bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and correlates of occupational noise-induced hearing loss among workers in the steel industry
Authors: Elshaer Noha , Meleis Dorria , Mohamed Abdelrahman
Published: June 2023

Background

The steel industry is one of the noisiest industries, which can predispose workers to hearing loss. In Egypt, the demand for steel is increasing due to the construction of new infrastructures as bridges, flyover roads, buildings, and towers; however, little is known about the prevalence of occupational noise-induced hearing loss (NIHL) among steel workers. Understanding the distribution of the affected workers is crucial for planning prevention strategies. This study aimed to estimate the prevalence of occupational NIHL among Egyptian steel workers and identify its correlates.

Methods

This study was conducted at two steel factories in Egypt in November 2021. It involved an initial retrospective review of the factory medical records of the latest periodic medical examination conducted on workers from July to September in the year 2021 representing workers’ health status in that year. Then, a case–control approach analysis was carried out. Eligible workers (n = 606) were enrolled and divided into two groups: noise-exposed workers (n = 396) and unexposed workers (n = 210). Univariate and multivariate regression analyses were performed.

Results

Occupational exposure to hazardous A-weighted equivalent noise level (> 85 dB) was associated with higher hearing thresholds at all frequencies (highest at 4 kHz followed by 6 kHz), particularly in younger workers below the age of 40 years. Nearly 71% of noise-exposed workers had hearing impairment, and 47% had NIHL compared with unexposed workers (45.7% and 11.9%, respectively). The probability of NIHL in noise-exposed workers was 6.55 times higher than that in unexposed workers (OR = 6.55, 95%CI = 4.13, 10.40; p < 0.001). In noise-exposed workers, age and tinnitus were independent predictors of hearing thresholds, while tinnitus was found to be an independent predictor of NIHL after adjusting for age and job duration (OR = 2.06, 95%CI = 1.01, 4.20; p = 0.045).

Conclusion

Almost half of noise-exposed workers had NIHL. Tinnitus was found to be an independent predictor of NIHL. Decreasing noise exposure levels in steel plants is recommended to reduce hearing loss. Future research is required to study the effect of tinnitus on audiometry measurements among workers with NIHL.
A joint InSAR-GNSS workflow for correction and selection of interferograms to estimate high-resolution interseismic deformations
Authors: Liu Hongzhi , Xie Lei , Zhao Guoqiang , Ali Eslam , Xu Wenbin
Published: June 2023

Knowledge of the spatial distribution of interseismic deformations is essential to better understand earthquake cycles. The existing methods for improving the reliability of the obtained deformations often rely on visual inspection and prior model corrections that are time-consuming, labor-intensive, and do not consider the spatial distribution of interseismic deformations. Interferometric Synthetic Aperture Radar (InSAR) data provides wide-scale coverage for interseismic deformation monitoring over a wide area. However, the interseismic signal featured as millimeter-scale and long-wave deformations is often contaminated with noise. In the present study, a new workflow to correct the interferometric phase and quantitatively select interferograms is proposed to improve the accuracy of interseismic deformation measurements. Initially, the Generic Atmospheric Correction Online Service (GACOS), Intermittent Code for Atmospheric Noise Depression through Iterative Stacking (I-CANDIS), and plate model are combined to correct the atmospheric screen and long-wave ramp phase. Subsequently, the Pearson’s Correlation Coefficient (PCC) between the interferometric phase and the Global Navigation Satellite System (GNSS) constrained interseismic model as well as the STandard Deviation (STD) of the interferometric phase are introduced as criteria to optimize the selection of interferograms. Finally, the intermittent stacking method is used to generate an average velocity map. A comprehensive test using Sentinel-1 images covering the Haiyuan Fault Zone validate the effectiveness of our workflow in measuring interseismic deformations. This demonstrates that the proposed joint InSAR-GNSS workflow can be extended to study the subtle interseismic deformations of major fault systems in Tibet and worldwide.
Growth hormone therapy response in children with short stature
Authors: Gad Amira Ahmed , Shamma Radwa , Elmonem Mohamed A. , Badawi Nora E. , Fawaz Lubna , Hassan Mona Mamdouh
Published: June 2023

Background

Short stature is one of the main causes of children referral to pediatric endocrinologists. Common etiologies include idiopathic growth hormone deficiency (IGHD), small for gestational age (SGA), and idiopathic short stature (ISS).

