BACKGROUND AND PURPOSE: Recent advances in molecular techniques have characterized distinct subtypes of diffuse intrinsic pontine gliomas. Our aim was the identification of MR imaging correlates of these subtypes. MATERIALS AND METHODS: Initial MRIs from subjects with diffuse intrinsic pontine gliomas recruited for a prospective clinical trial before treatment were analyzed. Retrospective imaging analyses included FLAIR/T2 tumor volume, tumor volume enhancing, the presence of cyst and/or necrosis, median, mean, mode, skewness, kurtosis of ADC tumor volume based on FLAIR, and enhancement at baseline. Molecular subgroups based on EGFR and MGMT mutations were established. Histone mutations were also determined (H3F3A, HIST1H3B, HIST1H3C). Univariate Cox proportional hazards regression was used to test the association of imaging predictors with overall and progression-free survival. Wilcoxon rank sum, Kruskal-Wallis, and Fisher exact tests were used to compare imaging measures among groups. RESULTS: Fifty patients had biopsy and MR imaging. The median age at trial registration was 6?years (range, 3.3?17.5?years); 52% were female. On the basis of immunohistochemical results, 48 patients were assigned to 1 of 4 subgroups: 28 in MGMT?/epidermal growth factor receptor (EGFR)?, 14 in MGMT?/EGFR+, 3 in MGMT+/EGFR?, and 3 in MGMT+/EGFR+. Twenty-three patients had histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HIST1H3C. Enhancing tumor volume was near-significantly different across molecular subgroups (P?=?.04), after accounting for the false discovery rate. Tumor volume enhancing, median, mode, skewness, and kurtosis ADC T2-FLAIR/T2 were significantly different (P???.048) between patients with H3F3A and HIST1H3B/C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters are correlated with molecular subgroups and mutations in children with diffuse intrinsic pontine gliomas. Initial MRIs from 50 subjects with diffuse intrinsic pontine gliomas recruited for a prospective clinical trial before treatment were analyzed. Retrospective imaging analyses included FLAIR/T2 tumor volume, tumor volume enhancing, the presence of cyst and/or necrosis, median, mean, mode, skewness, kurtosis of ADC tumor volume based on FLAIR, and enhancement at baseline. Molecular subgroups based on EGFR and MGMT mutations were established. Histone mutations were also determined (H3F3A, HIST1H3B, HIST1H3C). Enhancing tumor volume was near-significantly different across molecular subgroups, after accounting for the false discovery rate. Tumor volume enhancing, median, mode, skewness, and kurtosis ADC T2-FLAIR/T2 were significantly different between patients with H3F3A and HIST1H3B/C mutations.

Purpose: Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. Methods: Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. Results: Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium x phosphorus product (Ca x Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03). Conclusions: Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca x Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

