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Purpose: In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome., Methods: Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4)., Results: Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001)., Conclusion: After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Osteonecrosis (ON) is a serious complication of childhood acute lymphoblastic leukemia. We determined the prevalence of osteonecrotic lesions in our patient population by a one-time multisite magnetic resonance imaging (MRI) more than 1 year following leukemia therapy. MRI findings were evaluated in relationship to clinical factors (including longitudinal changes in bone mineral density [BMD]). Eighty-six children enrolled in the Steroid Associated Osteoporosis in the Pediatric Population (STOPP) study were evaluated for ON at 3.1 ± 1.3 years following therapy. Thirty children had a total of 150 confirmed ON lesions (35%). Lumbar spine (LS) BMD Z-scores (mean ± SD) were low at diagnosis and similar between patients with and without ON (-1.09 ± 1.53 versus -1.27 ± 1.25, p = 0.549). LS BMD Z-scores declined from baseline to 12 months in children with ON (-0.31 ± 1.02) but not in those without (0.13 ± 0.82, p = 0.035); the hip BMD Z-scores from baseline to 24 months declined in both groups, but to a greater extent in those with ON (-1.77 ± 1.22) compared to those without (-1.03 ± 1.07, p = 0.045). At the time of the MRI, mean total hip and total body (TB) BMD Z-scores were lower in children with ON (hip -0.98 ± 0.95 versus -0.28 ± 1.06, p = 0.010; TB -1.36 ± 1.10 versus -0.48 ± 1.50, p = 0.018). Pain occurred in 11/30 (37%) with ON versus 20/56 (36%) without, p = 0.841. In multivariable models, older age at diagnosis (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.15-2.13; p = 0.004), and hip BMD Z-score at MRI (OR 2.23; 95% CI, 1.02-4.87; p = 0.046) were independently associated with ON. Overall, one-third of children demonstrated ON after leukemia therapy. Those with ON had greater reductions in spine and hip BMD Z-scores in the first 1 and 2 years of therapy, respectively. Older age and lower hip BMD Z-scores at MRI were significantly associated with prevalent, off-therapy ON. These data assist in identifying children at risk of ON. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Mercaptopurine is a cornerstone of maintenance chemotherapy in childhood acute lymphoblastic leukemia (ALL). Its cytotoxic effects are mediated by 6-thioguanine nucleotides (TGNs) incorporation into lymphocyte DNA. Thiopurine methyltransferase (TPMT) inactivates mercaptopurine, and deficiency resulting from genetic variants increases TGN exposure and hematopoietic toxicity. Although mercaptopurine-dose reduction reduces toxicity risk without compromising relapse rate in patients with TPMT deficiency, dosing recommendations for those with moderately reduced activity (intermediate metabolizer (IM)) are less clear and their clinical impacts have yet to be established. This cohort study assessed the effect of TPMT IM status on mercaptopurine-associated toxicity and TGN blood exposure in pediatric patients with ALL initiated on standard dose mercaptopurine. Of 88 patients studied (mean age 4.8 years), 10 (11.4%) were TPMT IM, and all had undergone ≥ 3 cycles of maintenance therapy (80% completed). A larger proportion of TPMT IM than normal metabolizers (NM) had febrile neutropenia (FN) during the first two cycles of maintenance, reaching significance in the second cycle (57% vs. 15%, respectively; odds ratio = 7.33, P < 0.05). Compared to NM, FN events occurred more frequently and with prolonged duration in IM in cycles 1 and 2 (adjusted P < 0.05). IM had a 2.46-fold increased hazard ratio for FN, and about twofold higher TGN level than NM (P < 0.05). Myelotoxicity was more common in IM than NM (86% vs. 42%, respectively) during cycle 2 (odds ratio = 8.2, P < 0.05). TPMT IM initiated at a standard mercaptopurine dose are at greater risk for FN during early cycles of maintenance therapy, thus our findings support genotype-guided dose adjustment to reduce toxicity., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers , approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS ( n = 396) with variant ( n = 374) or wildtype TP53 ( n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1 , ETV6 , and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633-0.810)., Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53 . More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals., Patients and Methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation., Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years., Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD., Competing Interests: Hagit N. BarisConsulting or Advisory Role: Sanofi, Igentify LtdSpeakers' Bureau: Sanofi, Takeda, Pfizer Donald BaselHonoraria: BioMarinConsulting or Advisory Role: iQvia Deborah T. BlumenthalConsulting or Advisory Role: AstraZeneca, Novocure, Takeda Miriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmune Sara RhodeHonoraria: Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, Expenses: Myriad Genetics Roula FarahHonoraria: Novo NordiskConsulting or Advisory Role: Novo Nordisk William D. FoulkesResearch Funding: AstraZeneca David GassEmployment: X4 PharmaceuticalsHonoraria: X4 PharmaceuticalsSpeakers' Bureau: Precisionscientia Heather HampelStock and Other Ownership Interests: Genome MedicalConsulting or Advisory Role: InVitae, Genome Medical, Promega, 23andMe Jordan R. HansfordConsulting or Advisory Role: Bayer Craig HarlosTravel, Accommodations, Expenses: GlaxoSmithKline Nobuko HijiyaHonoraria: NovartisConsulting or Advisory Role: Novartis, IncyteResearch Funding: Pfizer Junne KamiharaStock and Other Ownership Interests: PanTher Therapeutics, ROME Therapeutics, TellBioHonoraria: Pfizer, NanoString Technologies, Third Rock Ventures, Foundation MedicineConsulting or Advisory Role: ROME Therapeutics, Third Rock VenturesResearch Funding: PureTech, Ribon Therapeutics, ACD BiotechnePatents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics, Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics, Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc Jeffrey KnipsteinEmployment: PRA Health SciencesConsulting or Advisory Role: Atheneum Alvaro LassalettaStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche, ServierTravel, Accommodations, Expenses: Shire, Gilead Sciences Simon C. LingHonoraria: AbbvieResearch Funding: Abbvie, Gilead Sciences Michael P. LinkConsulting or Advisory Role: Incyte, ADC Therapeutics, Lilly, Steba Biotech, Mesoblast, GlaxoSmithKline, SyndaxResearch Funding: Seattle Genetics, Janssen Oncology Rebecca Loret de MolaEmployment: Huron Consulting Maura MassiminoConsulting or Advisory Role: Oncoscience, Novartis Gary MasonEmployment: Janssen Research & Development, MerckStock and Other Ownership Interests: Johnson & Johnson, MerckTravel, Accommodations, Expenses: Janssen Research & Development Kim E. NicholsStock and Other Ownership Interests: IncyteResearch Funding: Incyte/Novartis, Alpine Immune Sciences Enrico OpocherConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Michael OsbornTravel, Accommodations, Expenses: Amgen, Pfizer Benjamin OshrineHonoraria: Mesoblast Alyssa ReddyConsulting or Advisory Role: Novartis, AstraZeneca Lara ReichmanResearch Funding: Illumina Marc RemkeStock and Other Ownership Interests: Bayer, BB Biotech Ventures, BioNTech AG, InVitae, IDEXX Laboratories Kami Wolfe SchneiderOther Relationship: Journal of Genetic Counseling Duncan StearnsConsulting or Advisory Role: AstraZenecaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/792397 Patrick TombocHonoraria: Unicare Health PlanConsulting or Advisory Role: UniCare Health Plan An Van DammeConsulting or Advisory Role: Octapharm, Pfizer, BayerResearch Funding: Johnson & JohnsonTravel, Accommodations, Expenses: Pfizer, Sobi, Shire, Roche Ira WinerResearch Funding: Oncoceutics David S. ZieglerConsulting or Advisory Role: Bayer, AmgenTravel, Accommodations, Expenses: Bayer Cynthia HawkinsConsulting or Advisory Role: BayerPatents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel David MalkinConsulting or Advisory Role: Bayer Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche, Bristol Myers SquibbNo other potential conflicts of interest were reported.

