Publications by authors named "Lucy Matthews"

59 Publications

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis.

Mult Scler 2021 Oct 4:13524585211045545. Epub 2021 Oct 4.

Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Background: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet.

Objective: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort.

Methods: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12).

Results: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4-C6 ( < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC ( < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS ( < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3-C6 ( < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3-C6 correlated with concomitant and 1-year disability ( = -0.40/-0.62, < 0.05, corrected).

Conclusions: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.
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http://dx.doi.org/10.1177/13524585211045545DOI Listing
October 2021

Association of Gray Matter Atrophy Patterns With Clinical Phenotype and Progression in Multiple Sclerosis.

Neurology 2021 03 13;96(11):e1561-e1573. Epub 2021 Jan 13.

From the Neuroimaging Research Unit (M.A.R., P.V., A.M., P.P., M.F.), Division of Neuroscience, Neurology Unit (M.A.R., P.P., M.F.), Neurorehabilitation Unit, and Neurophysiology Service (M.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University (M.A.R., M.F.), Milan, Italy; Multiple Sclerosis Center (C.G., C.Z.), Department of Neurology, Neurocenter of Southern Switzerland, Civic Hospital; Faculty of Biomedical Sciences Università della Svizzera Italiana (C.G., C.Z.), Lugano, Switzerland; Section of Neuroradiology (A.R.), Department of Radiology, and Department of Neurology/Neuroimmunology (J.S.-G.), Multiple Sclerosis Center of Catalonia, Hospital Universitari Vall d'Hebron, Barcelona, Spain; NMR Research Unit (H.K., O.C.), Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, London; Nuffield Department of Clinical Neurosciences (L.M., J.P.), University of Oxford, UK; Department of Advanced Medical and Surgical Sciences (A.G., A.B.) and 3T MRI-Center (A.G., A.B.), University of Campania Luigi Vanvitelli, Naples, Italy; Institute of Neuroradiology at the Department of Radiology and Nuclear Medicine (C.L., B.B.), St. Josef Hospital, Ruhr University Bochum, Germany; Department of Radiology and Nuclear Medicine (F.B., H.V.), MS Center Amsterdam, Amsterdam Neuroscience Amsterdam UMC, location VUmc, the Netherlands; and Institutes of Neurology and Healthcare Engineering (F.B.), University College London, UK.

Objectives: Gay matter (GM) involvement is clinically relevant in multiple sclerosis (MS). Using source-based morphometry (SBM), we characterized GM atrophy and its 1-year evolution across different MS phenotypes.

Methods: Clinical and MRI data were obtained at 8 European sites from 170 healthy controls (HCs) and 398 patients with MS (34 with clinically isolated syndrome [CIS], 226 with relapsing-remitting MS [RRMS], 95 with secondary progressive MS [SPMS], and 43 with primary progressive MS [PPMS]). Fifty-seven HCs and 144 with MS underwent 1-year follow-up. Baseline GM loss, atrophy progression, and correlations with disability and 1-year clinical worsening were assessed.

Results: SBM identified 26 cerebellar, subcortical, sensory, motor, and cognitive GM components. GM atrophy was found in patients with MS vs HCs in almost all components ( range <0.001-0.04). Compared to HCs, patients with CIS showed circumscribed subcortical, cerebellar, temporal, and salience GM atrophy, while patients with RRMS exhibited widespread GM atrophy. Cerebellar, subcortical, sensorimotor, salience, and frontoparietal GM atrophy was found in patients with PPMS vs HCs and in patients with SPMS vs those with RRMS. At 1 year, 21 (15%) patients had clinically worsened. GM atrophy progressed in MS in subcortical, cerebellar, sensorimotor, and fronto-temporo-parietal components. Baseline higher disability was associated ( = 0.65) with baseline lower normalized brain volume (β = -0.13, = 0.001), greater sensorimotor GM atrophy (β = -0.12, = 0.002), and longer disease duration (β = 0.09, = 0.04). Baseline normalized GM volume (odds ratio 0.98, = 0.008) and cerebellar GM atrophy (odds ratio 0.40, = 0.01) independently predicted clinical worsening (area under the curve 0.83).

Conclusion: GM atrophy differed across disease phenotypes and progressed at 1 year in MS. In addition to global atrophy measures, sensorimotor and cerebellar GM atrophy explained baseline disability and clinical worsening.
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http://dx.doi.org/10.1212/WNL.0000000000011494DOI Listing
March 2021

Clinically relevant cranio-caudal patterns of cervical cord atrophy evolution in MS.

Neurology 2019 11 14;93(20):e1852-e1866. Epub 2019 Oct 14.

