Development and multicenter validation of a multiparametric imaging model to predict treatment response in rectal cancer.

OBJECTIVES: To develop and validate a multiparametric model to predict neoadjuvant treatment response in rectal cancer at baseline using a heterogeneous multicenter MRI dataset. METHODS: Baseline staging MRIs (T2W (T2-weighted)-MRI, diffusion-weighted imaging (DWI) / apparent diffusion coefficient (ADC)) of 509 patients (9 centres) treated with neoadjuvant chemoradiotherapy (CRT) were collected. Response was defined as (1) complete versus incomplete response, or (2) good (Mandard tumor regression grade (TRG) 1-2) versus poor response (TRG3-5). Prediction models were developed using combinations of the following variable groups: (1) Non-imaging: age/sex/tumor-location/tumor-morphology/CRT-surgery interval (2) Basic staging: cT-stage/cN-stage/mesorectal fascia involvement, derived from (2a) original staging reports, or (2b) expert re-evaluation (3) Advanced staging: variables from 2b combined with cTN-substaging/invasion depth/extramural vascular invasion/tumor length (4) Quantitative imaging: tumour volume + first-order histogram features (from T2W-MRI and DWI/ADC) Models were developed with data from 6 centers (n = 412) using logistic regression with the Least Absolute Shrinkage and Selector Operator (LASSO) feature selection, internally validated using repeated (n = 100) random hold-out validation, and externally validated using data from 3 centers (n = 97). RESULTS: After external validation, the best model (including non-imaging and advanced staging variables) achieved an area under the curve of 0.60 (95%CI=0.48-0.72) to predict complete response and 0.65 (95%CI=0.53-0.76) to predict a good response. Quantitative variables did not improve model performance. Basic staging variables consistently achieved lower performance compared to advanced staging variables. CONCLUSIONS: Overall model performance was moderate. Best results were obtained using advanced staging variables, highlighting the importance of good-quality staging according to current guidelines. Quantitative imaging features had no added value (in this heterogeneous dataset). CLINICAL RELEVANCE STATEMENT: Predicting tumour response at baseline could aid in tailoring neoadjuvant therapies for rectal cancer. This study shows that image-based prediction models are promising, though are negatively affected by variations in staging quality and MRI acquisition, urging the need for harmonization. KEY POINTS: This multicenter study combining clinical information and features derived from MRI rendered disappointing performance to predict response to neoadjuvant treatment in rectal cancer. Best results were obtained with the combination of clinical baseline information and state-of-the-art image-based staging variables, highlighting the importance of good quality staging according to current guidelines and staging templates. No added value was found for quantitative imaging features in this multicenter retrospective study. This is likely related to acquisition variations, which is a major problem for feature reproducibility and thus model generalizability.

Evolutions in rectal cancer MRI staging and risk stratification in The Netherlands.

PURPOSE: To analyze how the MRI reporting of rectal cancer has evolved (following guideline updates) in The Netherlands. METHODS: Retrospective analysis of 712 patients (2011-2018) from 8 teaching hospitals in The Netherlands with available original radiological staging reports that were re-evaluated by a dedicated MR expert using updated guideline criteria. Original reports were classified as "free-text," "semi-structured," or "template" and completeness of reporting was documented. Patients were categorized as low versus high risk, first based on the original reports (high risk = cT3-4, cN+, and/or cMRF+) and then based on the expert re-evaluations (high risk = cT3cd-4, cN+, MRF+, and/or EMVI+). Evolutions over time were studied by splitting the inclusion period in 3 equal time periods. RESULTS: A significant increase in template reporting was observed (from 1.6 to 17.6-29.6%; p < 0.001), along with a significant increase in the reporting of cT-substage, number of N+ and extramesorectal nodes, MRF invasion and tumor-MRF distance, EMVI, anal sphincter involvement, and tumor morphology and circumference. Expert re-evaluation changed the risk classification from high to low risk in 18.0% of cases and from low to high risk in 1.7% (total 19.7%). In the majority (17.9%) of these cases, the changed risk classification was likely (at least in part) related to use of updated guideline criteria, which mainly led to a reduction in high-risk cT-stage and nodal downstaging. CONCLUSION: Updated concepts of risk stratification have increasingly been adopted, accompanied by an increase in template reporting and improved completeness of reporting. Use of updated guideline criteria resulted in considerable downstaging (of mainly high-risk cT-stage and nodal stage).

Sources of variation in multicenter rectal MRI data and their effect on radiomics feature reproducibility.