Objectives

The aim of this study was to assess and compare the response of children with IGHD, ISS, and SGA to growth hormone (GH) therapy.

Methods

This was a mixed cohort study that included 40 children with short stature (classified into IGHD, ISS, and SGA) following up at Diabetes, Endocrine, and Metabolism Pediatric Unit (DEMPU), Cairo University Children’s Hospital. Ages ranged between 3 and 18 years. Recruited cases were evaluated for their 1-year response to GH therapy. In addition to history taking, physical examination, and anthropometric measurements, serum levels of IGF-1 were assayed at recruitment.

Results

Among the 3 groups, height gain (cm/year) was significantly higher in the IGHD group (6.59 cm/year), followed by the ISS (4.63 cm/year) and SGA groups (4.46 cm/year) (p = 0.039). Using the Bang criterion for first-year responsiveness to GH therapy, most cases (30/40, 75%) were considered poor responders.

Conclusion

There is a male predominance in children seeking medical advice for short stature. Starting GH therapy at an older age was associated with poor response. Children with IGHD respond better to GH therapy than those with ISS and SGA.
The phytochemical screening, total cucurbitacin content, and in vitro anti-breast cancer activity of Leucopaxillus gentianeus mushroom
Authors: Kanani Sonal H. , Pandya Devang J.
Published: June 2023

Background

The popular Leucopaxillus gentianeus mushroom contains very high nutrients and bioactive compounds with good anti-breast cancer activity. The til oil extract seems to be the most active in preparation. This study aims to find the best extract using different solvents for extraction, to measure the total cucurbitacin content and anti-breast cancer activity in vitro of til oil extract of leucopaxillus gentianeus.

Result

The dry mushroom material was extracted using continuous hot extraction with til oil, petroleum ether, ethyl acetate, chloroform, methanol, and water of leucopaxillus gentianeus which were used for phytochemical analysis, HPLC method was used for no of phytochemical and anti-breast cancer activity in vitro. The total cucurbitacin content was found based on the HPTLC method. The anti-breast cancer activity was carried out using progesterone and estrogen activity. The number of pecks found during HPLC it is indicated that the list of phytochemical presents in a different extract, also good yield found with til oil extract was 6.8 gm. Progesterone and estrogen inhibited high with til oil extract and cucurbitacin content was found to be 264.00 ng.

Conclusion

The significance of the biotherapeutic effects increases with the number of bioactive components in the preparation. Leucopaxillus gentianeus til oil extract has high cucurbitacin content and strong anti-breast cancer properties.

Graphical abstract
Benign hepatic tumors in childhood: surgical resection and outcomes
Authors: Younes Alaa , Elgendy Ahmed , Fadel Sayed , Elfandy Habiba , Romeih Marwa , Elwakeel Madeeha , Ahmed Gehad
Published: June 2023

Background

Primary hepatic neoplasms in pediatric age are rare entities. Clinical and survival data in children with benign liver tumors who were treated by surgery are still negligible. We aimed to present a tertiary oncological center experience regarding surgical management and outcomes of pediatric benign hepatic tumors.

Material and methods

A retrospective chart review was performed including all children with benign liver tumors who were surgically managed at our institution from January 2014 to January 2022. Patients’ demographics, presentations, imaging scans, pathological subtypes, operative details, complications that happened, and overall outcomes were discussed.

