Isocitrate Dehydrogenase 1/2 Wildtype Adult Astrocytoma with WHO Grade 2/3 Histological Features: Molecular Re-Classification, Prognostic Factors, Clinical Outcomes.

BACKGROUND: Isocitrate Dehydrogenase 1/2 (IDH 1/2)-wildtype (WT) astrocytomas constitute a heterogeneous group of tumors and have undergone a series of diagnostic reclassifications over time. This study aimed to investigate molecular markers, clinical, imaging, and treatment factors predictive of outcomes in WHO grade 2/3 IDH-WT astrocytomas ('early glioblastoma'). METHODOLOGY: Patients with WHO grade 2/3 IDH-WT astrocytomas were identified from the hospital archives. They were cross-referenced with the electronic medical records systems, including neuroimaging. The expert neuro-pathology team retrieved data on molecular markers-MGMT, TERT, IDH, and EGFR. Tumors with a TERT mutation and/or EGFR amplification were reclassified as glioblastoma. RESULTS: Fifty-four patients were identified. Sixty-three percent of the patients could be conclusively reclassified as glioblastoma based on either TERT mutation, EGFR amplification, or both. On imaging, 65% showed gadolinium enhancement on MRI. Thirty-nine patients (72%) received long-course radiotherapy, of whom 64% received concurrent chemotherapy. The median follow-up of the group was 16 months (range: 2-90), and the median overall survival (OS) was 17.3 months. The 2-year OS of the whole cohort was 31%. On univariate analysis, older age, worse performance status (PS), and presence versus absence of contrast enhancement on diagnostic MRI were statistically significant for poorer OS. CONCLUSION: IDH-WT WHO grade 2/3 astrocytomas are a heterogeneous group of tumors with poor clinical outcomes. The majority can be reclassified as glioblastoma, based on current WHO classification criteria, but further understanding of the underlying biology of these tumors and the discovery of novel targeted agents are needed for better outcomes.

Early MRI Predictors of Relapse in Primary Central Nervous System Lymphoma Treated with MATRix Immunochemotherapy.

Primary Central Nervous System Lymphoma (PCNSL) is a highly malignant brain tumour. We investigated dynamic changes in tumour volume and apparent diffusion coefficient (ADC) measurements for predicting outcome following treatment with MATRix chemotherapy in PCNSL. Patients treated with MATRix (n = 38) underwent T1 contrast-enhanced (T1CE) and diffusion-weighted imaging (DWI) before treatment, after two cycles and after four cycles of chemotherapy. Response was assessed using the International PCNSL Collaborative Group (IPCG) imaging criteria. ADC histogram parameters and T1CE tumour volumes were compared among response groups, using one-way ANOVA testing. Logistic regression was performed to examine those imaging parameters predictive of response. Response after two cycles of chemotherapy differed from response after four cycles; of the six patients with progressive disease (PD) after four cycles of treatment, two (33%) had demonstrated a partial response (PR) or complete response (CR) after two cycles. ADCmean at baseline, T1CE at baseline and T1CE percentage volume change differed between response groups (0.005 < p < 0.038) and were predictive of MATRix treatment response (area under the curve: 0.672-0.854). Baseline ADC and T1CE metrics are potential biomarkers for risk stratification of PCNSL patients early during remission induction therapy with MATRix. Standard interim response assessment (after two cycles) according to IPCG imaging criteria does not reliably predict early disease progression in the context of a conventional treatment approach.

Radiomic Analysis of Tumour Heterogeneity Using MRI in Head and Neck Cancer Following Chemoradiotherapy: A Feasibility Study.

