bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying osteosarcoma signatures in cell free DNA using 5-hydroxymethylcytosine profiling.
Authors: Neczypor Evan W , Moore Kelly , Zeldin Elizabeth , Nie Linda , Hayashi Masanori , Weiser Daniel A. , Applebaum Mark A. 
Published: June 2023

10022 Background: Osteosarcoma is the most common primary bone tumor in children and adolescents. Prognostic biomarkers are limited, and post-treatment surveillance relies heavily on radiologic imaging. Capture and analysis of cell-free DNA (cfDNA) from the bloodstream is an emerging technique that could be used to provide additional prognostic information and track residual disease following treatment. 5-hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression, and tumor specific patterns of global 5-hmC deposition are identifiable in several cancers and vary according to disease burden. We profiled 5-hmC using plasma-derived cfDNA from osteosarcoma patients and healthy children to assess its utility as a biomarker of disease status. Methods: cfDNA was isolated from patients diagnosed with osteosarcoma and well child controls. Nano-hmC-Seal, a technique developed to isolate 5-hmC-modified DNA fragments, was used to generate sequencing libraries of cfDNA. Genomic DNA from osteosarcoma cell lines was serially diluted with healthy donor-derived cfDNA. DESeq2 was used to identify genes with high 5-hmC deposition in osteosarcoma cell line DNA relative to serial dilutions. In patient cfDNA samples, the relative abundance of 5-hmC deposition on these osteosarcoma genes was determined using gene set variation analysis (GSVA). GSVA returns a score ranging from -1 to 1, with positive values indicating a relative abundance of 5-hmC deposition on osteosarcoma genes. Results: The cohort consisted of 33 healthy children and 17 patients with osteosarcoma including 53 serially collected samples from these patients. 139 osteosarcoma genes were identified and used for GSVA analysis. Patients with osteosarcoma had significantly higher GSVA scores than well children (0.26 vs -0.38; p < 0.001). Hierarchal clustering identified two clusters of samples from children with osteosarcoma. Cluster 1 contained samples with scores correlating with osteosarcoma-derived DNA compared to Cluster 2 (0.14 vs -0.18; p < 0.001). Furthermore, Cluster 1 contained 17 of 23 samples from patients with active disease on clinical imaging (sensitivity = 74%, specificity = 57%). High 5-hmC deposition on MYC was readily identified in one sample obtained at diagnosis from the only patient with a MYC amplified tumor. Additional samples from this patient during treatment showed decreasing 5-hmC deposition on MYC, consistent with a treated tumor shedding less DNA into the blood. Additionally, decreased disease burden following surgical resection was identifiable in 5-hmC profiles (presurgical GSVA score 0.22 vs postsurgical -0.08; p = 0.004). Conclusions: Osteosarcoma 5-hmC signatures can identify patients with active disease. Monitoring cfDNA in osteosarcoma using 5-hmC profiling is a promising technique that warrants further investigation with larger patient cohorts.
Real-world use of tisagenlecleucel in children and young adults with relapsed or refractory B-cell lymphomas.
Authors: Bender Jonathan , Damodharan Sudarshawn , Moskop Amy , Toner Keri , Vatsayan Anant , Capitini Christian , Baggott Christina , Schiff Deborah E. , Katsanis Emmanuel , Raikar Sunil S. , Talano Julie-An M. , Schultz Liora M. , Pommert Lauren 
Published: June 2023

10031 Background: Survival for pediatric B-cell lymphomas (BCL) exceeds 90% with modern regimens, however outcomes remain poor for patients with relapsed or refractory (R/R) disease. Tisagenlecleucel is a CD19-directed CAR T-cell therapy (CART) that is FDA approved for adults with R/R BCL. No data exists for use of tisagenlecleucel in R/R pediatric BCL. Methods: We surveyed 48 sites in the Pediatric Real-World CAR Consortium to retrospectively describe use and outcomes of tisagenlecleucel for pediatric patients with R/R BCL. This cohort included 10 patients from 7 centers aged ≤25 years who were infused between 2019-2022 and were ≥3 months from CART. We aimed to describe response rates, as determined by each institution based on positron emission tomography, bone marrow evaluation, and/or cerebrospinal fluid (CSF) studies, along with toxicity and outcomes in this population. Results: Ten patients received CART with a median age at infusion of 19 (range, 7-24) years. Five patients had B-lymphoblastic lymphoma (B-LLy), 2 had primary mediastinal BCL, and 1 each had Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and post-transplant lymphoproliferative disorder related DLBCL. Five patients had primary refractory disease, and 5 were in ≥2nd relapse. Three had received prior hematopoietic stem cell transplant (HSCT). Two had CSF involvement, and 1 had central nervous system parenchymal disease at time of infusion. CART was well tolerated with 1 patient experiencing grade 3 cytokine release syndrome and 2 patients experiencing neurotoxicity (grade 2 n = 1, grade 3 n = 1), both of whom had CSF involvement at time of CART infusion. Best overall response was complete response (CR) for 6, partial response (PR) for 2, and refractory disease for 2. Two patients, both with B-LLy, underwent allogeneic HSCT while in CART-mediated CR with B-cell aplasia. Both patients with PR (1 DLBCL, 1 Burkitt) subsequently relapsed with CD19-negative disease; the patient with DLBCL subsequently achieved CR with salvage immuno-chemotherapy and HSCT. All 6 CR patients remain in remission at a median time to follow-up of 31 (range, 14-47) months. Conclusions: This multicenter case series of CD19-directed CART for R/R pediatric BCL suggests that tisagenlecleucel may be safe and active in this population with all CR patients currently in sustained remission. Larger studies are needed to understand how best to incorporate CART into treatment for R/R pediatric BCL. [Table: see text]
Outcomes in pediatric relapsed/refractory anaplastic large cell lymphoma: A multi-institutional retrospective analysis.