OBJECTIVES: To investigate sources of variation in a multicenter rectal cancer MRI dataset focusing on hardware and image acquisition, segmentation methodology, and radiomics feature extraction software. METHODS: T2W and DWI/ADC MRIs from 649 rectal cancer patients were retrospectively acquired in 9 centers. Fifty-two imaging features (14 first-order/6 shape/32 higher-order) were extracted from each scan using whole-volume (expert/non-expert) and single-slice segmentations using two different software packages (PyRadiomics/CapTk). Influence of hardware, acquisition, and patient-intrinsic factors (age/gender/cTN-stage) on ADC was assessed using linear regression. Feature reproducibility was assessed between segmentation methods and software packages using the intraclass correlation coefficient. RESULTS: Image features differed significantly (p < 0.001) between centers with more substantial variations in ADC compared to T2W-MRI. In total, 64.3% of the variation in mean ADC was explained by differences in hardware and acquisition, compared to 0.4% by patient-intrinsic factors. Feature reproducibility between expert and non-expert segmentations was good to excellent (median ICC 0.89-0.90). Reproducibility for single-slice versus whole-volume segmentations was substantially poorer (median ICC 0.40-0.58). Between software packages, reproducibility was good to excellent (median ICC 0.99) for most features (first-order/shape/GLCM/GLRLM) but poor for higher-order (GLSZM/NGTDM) features (median ICC 0.00-0.41). CONCLUSIONS: Significant variations are present in multicenter MRI data, particularly related to differences in hardware and acquisition, which will likely negatively influence subsequent analysis if not corrected for. Segmentation variations had a minor impact when using whole volume segmentations. Between software packages, higher-order features were less reproducible and caution is warranted when implementing these in prediction models. KEY POINTS: • Features derived from T2W-MRI and in particular ADC differ significantly between centers when performing multicenter data analysis. • Variations in ADC are mainly (> 60%) caused by hardware and image acquisition differences and less so (< 1%) by patient- or tumor-intrinsic variations. • Features derived using different image segmentations (expert/non-expert) were reproducible, provided that whole-volume segmentations were used. When using different feature extraction software packages with similar settings, higher-order features were less reproducible.

Short-term Results of the RAPID Randomized Trial of the Legflow Paclitaxel-Eluting Balloon With Supera Stenting vs Supera Stenting Alone for the Treatment of Intermediate and Long Superficial Femoral Artery Lesions.

PURPOSE: To report a randomized trial comparing the Legflow paclitaxel-eluting balloon (PEB) + Supera stenting to Supera stenting alone in patients with intermediate to long superficial femoral artery (SFA) lesions. METHODS: The multicenter RAPID trial ( controlled-trials.com ; identifier ISRCTN47846578) randomized (1:1) 160 patients (mean age 67 years; 102 men) with Rutherford category 2-6 ischemia to treatment with Legflow PEB + Supera stent or Supera stent alone in intermediate to long SFA lesions (mean lesion length 15.8±7.4 vs 15.8±7.6 cm, respectively). The efficacy outcome was primary patency, defined as freedom from restenosis on duplex ultrasound or angiography. RESULTS: Baseline characteristics including the percentage of occlusions were similar between groups. In the intention-to-treat analysis, the estimated primary patency at 1 year was 68.3% (95% CI 56.7% to 79.9%) in the PEB + Supera group vs 62.0% (95% CI 49.1% to 74.9%) in the Supera group (p=0.900). Per-protocol analysis showed a 12-month primary patency estimate of 74.7% (95% CI 63.1% to 86.3%) in the PEB + Supera group vs 62.0% (95% CI 49.1% to 74.9%) in the control group (p=0.273). Secondary patency estimates at 12 months (per-protocol analysis) were 89.0% (95% CI 80.6% to 97.4%) vs 98.0% (95% CI 94.1% to 100%; p=0.484); the estimates for freedom from clinically driven target lesion revascularization (CD-TLR) were 83.0% (95% CI 72.8% to 93.2%) and 77.8% (95% CI 66.6% to 89.0%; p=0.277), respectively. CONCLUSION: The short-term results from the multicenter RAPID randomized controlled trial indicate that the Legflow PEB is safe and feasible for the treatment of intermediate to long SFA lesions. In this trial, at least 70% of the patients suffered an occlusion. The PEB group had higher rates of primary patency and freedom from CD-TLR, although there were no statistically significant differences vs controls.

Brain involvement in rheumatoid arthritis: a magnetic resonance spectroscopy study.

