One-year TRM was 38.2%. Conclusion: The prevalence of TA-TMA at our institution is 16%, lower than other reports using the same diagnostic criteria. 83% (31/37) of patients who met criteria for TA-TMA were retrospectively identified while being treated for another transplant complication, highlighting the challenge of a clinical diagnosis in the setting of non-specific criteria. Patients with TA-TMA had worse overall survival and increased TRM, even when adjusting for the development of aGVHD and engraftment failure (HR 9.1). It is important to develop multi-institutional, prospective studies to identify risk factors for TA-TMA and further study therapies and outcomes. Disclosures No relevant conflicts of interest to declare.

Background: This study aimed to investigate the roles of tumour necrosis factor-α (TNF-α) gene polymorphisms in the spontaneous clearance of HBsAg after a hepatitis B virus (HBV) infection. Methods: Polymorphisms in the TNF-α (−1031 T to C, −863 C to A, −857 C to T, −308 G to A and −238 G to A transition) gene were evaluated in 274 chronic HBV-infected patients and 194 patients with resolved HBV infection. The peripheral blood mononuclear cells (PBMC) isolated from 77 (28%) of the 274 chronic HBV-infected patients with negative HBeAg and positive antibody to HBeAg were stimulated with HBcAg. Data on TNF-α genotypes and phenotypes in subjects with/without the A allele at the TNF-α−863 promoter single nucleotide polymorphism (rs1800630) were compared. Results: The A allele in the −863 promoter region of the TNF-α gene was present in 154 (56.2%) chronic HBV-infected patients and 87 (44.8%) patients who recovered from HBV infection (odds ratio 1.58; P

Neuropeptide tachykinins, present within sensory nerves, have been implicated as neurotransmitters involved in nonadrenergic and noncholinergic airway muscle contraction. The signal transduction pathways of tachykinins on muscle contraction and Ca2+ mobilization were investigated in swine trachea. Tachykinins, substance P (SP) and neurokinin A (NKA), concentration (1 nM to 1 microM)-dependently induced contractile responses with removal of epithelium, whereas neurokinin B (NKB) did not alter the muscle tension. The SP- and NKA-evoked muscle contractions were inhibited by NK1-R antagonist L732138, but not by either NK2-R antagonist MDL29913 or NK3-R antagonist SB218795. Consistently, SP-elicited increase in [Ca2+]i was abolished by NK1-R antagonist, neither by NK2-R nor NK3-R antagonists. The SP-induced muscular responses were significantly inhibited by L-type Ca2+ channel blocker verapamil and withdrawal of external Ca2+. Caffeine (10 mM) or ryanodine (50 microM) also partly suppressed the SP-induced muscle responses. Inhibition of inositol 1,4,5-trisphosphate (InsP3) receptor with 2-APB (75 microM) potently attenuated SP-evoked Ca2+ mobilization and muscle contraction, which was further inhibited by 2-APB under Ca2+-free external solution, but not completely. Unexpectedly, simultaneous blockade of InsP3 receptor and ryanodine receptor (RyR) by 2-APB and ryanodine enhanced SP-evoked muscle contraction and Ca2+ mobilization. This potentiation was virtually abolished by removal of external Ca2+, suggesting native Ca2+ channels may contribute to this phenomenon. These results demonstrate that tachykinins produce a potent muscle contraction associated with Ca2+ mobilization via tachykinin NK1- R-dependent activation of multiple signal transduction pathways involving Ca2+ influx and release of Ca2+ from InsP3- and ryanodine-sensitive Ca2+ stores. Blockade of both InsP3 receptor and RyR enhances the Ca2+ influx through native Ca2+ channels in plasma membrane, which is crucial to Ca2+ signaling in response to NK1 receptor activation.