Authors: Marks Lianna Jean , Ritter Victor , Schultz Liora M. , Lowe Eric J. , Aftandilian Catherine ,   Relapsed ALCL (REAL) Consortium
Published: June 2023

10032 Background: Treatment options for relapsed or refractory (R/R) anaplastic large cell lymphoma (ALCL) have increased in the era of targeted therapies such as brentuximab vedotin (BV) and Anaplastic Lymphoma Kinase (ALK)-inhibitors. However, there is no standard treatment and limited published data evaluating their use in this patient population. Methods: We conducted a retrospective, multi-institutional study of patients <22 yrs old at initial diagnosis with R/R ALCL treated between 2011-2021 across 18 institutions. Results: We identified 85 patients with R/R ALCL (median age at initial diagnosis 12 yrs, 67% male, 96% ALK+). Treatment for initial diagnosis included ALCL99 (31%), ANHL12P1 + BV (32%), ANHL12P1 + crizotinib (CZ) (11%), ANHL0131 (14%), or other (13%). Median time from diagnosis to relapse was 0.7 yrs (range 0.2-10.8 yrs) with sixteen patients (18%) relapsing on initial chemotherapy. Stage at relapse for 82 ALK+ patients: I (9%), II (15%), III (41%), IV (35%). Initial re-induction regimens shown in the table. Fifty-nine (72%) patients received a hematopoietic stem cell transplant (HSCT), 11 autologous and 49 allogeneic with one receiving both. Of 59 transplanted patients, 10 relapsed (6 allo 4 auto) and 7 died. All but one of the patients who relapsed post-HSCT responded to additional therapy and remain alive. Of 23 ALK+ patients who never had a transplant, 4 patients died and 19 are alive in remission. Eleven remain on active therapy (6 CZ, 3 BV, 1 BV+CZ, 1 vinblastine) with eight off therapy. Patients who received a transplant more likely to be off therapy and alive. Duration of treatment for patients receiving BV or the ALK-inhibitor CZ varied widely (BV 1-11 yrs; CZ 2-10 yrs) with 20 patients continuing on therapy at the time of data collection. Five-year overall survival for patients with or without transplant was 91% (CI 84-99%) and 86% (CI 73-100%) respectively. Conclusions: This is the largest collection of patients with R/R ALK+ ALCL treated in the era of targeted therapy. Patients achieved excellent responses to ALK-inhibitor or BV monotherapy, but questions remain about duration of therapy. Transplant may not be necessary for all R/R patients including those with high-risk disease. [Table: see text]
Stage 4N neuroblastoma before and during the era of anti-GD2 immunotherapy.
Authors: Kushner Brian H. , Modak Shakeel , LaQuaglia Michael P. , Basu Ellen M. , Gerstle Justin T , Iglesias Cardenas Fiorella , Kramer Kim , Roberts Stephen S. , Wolden Suzanne L. , Cheung Nai-Kong V. 