OBJECTIVE: Tumor necrosis factor alpha was recently implicated as an important mediator of communication between the peripheral and cerebral immune systems in an animal model of chronic inflammation. The purpose of this study was to examine by proton magnetic resonance spectroscopy ((1)H-MRS) the influence of inflammation on cerebral metabolism in patients with rheumatoid arthritis (RA). METHODS: Single-voxel (1)H-MRS of the centrum semiovale was performed on 35 RA patients (6 men and 29 women; mean +/- SD age 51.8 +/- 14.6 years) and 28 healthy age- and sex-matched control subjects (9 men and 19 women; mean +/- SD age 50.2 +/- 10.4 years). None of the study subjects had any neurologic signs or symptoms. Clinical markers of disease activity were correlated with the (1)H-MRS findings. RESULTS: Patients with active RA, as reflected by an elevated erythrocyte sedimentation rate (ESR), had a significantly higher ratio of choline to creatine and a significantly lower ratio of N-acetylaspartate to choline than did patients with inactive RA, as reflected by a normal ESR. Moreover, the ratios of choline to creatine and NAA to choline were significantly correlated with the ESR after correction for age, sex, smoking status, handedness, alcohol consumption, medication use, and disease duration. Medication use had no additional effect on these associations. CONCLUSION: Our data show that systemic inflammation in RA is associated with metabolic changes in the brain.

Detection of change in CNS involvement in neuropsychiatric SLE: a magnetization transfer study.

PURPOSE: To assess whether magnetization transfer imaging (MTI) parameters change in correspondence with clinical changes in NPSLE patients. MATERIALS AND METHODS: Nineteen female patients (mean age=37.5 years, range=19-64) underwent MTI on at least two separate occasions (mean time between scans=25.4 months, range=5.4-52.3 months). Twenty-four pairs of scans of 19 patients were available. Each patient's clinical course was classified as improved, stable, or deteriorated. Whole-brain magnetization transfer ratio (MTR) histograms were generated. The peak height of these histograms was used as an estimate of parenchymal integrity. Based on the change in clinical status, paired examinations were grouped and tested for significant differences between the first and second examinations using paired-samples t-tests. RESULTS: Four patients clinically deteriorated, all patients showed a significant peak height decrease (mean decrease=8.6%, P=0.02), and in 14 patients with stable disease the peak height did not change significantly (mean increase=0.4%). Six patients clinically improved, and all showed a significant relative peak height increase (mean increase=12.0%, P=0.02). CONCLUSION: The peak height of whole-brain MTR histograms corresponds to changes in the clinical status of individual NPSLE patients. This suggests that MTI can be a valuable tool in the clinical assessment of such patients.

Association between microscopic brain damage as indicated by magnetization transfer imaging and anticardiolipin antibodies in neuropsychiatric lupus.

The pathogenetic role of anticardiolipin antibodies (aCLs) in patients with neuropsychiatric systemic lupus erythematosus (NPSLE) without cerebral infarcts remains elusive. Magnetization transfer imaging (MTI) has proved to be a sensitive tool for detecting diffuse microscopic brain damage in NPSLE patients. In this study we examined the correlation between grey and white matter magnetization transfer ratio (MTR) parameters and the presence of IgM and IgG aCLs and lupus anticoagulant in 18 patients with systemic lupus erythematosus and a history of NPSLE but without cerebral infarcts on conventional magnetic resonance imaging. Lower grey matter mean MTR (P < 0.05), white matter mean MTR (P < 0.05), white matter peak location (P < 0.05) and grey matter peak location (trend toward statistical significance) were observed in IgM aCL-positive patients than in IgM aCL-negative patients. No significant differences were found in MTR histogram parameters with respect to IgG aCL and lupus anticoagulant status, nor with respect to anti-dsDNA or anti-ENA (extractable nuclear antigen) status. This is the first report of an association between the presence of aCLs and cerebral damage in grey and white matter in NPSLE. Our findings suggest that aCLs are associated with diffuse brain involvement in NPSLE patients.

The effect of corticosteroid medication on quantitative MR parameters of the brain.

BACKGROUND AND PURPOSE: Quantitative MR imaging techniques such as magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), and MR spectroscopy are promising diagnostic tools for use with patients with diffuse brain diseases such as neuropsychiatric systemic lupus erythematosus (NPSLE). Such patients are often on corticosteroid (CS) treatment. Presently, it is unknown whether CSs per se influence quantitative MR imaging measurements. The aim of this study was to evaluate the effect of low-dose oral CSs on MTI, DWI, and MR spectroscopy parameters of the brain. METHODS: Twenty-seven rheumatoid arthritis (RA) patients with and without CS medication and 15 healthy controls were subjected to conventional MR imaging, whole-brain MTI and DWI, and single-voxel MR spectroscopy. Oral CSs were used by 13 of the RA patients. Univariate analyses with age as a covariate were performed on MTI, DWI, and MR spectroscopy parameters between RA patients with and without CSs and healthy controls. Pearson correlations were calculated between all imaging parameters and duration of disease, duration of CS use, and CS dosage. RESULTS: No significant differences between the groups of subjects or significant correlations with clinical parameters were found for MTI, DWI and MR spectroscopy parameters. CONCLUSION: In this study, we found no evidence for an effect of low-dose oral CSs on whole-brain MTI and DWI histogram parameters and single-voxel MR spectroscopy measurements of the brain. The results of this study demonstrate that it is unlikely that MTI, DWI, and MR spectroscopy parameters reported in NPSLE studies are confounded by low-dose oral CS.