Results

One-hundred ninety-three children with liver tumors were referred to our center, and 28 of them had benign tumors (14.5%). Ten patients were managed by medical therapy (all were IHH/hemangiomas), and the remaining 18 were treated by surgery. Of the 18 patients; there were 10 females (55.5%), and the median age at diagnosis was 24 months (range: 5–108 months). Palpable abdominal mass was the main symptom in 14 patients (77.8%). Eleven patients (61%) were PRETEXT II, while the remaining 7 (39%) were PRETEXT I. The median tumor size was 10.9 cm (range: 7.2–18 cm). Preoperative biopsy was conducted in 12 patients (66.7%). Seventeen patients had primary resection, while the remaining child with IHH/hemangioma underwent delayed surgery. Twelve cases had segmental resection or sectionectomy, and hemihepatectomy was performed in the remaining six. The resection rate of benign tumors versus all liver resections at our center during the study period was 12% (18/151). There were no intraoperative complications encountered in any patient. Only one patient developed biliary leakage on the 5th postoperative day which was managed conservatively. At a median follow-up time of 40 months, there were no deaths or recurrences among the included patients.

Conclusions

Surgical resection is the principal modality of management for the majority of pediatric benign liver tumors, which constituted 12% of our hepatic resection rate. Complete excision with negative margins can be performed without significant morbidity for such tumors, and it achieves excellent clinical and long-term oncological outcomes.
Isolated anterior mitral valve leaflet cleft repair with minimally invasive cardiac surgery using ORBEYETM
Authors: Hayama Masato , Sumi Mizuki , Amako Mau , Eishi Kiyoyuki , Wada Hideichi
Published: June 2023

The cleft mitral valve leaflet is a common cause of congenital mitral regurgitation and is most often associated with other congenital heart defects, usually endocardial cushion defects. Cases in which cleft mitral valve leaflet is found without an associated defect are called isolated mitral valve clefts. We report a case of mitral valve repair for severe MR due to an isolated cleft with minimally invasive cardiac surgery using ORBEYETM in a 16-year-old male patient. Mitral regurgitation caused due to a defect in the anterior leaflet of the isolated mitral valve was observed on echocardiography. Minimally invasive cardiac surgery was performed using ORBEYETM, a newly developed surgical microscope, and the cleft was closed using interrupted sutures. The postoperative course was uneventful, with minimal mitral regurgitation observed. Therefore, early intervention should be considered for severe mitral regurgitation due to a mitral valve leaflet cleft.
Staged definitive repair for pulmonary atresia and ventricular septal defect 40 years after palliative surgery: a case report
Authors: Ebuoka Noriyoshi , Ando Norihiro , Asai Hidetsugu , Kato Nobuyasu , Tachibana Tsuyoshi , Wakasa Satoru
Published: June 2023

We present a very rare case of pulmonary atresia and ventricular septal defect with staged definitive repair more than 40 years after palliative surgery. The patient, a 43-year-old male, had undergone a Waterston operation at the age of one and had been untreated since then. Two years ago, he underwent an urgent surgery for impending rupture of a huge pulmonary artery aneurysm. Then, after evaluation of cardiac and pulmonary functions, a definitive repair was performed concomitantly with aortic root replacement for the dilated aortic root. He was discharged uneventfully and received ambulatory care 5 years after surgery.
Treatment of focal anaplastic Wilms tumor (FAWT): A report from the Children’s Oncology Group (COG) AREN0321 and AREN03B2 studies.
Authors: Armstrong Amy E. , Daw Najat C. , Renfro Lindsay A. , Geller James I. , Kalapurakal John A. , Khanna Geetika , Paulino Arnold , Perlman Elizabeth J. , Ehrlich Peter F. , Gow Kenneth W. , Warwick Anne B. , Grundy Paul E. , Fernandez Conrad V. , Mullen Elizabeth A. , Dome Jeffrey ,   on behalf of AREN0321 and AREN03B2 Study Committees
Published: June 2023