OBJECTIVES: To evaluate interval changes in heterogeneity on diffusion-weighted apparent diffusion coefficient (ADC) maps and T1-weighted post-gadolinium (T1w post gad) MRI in head and neck carcinoma (HNSCC), with and without chemo-radiotherapy (CRT) response. METHODS: This prospective observational cohort study included 24 participants (20 men, age 62.9 ± 8.8 years) with stage III and IV HNSCC. The primary tumour (n = 23) and largest lymph node (n = 22) dimensions, histogram parameters and grey-level co-occurrence matrix (GLCM) parameters were measured on ADC maps and T1w post gad sequences, performed pretreatment and 6 and 12 weeks post CRT. The 2-year treatment response at primary and nodal sites was recorded. The Wilcoxon signed-rank test was used to compare interval changes in parameters after stratifying for treatment response and failure (p < 0.001 statistical significance). RESULTS: 23/23 primary tumours and 18/22 nodes responded to CRT at 2 years. Responding HNSCC demonstrated a significant interval change in ADC histogram parameters (kurtosis, coefficient of variation, entropy, energy for primary tumour; kurtosis for nodes) and T1w post gad GLCM (entropy and contrast in the primary tumour and nodes) by 6 weeks post CRT (p < 0.001). Lymph nodes with treatment failure did not demonstrate an interval alteration in heterogeneity parameters. CONCLUSIONS: ADC maps and T1w post gad MRI demonstrate the evolution of heterogeneity parameters in successfully treated HNSCC by 6 weeks post CRT; however, this is not observed in lymph nodes failing treatment. ADVANCES IN KNOWLEDGE: Early reduction in heterogeneity is demonstrated on MRI when HNSCC responds to CRT.

The impact of Human Papilloma Virus status on the prediction of head and neck cancer chemoradiotherapy outcomes using the pre-treatment apparent diffusion coefficient.

OBJECTIVE: To determine the impact of Human Papilloma Virus (HPV) oropharyngeal cancer (OPC) status on the prediction of head and neck squamous cell cancer (HNSCC) chemoradiotherapy (CRT) outcomes with pre-treatment quantitative diffusion-weighted magnetic resonance imaging (DW-MRI). METHODS: Following ethical approval, 65 participants (53 male, age 59.9 ± 7.86) underwent pre-treatment DW-MRI in this prospective cohort observational study. There were 46 HPV OPC and 19 other HNSCC cases with Stage III/IV HNSCC. Regions of interest (ROIs) (volume, largest area, core) at the primary tumour (n = 57) and largest pathological node (n = 59) were placed to analyse ADCmean and ADCmin. Unpaired t-test or Mann-Whitney test evaluated the impact of HPV OPC status and clinical parameters on their prediction of post-CRT 2 year locoregional and disease-free survival (LRFS and DFS). Multivariate logistic regression compared significant variables with 2 year outcomes. RESULTS: On univariate analysis of all participants, the primary tumour area ADCmean was predictive of 2 year LRFS (p = 0.04). However, only the HPV OPC diagnosis (LFRS p = 0.03; DFS p = 0.02) predicted outcomes on multivariate analysis. None of the pre-treatment ADC values were predictive of 2 year DFS in the HPV OPC subgroup (p = 0.21-0.68). Amongst participants without 2 year disease-free survival, HPV-OPC was found to have much lower primary tumour ADCmean values than other HNSCC. CONCLUSION: Knowledge of HPV OPC status is required in order to determine the impact of the pre-treatment ADC values on post-CRT outcomes in HNSCC. ADVANCES IN KNOWLEDGE: Pre-treatment ADCmean and ADCmin values acquired using different ROI methods are not predictive of 2 year survival outcomes in HPV OPC.

Apparent diffusion coefficient agreement and reliability using different region of interest methods for the evaluation of head and neck cancer post chemo-radiotherapy.

OBJECTIVES: Post chemoradiotherapy (CRT) interval changes in apparent diffusion coefficient (ADC) have prognostic value in head and neck squamous cell cancer (HNSCC). The impact of using different region of interest (ROI) methods on interobserver agreement and their ability to reliably detect the changes in the ADC values was assessed. METHODS: Following ethical approval, 25 patients (mean age 59.5 years, 21 male) with stage 3-4 HNSCC undergoing CRT were recruited for this prospective cohort study. Diffusion weighted MRI (DW-MRI) was performed pre-treatment and at 6 and 12 weeks following CRT. Two radiologists independently delineated ROIs using whole volume (ROIv), largest area (ROIa) or representative area (ROIr) methods at primary tumour (n = 22) and largest nodal (n = 24) locations and recorded the ADCmean. When no clear focus of increased DWI signal was evident at follow-up, a standardised ROI was placed (non-measurable or NM). Bland-Altman plots and interclass correlation coefficient (ICC) were assessed. Paired t-tests evaluated interval changes in pre- and post-treatment ADCmean at each location, which were compared to the smallest detectable difference (SDD). RESULTS: Excellent agreement was obtained for all ROI methods at pre-treatment (ICC 0.94-0.98) and 6-week post-treatment (ICC 0.94-0.98). At 12-week post-treatment, agreement was excellent (ICC 0.91-0.94) apart from ROIr (ICC 0.86) and the NM nodal disease (ICC 0.87). There were significant interval increases in ADCmean between pre-treatment and post-treatment studies, which were greater than the SDD for all ROIs. CONCLUSIONS: ADCmean values can be reproducibly obtained in HNSCC using the different ROI techniques on pre- and post-CRT MRI, and this reliably detects the interval changes.