Published: June 2023

10037 Background: Patients with stage 4N neuroblastoma (distant metastases limited to lymph nodes) stand out as virtually the only survivors of high-risk neuroblastoma (HR-NB) before myeloablative therapy (MAT) and immunotherapy with anti-GD2 monoclonal antibodies (mAb) became standard. No report presents results with contemporary treatment programs for 4N. The only large study to date (from the International Neuroblastoma Risk Group) analyzed patients diagnosed 1990-2002, found 4N to have significantly better event-free (EFS) and overall survival (OS) compared to other stage 4 patients, and recommended considering less intensive therapy for 4N. Methods: We conducted a retrospective analysis of patients treated at our center from 1985-2021 to analyze our large experience to fill the gap in the literature on treatment of 4N, namely, results with contemporary multi-modality therapy including MAT and anti-GD2 mAbs. Results: We found and reviewed 48 pediatric 4N patients ( < 18 years old) treated 1985-2021 at our center. Biological features included segmental chromosomal aberrations in 21/21 MYCN-non-amplified patients, mutations of ALK in 4/22 (18%), ATRX in 4/16 (25%), and TERT in 4/12 (33%) patients. Among 33 MYCN-non-amplified high-risk patients ( > 18 months old), 19 are relapse-free 1.6+-to-36.9+ (median 12.2+) years post-diagnosis, including 13 without prior MAT and 3 with no mAb, while 14 patients (7 without prior immunotherapy) relapsed (all in soft tissue initially). Eleven of the 14 died, including 3 who developed late osteomedullary metastases after 3-5 relapses in soft tissue alone. Of 13 MYCN-amplified 4N patients, 6 are relapse-free 4.5+-to-25.8+ (median 11.7+) post-diagnosis (all received mAbs; 3 underwent MAT) and 3 are in 2nd remission 4.4+-to-21.1+ years post-relapse (all soft tissue). For all high-risk 4N patients, 5/10-year EFS was 55%/52%, and OS was 76%/64%. MAT was not prognostic. The 2 patients with intermediate-risk 4N (14 months old) are relapse-free 7+ years post-resection of primary tumors; distant disease spontaneously regressed. Conclusions: The natural history of 4N is marked by NB confined to soft tissue without early relapse in bones or bone marrow, sites where mAbs have proven efficacy. These findings plus the possibility of survival without MAT and/or mAb immunotherapy, as seen elsewhere and at our center, support consideration of treatment reduction for selected MYCN-non-amplified 4N patients.
Safety and PK (pharmacokinetic) profile of niraparib (nir) + dostarlimab (dost) in pediatric patients (pts) with recurrent or refractory (RR) solid tumors: SCOOP study.
Authors: Doz Francois , André Nicolas , Guerra-García Pilar , Juan-Ribelles Antonio , Mora Jaume , Moreno Lucas , Corradini Nadège , Huff Anne , Nugent Courtney , Snyder Michele , Moroz Veronica , Wanik Danielle , Gupta Divya , Tarek Nidale , Rubio-San-Simón Alba 
Published: June 2023

10040 Background: Combination therapies may improve clinical outcomes in pediatric pts with tumors with single-agent resistance. Emerging preclinical and clinical data have shown a positive effect for combination PARP/immune checkpoint inhibition. The SCOOP study was designed to evaluate combination nir+dost in pediatric pts with non-central nervous system (CNS) RR solid tumors. Herein we present the safety, dose-limiting toxicities (DLTs), PK, and recommended phase 2 dose (RP2D) of nir+dost. Methods: SCOOP is a phase 1, multicenter, open-label, dose-escalation, and cohort-expansion study in pts aged ≥6 mo to <18 y with non-CNS tumor types reported to have a BRCAness gene signature. Part 1A comprised multiple dose-level cohorts (0, 1A, 1B, and 2; Table) of pts ≥20 kg able to swallow nir tablets. The primary endpoint was determination of the RP2D of nir+dost based on DLT incidence during the first 2 cycles. Plasma concentrations were compared with simulated adult concentrations using population PK models. Results: A total of 23 pts with non-CNS RR solid tumors were enrolled with 16 evaluated for DLTs and 23 for PK analysis (see Table for dose-level cohorts and observed DLTs). Grade (Gr) ≥3 drug-related (DR) treatment-emergent adverse events (TEAEs) in part 1A included hematologic toxicities, decreased appetite, and fatigue, with DR serious TEAEs of immune-mediated encephalitis, headache, nausea, vomiting, cerebral hemorrhage, and hyponatremia. Observed plasma nir concentrations at 100 and 200 mg once daily (QD) in pediatric pts were similar to simulated adult concentrations at 200 or 300 mg QD. Observed dost concentrations at 7.5 mg/kg every 3 weeks (Q3W) in pediatric pts were in the expected range for adults at 500 mg Q3W. Conclusions: Observed DLTs were consistent with the individual safety profile of each drug; overall no unexpected safety issues were observed. Based on these results, nir 100 mg QD + dost 7.5 mg/kg Q3W was selected as the RP2D for the SCOOP expansion cohorts in neuroblastoma and osteosarcoma. Pts in the expansion study will receive nir+dost at the RP2D until disease progression. Clinical trial information: NCT04544995 . [Table: see text]
Reduction in curie score in neuroblastoma patients treated with naxitamab.