10005

Background: FAWT represents tumors with circumscribed small areas of anaplastic nuclear changes confined to the kidney within an otherwise favorable histology WT. In National Wilms Tumor Study-5, patients with stage I FAWT treated with vincristine and dactinomycin (VA) without flank radiation had 4-year event-free survival (EFS) and overall survival (OS) of 67.5% and 88.9%, respectively. Patients with stage II-IV FAWT were treated with VA plus doxorubicin and radiation (DD4A). Of the 20 patients with stage II-III FAWT, 4 had a relapse and 3 died. The 4-year EFS and OS for stage IV FAWT/upfront nephrectomy were 61.4% and 71.6%, respectively. The COG AREN0321 study evaluated whether intensifying therapy for stage I and IV FAWT would improve survival of these patients. Methods: Tumor histology and stage were confirmed for all patients by real-time central pathology, surgery, and radiology review on protocol AREN03B2, the COG renal tumor classification, biology, and banking study. Patients then enrolled on AREN0321 with stage I-III FAWT received DD4A and those with stage IV FAWT received vincristine, doxorubicin, cyclophosphamide, carboplatin and etoposide with radiation (UH-1). We analyzed outcomes of patients with FAWT treated on AREN0321 and those enrolled only on AREN03B2 who received the same chemotherapy regimens. Results: A total of 46 patients (25 AREN0321 and 21 AREN03B2) were included in the analyses. Of the 25 AREN0321 patients, 17 (68%) had upfront nephrectomy and all 25 received radiation. Of the 5 AREN0321 patients with stage IV FAWT, 4 had metastasis to lung and 1 to lung and liver. Of the 21 AREN03B2 patients, 19 (90%) had upfront nephrectomy and 17 (81%) reported receiving radiation. The 2 AREN03B2 stage IV patients had lung only metastases. The 4-year EFS and OS are displayed in the table below. No events occurred in stage I-II AREN0321 patients nor in any AREN03B2 patients. Of 10 patients with stage III FAWT on AREN0321, 3 had a relapse. None of the 7 stage IV FAWT patients who received UH-1 had a relapse, but one patient died due to toxicity. Conclusions: Patients with stage I and II FAWT had outstanding survival when treated with DD4A and radiation. Intensification of therapy may be warranted for stage III FAWT and appears to have improved patient survival for stage IV FAWT but with increased risk of toxicity. Strategies to alleviate toxicity of UH-1 therapy have been incorporated into the ongoing COG trial for high-risk patients. Clinical trial information: NCT00335556 . [Table: see text]
Medicaid enrollment changes among U.S. adult survivors of childhood cancer following medicaid expansion: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Ji Xu , Hu Xin , Mertens Ann C. , Leisenring Wendy M. , Nathan Paul C. , Armstrong Gregory T. , Castellino Sharon M. , Kirchhoff Anne C.
Published: June 2023

