ORCID Profile
0000-0002-1190-9469
Current Organisation
Northumbria University
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Publisher: Elsevier BV
Date: 07-2017
Publisher: Wiley
Date: 02-05-2021
DOI: 10.1111/NAN.12716
Abstract: Application of advanced molecular pathology in rare tumours is hindered by low s le numbers, access to specialised expertise/technologies and tissue/assay QC and rapid reporting requirements. We assessed the feasibility of co‐ordinated real‐time centralised pathology review (CPR), encompassing molecular diagnostics and contemporary genomics (RNA‐seq/DNA methylation‐array). This nationwide trial in medulloblastoma ( UK diagnoses/year) introduced a national reference centre (NRC) and assessed its performance and reporting to World Health Organisation standards. Paired frozen/formalin‐fixed, paraffin‐embedded tumour material were co‐submitted from 135 patients (16 referral centres). Complete CPR diagnostics were successful for 88% (120/135). Inadequate s ling was the most common cause of failure biomaterials were typically suitable for methylation‐array (129/135, 94%), but frozen tissues commonly fell below RNA‐seq QC requirements (53/135, 39%). Late reporting was most often due to delayed submission. CPR assigned or altered histological variant (vs local diagnosis) for 40/135 tumours (30%). Benchmarking/QC of specific biomarker assays impacted test results fluorescent in‐situ hybridisation most accurately identified high‐risk MYC / MYCN lification (20/135, 15%), while combined methods ( CTNNB1 /chr6 status, methylation‐array subgrouping) best defined favourable‐risk WNT tumours (14/135 10%). Engagement of a specialist pathologist panel was essential for consensus assessment of histological variants and immunohistochemistry. Overall, CPR altered clinical risk‐status for 29% of patients. National real‐time CPR is feasible, delivering robust diagnostics to WHO criteria and assignment of clinical risk‐status, significantly altering clinical management. Recommendations and experience from our study are applicable to advanced molecular diagnostics systems, both local and centralised, across rare tumour types, enabling their application in biomarker‐driven routine diagnostics and clinical/research studies.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2017
DOI: 10.1038/S41598-017-13644-1
Abstract: Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of mi nimal m ethylat i on c lassifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality s les remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2019
Publisher: Springer Science and Business Media LLC
Date: 09-11-2013
Publisher: Wiley
Date: 28-11-2016
DOI: 10.1111/BJH.14440
Abstract: Burkitt lymphoma is the most common malignancy in children in Malawi, the world's poorest country, where there is a long history of treating this disease using a 28-day cyclophosphamide-based protocol. Stage III/IV disease has had poor outcomes. In an attempt to improve the outcome for higher stage disease, anthracyclines were added to the existing protocol. The disease-free (DFS) and overall survival (OS) of 58 children with cytologically confirmed Burkitt lymphoma admitted during 2012-2014 and treated using this protocol were calculated. Six (10%) children had stage I disease, ten (17%) stage II and 42 stage III or IV (73%). Overall 12-month DFS (OS) was 68·5% (72·9%) for stage I disease 100% (100%), stage II 56·2% (60%), stage III/IV 66·3% (72·2%). The DFS was significantly improved from the previous protocol (P = 8 × 10
Publisher: Springer Science and Business Media LLC
Date: 03-12-2011
DOI: 10.1007/S00401-011-0923-Y
Abstract: The MYC oncogenes are the most commonly lified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and comprehensive investigations of MYCC, MYCN and MYCL in an extensive medulloblastoma cohort (n = 292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and in idualisation of therapy. MYCC and MYCN expression elevations were multifactorial, associated with high-risk (gene lification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene lification patterns underlay overall MYC copy number elevations observed in tumour biopsies we used these alternative measures together to define quantitative methodologies and thresholds for lification detection in routinely collected tumour material. MYCC and MYCN lification, but not gain, each had independent prognostic significance in non-infants (≥3.0-16.0 years), but MYCC conferred a greater hazard to survival than MYCN when considered across this treatment group. MYCN's weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups MYCN predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or MYCC/MYCN lification). This cumulative-risk model defines a patient group characterised by ≥2 independent risk-factors and an extremely poor prognosis (<15% survival), which can be identified straightforwardly using the reported MYC lification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies.
Publisher: Wiley
Date: 09-2020
DOI: 10.1111/NAN.12656
Abstract: Biomarker‐driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub‐classify iMB, and proffer strategies for personalized, risk‐adapted therapies. We characterized the iMB molecular landscape, including second‐generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). iMB Grp3 (42%) and iMB SHH (40%) subgroups predominated. iMB Grp3 harboured second‐generation subtypes II/III/IV. Subtype II strongly associated with large‐cell/anaplastic pathology (LCA 23%) and MYC lification (19%), defining a very‐high‐risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies novel approaches are urgently required. Subtype VII (predominant within iMB Grp4 ) and subtype IV tumours were standard risk (80% OS) using upfront CSI‐based therapies randomized‐controlled trials of upfront radiation‐sparing and/or second‐line radiotherapy should be considered. Seventy‐five per cent of iMB SHH showed DN/MBEN histopathology in discovery and validation cohorts ( P 0.0001) central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non‐DN/MBEN pathology was associated significantly with worse outcomes within iMB SHH . iMB SHH harboured two distinct subtypes (iMB SHH‐I/II ). Within the discriminated favourable‐risk iMB SHH DN/MBEN patient group, iMB SHH‐II had significantly better progression‐free survival than iMB SHH‐I , offering opportunities for risk‐adapted stratification of upfront therapies. Both iMB SHH‐I and iMB SHH‐II showed notable rescue rates (56% combined post‐relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup‐dependent survival models highlight opportunities for biomarker‐directed therapies.
Publisher: Oxford University Press (OUP)
Date: 06-2016
Publisher: Oxford University Press (OUP)
Date: 06-2016
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 16-08-2012
Publisher: Oxford University Press (OUP)
Date: 06-2016
Publisher: Oxford University Press (OUP)
Date: 31-05-2017
Publisher: Oxford University Press (OUP)
Date: 06-2016
Publisher: Oxford University Press (OUP)
Date: 06-2016
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ed Schwalbe.