Authors: Mora Jaume , Chan Godfrey Chi-Fung , Morgenstern Daniel A. , Amoroso Loredana , Nysom Karsten , Faber Joerg , Wingerter Arthur , Bear Melissa , Rubio-San-Simón Alba , Kushner Brian H. , Tornøe Karen , DePont Christensen Rene 
Published: June 2023

10042 Background: Patients with high-risk neuroblastoma (HR-NB) most frequently present with metastases in the bone marrow (BM; 70–89%) and bone (56–65%). Approximately 15% of HR-NB patients will be refractory to induction therapy and 50% will relapse. Naxitamab is a humanized GD2-binding monoclonal antibody approved in the US with granulocyte-macrophage colony-stimulating factor (GM-CSF) for treatment of patients ≥1-yr with refractory/relapsed (R/R) HR-NB in the bone or BM with partial response, minor response, or stable disease to prior therapy. Curie Score (CS) is an important tool for assessing extent of disease and treatment response. The reduction in CS by baseline disease status, i.e., refractory or relapsed, from Trial 201 pre-specified interim analysis (data cut-off 31-dec-2021) is reported. Methods: Ongoing Trial 201 (phase II, NCT03363373) evaluates naxitamab+GM-CSF in patients with R/R HR-NB with residual disease limited to bone/BM. Soft tissue and actively progressing disease were addressed prior to enrollment. Naxitamab was administered (intravenously) at 3mg/kg/day over 30-60 min on Days 1/3/5 with GM-CSF (subcutaneous) on Days -4 to 5 at 4-week cycles. 123I-MIBG scans were used to assess CS and treatment response according to INRC criteria per independent review. Results: Interim analysis included 52 (efficacy group) and 74 (safety) patients. The primary endpoint achieved an overall response rate (ORR) of 50% [95% CI: 35.8- 64.2] with complete response rate (CR) of 38%. A summary of changes in overall CS by disease status is reported in the table. Median change in CS from baseline to end of treatment (EOT) was −1 across refractory and relapsed subgroups and ranged from −18 to 18. Baseline CS (≤ 2 vs. ≥3) did not affect the safety profile. The most common adverse events were pain, hypotension, urticaria, and bronchospasm. The frequency of Grade 3 or higher and serious related adverse events was lower for patients with refractory vs. relapsed disease, i.e. lower rates of severe hypotension (51% vs. 68%), increased ALT (0% vs. 14%), and hypoxia (3% vs. 16%). Conclusions: Clinically meaningful reductions in CS were seen in patients regardless of baseline disease status (relapsed or refractory HR-NB). Baseline CS did not affect the safety profile. Refractory patients had a lower frequency of severe and serious related adverse events.. Clinical trial information: NCT03363373 . [Table: see text]
Quality of cancer family history taking in pediatric solid tumor patients.
Authors: Hu Benjamin , Kirkey Danielle , McGuinness Molly , Wakeling Adrienne , Kreimer Sara R. , Crane Jacquelyn , Rangaswami Arun A. , Spunt Sheri L. 