From the Neuroimaging Research Unit (M.A.R., P.V., A.M., P.P., M.F.) and Neurology Unit (M.A.R., P.P., G.C., M.F.), Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Neurology (C.G., C.Z.), Neurocenter of Southern Switzerland, Regional Hospital Lugano (EOC), Lugano; Faculty of Biomedical Sciences (C.G., C.Z.), Università della Svizzera Italiana, Lugano, Switzerland; Section of Neuroradiology and MRI Unit, Department of Radiology (A.R.), and Department of Neurology/Neuroimmunology (X.M.), Multiple Sclerosis Centre of Catalonia, Hospital Universitari Vall d'Hebron, Barcelona, Spain; NMR Research Unit (H.K., O.C.), Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, London; Nuffield Department of Clinical Neurosciences (L.M., J.P.), University of Oxford, UK; Department of Advanced Medical and Surgical Sciences, and 3T MRI Center, (A.G., A.B.), University of Campania "Luigi Vanvitelli," Naples, Italy; Department of Neurology (A.G., P.E.), Universitätsmedizin Mannheim, University of Heidelberg, Germany; Department of Radiology and Nuclear Medicine (C.L., B.B.) and Institute of Neuroradiology (C.L., B.B.), St. Josef Hospital, Ruhr-University Bochum, Germany; Department of Radiology and Nuclear Medicine (F.B., H.V.), MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, location VUmc, the Netherlands; Institutes of Neurology and Healthcare Engineering (F.B.), University College London, UK; and Vita-Salute San Raffaele University (P.P., G.C., M.F.), Milan, Italy.

Objective: To characterize the distribution and regional evolution of cervical cord atrophy in patients with multiple sclerosis (MS) in a multicenter dataset.

Methods: MRI and clinical evaluations were acquired from 179 controls and 435 patients (35 clinically isolated syndromes [CIS], 259 relapsing-remitting multiple sclerosis [RRMS], 99 secondary progressive multiple sclerosis [SPMS], and 42 primary progressive multiple sclerosis [PPMS]). Sixty-nine controls and 178 patients underwent a 1-year MRI and clinical follow-up. Patients were classified as clinically stable/worsened according to their disability change. Longitudinal changes of cord atrophy were investigated with linear mixed-effect models. Sample size calculations were performed using age-, sex- and site-adjusted annualized percentage normalized cord cross-sectional area (CSAn) changes.

Results: Baseline CSAn was lower in patients with MS vs controls ( < 0.001), but not different between controls and patients with CIS or between patients with early RRMS (disease duration ≤5 years) and patients with CIS. Patients with late RRMS (disease duration >5 years) showed significant cord atrophy vs patients with early RRMS ( = 0.02). Patients with progressive MS had decreased CSAn ( < 0.001) vs patients with RRMS. Atrophy was located between C1/C2 and C5 in patients with RRMS vs patients with CIS, and widespread along the cord in patients with progressive MS vs patients with RRMS, with an additional C5/C6 involvement in patients with SPMS vs patients with PPMS. At follow-up, CSAn decreased in all phenotypes ( < 0.001), except CIS. Cord atrophy rates were highest in patients with early RRMS and clinically worsened patients, who had a more widespread cord involvement than stable patients. The sample size per arm required to detect a 50% treatment effect was 118 for patients with early RRMS.

Conclusions: Cord atrophy increased in MS during 1 year, except for CIS. Faster atrophy contributed to explain clinical worsening.
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http://dx.doi.org/10.1212/WNL.0000000000008466DOI Listing
November 2019

Patients' and partners' views of care and treatment provided for metastatic castrate-resistant prostate cancer in the UK.

Eur J Cancer Care (Engl) 2019 Nov 1;28(6):e13140. Epub 2019 Sep 1.

Sussex Health Outcomes Research & Education in Cancer (SHORE-C), Brighton & Sussex Medical School, University of Sussex, Brighton, UK.

Objective: Documentations of the experiences of patients with advanced prostate cancer and their partners are sparse. Views of care and treatment received for metastatic castrate-resistant prostate cancer (mCRPC) are presented here.

Methods: Structured interviews conducted within 14 days of a systemic therapy for mCRPC starting and 3 months later explored the following: treatment decisions, information provision, perceived benefits and harms of treatment, and effects of these on patients' and partners' lives.

Results: Thirty-seven patients and 33 partners recruited from UK cancer centres participated. The majority of patients (46%) reported pain was their worst symptom and many wanted to discuss its management (baseline-50%; 3 months-33%). Patients and partners believed treatment would delay progression (>75%), improve wellbeing (33%), alleviate pain (≈12%) and extend life (15% patients, 36% partners). At 3 months, most men (42%) said fatigue was the worst treatment-related side effect (SE), 27% experienced unexpected SEs and 54% needed help with SEs. Most patients received SE information (85% written; 75% verbally); many additionally searched the Internet (33% patients; 55% partners). Only 54% of patients said nurse support was accessible.

Conclusion: Pain and other symptom management are not optimal. Increased specialist nurse provision and earlier palliative care links are needed. Dedicated clinics may be justified.
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http://dx.doi.org/10.1111/ecc.13140DOI Listing
November 2019

Brain and cord imaging features in neuromyelitis optica spectrum disorders.