DTI and dynamic contrast-enhanced MR imaging using T1-mapping with flip angles of 2 degrees, 5 degrees, 10 degrees, and 15 degrees, followed by a 0.1-mmol/kg body weight gadolinium-based bolus was performed on 41 patients in addition to standard MR imaging. Permeability data were processed and transfer constant from the blood plasma into the extracellular extravascular space, rate constant from the extracellular extravascular space back into blood plasma, extracellular extravascular volume fraction, and fractional blood plasma volume were calculated from 3D tumor volumes. Apparent diffusion coefficient histogram metrics were calculated. Wilcoxon tests showed a higher transfer constant from blood plasma into extracellular extravascular space and rate constant from extracellular extravascular space back into blood plasma, and lower extracellular extravascular volume fraction in high-grade tumors. The mean ADCs of FLAIR and enhancing tumor volumes were significantly lower in high-grade tumors. The authors conclude that ADC histogram metrics combined with permeability metrics differentiate low- and high-grade pediatric brain tumors with high accuracy. BACKGROUND AND PURPOSE: Accurate tumor grading is essential for treatment planning of pediatric brain tumors. We hypothesized that multiparametric analyses of a combination of permeability metrics and ADC histogram metrics would differentiate high- and low-grade tumors with high accuracy. MATERIALS AND METHODS: DTI and dynamic contrast-enhanced MR imaging using T1-mapping with flip angles of 2 degrees, 5 degrees, 10 degrees, and 15 degrees, followed by a 0.1-mmol/kg body weight gadolinium-based bolus was performed on all patients in addition to standard MR imaging. Permeability data were processed and transfer constant from the blood plasma into the extracellular extravascular space, rate constant from the extracellular extravascular space back into blood plasma, extravascular extracellular volume fraction, and fractional blood plasma volume were calculated from 3D tumor volumes. Apparent diffusion coefficient histogram metrics were calculated for 3 separate tumor volumes derived from T2-FLAIR sequences, T1 contrast-enhanced sequences, and permeability maps, respectively. RESULTS: Results from 41 patients (0.3-16.76 years of age; mean, 6.22 years) with newly diagnosed contrast-enhancing brain tumors (16 low-grade; 25 high-grade) were included in the institutional review board-approved retrospective analysis. Wilcoxon tests showed a higher transfer constant from blood plasma into extracellular extravascular space and rate constant from extracellular extravascular space back into blood plasma, and lower extracellular extravascular volume fraction (P < .001) in high-grade tumors. The mean ADCs of FLAIR and enhancing tumor volumes were significantly lower in high-grade tumors (P < .001). ROC analysis showed that a combination of extravascular volume fraction and mean ADC of FLAIR volume differentiated high- and low-grade tumors with high accuracy (area under receiver operating characteristic curve = 0.918). CONCLUSIONS: ADC histogram metrics combined with permeability metrics differentiate low- and high-grade pediatric brain tumors with high accuracy.

BRAF V600 mutations are present in 15%-20% patients (pts) with pediatric low-grade gliomas (pLGG). Relative to pts with BRAF V600–wild type pLGG, pts with BRAF V600E–mutant pLGG had poor survival and lower objective response rates (ORR) to initial (29%) and 2nd-line (11%) chemotherapy (Lassaletta A, ASCO 2016). There remains a need for improved treatment options for this pLGG subgroup. Dabrafenib is a potent and selective inhibitor of the V600–mutant form of the BRAF kinase. We report the results of the first study of dabrafenib in pediatric pts with BRAF V600–mutant recurrent or progressive LGG. Thirty-two pts aged 2-17 y with BRAF V600–mutant relapsed or refractory LGG were enrolled Dec 2013 to Jul 2015 across 4 dose levels of dabrafenib monotherapy up to and including the recommended phase 2 dose (RP2D; 4.5 mg/kg/day in pts ≥ 12 y, 5.25 mg/kg/day in pts < 12 y, divided into 2 equal doses per day [Kieran MW, ASCO 2015]). The results presented are from all 32 pts with pLGG (15 pts enrolled into the dose-finding and 17 pts treated after determination of the RP2D). Overall, 24 pts were treated at the RP2D. Twenty-two of the 32 pts remained on study as of April 2016. Adverse events were generally similar to those observed in adults, with frequent low-grade pyrexia, vomiting, fatigue, headache and rash. There have been no reports of cutaneous squamous cell carcinoma. The most frequent grade 3 or 4 AE was pneumonia, in 3 pts. 1 pt experienced a significant allergic reaction on day 2 of dosing and again upon rechallenge and was discontinued from study. Independent confirmed overall response by RANO criteria was 2 CRs and 11 PRs in this 2nd-line setting (N = 32, ORR 41% [95% CI, 24%-59%]), with a median duration of response of 11 months (8 responders ongoing). There were an additional 13 pts (41%) with SD of 6 months or greater duration (11 ongoing). Investigator confirmed overall response was 1 CR and 22 PRs (ORR 72% [95% CI, 53%-86%]). Targeted therapy using dabrafenib showed promising activity, with an independently confirmed ORR of 41%, and was well tolerated in this population with recurrent or progressive BRAF V600–mutant pLGG, comparing favorably to historical data.