Published: June 2023

10045 Background: Approximately 10% of childhood solid tumors occur in individuals with a cancer genetic predisposition. Identifying cancer predisposition permits interventions for prevention and early detection of future cancers in the child and their affected family members and may have other important medical care implications. The American Society of Clinical Oncology (ASCO) guidelines recommend reviewing family history (FHx) to identify high-risk patients who should be offered genetic testing. To our knowledge, adherence to ASCO guidelines by pediatric oncology providers (POPs) has not been studied. Methods: Retrospective chart review of solid tumor patients <18 years of age referred for genetic counseling 1/1/2017-1/31/2019. POP and genetic counselor (GC) FHx documentation was assessed for adherence with the ASCO minimum quality metrics: 2 generation pedigree, patient ethnicity, cancer genetic testing results in relatives (GTRR), and cancer type, age at diagnosis, and lineage (maternal/paternal) for each relative with cancer (RWC). Comparisons of FHx quality between POPs and GCs were evaluated with 1-sided t-tests. Ethnicity was considered assessed if both maternal and paternal ethnicities were documented. GTRR was considered assessed if the results of all relatives who had undergone genetic testing were noted. Cancer type, age at diagnosis, and lineage were considered assessed if they were checked for all RWCs. Whether or not the child underwent genetic testing and their testing results were also documented. Results: Of 129 eligible patients, 102 underwent germline genetic testing. Twelve (12%) had pathogenic alterations in cancer predisposition genes. The POP failed to document FHx in 20 patients (16%), including 2 with pathogenic germline alterations. The POP missed first/second degree RWCs in 32 of 88 patients with RWCs (36%). GCs achieved >99% on each of the 6 ASCO quality metrics, whereas POPs performed significantly more poorly (Table). In patients with RWCs, GCs achieved all 6 metrics in more cases than POPs (99% vs. 3%, p<0.001). Conclusions: POPs performed significantly worse than GCs in documenting family history compliant with ASCO minimum family history guidelines, raising concern for missed genetic cancer predisposition syndrome diagnoses in those not referred to a GC. Routine referral of pediatric solid tumor patients to a GC for family history review and interventions to improve the quality of family history taking by POPs may improve germline cancer predisposition detection, improving care of both patients and their affected family members. [Table: see text]
Adherence to surveillance guidelines in survivors of hodgkin lymphoma: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Shoag Jamie Michelle , Chen Yan , Yasui Yutaka , Ness Kirsten K. , Leisenring Wendy M. , Neglia Joseph Philip , Hudson Melissa M. , Oeffinger Kevin C. , Armstrong Gregory T. , Henderson Tara O. , Nathan Paul C. 
Published: June 2023

10047 Background: Pediatric Hodgkin lymphoma (HL) is a highly curable disease. However, survivors are at high risk for long-term complications of therapy. The impact of sociodemographic and clinical factors on adherence to late effects surveillance guidelines is unknown. Methods: The CCSS is a retrospective cohort with prospective follow-up of survivors diagnosed from 1970-1999. HL survivors enrolled in CCSS who responded to a 2017 questionnaire were included. We assessed adherence to the Children’s Oncology Group surveillance guidelines for cardiomyopathy, breast cancer, colorectal cancer, and skin cancer. Multivariate logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals (aOR [95% CI]) for sociodemographic and clinical risk factors associated with adherence. Estimates were adjusted for area deprivation index (ADI); chronic health conditions; recent (≤2 years) routine check-up, cancer center or survivorship clinic visit; and possession of a survivorship care plan (SCP). Results: 1,380 HL survivors (45.6% male; median age 43.6 years, range 21.6-65.9 years) responded, of whom 55.5% were at elevated risk for cardiac dysfunction, 71.0% for breast cancer, 83.5% for skin cancer, and 39.4% for colorectal cancer. Of those at elevated risk, 42.7%, 19.9%, 31.3% and 48.9% were adherent to the guidelines for cardiac, breast, skin, and colorectal screening, respectively. Predictors of adherence to cardiac dysfunction guidelines were male sex (aOR 1.7 [1.1-2.6]), having children (aOR 1.6 [1.1-2.4]), recent routine checkup (aOR 4.0 [1.3-13.1]), recent visit to a cancer center or survivorship clinic (aOR 6.2 [3.9-10.0]), and possession of a SCP (aOR 3.1 [1.9-5.0]). Adherence to breast cancer guidelines was higher in those who were unmarried (aOR 2.1 [1.0-4.1]), had a recent visit to a cancer center or survivorship clinic (aOR 3.7 [2.0-7.0]), and possessed a SCP (aOR 3.5 [1.5-8.3]). Adherence to skin cancer guidelines was higher in those > 14 years at diagnosis (aOR 1.8 [1.3-2.4]), living in a low deprivation area (ADI 1-24.9) compared to a high deprivation area (ADI 75-100) (aOR 3.4 [1.9-5.9]), employed (aOR 1.8 [1.1-2.9]), > 30 years from diagnosis (aOR 2.4 [1.6-3.6]), with a recent routine check-up (aOR 3.6 [1.1-12.5]), and recent cancer care (aOR 2.4 [1.6-3.5]). Adherence to colorectal cancer guidelines was higher in those with grade 3-4 chronic health conditions (aOR 1.9 [1.1-3.3]). Conclusions: Less than 50% of HL survivors are adherent to screening guidelines. Sociodemographic risk factors are significant predictors of non-adherence, particularly to skin cancer screening guidelines. This threatens to potentiate outcome disparities among HL survivors.