Diffuse midline gliomas (DMG) harbouring H3K27M mutation are paediatric tumours with a dismal outcome. Recently, a new subtype of midline gliomas has been described with similar features to DMG, ...including loss of H3K27 trimethylation, but lacking the canonical H3K27M mutation (H3-WT). Here, we report a cohort of five H3-WT tumours profiled by whole-genome sequencing, RNA sequencing and DNA methylation profiling and combine their analysis with previously published cases. We show that these tumours have recurrent and mutually exclusive mutations in either ACVR1 or EGFR and are characterised by high expression of EZHIP associated to its promoter hypomethylation. Affected patients share a similar poor prognosis as patients with H3K27M DMG. Global molecular analysis of H3-WT and H3K27M DMG reveal distinct transcriptome and methylome profiles including differential methylation of homeobox genes involved in development and cellular differentiation. Patients have distinct clinical features, with a trend demonstrating ACVR1 mutations occurring in H3-WT tumours at an older age. This in-depth exploration of H3-WT tumours further characterises this novel DMG, H3K27-altered sub-group, characterised by a specific immunohistochemistry profile with H3K27me3 loss, wild-type H3K27M and positive EZHIP. It also gives new insights into the possible mechanism and pathway regulation in these tumours, potentially opening new therapeutic avenues for these tumours which have no known effective treatment. This study has been retrospectively registered on clinicaltrial.gov on 8 November 2017 under the registration number NCT03336931 ( https://clinicaltrials.gov/ct2/show/NCT03336931 ).
Diffuse leptomeningeal glioneuronal tumours (DLGNT) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the ...clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of 'oligodendroglioma-like' appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochemistry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours.
Abstract BACKGROUND Metastatic infant medulloblastoma (MB) is a major challenge given the devastating long-term effects of craniospinal irradiation to the developing brain. However large cohorts of ...metastatic infant medulloblastoma have not been analysed to date. METHODS A multicentre molecularly informed international cohort of children <6 years old with metastatic medulloblastoma was assembled and analysed. RESULTS Eighty-four patients with a median age of 2.95 (0.66-6.58) years were identified. 48.8% were Group3-MB, 23.8% Group4-MB and 27.4% SHH-MB. 78% of Group3-MB were subtype II (40.4%) and IV (38.1%), 50% of Group 4 were subtype VII, and within SHH, SHHß and SHHγ were 52.2% and 43.5% respectively. 28.5% of all Group3-MB harboured MYC amplification. A multivariable analysis incorporating subgroup, MYC amplification and upfront craniospinal irradiation revealed that survival was superior for SHH patients compared to Group 3 irrespective of MYC status (Group3-veMYCamp: HR 3.05 95%-CI 1.05-8.87 p=0.04, Group3+veMYCamp HR 7.87 95%-CI 2.49-24.87 p=0.00044). Group 4 had a trend to a poor outcome (HR 2.63 95%-CI 0.82-8.39 p=0.1). SHH subjects had a superior outcome with 5-year PFS of 0.657 (95%-CI 0.47-0.92), without a significant difference between SHHß and SHHγ. High-dose chemotherapy regimens portended to a superior outcome for both subtypes of SHH-MB. 5-year PFS for non-radiated SHH-MB was 61% (95%-CI 40.8-91.4), compared to non-radiated Group3-MB (18.5%; 95%-CI 5.4-62.8) and Group4-MB (20%; 95%-CI 3.4-100). SHH-MB patients had more local than metastatic relapses compared to non-SHH-MB (p=0.01). CONCLUSIONS In the largest study dedicated to metastatic infant medulloblastoma assembled to date, outcomes for infants with Group 3- and 4-MB with metastatic disease treated with radiation sparing approaches is dismal despite intensified regimens. MYC amplification portends to a near uniformly fatal prognosis with current treatment irrespective of upfront radiotherapy. Novel radiation sparing approaches are urgently needed for this group. Infants with both metastatic SHHß and SHHγ benefit from intensified therapy.
Abstract only Background: Annual or biannual coronary angiography is recommended after heart transplantation. This is associated with radiation and contrast exposure in addition to being invasive. ...Absence of coronary calcium on CT in non-transplanted patients has a high negative predictive value (NPV) to rule out obstructive CAD. Objective: To determine whether the absence of coronary calcium on non-contrast, non-gated MDCT has a high NPV to rule out obstructive CAD in heart transplant recipients. Methods: We included patients with a non-contrast, non-gated chest CT within 1 year of undergoing a coronary angiogram from 2006 to 2016. Obstructive CAD was defined as stenosis >50%. Coronary artery calcium scores (CACS) were calculated by the Agatston method using the syngo.via platform (Siemens Healthcare GmbH, Germany). For analysis, CACS were categorized based on a) presence or absence of coronary calcium (i.e., CACS=0 or CACS>0) or b) severity of calcification (i.e., CACS=0, CACS 0-100 and CACS>100). Results: We reviewed 76 consecutive angiograms and corresponding CTs. Prevalence of obstructive CAD was 9.2% (n=7). Prevalence of CACS=0 was 89.5% (n=68) of which 5 had obstructive CAD presenting a NPV of 93%. 8 patients had CACS>0 of which 2 had obstructive CAD on angiogram (positive predictive value=25%). CACS was found to correlate with severity of CAD by angiography(p<0.05). Of 7 angiograms with obstructive CAD, stenosis >50% was found in 10 vessels - 5 LAD, 1 D1, 1 LCx, 2 OM branches and 1 RCA. Calculating CACS enabled detection of 1/5 LAD lesions; lesion in D1 was detected as an LAD lesion; lesions in the OM branches and RCA were not detected. Conclusion: Absence of coronary calcium on MDCT has a high NPV in ruling out obstructive CAD in heart transplant recipients. However, only 2/10 obstructive lesions on angiogram had calcification plaques detected on corresponding vessels on CT. The clinical significance of this is yet to be determined.
Abstract only Background: Coronary angiography (CAG) remains the gold standard to diagnose coronary artery disease (CAD). However, it is associated with multiple risks and its utility is not well ...defined in the liver transplant population. Alternatives to evaluate for CAD such as coronary artery calcium score (CACS) are being increasingly investigated. Hypothesis: To determine if the absence of coronary arterial calcium (CACS=0) on non-contrast, non-ECG gated chest CT scan can exclude obstructive CAD in liver transplant patients. Methods: We performed a retrospective analysis of data collected from liver transplant recipients. We included patients who had a CT chest without contrast and CAG less than one year apart. Agatston score was derived from non-IV contrast, non-ECG gated chest CT’s utilizing the syngo.via platform (Siemens Healthcare). CACS was compared against CAG. Patients with coronary stents were excluded. We determined NPV, PPV, sensitivity and specificity of using CACS = 0 as predictor of the absence of obstructive CAD. Results: Mean age at date of transplant was 59.03 and males accounted for 68.8% of our population. The negative predictive value for CACS=0 as a predictor of non-obstructive CAD was 100%. Positive predictive value for CACS≥1 was 6.8%. Sensitivity and specificity for the correlation between CACS and CAD were 100% and 33% respectively (Figure 1). CACS was stratified into four subgroups based severity, and we found that all patients with obstructive CAD had scores >400 (Figure 2). Conclusion: The absence of coronary arterial calcium (CACS=0) on non-contrast, non ECG gated chest CT has a high negative predictive value and can exclude the presence of obstructive CAD.
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