Abnormal brain diffusivity in patients with neuropsychiatric systemic lupus erythematosus.

BACKGROUND AND PURPOSE: Neuroimaging techniques have increased our knowledge of the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) and have been useful in supporting the diagnosis. Nevertheless, new imaging techniques are needed to unravel the exact pathogenesis and to provide diagnostic criteria for NPSLE. In this preliminary study, we investigated whether diffusion-weighted imaging (DWI) can depict cerebral abnormalities in patients with a history of NPSLE, and we assessed whether apparent diffusion coefficient (ADC) histograms in these patients differ from those of healthy control subjects. METHODS: Eleven female patients with a history of NPSLE (mean age [+/- SD], 35 years +/- 9) and 10 healthy control subjects (eight female, two male; mean age, 37 years +/- 16) underwent DWI. DWI and ADC images were assessed by means of visual inspection, and histograms were composed from the ADC images. From these, we derived a variety of parameters that quantitatively reflect the diffusivity of brain parenchyma. RESULTS: Visual inspection of ADC images and DWIs did not reveal any abnormalities in either patients with NPSLE or control subjects. In contrast, ADC histograms of the NPSLE group were, on average, significantly lower and broader, with a higher mean ADC value. CONCLUSION: The data suggest an increased general diffusivity in brain parenchyma of patients with NPSLE, probably based on loss of tissue integrity. In addition to increasing our battery of highly wanted diagnostic tools and our understanding of the pathogenesis of NPSLE, the present method seems to be useful in quantifying the disease burden, enabling monitoring in treatment trials and the study of disease progression.

Production of IL-1beta and IL-1Ra as risk factors for susceptibility and progression of relapse-onset multiple sclerosis.

Interleukin-1beta (IL-1beta) is present in multiple sclerosis (MS) lesions. Interleukin-1 receptor antagonist (IL-1Ra) moderates the induction of experimental autoimmune encephalomyelitis (EAE). Here, we show that families that are characterized by high IL-1beta over IL-1Ra production ratio are at 2.2-fold (95% CI, 1.0-4.8; p=0.05) increased risk to have a patient relative with relapse-onset MS than families with a low ratio. It is also related to the reduction of volumetric magnetization transfer ratio (MTR) histogram height, a measure of parenchymal integrity (p=0.04). Those families who combine a high IL-1beta over IL-1Ra ratio with a high tumor necrosis factor (TNF) over IL-10 production ratio have a 6.2-fold (95% CI, 1.8-21; p=0.002) increased risk. Innate production of IL-1beta and IL-1Ra is not related to the outcome of primary progressive MS. Taq1 polymorphism in the IL-1beta gene and the variable number of tandem repeats (VNTR) polymorphism of 86-base pairs within the IL-1Ra gene cannot explain these findings.

Systemic lupus erythematosus: diagnostic application of magnetization transfer ratio histograms in patients with neuropsychiatric symptoms--initial results.

PURPOSE: To explore the diagnostic potential of magnetization transfer ratio (MTR) histogram analysis in patients with neuropsychiatric systemic lupus erythematosus (SLE) by using multivariate discriminant analysis (MDA). MATERIALS AND METHODS: Volumetric magnetization transfer imaging was performed in nine patients with active non-thromboembolic, neuropsychiatric SLE, 10 patients with SLE who had had neuropsychiatric SLE previously, 10 patients with SLE but no history of neuropsychiatric SLE, 10 patients with inactive multiple sclerosis, and 10 healthy control subjects. For each subject, an MTR histogram of the whole brain was generated, and an MDA score was produced for each histogram. Each patient was assigned to a clinical subgroup on the basis of these MDA scores. For assignment, binary comparisons between subgroups were made. The accuracy of this classification method was assessed and compared with that of conventional MTR histogram analysis. RESULTS: With MDA, the success rate of binary classification was 60%-100%, depending on which two groups were compared. When the different clinical subgroups were separated, MDA parameters were always better than conventional MTR histogram parameters, with P values ranging from.05 to less than 1 x 10(-6) of those attained with the best conventional parameter. CONCLUSION: With MDA, MTR histograms of brain tissue may provide diagnostic information for individual patients in the clinical context of SLE.