Correlations between DW-MRI and 18 F-FDG PET/CT parameters in head and neck squamous cell carcinoma following definitive chemo-radiotherapy.

BACKGROUND: Posttreatment diffusion-weighted magnetic resonance imaging (DW-MRI) and 18F-fluorodeoxygluocose (18 F-FDG) positron emission tomography (PET) with computed tomography (PET/CT) have potential prognostic value following chemo-radiotherapy (CRT) for head and neck squamous cell carcinoma (HNSCC). Correlations between these PET/CT (standardized uptake value or SUV) and DW-MRI (apparent diffusion coefficient or ADC) parameters have only been previously explored in the pretreatment setting. AIM: To evaluate stage III and IV HNSCC at 12-weeks post-CRT for the correlation between SUVmax and ADC values and their interval changes from pretreatment imaging. METHODS: Fifty-six patients (45 male, 11 female, mean age 59.9 + - 7.38) with stage 3 and 4 HNSCC patients underwent 12-week posttreatment DW-MRI and 18 F-FDG PET/CT studies in this prospective study. There were 41/56 patients in the cohort with human papilloma virus-related oropharyngeal cancer (HPV OPC). DW-MRI (ADCmax and ADCmin) and 18 F-FDG PET/CT (SUVmax and SUVmax ratio to liver) parameters were measured at the site of primary tumors (n = 48) and the largest lymph nodes (n = 52). Kendall's tau evaluated the correlation between DW-MRI and 18 F-FDG PET/CT parameters. Mann-Whitney test compared the post-CRT PET/CT and DW-MRI parameters between those participants with and without 2-year disease-free survival (DFS). RESULTS: There was no correlation between DW-MRI and 18 F-FDG PET/CT parameters on 12-week posttreatment imaging (P = .455-.794; tau = -0.075-0.25) or their interval changes from pretreatment to 12-week posttreatment imaging (P = .1-.946; tau = -0.194-0.044). The primary tumor ADCmean (P = .03) and the interval change in nodal ADCmin (P = .05) predicted 2-year DFS but none of the 18 F-FDG PET/CT parameters were associated with 2-year DFS. CONCLUSIONS: There is no correlation between the quantitative DWI-MRI and 18 F-FDG PET/CT parameters derived from 12-week post-CRT studies. These parameters may be independent biomarkers however in this HPV OPC dominant cohort, only selected ADC parameters demonstrated prognostic significance. Study was prospectively registered at http://www.controlled-trials.com/ISRCTN58327080.

Conventional MRI features of adult diffuse glioma molecular subtypes: a systematic review.

PURPOSE: Molecular parameters have become integral to glioma diagnosis. Much of radiogenomics research has focused on the use of advanced MRI techniques, but conventional MRI sequences remain the mainstay of clinical assessments. The aim of this research was to synthesize the current published data on the accuracy of standard clinical MRI for diffuse glioma genotyping, specifically targeting IDH and 1p19q status. METHODS: A systematic search was performed in September 2019 using PubMed and the Cochrane Library, identifying studies on the diagnostic value of T1 pre-/post-contrast, T2, FLAIR, T2*/SWI and/or 3-directional diffusion-weighted imaging sequences for the prediction of IDH and/or 1p19q status in WHO grade II-IV diffuse astrocytic and oligodendroglial tumours as defined in the WHO 2016 Classification of CNS Tumours. RESULTS: Forty-four studies including a total of 5286 patients fulfilled the inclusion criteria. Correlations between key glioma molecular markers, namely IDH and 1p19q, and distinctive MRI findings have been established, including tumour location, signal composition (including the T2-FLAIR mismatch sign) and apparent diffusion coefficient values. CONCLUSION: Consistent trends have emerged indicating that conventional MRI is valuable for glioma genotyping, particularly in presumed lower grade glioma. However, due to limited interobserver testing, the reproducibility of qualitatively assessed visual features remains an area of uncertainty.