Ann Neurol 2019 03 28;85(3):371-384. Epub 2019 Jan 28.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Objectives: To validate imaging features able to discriminate neuromyelitis optica spectrum disorders from multiple sclerosis with conventional magnetic resonance imaging (MRI).

Methods: In this cross-sectional study, brain and spinal cord scans were evaluated from 116 neuromyelitis optica spectrum disorder patients (98 seropositive and 18 seronegative) in chronic disease phase and 65 age-, sex-, and disease duration-matched multiple sclerosis patients. To identify independent predictors of neuromyelitis optica diagnosis, after assessing the prevalence of typical/atypical findings, the original cohort was 2:1 randomized in a training sample (where a multivariate logistic regression analysis was run) and a validation sample (where the performance of the selected variables was tested and validated).

Results: Typical brain lesions occurred in 50.9% of neuromyelitis optica patients (18.1% brainstem periventricular/periaqueductal, 32.7% periependymal along lateral ventricles, 3.4% large hemispheric, 6.0% diencephalic, 4.3% corticospinal tract), 72.2% had spinal cord lesions (46.3% long transverse myelitis, 36.1% short transverse myelitis), 37.1% satisfied 2010 McDonald criteria, and none had cortical lesions. Fulfillment of at least 2 of 5 of absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson fingers, presence of long transverse myelitis, and presence of periependymal lesions along lateral ventricles discriminated neuromyelitis optica patients in both training (sensitivity = 0.92, 95% confidence interval [CI] = 0.84-0.97; specificity = 0.91, 95% CI = 0.78-0.97) and validation samples (sensitivity = 0.82, 95% CI = 0.66-0.92; specificity = 0.91, 95% CI = 0.71-0.99). MRI findings and criteria performance were similar irrespective of serostatus.

Interpretation: Although up to 50% of neuromyelitis optica patients have no typical lesions and a relatively high percentage of them satisfy multiple sclerosis criteria, several easily applicable imaging features can help to distinguish neuromyelitis optica from multiple sclerosis. ANN NEUROL 2019;85:371-384.
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http://dx.doi.org/10.1002/ana.25411DOI Listing
March 2019

Clinical commentary on 'Relapsing remitting multiple sclerosis in progressive external ophthalmoplegia: A report of two cases'.

Authors:
Lucy Matthews

Mult Scler 2019 05 17;25(6):882-883. Epub 2018 Dec 17.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1177/1352458518816621DOI Listing
May 2019

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.

Nat Genet 2018 05 16;50(5):682-692. Epub 2018 Apr 16.

The Institute of Cancer Research, London, UK.

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials.
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http://dx.doi.org/10.1038/s41588-018-0086-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372064PMC
May 2018

The effect of kidney volume estimation on dosimetry in lutetium-177 DOTATATE therapy.

Nucl Med Commun 2018 Jun;39(6):527-532

Department of Clinical & Radiation Physics, Plymouth Hospitals NHS Trust, Plymouth, UK.

Background: The kidneys are the dose-limiting organ in lutetium-177 DOTATATE therapy. Therefore, it is advisable to perform critical organ dosimetry focussed on renal dose in treated patients. A key uncertainty in such dose estimates is the use of standard phantoms to represent the individual patient. The primary aim of this study was to investigate the accuracy of methods for estimating kidney size, and hence absorbed kidney dose, by comparison with individual measurements from computed tomography (CT) imaging.

Materials And Methods: Kidney volume was measured using diagnostic CT images for 57 patients who underwent lutetium-177 DOTATATE therapy. Kidney mass was also estimated in two ways: using the standard adult phantoms, as well as through the application of a weight scaling factor to these phantoms and their organs. Dose calculations were performed for each of the three methods using OLINDA/EXM software.

Results: Scaling of the phantom by patient weight gave a more accurate result when compared with the CT gold standard than the standard phantom. The dose difference from the CT method had mean values of 1.4% (SD=22.6%) and 8.4% (SD=21.5%) for scaled and unscaled, respectively. Patient weight was not found to be a good predictor of kidney mass in these patients (r of 0.12 from linear regression analysis).

Conclusion: The most accurate method of organ volume estimation would be individual measurements from CT imaging; however, where this is not possible, scaling of organ masses by weight ratio is more accurate than the use of the standard phantom.
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http://dx.doi.org/10.1097/MNM.0000000000000821DOI Listing
June 2018

Enhancing decision-making about adjuvant chemotherapy in early breast cancer following EndoPredict testing.

Psychooncology 2018 04 25;27(4):1264-1269. Epub 2018 Mar 25.

Sussex Cancer Centre, Brighton and Sussex University Hospitals Trust, Brighton, UK.

Objective: Chemotherapy side-effects can be substantial. There is increasing recognition that some oestrogen receptor positive (ER +ve), human epidermal growth factor receptor 2 negative (HER2 -ve) patients with breast cancer derive no benefit from chemotherapy and experience only iatrogenic harm. Gene expression profiling tests help refine recurrence risk and likely chemotherapy benefit. EndoPredict® is one such test, which classifies risks of distant recurrence as low or high in patients treated with surgery and adjuvant endocrine therapy alone. We compared treatment decisions pre-test and post-test results, patients' anxiety, decisional conflict, and oncologists' confidence about the decisions made.