Objective: To assess the effect of vertebral fractures (VF) and glucocorticoid (GC) exposure on height deficits in children during treatment of acute lymphoblastic leukemia (ALL)., Methods: Children with ALL treated without cranial radiation therapy (n = 160; median age, 5.1 years; 58.1% male) were followed prospectively for 6 years. Spinal deformity index (SDI) was used to quantify VF status., Results: Baseline height z score ± SD was 0.3 ± 1.2. It fell by 0.5 ± 0.4 in the first 6 months for boys and by 0.4 ± 0.4 in the first 12 months for girls (P < 0.01 for both) and then subsequently recovered. The prevalence of VF peaked at 1 year (17.6%). Among those with VF, median SDI rose from 2 [interquartile range (IQR): 1, 7] at baseline to 8 (IQR: 1, 8) at 1 year. A mixed model for repeated measures showed that height z score declined by 0.13 (95% CI: 0.02 to 0.24; P = 0.02) for each 5-unit increase in SDI during the previous 12 months. Every 10 mg/m2 increase in average daily GC dose (prednisone equivalent) in the previous 12 months was associated with a height z score decrement of 0.26 (95% CI: 0.20 to 0.32; P < 0.01)., Conclusions: GC likely plays a major role in the observed height decline during therapy for ALL. Because only a minority of children had VF, fractures could not have contributed significantly to the height deficit in the entire cohort but may have been important among the subset with VF.

Osteoporotic fractures are a significant cause of morbidity in acute lymphoblastic leukemia (ALL). Our objective was to determine the incidence and predictors of fractures and recovery from osteoporosis in pediatric ALL over 6 years following glucocorticoid initiation. Vertebral fractures (VF) and vertebral body reshaping were assessed on annual spine radiographs, low-trauma non-VF were recorded at regular intervals and spine bone mineral density (BMD) was captured every 6 months for 4 years and then annually. A total of 186 children with ALL were enrolled (median age 5.3 years; range, 1.3 to 17.0 years). The cumulative fracture incidence was 32.5% for VF and 23.0% for non-VF; 39.0% of children with VF were asymptomatic. No fractures occurred in the sixth year and 71.3% of incident fractures occurred in the first 2 years. Baseline VF, cumulative glucocorticoid dose, and baseline lumbar spine (LS) BMD Z-score predicted both VF and non-VF. Vertebral body reshaping following VF was incomplete or absent in 22.7% of children. Those with residual vertebral deformity following VF were older compared to those without (median age 8.0 years at baseline [interquartile range {IQR}, 5.5 to 9.4] versus 4.8 years [IQR, 3.6 to 6.2], p = 0.04) and had more severe vertebral collapse (median maximum spinal deformity index 3.5 [IQR, 1.0 to 8.0] versus 0.5 [IQR, 0.0 to 1.0], p = 0.01). VF and low LS BMD Z-score at baseline as well as glucocorticoid exposure predicted incident VF and non-VF. Nearly 25% of children had persistent vertebral deformity following VF, more frequent in older children, and in those with more severe collapse. These results suggest the need for trials addressing interventions in the first 2 years of chemotherapy, targeting older children and children with more severe vertebral collapse, because these children are at greatest risk for incident VF and subsequent residual vertebral deformity. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Background: Children with Down syndrome (DS) have an elevated risk of developing acute leukemia, but little is known about treatment-related neuropsychological morbidity because they are systematically excluded from research in this area. The current study investigated neuropsychological outcomes in children with DS treated for acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) compared to children with DS with no history of cancer., Procedure: Participants were 4 to 17 years of age at testing and were administered measures of intelligence, academic achievement, language, visual-motor and fine-motor skills, and adaptive function. Patients had been off treatment for at least 2 years., Results: The AML group (N = 12) had significantly lower verbal intelligence and receptive vocabulary compared to controls (N = 21). By contrast, the ALL group (N = 14) performed significantly worse than controls on measures of verbal intelligence, spelling, receptive and expressive vocabulary, visual-motor skills, and adaptive function., Conclusions: Patients with DS treated for AML may have specific post-treatment morbidity in verbal function, whereas those treated for ALL have broader morbidity affecting multiple neuropsychological domains and overall adaptive function. We hypothesize that the broader impairment profile of ALL survivors may be related to a combination of the longer duration of central nervous system-directed treatment for ALL compared to AML and the concomitant limited access to intervention opportunities during active treatment., (© 2014 Wiley Periodicals, Inc.)