Glioma surveillance imaging: current strategies, shortcomings, challenges and outlook.

Inaccurate assessment of surveillance imaging to assess response to glioma therapy may have life-changing consequences. Varied management plans including chemotherapy, radiotherapy or immunotherapy may all contribute to heterogeneous post-treatment appearances and the overlap between the morphological features of pseudoprogression, pseudoresponse and radiation necrosis can make their discrimination very challenging. Therefore, there has been a drive to develop objective strategies for post-treatment assessment of brain gliomas. This review discusses the most important of these approaches such as the RANO "Response Assessment in Neuro-Oncology", iRANO "Immunotherapy Response Assessment in Neuro-Oncology" and RAPNO "Response Assessment in Paediatric Neuro-Oncology" models. In addition to these systematic approaches for glioma surveillance, the relatively limited information provided by conventional imaging modalities alone has motivated the development of novel advanced magnetic resonance (MR) and metabolic imaging methods for further discrimination between viable tumour and treatment induced changes. Multiple clinical trials and meta-analyses have investigated the diagnostic performance of these novel techniques in the follow up of brain gliomas, including both single modality descriptive studies and comparative imaging assessment. In this manuscript, we review the literature and discuss the promises and pitfalls of frequently studied modalities in glioma surveillance imaging, including MR perfusion, MR diffusion and MR spectroscopy. In addition, we evaluate other promising MR techniques such as chemical exchange saturation transfer as well as fludeoxyglucose and non-FDG positron emission tomography techniques.

Strain maps of the left atrium imaged with a novel high-resolution CINE MRI protocol.

To date, regional atrial strains have not been imaged in vivo, despite their potential to provide useful clinical information. To address this gap, we present a novel CINE MRI protocol capable of imaging the entire left atrium at an isotropic 2-mm resolution in one single breath-hold. As proof of principle, we acquired data in 10 healthy volunteers and 2 cardiovascular patients using this technique. We also demonstrated how regional atrial strains can be estimated from this data following a manual segmentation of the left atrium using automatic image tracking techniques. The estimated principal strains vary smoothly across the left atrium and have a similar magnitude to estimates reported in the literature.

Radiomic analysis for response assessment in advanced head and neck cancers, a distant dream or an inevitable reality? A systematic review of the current level of evidence.

OBJECTIVE: The recent increase in publications on radiomic analysis as means to produce diagnostic and predictive biomarkers in head and neck cancers (HNCC) reveal complicated and often conflicting results. The objective of this paper is to systematically review the published data, and evaluate the current level of evidence accumulated that would determine clinical application. METHODS: Data sources: Articles in the English language available on the Ovid-MEDLINE and Embase databases were used for the literature search. Study selection:Studies which evaluated the role of radiomics as a predictive or prognostic tool for response assessment in HNCC were included in this review.Study appraisal and synthesis methods: The authors set-out to perform a meta-analysis, however given the small number of studies retrieved that presented adequate data, combined with excessive methodological heterogeneity, we could only perform a structured descriptive systematic review summarizing the key findings. Independent extraction of articles was performed by two authors using predefined data fields and any disagreement was resolved by consensus. RESULTS: Though most papers concluded that radiomics is an effective predictive and prognostic biomarker in the management of HNCC, significant heterogeneity exists in the study methodology and statistical modelling; thus precluding accurate mathematical comparison or the ability to make clear recommendations going forwards. Moreover, most studies have not been validated and the reproducibility of their results will be a challenge. CONCLUSION: Until robust external validation studies on the reproducibility and accuracy of radiomic analysis methods on HNCC are carried out, the current level of evidence remains low, with the authors advising caution against hasty implementation of these tools in the multidisciplinary clinic. ADVANCES IN KNOWLEDGE: This review is the first attempt to critically analyze the merits and demerits of currently published literature on tumour heterogeneity studies in HNCC, and identifies specific loop holes that need to be addressed by research groups, for a meaningful clinical translation of this potential biomarker.