Methods: Fourteen oncologists in 7 UK hospitals saw 149 pts judged to have equivocal indications for chemotherapy. Provisional treatment decisions were recorded then reconsidered when EPClin results were available. Pre-test and post-test results, patients completed State/Trait Anxiety Inventories (STAI), and the decisional conflict scale. Oncologists also recorded basic clinical details, their agreement with, and confidence about treatment decisions.

Results: Sixty-seven percent patients initially prescribed endocrine alone with high risk result upgraded to endocrine+chemotherapy (E + C); 83% prescribed E + C and had low risk scores, downgraded to E. None of 46 patients initially favouring E alone, who were low risk, changed decisions. Oncologists' confidence about decisions was significantly increased following the results (P = 0.002). Patients with downgraded treatment decisions had significantly lower anxiety scores (P = 0.045); those upgraded had increased scores (P = 0.001). Overall decisional conflict and uncertainty fell significantly post-test (P < 0.022).

Conclusions: EndoPredict scores increased oncologists' and patients' decision-making confidence, generally improving the matching of risk with therapy decisions.
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http://dx.doi.org/10.1002/pon.4664DOI Listing
April 2018

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

PLoS Genet 2017 Sep 25;13(9):e1007001. Epub 2017 Sep 25.

Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.
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http://dx.doi.org/10.1371/journal.pgen.1007001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628936PMC
September 2017

Focal precentral gyrus involvement in osmotic demyelination.

Pract Neurol 2017 Oct 19;17(5):410-411. Epub 2017 Aug 19.

Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK.

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http://dx.doi.org/10.1136/practneurol-2017-001682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629936PMC
October 2017

Cervical cord myelin water imaging shows degenerative changes over one year in multiple sclerosis but not neuromyelitis optica spectrum disorder.

Neuroimage Clin 2017 16;16:17-22. Epub 2017 Jun 16.

Department of Radiology, Faculty of Medicine, University of British Columbia, Vancouver, Canada.

Spinal cord pathology is a feature of both neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (MS). While subclinical disease activity has been described in MS using quantitative magnetic resonance imaging measures, current evidence suggests that neurodegeneration is absent between relapses in NMOSD, although most evidence comes from brain studies. We aimed to assess cross-sectional differences and longitudinal changes in myelin integrity in relapse-free MS and NMOSD subjects over one year. 15 NMOSD, 15 MS subjects, and 17 healthy controls were scanned at 3 T using a cervical cord mcDESPOT protocol. A subset of 8 NMOSD, 11 MS subjects and 14 controls completed follow-up. Measures of the myelin water fraction (f) within lesioned and non-lesioned cord segments were collected. At baseline, f in lesioned and non-lesioned segments was significantly reduced in MS (lesioned: p = 0.002; non-lesioned: p = 0.03) and NMOSD (lesioned: p = 0.0007; non-lesioned: p = 0.002) compared to controls. Longitudinally, f decreased within non-lesioned cord segments in the MS group (- 7.3%, p = 0.02), but not in NMOSD (+ 5.8%, p = 0.1), while change in lesioned segments f did not differ from controls' in either patient group. These results suggest that degenerative changes outside of lesioned areas can be observed over a short time frame in MS, but not NMOSD, and support the use of longitudinal myelin water imaging for the assessment of pathological changes in the cervical cord in demyelinating diseases.
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http://dx.doi.org/10.1016/j.nicl.2017.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503831PMC
April 2018

Quantitative FLAIR MRI in Amyotrophic Lateral Sclerosis.

Acad Radiol 2017 10 29;24(10):1187-1194. Epub 2017 May 29.

Centre for Functional Magnetic Resonance Imaging of the Brain, Oxford University, John Radcliffe Hospital, West Wing Level 6, Oxford OX3 9DU, UK; Nuffield Department of Clinical Neurosciences, Oxford University, John Radcliffe Hospital, West Wing Level 6, Oxford OX3 9DU, UK; Oxford University Centre for Magnetic Resonance Research, John Radcliffe Hospital, West Wing Level 6, Oxford OX3 9DU, UK. Electronic address:

Rationale And Objectives: T2-weighted magnetic resonance imaging (MRI) hyperintensity assessed visually in the corticospinal tract (CST) lacks sensitivity for a diagnosis of amyotrophic lateral sclerosis (ALS). We sought to explore a quantitative approach to fluid-attenuated inversion recovery (FLAIR) MRI intensity across a range of ALS phenotypes.

Materials And Methods: Thirty-three classical ALS patients, 10 with a flail arm presentation, and six with primary lateral sclerosis underwent MRI at 3 Tesla. Comparisons of quantitative FLAIR intensity in the CST and corpus callosum were made between 21 healthy controls and within patient phenotypic subgroups, some of whom were studied longitudinally.

