The clinical significance of magnetic resonance imaging (MRI) changes after radiation therapy (RT) in children with ependymoma is not well defined. We compared imaging changes following proton beam ...radiation therapy (PBRT) to those after photon-based intensity modulated RT (IMRT).
Seventy-two patients with nonmetastatic intracranial ependymoma who received postoperative RT (37 PBRT, 35 IMRT) were analyzed retrospectively. MRI images were reviewed by 2 neuroradiologists.
Sixteen PBRT patients (43%) developed postradiation MRI changes at 3.8 months (median) with resolution by 6.1 months. Six IMRT patients (17%) developed changes at 5.3 months (median) with 8.3 months to resolution. Mean age at radiation was 4.4 and 6.9 years for PBRT and IMRT, respectively (P = .06). Age at diagnosis (>3 years) and time of radiation (≥3 years) was associated with fewer imaging changes on univariate analysis (odds ratio OR: 0.35, P = .048; OR: 0.36, P = .05). PBRT (compared to IMRT) was associated with more frequent imaging changes, both on univariate (OR: 3.68, P = .019) and multivariate (OR: 3.89, P = .024) analyses. Seven (3 IMRT, 4 PBRT) of 22 patients with changes had symptoms requiring intervention. Most patients were treated with steroids; some PBRT patients also received bevacizumab and hyperbaric oxygen therapy. None of the IMRT patients had lasting deficits, but 2 patients died from recurrent disease. Three PBRT patients had persistent neurological deficits, and 1 child died secondarily to complications from radiation necrosis.
Postradiation MRI changes are more common with PBRT and in patients less than 3 years of age at diagnosis and treatment. It is difficult to predict causes for development of imaging changes that progress to clinical significance. These changes are usually self-limiting, but some require medical intervention, especially those involving the brainstem.
Background
An objective of the Children's Oncology Group AREN0534 Study was to improve the survival of patients with bilateral Wilms tumors (BWT) by using preoperative chemotherapy of limited ...duration and tailoring postoperative therapy based on histopathologic response. The authors report outcomes based on postoperative histopathologic responses.
Methods
Patients with BWT received treatment with vincristine, dactinomycin, and doxorubicin for 6 or 12 weeks followed by surgery. Postoperative therapy was prescribed based on the highest risk tumor according to the International Society of Pediatric Oncology classification and the Children's Oncology Group staging system.
Results
Analyses were performed on data from 180 evaluable children. The 4‐year event‐free survival (EFS) and overall survival (OS) rates were 81% (95% CI, 74%‐87%) and 95% (95% CI, 91%‐99%), respectively. Seven patients who had completely necrotic tumors had a 4‐year EFS rate of 100%. Of 118 patients who had tumors with intermediate‐risk histopathology, the 4‐year EFS and OS rates were 82% (95% CI, 74%‐90%) and 97% (95% CI, 94%‐100%), respectively. Fourteen patients who had blastemal‐type tumors had 4‐year EFS and OS rates of 79% (95% CI, 56%‐100%) and 93% (95% CI, 79%‐100%), respectively. Eighteen patients who had diffuse anaplasia had 4‐year EFS and OS rates of 61% (95% CI, 35%‐88%) and 72% (95% CI, 47%‐97%), respectively; and the 4‐year EFS and OS rates of 7 patients who had focal anaplasia were 71% (95% CI, 38%‐100%) and 100%, respectively. There was no difference in the outcomes of patients who had different histopathologic subtypes within the intermediate‐risk group (P = .54).
Conclusions
A risk‐adapted treatment approach for BWT results in excellent outcomes. This approach was not successful in improving the outcome of patients who had diffuse anaplasia.
A risk‐adapted treatment approach for bilateral Wilms tumors resulted in excellent outcomes. Patients who had blastemal‐predominant histopathology appeared to have an improved outcome.
Abstract
Background
Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to ...evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI.
Methods
Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10−5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10−8) in a meta-analysis across ancestry groups.
Results
Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at a median age of 8.3 years. Overall, 1150 neurocognitive evaluations were obtained (median = 5, range: 2–10 per participant). One of the five loci previously associated with cognitive outcomes in pediatric CNS tumors survivors demonstrated significant time-dependent IQ declines (PPARA rs6008197, P = .004). Two variants associated with IQ in the general population were associated with declines in IQ after Bonferroni correction (rs9348721, P = 1.7 × 10−5; rs31771, P = 7.8 × 10−4). In genome-wide analyses, we identified novel loci associated with accelerated declines in IQ (rs116595313, meta-P = 9.4 × 10−9), WM (rs17774009, meta-P = 4.2 × 10−9), and PS (rs77467524, meta-P = 1.5 × 10−8; rs17630683, meta-P = 2.0 × 10−8; rs73249323, meta-P = 3.1 × 10−8).
Conclusions
Inherited genetic variants involved in baseline cognitive functioning and novel susceptibility loci jointly influence the degree of treatment-associated cognitive decline in pediatric CNS tumor survivors.
The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time "liquid biopsy" for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. ...We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.
Purpose
Cerebral edema from brain tumors can cause neurological impairment. Steroids treat edema but with possible adverse effects. We surveyed providers regarding steroid use in newly diagnosed ...patients with brain tumors to determine if practices are standard or markedly variable.
Methods
An anonymous voluntary online survey was sent to members of neuro-oncology consortiums. Four clinical scenarios were provided and questions regarding initiation of steroids, type, dose, formulation, and duration were asked. Demographic information was collected.