An optimised tract-based spatial statistics protocol for neonates: applications to prematurity and chronic lung disease.

Preterm birth is associated with altered white matter microstructure, defined by metrics derived from diffusion tensor imaging (DTI). Tract-based spatial statistics (TBSS) is a useful tool for investigating developing white matter using DTI, but standard TBSS protocols have limitations for neonatal studies. We describe an optimised TBSS protocol for neonatal DTI data, in which registration errors are reduced. As chronic lung disease (CLD) is an independent risk factor for abnormal white matter development, we investigate the effect of this condition on white matter anisotropy and diffusivity using the optimised protocol in a proof of principle experiment. DTI data were acquired from 93 preterm infants (48 male) with a median gestational age at birth of 28(+5) (23(+4)-35(+2))weeks at a median postmenstrual age at scan of 41(+4) (38(+1)-46(+6))weeks. Nineteen infants developed CLD, defined as requiring supplemental oxygen at 36weeks postmenstrual age. TBSS was modified to include an initial low degrees-of-freedom linear registration step and a second registration to a population-average FA map. The additional registration steps reduced global misalignment between neonatal fractional anisotropy (FA) maps. Infants with CLD had significantly increased radial diffusivity (RD) and significantly reduced FA within the centrum semiovale, corpus callosum and inferior longitudinal fasciculus (p<0.05) compared to their peers, controlling for degree of prematurity and age at scan. The optimised TBSS protocol improved reliability for neonatal DTI analysis. These data suggest that potentially modifiable respiratory morbidity is associated with widespread altered white matter microstructure in preterm infants at term-equivalent age.

Magnetic resonance imaging of white matter diseases of prematurity.

Periventricular leucomalacia (PVL) and parenchymal venous infarction complicating germinal matrix/intraventricular haemorrhage have long been recognised as the two significant white matter diseases responsible for the majority of cases of cerebral palsy in survivors of preterm birth. However, more recent studies using magnetic resonance imaging to assess the preterm brain have documented two new appearances, adding to the spectrum of white matter disease of prematurity: punctate white matter lesions, and diffuse excessive high signal intensity (DEHSI). These appear to be more common than PVL but less significant in terms of their impact on individual neurodevelopment. They may, however, be associated with later cognitive and behavioural disorders known to be common following preterm birth. It remains unclear whether PVL, punctate lesions, and DEHSI represent a continuum of disorders occurring as a result of a similar injurious process to the developing white matter. This review discusses the role of MR imaging in investigating these three disorders in terms of aetiology, pathology, and outcome.

The association of lung disease with cerebral white matter abnormalities in preterm infants.

OBJECTIVE: Preterm infants have a high incidence of neurodevelopmental impairment associated with diffuse cerebral white matter abnormalities and also a high incidence of serious respiratory disease. However, it is unclear if lung disease and brain injury are related, and previous research has been impeded by confounding effects, including prematurity and infection. Using a new approach that permits multivariate statistical analysis, we tested the hypothesis that lung disease is associated with specific white matter abnormalities, detected as reduced fractional anisotropy (FA) in diffusion tensor imaging data. METHODS: Fifty-three preterm infants with no evidence of focal abnormality on conventional MRI were studied at term-equivalent age by using tract-based spatial statistics, an automated observer-independent method for voxelwise analysis of major white matter pathways. RESULTS: In several white matter tracts, FA decreased with a linear relation to the gestational age at birth. Independent of the confounding effects of prematurity and age at scan, respiratory disease was associated with specific white matter abnormalities in preterm infants; those infants receiving mechanical ventilation for >2 days in the perinatal period (n = 10) showed reduced FA in the genu of the corpus callosum, whereas subjects with chronic lung disease (n = 15) displayed a reduction in FA in the left inferior longitudinal fasciculus. CONCLUSION: Independent of the degree of prematurity, respiratory disease is associated with cerebral white matter abnormalities.

Diffusion tensor imaging (DTI) of the brain in moving subjects: application to in-utero fetal and ex-utero studies.