Results: Mean FLAIR intensity was greater in patient groups. The cerebral peduncle intensity provided the strongest subgroup classification. FLAIR intensity increased longitudinally. The rate of change of FLAIR within CST correlated with rate of decline in executive function and ALS functional rating score.

Conclusions: FLAIR MRI encodes quantifiable information of potential diagnostic, stratification, and monitoring value.
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http://dx.doi.org/10.1016/j.acra.2017.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605225PMC
October 2017

Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease.

J Neurol Neurosurg Psychiatry 2017 Feb 8;88(2):132-136. Epub 2016 Oct 8.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Importance: Neuromyelitis optica spectrum disorders (NMOSD) can present with very similar clinical features to multiple sclerosis (MS), but the international diagnostic imaging criteria for MS are not necessarily helpful in distinguishing these two diseases.

Objective: This multicentre study tested previously reported criteria of '(1) at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or (2) the presence of a subcortical U-fibre lesion or (3) a Dawson's finger-type lesion' in an independent cohort of relapsing-remitting multiple sclerosis (RRMS) and AQP4-ab NMOSD patients and also assessed their value in myelin oligodendrocyte glycoprotein (MOG)-ab positive and ab-negative NMOSD.

Design: Brain MRI scans were anonymised and scored on the criteria by 2 of 3 independent raters. In case of disagreement, the final opinion was made by the third rater.

Participants: 112 patients with NMOSD (31 AQP4-ab-positive, 21 MOG-ab-positive, 16 ab-negative) or MS (44) were selected from 3 centres (Oxford, Strasbourg and Liverpool) for the presence of brain lesions.

Results: MRI brain lesion distribution criteria were able to distinguish RRMS with a sensitivity of 90.9% and with a specificity of 87.1% against AQP4-ab NMOSD, 95.2% against MOG-ab NMOSD and 87.5% in the heterogenous ab-negative NMOSD cohort. Over the whole NMOSD group, the specificity was 89.7%.

Conclusions: This study suggests that the brain MRI criteria for differentiating RRMS from NMOSD are sensitive and specific for all phenotypes.
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http://dx.doi.org/10.1136/jnnp-2016-314005DOI Listing
February 2017

Time- and Region-Specific Season of Birth Effects in Multiple Sclerosis in the United Kingdom.

JAMA Neurol 2016 Aug;73(8):954-60

Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, England.

Importance: The reports of seasonal variation in the births of people who later develop multiple sclerosis (MS) have been challenged and attributed to the background pattern in the general population, resulting in a false association.

Objective: To study the seasonality of MS births after adjusting for temporal and regional confounding factors.

Design, Setting, And Participants: A study was conducted using case-control data from 8 MS-specialized centers from the United Kingdom, MS cases from a population-based study in the Lothian and Border regions of Scotland, and death records from the UK Registrar General. Participants included 21 138 patients with MS and control data from the UK Office of National Statistics and the UK government office regions. The seasonality of MS births was evaluated using the Walter and Elwood test, after adjusting for temporal and regional variations in the live births of the UK population. The study was conducted from January 16, 2014, to September 2, 2015.

Main Outcomes And Measures: Diagnosis of multiple sclerosis.

Results: Analysis of the general population indicated that seasonal differences are present across time and region in the United Kingdom, with both factors contributing to the monthly distribution of live births. We were able to demonstrate that, when adjusting for the temporal and regional variations in the live births of the UK population, there was a significant season of birth effect in patients with MS, with an increased risk of disease in the peak month (April) compared with the trough month (November) (odds ratio, 1.24; 95% CI, 1.10-1.41) and 15.68% fewer people who developed MS being born in November (observed to expected birth ratio, 0.840; 95% CI, 0.76-0.92).

Conclusions And Relevance: Season of birth is a risk factor for MS in the United Kingdom and cannot be attributed to the background pattern in the general population. The reasons for the variations in birth rates in the general population are unclear, but not taking them into consideration could lead to false-positive associations.
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http://dx.doi.org/10.1001/jamaneurol.2016.1463DOI Listing
August 2016

A feasibility study exploring the role of pre-operative assessment when examining the mechanism of 'chemo-brain' in breast cancer patients.

Springerplus 2016 31;5:390. Epub 2016 Mar 31.

Sussex Health Outcomes Research and Education in Cancer (SHORE-C), Brighton and Sussex Medical School, University of Sussex, Brighton, UK.

Background: Women receiving chemotherapy treatment for breast cancer may experience problems with their memory and attention (cognition), which is distressing and interferes with quality of life. It is unclear what causes or contributes to the problems they report: psychological distress, fatigue, coping style, or specific biological changes for example to pro inflammatory cytokines. Research shows however, that approximately a third of women with breast cancer perform poorly on tests of cognition before commencing chemotherapy. We aimed to examine the acceptability and relevance of pre-surgical assessments (bloods, brain imaging, cognitive tests and self-report questionnaires) when investigating the phenomenon of 'chemo-brain' and investigate whether inflammatory markers mediate chemotherapy-induced neuropsychological impairments in women treated for breast cancer.