Results
369 providers received the survey, 76 responded (20.6% response rate). The proportion of providers who would start steroids significantly differed among scenarios (scenario 1 vs 2, p < 0.001; 2 vs 3, p < 0.001; 1 vs 3, p < 0.001). 75 (98.7%) providers would start steroids for vasogenic edema (scenario 1) and 55 (72.4%) for obstructive hydrocephalus (scenario 2). 16 (21.1%) would start steroids for vasogenic edema but not obstructive hydrocephalus. The odds of choosing to start steroids in patients with obstructive hydrocephalus were 7.59 times more (95% CI: 2.29, 25.13) if providers felt symptoms would improve within 24 h. All would use dexamethasone. A significant difference was seen between the proportion of providers who would give a loading dose if vasogenic edema with neurological deficits were noted versus vasogenic edema alone (57.9% vs 43.4%; p = 0.002).
Conclusions
These results suggest that providers recommend dexamethasone for patients with vasogenic edema and obstructive hydrocephalus. Variability remains with dosing schedule. Further studies are needed to identify the most appropriate use of steroids for newly diagnosed CNS tumor patients with the goal to create steroid management guidelines.
Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable ...molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs (CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and potential booster DMRs (PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies.
Background
Patients with chiasmatic‐hypothalamic low‐grade glioma (CHLGG) have frequent MRIs with gadolinium‐based contrast agents (GBCA) for disease monitoring. Cumulative gadolinium deposition in ...the brains of children is a potential concern. The purpose of this study is to evaluate whether MRI with GBCA is necessary for determining radiographic tumor progression in children with CHLGG.
Methods
Children who were treated for progressive CHLGG from 2005 to 2019 at Texas Children's Cancer Center were identified. Pre‐ and post‐contrast MRI sequences were separately reviewed by one neuroradiologist who was blinded to the clinical course. Three dimensional measurements and tumor characteristics were evaluated. Radiographic progression was defined as a 25% increase in size (product of two largest dimensions) compared with baseline or best response after initiation of therapy.
Results
A total of 28 patients with progressive CHLGG were identified with a total of 683 MRIs with GBCA reviewed (mean 24 MRIs/patient; range, 11‐43 MRIs). Radiographic progression was observed 92 times, 91 (99%) on noncontrast and 90 (98%) on contrast imaging. Sixty‐seven progressions necessitating management changes were identified in all (100%) noncontrast sequences and 66 (99%) contrast sequences. Tumor growth > 2 mm in any dimension was identified in 184/187 (98%) noncontrast and 181/187 (97%) with contrast imaging. Metastatic tumors were better visualized on contrast imaging in 4/7 (57%).
Conclusion
MRI without GBCA effectively identifies patients with progressive disease. When imaging children with CHLGG, eliminating GBCA should be considered unless monitoring patients with metastatic disease.
Pseudoprogression (PsP) is a recognized phenomenon after radiotherapy (RT) for high-grade glioma but is poorly characterized for low-grade glioma (LGG). We sought to characterize PsP for pediatric ...LGG patients treated with RT, with particular focus on the role of RT modality using photon-based intensity-modulated RT (IMRT) or proton beam therapy (PBT).
Serial MRI scans from 83 pediatric LGG patients managed at 2 institutions between 1998 and 2017 were evaluated. PsP was scored when a progressive lesion subsequently decreased or stabilized for at least a year without therapy.
Thirty-two patients (39%) were treated with IMRT, and 51 (61%) were treated with PBT. Median RT dose for the cohort was 50.4 Gy(RBE) (range, 45-59.4 GyRBE). PsP was identified in 31 patients (37%), including 8/32 IMRT patients (25%) and 23/51 PBT patients (45%). PBT patients were significantly more likely to have post-RT enlargement (hazard ratio HR 2.15, 95% CI: 1.06-4.38, P = 0.048). RT dose >50.4 Gy(RBE) similarly predicted higher rates of PsP (HR 2.61, 95% CI: 1.20-5.68, P = 0.016). Multivariable analysis confirmed the independent effects of RT modality (P = 0.03) and RT dose (P = 0.01) on PsP incidence. Local progression occurred in 10 patients: 7 IMRT patients (22%) and 3 PBT patients (6%), with a trend toward improved local control for PBT patients (HR 0.34, 95% CI: 0.10-1.18, P = 0.099).
These data highlight substantial rates of PsP among pediatric LGG patients, particularly those treated with PBT. PsP should be considered when assessing response to RT in LGG patients within the first year after RT.
Background
As treatment modalities for medulloblastoma have developed and overall survival (OS) has improved, there are relatively limited data on the impact of long‐term effects such as risk of ...second primary tumors (SPT). To address the knowledge gap, we analyzed factors associated with the risk of SPT and OS by treatment modality for medulloblastoma.
Methods
We queried the Surveillance, Epidemiology, and End Results (SEER)‐18 database for patients diagnosed with medulloblastoma in 1973‐2014. Patients were then grouped by age, gender, race, geographic region, histology, adjuvant treatment (no radiation RT and no chemotherapy CT, RT and CT, RT alone, or CT alone), era of diagnosis (1973‐1994 or 1995‐2014), and survival time. Cumulative incidence, factors associated with SPT and OS were analyzed.
Results
Of 2271 patients, 146 developed SPT, of which 42 were benign. The incidence of SPT was 3.1% and 4.9% at 10 and 15 years, respectively. The incidence of SPT was 3.1% with RT + CT versus 3.7% with RT alone at 10 years. The most common site for an SPT was the central nervous system. Female gender (P = 0.01) and longer OS of ≥21 years (P < 0.01) were associated with higher risk of SPT. RT + CT led to better OS than RT only (66.1% and 61.4% vs 55.6% and 49.7% at 10 and 15 years) (P < 0.01).
Conclusions
Medulloblastoma patients have a relatively low risk of SPT at 10 years with treatment. Use of RT + CT led to better OS with no statistical difference in SPT compared with the RT alone.
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