10011

Background: Little is known about whether Medicaid expansion under the Affordable Care Act (ACA) affected insurance coverage among adult survivors of childhood cancer, a population at high-risk for poor health outcome. We addressed this gap by evaluating the association between ACA Medicaid expansion and Medicaid enrollment among participants in the Childhood Cancer Survivor Study (CCSS). Methods: The CCSS cohort of 5-year survivors of childhood cancer was linked to administrative Medicaid insurance data in 2010-2016. We identified 13,895 adult survivors (aged 18-64 years) diagnosed with cancer under age 21 and between 1970 and 1999. Outcomes included (1) percentage with any Medicaid enrollment by year; and (2) Medicaid-covered days (number of days when a survivor was enrolled in Medicaid) during each year. Multivariable difference-in-differences (DD) models were used to examine outcome changes pre vs. post ACA Medicaid expansion, in expansion- vs. non-expansion states, adjusting for age, sex, race/ethnicity, income, education, and chronic conditions. Multivariable models were conducted overall and then stratified by cancer type, race/ethnicity, income, and education. Results: Medicaid enrollment rates increased more in expansion states (17.6% pre-expansion to 24.1% post-expansion) than non-expansion states (16.4% to 16.9%), leading to a net increase in enrollment of 6.6 percentage points (ppt; 95% CI = 5.5-7.7) in the multivariable DD model. Multivariable DD model showed a net increase of 18.4 days (95% CI = 13.8-23.1) in Medicaid-covered days in expansion states relative to non-expansion states. The expansion-associated increase in Medicaid enrollment rates was greatest among survivors of leukemia (multivariable DD estimate: 8.9 ppt, 95% CI = 6.9-11.0) and non-Hodgkin lymphoma (8.0 ppt, 95% CI = 5.0-10.9). Greater increases in Medicaid enrollment were seen in non-Hispanic Black (13.5 ppt, 95% CI = 8.0-19.1) and Hispanic survivors (15.8 ppt, 95% CI = 10.6-21.0) than non-Hispanic White peers (5.1 ppt; 95% CI = 4.0-6.2); in survivors with < $20K household income (11.7 ppt, 95% CI = 8.9-14.4) compared to those with ≥$60K household income (2.9 ppt, 95% CI = 1.6-4.2); and in survivors with high school or lower education (9.3 ppt, 95% CI = 6.9-11.8) compared to those with a college or higher degree (3.9 ppt, 95% CI = 2.6-5.3). Similar patterns were observed across survivor subgroups when examining Medicaid-covered days. Conclusions: We provide the first evidence on increased Medicaid enrollment and longer coverage duration among adult survivors of childhood cancer following Medicaid expansion, with greater increases seen among survivors of underrepresented racial/ethnic populations, those with low socioeconomic status, and high medical need survivors.
Genomic determinants of outcome in acute lymphoblastic leukemia: A Children’s Oncology Group study.
Authors: Chang Ti-Cheng , Chen Wenan , Elsayed Abdelrahman , Pounds Stanley B. , Shago Mary , Rabin Karen R. , Raetz Elizabeth A. , Devidas Meenakshi , Cheng Cheng , Angiolillo Anne L. , Carroll Andrew J. , Heerema Nyla A , Iacobucci Ilaria , Maloney Kelly W. , Pui Ching-Hon , Ramirez Nilsa C. , Hunger Stephen , Wu Gang , Mullighan Charles Grenfell , Loh Mignon L.
Published: June 2023

10015

Background: While cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, half of relapses arise in those originally classified with standard risk (SR) disease. Methods: We performed genome/transcriptome sequencing of diagnostic and germline samples of children with SR (n=1381) B-ALL or high-risk (HR) B-ALL with favorable cytogenetics ( ETV6: RUNX1 or double trisomy (DT) of chromosomes (chr) 4+10; n=115) to identify predictors of relapse. We used a case-control study to analyze 439 patients who relapsed and 1057 who remained in complete remission for > 5 years. Results: Genomic subtype was associated with relapse. Unbalanced ETV6:RUNX1 translocations were more common than balanced in relapse patients (OR=2.01, CI=1.25-3.20, P=0.002). Conversely, balanced TCF3:PBX1 translocations were more often associated with relapse than unbalanced in TCF3:PBX1 ALL (OR=0.11, CI=0.01-0.50, P=0.003). A striking finding was the high relapse rate in PAX5 altered ALL (57 of 116 cases (49%); OR=3.29, CI=2.16-5.01, P=3.49x10-8). The nature of the heterogeneous PAX5 driver alterations of this subtype influenced relapse risk, with internal PAX5 amplifications and biallelic PAX5 alterations associated with the highest risk. Specific chr gains influenced outcome in hyperdiploid ALL, with gain of chr 10 and disomy of chr 7 associated with favorable outcome (OR=0.27, CI=0.17-0.42, P=8.02x10-10, St Jude Children’s Research Hospital (SJCRH) validation cohort: OR=0.22, CI=0.05-0.80, P=0.009), while disomy of chr 10 and 17 and gain of chr 6 were enriched in patients that relapsed (OR=7.16, CI=2.63-21.51, P=2.19x10-5; SJCRH cohort: OR=21.32, CI=3.62-119.30, P=0.0004). Genomic alterations were also associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6:RUNX1, IKZF1 and CREBBP in hyperdiploid, and FHIT in Ph-like ALL. Conclusions: Genetic subtype, aneuploidy patterns, and secondary genomic alterations influence risk of relapse in children otherwise classified with SR ALL, or HR ALL with favorable genetics. Comprehensive genomic analysis is required for optimal risk stratification and treatment allocation, and particularly to study reduction of therapy in the lowest risk patients. [Table: see text]
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.
Associations between psychosocial and lifestyle factors and biological age acceleration among long-term survivors of childhood cancer: A prospective study from the St. Jude Lifetime Cohort.
Authors: Streck Brennan , Hyun Geehong , Armstrong Gregory T. , Belsky Daniel W , Ehrhardt Matthew J. , Hudson Melissa , Green Paige , Robison Leslie L. , Tonorezos Emily S. , Yasui Yutaka , Wang Zhaoming , Wilson Carmen L , Brinkman Tara M. , Ness Kirsten K. , Guida Jennifer Lyn
Published: June 2023