Methods: Women with early stage breast cancer completed neuropsychological and quality of life assessments at T1 (pre-surgery), T2 (post-surgery before chemotherapy) and T3 (6 months later). Blood cytokine levels were measured at the same time points and brain imaging was performed at T1 and T3.

Results: In total, 14/58 women participated (8 chemotherapy, 6 non-chemotherapy). Prior to the start of chemotherapy a decline in cognitive performance compared to baseline was observed in one participant. At T3 women who received chemotherapy reported poorer quality of life and greater fatigue. Increases in soluble tumour necrosis factor receptor II (sTNFRII), interleukin-6, interleukin-10 and vascular endothelial growth factor occurred post chemotherapy only. Levels of sTNFRII were inversely correlated with grey matter volume (GMV) of the right posterior insula in both groups. At T3, the chemotherapy group displayed a greater reduction in GMV in the subgenual and dorsal anterior cingulate, and the inferior temporal gyrus.

Conclusions: Pre-operative recruitment to the study was challenging; however, the lack of significant changes in blood cytokine levels and neuropsychological tests at T2 implies that post surgery may be a valid baseline assessment, but this needs further investigation in a larger study. The preliminary results support the hypothesis that chemotherapy induced fatigue is mediated by a change in peripheral cytokine levels which could explain some symptoms of 'chemo brain' experienced by patients.
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http://dx.doi.org/10.1186/s40064-016-2030-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816933PMC
April 2016

Patient-reported outcome measures for cancer caregivers: a systematic review.

Qual Life Res 2016 08 12;25(8):1859-76. Epub 2016 Feb 12.

Sussex Health Outcomes Research and Education in Cancer, Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton, BN1 9QG, UK.

Purpose: Informal caregivers provide invaluable help and support to people with cancer. As treatments extend survival and the potential burdens on carers increase, there is a need to assess the impact of the role. This systematic review identified instruments that measure the impact of caregiving, evaluated their psychometric performance specifically in cancer and appraised the content.

Methods: A two-stage search strategy was employed to: (1) identify instruments that measure the impact of caregiving, and (2) run individual searches on each measure to identify publications evaluating psychometric performance in the target population. Searches were conducted in MEDLINE, EMBASE, CINAHL and PsycINFO and restricted to English for instrument used and article language. Psychometric performance was evaluated for content and construct validity, internal consistency, test-retest reliability, precision, responsiveness and acceptability. Individual scale items were extracted and systematically categorised into conceptual domains.

Results: Ten papers were included reporting on the psychometric properties of eight measures. Although construct validity and internal consistency were most frequently evaluated, no study comprehensively evaluated all relevant properties. Few studies met our inclusion criteria so it was not possible to consider the psychometric performance of the measures across a group of studies. Content analysis resulted in 16 domains with 5 overarching themes: lifestyle disruption; well-being; health of the caregiver; managing the situation and relationships.

Conclusions: Few measures of caregiver impact have been subject to psychometric evaluation in cancer caregivers. Those that have do not capture well changes in roles and responsibilities within the family and career, indicating the need for a new instrument.
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http://dx.doi.org/10.1007/s11136-016-1239-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945691PMC
August 2016

AN ASSESSMENT OF THE DOSE REDUCTION OF COMMERCIALLY AVAILABLE LEAD PROTECTIVE GLASSES FOR INTERVENTIONAL RADIOLOGY STAFF.

Radiat Prot Dosimetry 2016 Dec 13;172(4):443-452. Epub 2016 Jan 13.

Clinical and Radiation Physics, Plymouth Hospitals NHS Trust, Level 2, Derriford Hospital, Derriford Road, Plymouth, Devon PL6 8DH, UK.

In light of the proposal from the International Commission on Radiological Protection for a lowered eye dose limit, now adopted by a European Union Council Directive, lead glasses may be required for some staff in interventional radiology to ensure that occupational exposure is as low as reasonably practicable. To investigate the lens protection offered from various models of lead glasses exposed to X-rays coming from a source to the left and below, calibrated radiochromic film was positioned in the lens area of a head phantom. When the source-to-eye angles were large, the dose reduction factors (the ratio of eye dose without protection to dose with protection) to the right lens area were much lower than to the left lens area, particularly with smaller-lensed glasses, due to gaps in protection between the face and the glasses. The results of this study reiterate the importance of employers providing eyewear based on the morphology of, and fit to, individual workers' faces.
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http://dx.doi.org/10.1093/rpd/ncv540DOI Listing
December 2016

Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise.

Neuroimage 2016 05 2;131:162-70. Epub 2015 Dec 2.

FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show that hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting that gross morphometric hippocampal plasticity occurs faster than previously thought.
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http://dx.doi.org/10.1016/j.neuroimage.2015.10.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848119PMC
May 2016

Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis.