DIG (Desmoplastic Infantile Ganglioglioma) is a rare intracranial neoplasm classified as WHO grade I tumor under neuronal and mixed neuronal glial tumors (under 2007 World Health Organization brain tumor classification).It is usually considered to have a good prognosis but 40% of the cases require additional medical, radiation and/or further surgical intervention and 15% of infants and children develop leptomeningeal spread or die from DIG.We report a case of DIG presenting at 2 mo of age that showed aggressive behavior, requiring debulking at 2.5 mo age and subsequently at 10 mo age following a tumor recurrence.Chemotherapy following surgery was successful in suppressing the tumor growth for 7.5 yrs.He then presented with malignant transformation into glioblastoma.Successful debulking followed by chemotherapy was given.At 1 yr follow up, the child had moderate neurological deficits but had a subsequent rapid progression and died.Chromosome microarray analysis (CMA) using oligo array performed on the biopsy specimen obtained at 2 mo age did not show any significant abnormality.However, CMA of the glioblastoma was very abnormal showing significant genomic deletions and duplications.Genomic next generation sequencing showed a somatic single nucleotide non-synonymous variant, p.R248Q in Exon 7 of TP53 in the primary DIG and the GBM tumors.The non-synonymous variant in TP53 gene is predicted to be deleterious, altering the structure of the L2/L3 motif of the DNA binding domain tp53 protein.The TP53 gene which is a known primary site of genetic alteration that predisposes to malignant tumors provides a reason for the transformation of DIG to glioblastoma in our case.Therefore, molecular genetic testing is recommended on some DIG tumors which may provide a prognostic biological marker.

Purpose: MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. Experimental Design: We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Results: Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. Conclusion: JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma. Clin Cancer Res; 20(4); 912–25. ©2013 AACR.

Children with relapsed malignant brain tumours have a poor prognosis despite intensive treatment including high-dose chemotherapy with stem cell rescue [1, 2]. Angiogenesis, the formation of new blood vessels, is an important component of normal physiological processes such as wound healing and development. Moreover, tumour growth and metastasis is closely related to formation of new blood vessels [3, 4]. Antiangiogenic therapy inhibits neovascularization, thereby inhibiting tumour progression indirectly [5]. The term metronomic chemotherapy refers to the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and without prolonged drug-free breaks. Beside the antiangiogenic effect, metronomic chemotherapy has been shown to modulate anti-tumoural immunity and has the ability to induce tumour dormancy [6]. The combination of agents used in our metronomic antiangiogenic therapy is based on a four-drug regimen (thalidomide, celecoxib, etoposide and cyclophosphamide) published by Kieran et al. in 2005 [7]. We augmented this regimen with bevacizumab, fenofibrate, and intrathecal therapy with the goal to improve progression-free survival for patients with recurrent or refractory CNS tumours for whom no curative therapy is available. We report on our experience with an antiangiogenic metronomic chemotherapy for paediatric patients with recurrent CNS tumours of different histologies.

Purpose: A phase II study of temsirolimus was conducted in children and adolescents with high-grade glioma, neuroblastoma or rhabdomyosarcoma.Patients and methods: Temsirolimus 75 mg/m(2) was administered once weekly until disease progression or intolerance. Using the Simon 2-stage design, further enrolment in each disease cohort required >= 2 objective responses within the first 12 weeks for the first 12 evaluable patients (those who received >= 3 temsirolimus doses).Results: Fifty-two heavily pretreated patients with relapsed (12%) or refractory (88%) disease, median age 8 years (range 1-21 years), were enroled and treated. One patient with neuroblastoma achieved confirmed partial response within the first 12 weeks; thus, none of the 3 cohorts met the criterion for continued enrolment. Disease stabilisation at week 12 was observed in 7 of 17 patients (41%) with high-grade glioma (5 diffuse pontine gliomas, 1 glioblastoma multiforme and 1 anaplastic astrocytoma), 6 of 19 (32%) with neuroblastoma and 1 of 16 (6%) with rhabdomyosarcoma (partial response confirmed at week 18). In the three cohorts, median duration of stable disease or better was 128, 663 and 75 d, respectively. The most common treatment-related adverse events were thrombocytopaenia, hyperlipidaemia and aesthenia. Pharmacokinetic findings were similar to those observed in adults.Conclusions: Temsirolimus administered weekly at the dose of 75 mg/m(2) did not meet the primary objective efficacy threshold in children with high-grade glioma, neuroblastoma or rhabdomyosarcoma; however, meaningful prolonged stable disease merits further evaluation in combination therapy. (C) 2011 Elsevier Ltd. All rights reserved.