10049

Background: Survivors of childhood cancers may be at risk for premature, or accelerated, biological age aging, which is associated with cancer treatment exposures. However, life course theory and a growing body of evidence suggest that psychosocial and lifestyle factors may also contribute. The objective of this study was to explore associations between psychosocial and lifestyle factors and biological age acceleration in the St. Jude Lifetime Cohort. Methods: In this cross-sectional study, we applied physiology-based methods (Klemera-Doubal method and Phenotypic Age) and DNA methylation-based epigenetic clocks (Horvath’s, Hannum’s, Levine’s PhenoAge, GrimAge, and DunedinPACE clocks) to compare biological age acceleration, estimated as the residual from regressing biological age on chronological age, among survivors (n = 4,117) and age- and sex-frequency-matched non-cancer community controls (n = 606). We compared psychosocial and lifestyle factors between survivors and controls using t-tests/Wilcoxan rank sums, and chi-square. Multivariable linear regression was used to assess associations of self-reported smoking, alcohol use, physical activity, overweight/obesity, and depressive symptoms with biological age acceleration in survivors, adjusted for age, race/ethnicity, sex, education, and cancer treatment. Results: Childhood cancer survivors at a mean chronological age of 35.1 years (SD 10.2) were biologically older than controls according to KDM-BA, Phenotypic Age, Hannum’s clock, Levine’s PhenoAge clock, and DunedinPACE, with biological age acceleration ranging from 1.7-4.7 years (p < 0.05.) A greater proportion of survivors reported elevated depressive symptoms (10.3% v. 8.7%), current smoking (17.8% v. 12.3%), < 150 minutes of physical activity (47.3% v. 38.2%), and were overweight/obese (66.0% v. 59.9%) compared to controls (p’s < 0.001). In survivors, < 150 minutes of physical activity (B’s (difference in biological age acceleration [years]) = 1.10-2.68), current (B’s = 1.18-5.96) and former smoking (B’s = 2.53-4.29) were consistently associated with higher biological age acceleration across measures (p’s < 0.05). Risky drinking and higher depressive symptoms were associated with higher biological age acceleration, but only for KDM (B = 1.26, p < 0.021) and DunedinPACE measures (B = 0.15, p < 0.001), respectively. Conclusions: Biological aging in childhood cancer survivors is associated with psychosocial and lifestyle factors. Interventions designed to optimize healthy behaviors and mitigate poor emotional health may have potential to prevent or remediate this phenotype in childhood cancer survivors.