PLoS One 2015 18;10(9):e0137715. Epub 2015 Sep 18.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom; Neurology Department, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.

Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter) but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137715PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575169PMC
May 2016

Addressing overtreatment of screen detected DCIS; the LORIS trial.

Eur J Cancer 2015 Nov 18;51(16):2296-303. Epub 2015 Aug 18.

Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

Overdiagnosis, and thus overtreatment, are inevitable consequences of most screening programmes; identification of ways of minimising the impact of overdiagnosis demands new prospective research, in particular the need to separate clinically relevant lesions that require active treatment from those that can be safely left alone or monitored and only need treated if they change characteristics. Breast cancer screening has led to a large increase in ductal carcinoma in situ (DCIS) diagnoses. This is a widely heterogeneous disease and most DCIS detected through screening is of high cytonuclear grade and therefore likely to be important clinically. However, the historic practice of surgical treatment for all DCIS is unlikely to be optimal for lower risk patients. A clearer understanding of how to manage DCIS is required. This article describes the background and development of 'The low risk' DCIS trial (LORIS), a phase III trial of surgery versus active monitoring. LORIS will determine if it is appropriate to manage women with screen detected or asymptomatic, low grade and intermediate grade DCIS with low grade features, by active monitoring rather than by surgical treatment.
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http://dx.doi.org/10.1016/j.ejca.2015.07.017DOI Listing
November 2015

A practical method for skin dose estimation in interventional cardiology based on fluorographic DICOM information.

Radiat Prot Dosimetry 2016 Mar 20;168(3):381-7. Epub 2015 May 20.

Clinical & Radiation Physics, Plymouth Hospitals NHS Trust, Derriford Hospital, Derriford Road, Plymouth PL6 8DH, UK.

A practical method for skin dose estimation for interventional cardiology patients has been developed to inform pre-procedure planning and post-procedure patient management. Absorbed dose to the patient skin for certain interventional radiology procedures can exceed thresholds for deterministic skin injury, requiring documentation within the patient notes and appropriate patient follow-up. The primary objective was to reduce uncertainty associated with current methods, particularly surrounding field overlap. This was achieved by considering rectangular field geometry incident on a spherical patient model in a polar coordinate system. The angular size of each field was quantified at surface of the sphere, i.e. the skin surface. Computer-assisted design software enabled the modelling of a sufficient dataset that was subsequently validated with radiochromic film. Modelled overlap was found to agree with overlap measured using film to within 2.2° ± 2.0°, showing that the overall error associated with the model was < 1 %. Mathematical comparison against exposure data extracted from procedural Digital Imaging and Communication in Medicine files was used to generate a graphical skin dose map, demonstrating the dose distribution over a sphere centred at the interventional reference point. Dosimetric accuracy of the software was measured as between 3.5 and 17 % for different variables.
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http://dx.doi.org/10.1093/rpd/ncv342DOI Listing
March 2016

The role of imaging in diagnosing neuromyelitis optica spectrum disorder.

Mult Scler Relat Disord 2014 May 4;3(3):284-93. Epub 2013 Dec 4.

Oxford University Hospitals NHS Trust, United Kingdom; Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom.

Early identification of neuromyelitis optica allows aggressive acute and prophylactic relapse management aimed at preventing disability. Since the discovery of pathogenic aquaporin-4 antibodies the neuromyelitis optica spectrum has widened significantly: brain lesions no longer preclude the diagnosis and there are reports of symptoms of cerebral origin presenting as the first manifestation of the condition, prior to optic nerve or spinal cord disease. Defining antibody negative neuromyelitis optica, and distinguishing it from other inflammatory disorders such as multiple sclerosis can therefore be a challenge. In this review we discuss the role of conventional imaging in the diagnosis of neuromyelitis optica, and the scope of quantitative MRI modalities to identify more specific pathophysiological features to aid in the differentiation from other conditions and assess treatment response.
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http://dx.doi.org/10.1016/j.msard.2013.11.003DOI Listing
May 2014

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Nat Genet 2015 Apr 2;47(4):367-372. Epub 2015 Mar 2.

Department of Radiation Oncology, University of Toronto, Toronto, Canada.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
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http://dx.doi.org/10.1038/ng.3221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380509PMC
April 2015

Structural imaging of the cervical spinal cord with suppressed CSF signal using DANTE pulse trains.

Magn Reson Med 2015 Oct 25;74(4):971-7. Epub 2014 Sep 25.

FMRIB Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Purpose: We propose DANTE (Delays Alternating with Nutation for Tailored Excitation) moving fluid attenuation preparation pulse trains, in conjunction with T1 , T2 , and proton-density-weighted fast spin-echo (T1w-TSE, T2w-TSE and PDw-TSE) imaging readout, and three-dimensional fast low flip angle shots (3D-FLASH) T1 -weighted imaging readout to achieve CSF-suppressed high-spatial resolution multicontrast cervical spinal cord images.