We present a methodology to achieve 3D high-resolution diffusion tensor image reconstruction of the brain in moving subjects. The source data is diffusion-sensitized single-shot echo-planar images. After continuous scanning to acquire a repeated series of parallel slices with 15 diffusion directions, image registration is used to realign the images to correct for subject motion. Once aligned, the diffusion images are treated as irregularly-sampled data where each voxel is associated with an appropriately rotated diffusion direction. This data is used to estimate the diffusion tensor on a regular grid. The method has been tested on data acquired at 1.5T from adults who deliberately moved and from eight fetuses imaged in utero. Maps of apparent diffusion coefficient (ADC) were reliably produced in all cases and promising performance was achieved for fractional anisotropy maps. Results from normal fetal brains were found to be consistent with published data from premature infants of similar gestational age.

Specific relations between neurodevelopmental abilities and white matter microstructure in children born preterm.

Survivors of preterm birth have a high incidence of neurodevelopmental impairment which is not explained by currently understood brain abnormalities. The aim of this study was to test the hypothesis that the neurodevelopmental abilities of 2-year-old children who were born preterm and who had no evidence of focal abnormality on conventional MR imaging were consistently linearly related to specific local changes in white matter microstructure. We studied 33 children, born at a median (range) gestational age of 28(+5) (24(+4)-32(+1)) weeks. The children were recruited as infants from the Neonatal Intensive Care Unit at Queen Charlotte's and Hammersmith Hospital in the early neonatal period and imaged at a median corrected age of 25.5 (24-27) months. The children underwent diffusion tensor imaging to measure fractional anisotropy (FA) as a measure of tissue microstructure, and neurodevelopmental assessment using the Griffiths Mental Development Scales [giving an overall developmental quotient (DQ) and sub-quotients scores for motor, personal-social, hearing-language, eye-hand coordination and performance scales] at 2 years corrected age. Tract-based spatial statistics with linear regression analysis of voxel-wise cross-subject statistics were used to assess the relationship between FA and DQ/sub-quotient scores and results confirmed by reduced major axis regression of regions with significant correlations. We found that DQ was linearly related to FA values in parts of the corpus callosum; performance sub-scores to FA values in the corpus callosum and right cingulum; and eye-hand coordination sub-scores to FA values in the cingulum, fornix, anterior commissure, corpus callosum and right uncinate fasciculus. This study shows that specific neurodevelopmental impairments in infants born preterm are precisely related to microstructural abnormalities in particular regions of cerebral white matter which are consistent between individuals. FA may aid prognostication and provide a biomarker for therapeutic or mechanistic studies of preterm brain injury.

In-utero three dimension high resolution fetal brain diffusion tensor imaging.

We present a methodology to achieve 3D high resolution in-utero fetal brain DTI that shows excellent ADC as well as promising FA maps. After continuous DTI scanning to acquire a repeated series of parallel slices with 15 diffusion directions, image registration is used to realign the images to correct for fetal motion. Once aligned, the diffusion images are treated as irregularly sampled data where each voxel is associated with an appropriately rotated diffusion direction, and used to estimate the diffusion tensor on a regular grid. The method has been tested successful on eight fetuses and has been validated on adults imaged at 1.5T.

Diffusion tensor imaging with tract-based spatial statistics reveals local white matter abnormalities in preterm infants.

Infants born preterm have a high incidence of neurodevelopmental impairment in later childhood, often associated with poorly defined cerebral white matter abnormalities. Diffusion tensor imaging quantifies the diffusion of water within tissues and can assess microstructural abnormalities in the developing preterm brain. Tract-based spatial statistics (TBSS) is an automated observer-independent method of aligning fractional anisotropy (FA) images from multiple subjects to allow groupwise comparisons of diffusion tensor imaging data. We applied TBSS to test the hypothesis that preterm infants have reduced fractional anisotropy in specific regions of white matter compared to term-born controls. We studied 26 preterm infants with no evidence of focal lesions on conventional magnetic resonance imaging (MRI) at term equivalent age and 6 healthy term-born control infants. We found that the centrum semiovale, frontal white matter and the genu of the corpus callosum showed significantly lower FA in the preterm group. Infants born at less than or equal to 28 weeks gestational age (n=11) displayed additional reductions in FA in the external capsule, the posterior aspect of the posterior limb of the internal capsule and the isthmus and middle portion of the body of the corpus callosum. This study demonstrates that TBSS provides an observer-independent method of identifying white matter abnormalities in the preterm brain at term equivalent age in the absence of focal lesions.