Purpose: Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported., Patient and Methods: We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semiquantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain, and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures., Results: Of the 155 children, 25 (16%; 95% CI, 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen (52%) of the 25 children with incident vertebral fractures also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI, 2.3 to 23.1; P = .001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI, 1.2 to 2.7; P = .006)., Conclusion: Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.

Vertebral compression is a serious complication of childhood acute lymphoblastic leukemia (ALL). The prevalence and pattern of vertebral fractures, as well as their relationship to BMD and other clinical indices, have not been systematically studied. We evaluated spine health in 186 newly diagnosed children (median age, 5.3 yr; 108 boys) with ALL (precursor B cell: N = 167; T cell: N = 19) who were enrolled in a national bone health research program. Patients were assessed within 30 days of diagnosis by lateral thoraco-lumbar spine radiograph, bone age (also used for metacarpal morphometry), and BMD. Vertebral morphometry was carried out by the Genant semiquantitative method. Twenty-nine patients (16%) had a total of 75 grade 1 or higher prevalent vertebral compression fractures (53 thoracic, 71%; 22 lumbar). Grade 1 fractures as the worst grade were present in 14 children (48%), 9 patients (31%) had grade 2 fractures, and 6 children (21%) had grade 3 fractures. The distribution of spine fracture was bimodal, with most occurring in the midthoracic and thoraco-lumbar regions. Children with grade 1 or higher vertebral compression had reduced lumbar spine (LS) areal BMD Z-scores compared with those without (mean +/- SD, -2.1 +/- 1.5 versus -1.1 +/- 1.2; p < 0.001). LS BMD Z-score, second metacarpal percent cortical area Z-score, and back pain were associated with increased odds for fracture. For every 1 SD reduction in LS BMD Z-score, the odds for fracture increased by 80% (95% CI: 10-193%); the presence of back pain had an OR of 4.7 (95% CI: 1.5-14.5). These results show that vertebral compression is an under-recognized complication of newly diagnosed ALL. Whether the fractures will resolve through bone growth during or after leukemia chemotherapy remains to be determined.

Introduction: The purpose of this review was to analyze outcomes for pediatric patients treated for more common (non-low grade glioma) primary central nervous system (CNS) tumors at a Regional (tertiary) Cancer Center. Comparison to reported results from other regional centres and results from the contemporary literature were made., Material and Methods: The records of pediatric patients treated with radiotherapy at the London Regional Cancer Center (LRCC) for more common (non-low grade glioma) primary CNS tumors between 1980 and 2001 were reviewed. Details regarding tumor presentation, treatment and outcome were analyzed., Results: Eighty-eight patients were eligible for the review. Twenty-nine patients with malignant glioma, 37 patients with medulloblastoma or primitive neuroectodermal tumor (PNET), 15 patients with brainstem glioma, 4 with ependymoma and 3 with germ cell tumors were treated during this time period. Average follow-up for the group was 5 years (range 4 months to 19 years). Five-year overall, progression free and cause specific survival were 45, 42 and 50%, respectively. For patients with malignant glioma median progression free and overall survival was 20 and 29 months. For patients with brainstem glioma median progression free and overall survival was 9 and 13 months. For medulloblastoma, 5-year progression free, and overall survival was 60 and 59%., Conclusions: RESULTS of this retrospective review of pediatric patients treated at a regional cancer center for primary CNS tumors (other than low grade glioma) were comparable to contemporary results reported by other Canadian centers and North American co-operative group trials.