Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; ...however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.
The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3–21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549–BRAF fusion or the BRAFV600E Val600Glu mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.
Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% 95% CI 18–57) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72–45·59). In stratum 3, ten (40% 21–61) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14–51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five 10%) and maculopapular rash (five 10%). No treatment-realted deaths were reported.
Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.
National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
Abstract
Background
Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for ...alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes.
Methods
We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses.
Results
Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash.
Conclusions
Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.
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
There is great interest in positron emission tomography (PET)/magnetic resonance (MR) as a clinical tool due to its capacity to provide diverse diagnostic information in a single exam.
...Objective
The goal of this exam is to compare the diagnostic accuracy of PET/MR-acquired F-182-fluoro-2-deoxyglucose (FDG) brain exams to that of PET/CT with respect to identifying seizure foci in children with localization-related epilepsy.
Materials and methods
Institutional Review Board approval and informed consent were obtained for this Health Insurance Portability and Accountability Act-compliant, prospective study. All patients referred for clinical FDG-PET/CT exams of the brain at our institution for a diagnosis of localization-related epilepsy were prospectively recruited to undergo an additional FDG-PET acquisition on a tandem PET/MR system. Attenuation-corrected FDG images acquired at PET/MR and PET/CT were interpreted independently by five expert readers. Readers were blinded to the scanner used for acquisition and attenuation correction as well as all other clinical and imaging data. A Likert scale scoring system (1-5) was used to assess image quality. The locale of seizure origin determined at multidisciplinary epilepsy surgery work rounds was considered the reference standard. Non-inferiority testing for paired data was used to compare the diagnostic accuracy of PET/MR to that of PET/CT.
Results
The final study population comprised 35 patients referred for a diagnosis of localization-related epilepsy (age range: 2-19 years; median: 11 years; 21 males, 14 females). Image quality did not differ significantly between the two modalities. The accuracy of PET/MR was not inferior to that of PET/CT for localization of a seizure focus (
P
=0.017).
Conclusion
The diagnostic accuracy of FDG-PET images acquired on a PET/MR scanner and generated using MR-based attenuation correction was not inferior to that of PET images processed by traditional CT-based correction.
A standardized imaging protocol for pediatric oncology patients is essential for accurate and efficient imaging, while simultaneously promoting collaborative understanding of pathologies and ...radiologic assessment of treatment response. The objective of this article is to provide standardized pediatric imaging guidelines and parameters for evaluation of tumors of the pediatric orbit, calvarium, skull base, and temporal bone. This article was drafted based on current scientific literature as well as consensus opinions of imaging experts in collaboration with the Children's Oncology Group Diagnostic Imaging Committee, Society of Pediatric Radiology Oncology Committee, and American Society of Pediatric Neuroradiology.
The purpose of this study is to determine outcomes of a nonoperative treatment service for hip and knee osteoarthritis (OA), the “Joint Clinic,” at minimum 5-year follow-up, and investigate factors ...that may influence progression to joint replacement surgery.
This is an observational cohort study of 337 patients with hip (n = 151, 45%) or knee OA (n = 186, 55%) seen at the Joint Clinic, at 5-7 years of follow-up. Kaplan-Meier survival curves were used to determine survivorship of the affected joint and Cox regression used to determine factors associated with time to surgery.
At mean 6-year follow up, 188 (56%) patients had undergone or were awaiting total joint arthroplasty, 127 (38%) were still being managed nonoperatively, and 22 (7%) had died without having surgery. Patients with hip OA were more likely to have required surgery (111/151, 74%) than patients with knee OA (77/186, 41%) (chi-square = 33.6, P < .001). The 7-year surgery-free survival for hip OA was 23.7% and knee OA 55.9% (P < .001). Factors associated with increased likelihood of surgery were joint affected (hip, hazard ratio HR 2.80), Kellgren-Lawrence (KL) grade (KL 3, HR 2.02; KL 4, 4.79), and Oxford Hip/Knee Score (HR 1.34 for each 5 points worse at baseline).
More than 50% of the patients referred to secondary care with mild-moderate knee OA may not need surgery at 7 years. Patients with hip OA and those with severe radiographic changes are more likely to require surgery and should not be delayed if there is not an adequate response to conservative measures.
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.
Purpose
MRI methods that have reduced sensitivity to motion are attractive in pediatric applications. In spine imaging, physiologic motion such as respiration and cerebrospinal fluid pulsation can ...hamper diagnostic image quality. We compare a 3D T1-weighted non-Cartesian radial acquisition with a conventional Cartesian 2D turbo-spin-echo (TSE) acquisition in axial post-contrast spine imaging at 3T.
Methods
Thirty-two patients (mean age 12.2 ± 5.3 years) scheduled for routine clinical spine exams with contrast were enrolled. Three pediatric neuroradiologists compared the two sequences and assessed the presence of motion, the conspicuity of nerve roots, and whether one of the sequences was preferred in visualizing pathology using Likert scales.
Results
The Fleiss’ kappa statistic for inter-rater agreement was 0.29 (95% confidence interval, 0.15–0.43) for the presence of motion, 0.30 (0.21–0.38) for conspicuity, and 0.37 (0.19–0.55) for sequence preference. Radial images were less sensitive to motion than TSE (
p
< 0.01). Motion and consequent artifacts were present in all TSE cases, while it was absent in 51% of the radial cases. In depicting nerve roots, radial images were superior in the cervical (
p
< 0.05), thoracic (
p
< 0.01), and lumbar spines (
p
< 0.01). Lastly, in 28 of the 32 patients who demonstrated contrast-enhancing pathology, radial images were preferred in 51% of the cases, while both sequences were equally preferred in 41% of the cases.
Conclusion
We demonstrate the potential utility of radial MRI in post-contrast spine imaging. The free-breathing method is robust in generating diagnostic image quality and is superior in visualizing nerve roots and extramedullary metastases than traditional Cartesian TSE acquisitions.
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