Male predominance of hepatocellular carcinoma (HCC) occurs particularly among young children aged 6-9 years, indicative of a possible role of the Y chromosome–encoded oncogene in addition to an androgenic effect. The discovery of oncogenic activation of RBMY (RNA-binding motif on Y chromosome), which is absent in normal hepatocytes but present in male HCC tissues, sheds light on this issue. Herein, we report on a critical hepatocarcinogenic role of RBMY and its ontogenic origin. During liver development, the Ser/Thr phosphorylated RBMY is expressed in the cytoplasm of human and rodent fetal livers. It is then silenced in mature hepatocytes and restricted to scarce expression in the bile ductular cells. Upon hepatocarcinogenesis, a noteworthy increase of cytoplasmic and nuclear RBMY is observed in HCC tissues; however, only the former is expressed dominantly in hepatic cancer stem cells and correlates significantly to a poor prognosis and decreased survival rate in HCC patients. Cytoplasmic expression of RBMY, which is mediated by binding to nuclear exporter chromosome region maintenance 1 and further enriched upon Wnt-3a stimulation, confers upon tumor cells the traits of cancer stem cell by augmenting self-renewal, chemoresistance, cell-cycle progression, proliferation, and xenograft tumor growth. This is achieved mechanistically through increasing Ser9 phosphorylation-inactivation of glycogen synthase kinase 3β by RBMY, thereby impeding the glycogen synthase kinase 3β–dependent degradation of β-catenin and eventually inducing the nuclear entry of β-catenin for the transcription of downstream oncogenes. Conclusion: RBMY is a novel oncofetal protein that plays a key role in attenuating glycogen synthase kinase 3β activity, leading to aberrant activation of Wnt/β-catenin signaling, which facilitates malignant hepatic stemness; because of its absence from normal human tissues except the testis, RBMY represents a feasible therapeutic target for the selective eradication of HCC cells in male patients. (Hepatology 2015;62:1480–1496)

TPS10576 Background: CUDC-907 is an oral first-in-class small molecule inhibitor of histone deacetylases (HDACs) and phosphatidylinositol-3-kinases (PI3Ks), two enzyme classes commonly implicated in pediatric malignancies. Preclinical data demonstrate that inhibition of these enzymes decreases tumor growth across a range of histologies. Data from preclinical and clinical studies suggest that down-regulation of Myc or Mycn signaling may be important in the antineoplastic effects of CUDC-907. Myc or Mycn signaling appears to drive a number of pediatric cancers, heralds a poor prognosis in many of these diseases and has proven difficult to target. CUDC-907 has completed adult phase I testing in patients with hematologic malignancies. The drug was tolerable using a 5 days on/2 days off (5/2) dosing strategy, with a recommended phase II dose of 60 mg. Diarrhea, fatigue, nausea and thrombocytopenia were the most commonly reported side effects. Partial and complete responses were observed in patients with Myc-altered diffuse large B cell lymphoma. Methods: This study is a phase I, open-label, multicenter trial of CUDC-907 in patients 1-21 years of age with relapsed/refractory solid tumors, brain tumors and lymphomas (NCT02909777). The primary objectives are to determine the recommended phase II dose, describe toxicities, and describe pharmacokinetic parameters of CUDC-907 in this population. Other objectives include evaluation of disease response and exploration of the pharmacodynamic effects of CUDC-907. Patients receive CUDC-907 orally on a 5/2 schedule in 28-day cycles, with a pediatric mini-tab formulation available for younger children. Part A consists of a standard 3+3 design evaluating up to three dose levels. Following dose escalation, Part B consists of two expansion cohorts for patients with Mycn/Myc-driven neuroblastoma or mature B-cell lymphoma. Up to 44 patients may be enrolled across Parts A and B. Detailed pharmacokinetic testing is required in the first two cycles. Optional pharmacodynamic testing will quantify histone acetylation, Myc protein, and phospho-S6 in serial blood samples. Enrollment began in October 2016 and is ongoing. Clinical trial information: NCT02909777.

This study aimed to investigate the roles of tumour necrosis factor-α (TNF-α) gene polymorphisms in the spontaneous clearance of HBsAg after a hepatitis B virus (HBV) infection.Polymorphisms in the TNF-α (-1031 T to C, -863 C to A, -857 C to T, -308 G to A and -238 G to A transition) gene were evaluated in 274 chronic HBV-infected patients and 194 patients with resolved HBV infection. The peripheral blood mononuclear cells (PBMC) isolated from 77 (28%) of the 274 chronic HBV-infected patients with negative HBeAg and positive antibody to HBeAg were stimulated with HBcAg. Data on TNF-α genotypes and phenotypes in subjects with/without the A allele at the TNF-α-863 promoter single nucleotide polymorphism (rs1800630) were compared.The A allele in the -863 promoter region of the TNF-α gene was present in 154 (56.2%) chronic HBV-infected patients and 87 (44.8%) patients who recovered from HBV infection (odds ratio 1.58; P0.01). The TNF-α-863 A allele genotype predicted lower TNF-α production by PBMC after in vitro HBcAg stimulation (P0.02).The A allele at the -863 locus of the promoter region of the TNF-α gene predicts lower HBcAg-inducible TNF-α secretion. It is also associated with chronicity of HBV infection.