Methods: DANTE pulse trains, consisting of a rapid series of low flip angle radiofrequency pulses interspersed with gradients, were used to substantially attenuate the longitudinal magnetization of flowing spins relative to static tissue/fluid, whose longitudinal magnetization is mostly preserved. We hypothesized that the contrast between spinal cord and cerebrospinal fluid (CSF) could be maximized due to moving CSF signal suppression.

Results: We demonstrate that metrics of contrast-to-noise ratio between spinal cord, nerve root, and CSF regions (CNRcord-CSF and CNRnerve-CSF ) are improved by at least a factor of 2 when compared with images acquired with non-prepared approaches and with 2D multiple-echo data image combination (MEDIC) imaging. In addition, we find that sagittal image quality can be significantly improved due to flow suppression effects from the DANTE preparation pluses.

Conclusion: DANTE prepared imaging techniques for moving CSF signal attenuation are promising tools for cervical spinal cord imaging.
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http://dx.doi.org/10.1002/mrm.25474DOI Listing
October 2015

A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis.

Neurology 2014 Oct 24;83(17):1492-9. Epub 2014 Sep 24.

From the CR-UK/MRC Gray Institute for Radiation Oncology and Biology (A.M.D., J.R.L., N.R.S.), Department of Pharmacology (A.M.D., D.C.A.), Department of Chemistry (A.M.D., B.G.D., T.D.W.C.), Nuffield Department of Clinical Neurosciences (A.C., L.M., M.R.T.), and Nuffield Department of Medicine (G.K.W.), University of Oxford; and the Department of Biochemistry (J.L.G., J.P.), University of Cambridge, UK.

Objective: We tested whether it is possible to differentiate relapsing-remitting (RR) from secondary progressive (SP) disease stages in patients with multiple sclerosis (MS) using a combination of nuclear magnetic resonance (NMR) metabolomics and partial least squares discriminant analysis (PLS-DA) of biofluids, which makes no assumptions on the underlying mechanisms of disease.

Methods: Serum samples were obtained from patients with primary progressive MS (PPMS), SPMS, and RRMS; patients with other neurodegenerative conditions; and age-matched controls. Samples were analyzed by NMR and PLS-DA models were derived to separate disease groups.

Results: The PLS-DA models for serum samples from patients with MS enabled reliable differentiation between RRMS and SPMS. This approach also identified significant differences between the metabolite profiles of each of the MS groups (PP, SP, and RR) and the healthy controls, as well as predicting disease group membership with high specificity and sensitivity.

Conclusions: NMR metabolomics analysis of serum is a sensitive and robust method for differentiating between different stages of MS, yielding diagnostic markers without a priori knowledge of disease pathogenesis. Critically, this study identified and validated a type II biomarker for the RR to SP transition in patients with MS. This approach may be of considerable benefit in categorizing patients for treatment and as an outcome measure in future clinical trials.

Classification Of Evidence: This study provides Class II evidence that serum metabolite profiles accurately distinguish patients with different subtypes and stages of MS.
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http://dx.doi.org/10.1212/WNL.0000000000000905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222850PMC
October 2014

MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis.

J Neurol Neurosurg Psychiatry 2015 May 22;86(5):537-42. Epub 2014 Jul 22.

Oxford University Hospitals NHS Trust, Oxford, UK Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.

Background: Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON and MS (LMS) raises an important question about whether there could be a common pathophysiological mechanism involving mitochondrial dysfunction.

Objective: The primary aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions in the context of LHON.

Methods: A blinded standardised review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three independent experts in the field. MS-like MRI features were assessed.

Results: All patients with LMS and 26% of patients with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions consistent with MS compared with male patients (relative risk 8.3).

Conclusions: A blinded review of conventional brain MRIs shows that patients with LMS have a scan appearance indistinguishable from MS. Mitochondrial dysfunction could be a common pathophysiological pathway in the formation of white matter lesions. There appears to be a strong female influence on the radiological appearance as well as clinical development of MS in patients with LHON.
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http://dx.doi.org/10.1136/jnnp-2014-308186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413690PMC
May 2015

Low grade Ductal Carcinoma in situ (DCIS): how best to describe it?

Breast 2014 Oct 27;23(5):693-6. Epub 2014 Jun 27.

Cancer Research UK Clinical Trials Unit (CRCTU), School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.

Background: In the absence of definitive data about the natural history of DCIS the appropriateness of describing DCIS as cancer is controversial.

Methods: We conducted a survey amongst British Breast Group (BBG) members, to determine which descriptions of DCIS were deemed most accurate and appropriate.

Results: 54/73 (74%) attendees completed the survey: A majority (34/54; 63%) said they would be comfortable using the description that explained DCIS as abnormal cells in the milk ducts that had not spread into other breast tissue and which did not need urgent treatment as if it was breast cancer and this description was overall the most preferred (24/54; 44%).

Conclusions: Little consensus exists regarding how best to explain low grade DCIS to patients.
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http://dx.doi.org/10.1016/j.breast.2014.06.013DOI Listing
October 2014
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